48 results on '"Anjani K. Tiwari"'
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2. A Review on Modern Synthetic Route for the Construction of 1, 3-Diazanaphthalene Moiety
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Anjani K. Tiwari, Mohd. Faheem, and Vinay Kumar Singh
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chemistry.chemical_compound ,chemistry ,Organic Chemistry ,Diazanaphthalene ,Moiety ,Combinatorial chemistry - Abstract
Quinazoline is an organic heterocyclic molecule in which two six-membered aromatic rings are fused. Two nitrogen atoms are present in the quinazoline molecule at 1 and 3 positions that is why it is also known as 1,3-diazanaphthalene. The presence of these two nitrogen atoms in 1,3-diazanaphthalene increases the usefulness of this molecule in the field of pharmaceutical sciences. Many reactions have been reported to prepare 1,3- diazanaphthalene by aminobenzonitrile, o-aminobenzohydrazide, aminobenzamide, aminoacetophenone, and aminobenzoketone under different solvent conditions, but condensation of anthranilic acid with an aromatic aldehyde is the most common method. Later, metal-free and solvent-free conditions dominated over the old methods. This review describes the synthesis of 1,3-diazanaphthalene under different metal catalysts, reagents, solvent- free conditions and under microwave radiation through nucleophilic substitution reaction, condensation, and aromatization. In biological sciences, 1,3-diazanaphthalene derivatives have got an important place due to their ability to bind to different target sites and subsequent discovery of many drug structures.
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- 2020
3. A Review on the Modern Synthetic Approach of Benzimidazole Candidate
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Anjali Rathaur, Mohd. Faheem, Anjani K. Tiwari, Apoorva Pandey, and Vinay Kumar Singh
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Benzimidazole ,chemistry.chemical_compound ,chemistry ,o-Phenylenediamine ,Condensation ,General Chemistry ,Lewis acids and bases ,Combinatorial chemistry - Published
- 2020
4. Receptor mapping using methoxy phenyl piperazine derivative: Preclinical PET imaging
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Meganathan Thirumal, Anupama Datta, Anjani K. Tiwari, K. Ganesh Kadiyala, and Garima Mann
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Biodistribution ,Pharmacology ,Ligands ,Receptors, Metabotropic Glutamate ,Biochemistry ,Piperazines ,chemistry.chemical_compound ,Mice ,Drug Discovery ,Animals ,Humans ,Tissue Distribution ,Receptor ,Molecular Biology ,Mice, Inbred BALB C ,Molecular Structure ,Organic Chemistry ,Brain ,Ligand (biochemistry) ,Haemolysis ,Healthy Volunteers ,Rats ,Piperazine ,chemistry ,Metabotropic glutamate receptor ,Positron-Emission Tomography ,Metabotropic glutamate receptor 1 ,Specific activity - Abstract
This study aimed at assessing 2-methoxyphenyl piperazine derivative for its binding specificity and suitability in mapping metabotropic glutamate receptor subtype 1, which is implicated in several neuropsychiatric disorders. N-(2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl)-N-methylpyridin-2-amine was synthesised and evaluated for brain imaging subsequent to radiolabelling with [11C] radioisotope via methylation process in 98.9% purity and 52 ± 6% yield (decay corrected). The specific activity was in the range of 72–93 GBq/µmol. The haemolysis of blood was 2–5% for initial 4 hr and remained The PET as well as biodistribution studies also showed high activity in the brain with a direct correlation between receptor abundance distribution pattern and tracer activity. The biodistribution analyses revealed initial high brain uptake (4.18 ± 0.48). The highest uptake was found in cerebellum (SUV 4.7 ± 0.2), followed by thalamus (SUV 3.5 ± 0.1), and striatum (SUV 3 ± 0.1). In contrast, pons had negligible tracer activity. The high uptake observed in all the regions with known mGluR1 activity indicates suitability of the ligand for mGluR1 imaging.
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- 2021
5. Catalytic Hydrothermal Liquefaction of Microalgae using Fe-MCM 41 Catalyst in Presence of Carbon Monoxide
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Rohit Sharma, Anjani K. Tiwari, Ajay Singh, and Nishesh Sharma
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Chemistry ,020209 energy ,02 engineering and technology ,General Chemistry ,010501 environmental sciences ,01 natural sciences ,Catalysis ,chemistry.chemical_compound ,Hydrothermal liquefaction ,MCM-41 ,Chemical engineering ,0202 electrical engineering, electronic engineering, information engineering ,0105 earth and related environmental sciences ,Carbon monoxide - Abstract
Among the various types of biomass, microalgae have a potential to become a significant energy source for the production of third generation biofuel. The hydrothermal liquefaction is the direct biomass-to-liquid conversion route carried out in the hot compressed water with or without the presence of a catalyst. In this study, the process pressure and temperature is reduced, but at a lower temperature, bio-oil yield is not high enough to make hydrothermal liquefaction an economical technique. Thus, Fe-MCM 41 catalyst was used to increase the bio-oil yield at low temperatures (250 ºC). This catalyst increased the total bio-oil yield from 42.7 to 61.28 % in hydrothermal liquefaction of Chlorella pyrenoidosa. The bio-oil yield (%) of oil 1, 2 & 3 were 24.72, 17.08 & 19.48, respectively obtained at 250 ºC by using catalyst. Moreover, use of catalyst also resulted in the decrease in oxygen and nitrogen contents of bio-oil and consequently increases in its heating value.
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- 2019
6. Comparative evaluation of 99mTc-MBIP-X/11[C] MBMP for visualization of 18 kDa translocator protein
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Neelam Kumari, Anjani K. Tiwari, Pooja Srivastava, Ankur Kaul, Pravir Kumar, and Dipti Kakkar
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chemistry.chemical_classification ,Biodistribution ,biology ,medicine.diagnostic_test ,Chemistry ,02 engineering and technology ,General Chemistry ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Molecular biology ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Pharmacokinetics ,In vivo ,Positron emission tomography ,Materials Chemistry ,Translocator protein ,biology.protein ,medicine ,Propionate ,0210 nano-technology ,Acetamide ,Ex vivo - Abstract
An elevated translocator protein (18 kDa, TSPO) density is observed during inflammation in the brain and peripheral organs making it a viable target for imaging. Recently, our group has explored a pharmacophore skeleton acetamidobenzoxazolone for positron emission tomography (PET) and single photon emission computed tomography (SPECT) applications to target TSPO. 2-(2-(5-Bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate (MBIP-Br/Cl) were synthesized by using tryptophan methyl ester and compared with 2-[5-(4-methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenyl acetamide (MBMP) through tracer techniques. Computational docking showed similar results for MBIP-Br/Cl in comparison to MBMP. Their ex vivo and in vivo biodistributions were assessed in TSPO-rich organs as well as their release kinetics 0–120 min post injection. The ex vivo biodistribution showed a 7 fold higher uptake (5.16%ID per g vs. 0.72%ID per g) in the heart and a 2.5 fold higher uptake (12.91%ID per g vs. 4.69%ID per g) in the lungs for 99mTc-MBIP-Cl compared to that of 99mTc-MBIP-Br at 15 min. These findings demonstrated that 99mTc-MBIP-Cl has improved pharmacokinetic properties compared to 99mTc-MBIP-Br for SPECT application and is comparable to [11C]MBMP.
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- 2019
7. Chalcone Based Homodimeric PET Agent, 11C-(Chal)2DEA-Me, for Beta Amyloid Imaging: Synthesis and Bioevaluation
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Anjani K. Tiwari, Ankur Kaul, Anupama Datta, Ajai K. Singh, Nidhi Chadha, and Kanchan Chauhan
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0301 basic medicine ,Chalcone ,Stereochemistry ,Amyloidosis ,Pharmaceutical Science ,Plasma protein binding ,Ligand (biochemistry) ,medicine.disease ,Fibril ,Amyloid Beta 42 ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Monomer ,chemistry ,Drug Discovery ,medicine ,Molecular Medicine ,Specific activity ,030217 neurology & neurosurgery - Abstract
Homodimeric chalcone based 11C-PET radiotracer, 11C-(Chal)2DEA-Me, was synthesized, and binding affinity toward beta amyloid (Aβ) was evaluated. The computational studies revealed multiple binding of the tracer at the recognition sites of Aβ fibrils. The bivalent ligand 11C-(Chal)2DEA-Me displayed higher binding affinity compared to the corresponding monomer, 11C-Chal-Me, and classical Aβ agents. The radiolabeling yield with carbon-11 was 40–55% (decay corrected) with specific activity of 65–90 GBq/μmol. A significant (p 93% intact tracer at 30 min po...
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- 2018
8. Design, synthesis and biological evaluation of antimalarial activity of new derivatives of 2,4,6-s-triazine
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Himanshu Ojha, Mallika Pathak, Deepti Sharma, Rita Kakkar, Anjani K. Tiwari, and Manisha Saini
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Cycloguanil ,DHFR inhibitors ,Stereochemistry ,Antimalarial ,010402 general chemistry ,01 natural sciences ,chemistry.chemical_compound ,Dihydrofolate reductase ,parasitic diseases ,medicine ,s-Triazine ,QD1-999 ,ADME ,Triazine ,biology ,010405 organic chemistry ,Chemistry ,Plasmodium falciparum ,General Chemistry ,biology.organism_classification ,0104 chemical sciences ,Pyrimethamine ,Docking (molecular) ,Lipophilicity ,Molecular docking ,biology.protein ,Research Article ,medicine.drug ,3D7 strain - Abstract
Dihydrofolate reductase (DHFR) is an important enzyme for de novo synthesis of nucleotides in Plasmodium falciparum and it is essential for cell proliferation. DHFR is a well known antimalarial target for drugs like cycloguanil and pyrimethamine which target its inhibition for their pharmacological actions. However, the clinical efficacies of these antimalarial drugs have been compromising due to multiple mutations occurring in DHFR that lead to drug resistance. In this background, we have designed 22 s -triazine compounds using the best five parameters based 3D-QSAR model built by using genetic function approximation. In-silico designed compounds were further filtered to 6 compounds based upon their ADME properties, docking studies and predicted minimum inhibitory concentrations (MIC). Out of 6 compounds, 3 compounds were synthesized in good yield over 95% and characterized using IR, 1HNMR, 13CNMR and mass spectroscopic techniques. Parasitemia inhibition assay was used to evaluate the antimalarial activity of s -triazine compounds against 3D7 strain of P. falciparum. All the three compounds (7, 13 and 18) showed 30 times higher potency than cycloguanil (standard drug). It was observed that compound 18 was the most active while the compound 13 was the least active. On the closer inspection of physicochemical properties and SAR, it was observed that the presence of electron donating groups, number of hydrogen bond formation, lipophilicity of ligands and coulson charge of nitrogen atom present in the triazine ring enhances the DHFR inhibition significantly. This study will contribute to further endeavours of more potent DHFR inhibitors. Electronic supplementary material The online version of this article (10.1186/s13065-017-0362-5) contains supplementary material, which is available to authorized users.
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- 2017
9. Zinc complex of tryptophan appended 1,4,7,10-tetraazacyclododecane as potential anticancer agent: Synthesis and evaluation
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Neelam Kumari, Abha Shukla, Nitin Kumar, Anjani K. Tiwari, Anil K. Mishra, Manish Adhikari, Anupriya Adhikari, and Anupama Datta
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Biodistribution ,Stereochemistry ,DNA damage ,Clinical Biochemistry ,Mice, Nude ,Pharmaceutical Science ,Antineoplastic Agents ,Cyclams ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cyclen ,Heterocyclic Compounds ,Cell Line, Tumor ,Spect imaging ,Drug Discovery ,Organometallic Compounds ,Animals ,Humans ,DNA Cleavage ,Molecular Biology ,Cell Proliferation ,Dose-Response Relationship, Drug ,010405 organic chemistry ,Organic Chemistry ,Tryptophan ,Neoplasms, Experimental ,0104 chemical sciences ,Comet assay ,Zinc ,HEK293 Cells ,chemistry ,Phosphodiester bond ,Molecular Medicine ,Drug Screening Assays, Antitumor ,DNA - Abstract
With the rising incidences of cancer cases, the quest for new metal based anticancer drugs has led to extensive research in cancer biology. Zinc complexes of amino acid residue side chains are well recognized for hydrolysis of phosphodiester bond in DNA at faster rate. In the presented work, a Zn(II) complex of cyclen substituted with two l-tryptophan units, Zn(II)-Cyclen-(Trp)2 has been synthesized and evaluated for antiproliferative activity. Zn(II)-Cyclen-(Trp)2 was synthesized in ∼70% yield and its DNA binding potential was evaluated through QM/MM study which suggested good binding (G=-9.426) with B-DNA. The decrease in intensity of the positive and negative bands of CT-DNA at 278nm and 240nm, respectively demonstrated an effective unwinding of the DNA helix with loss of helicity. The complex was identified as an antiproliferative agent against U-87MG cells with 5 fold increase in apoptosis with respect to control (2h post incubation, IC50 25µM). Electrophoresis and comet assay studies exhibited an increase in DNA breakage after treatment with complex while caspase-3/β-actin cleavage established a caspase-3 dependent apoptosis pathway in U-87 MG cells after triggering DNA damage. In vivo tumor specificity of the developed ligand was validated after radiocomplexation with 99mTc (>98% radiochemical yield and specific activity of 2.56GBq/µmol). Avid tumor/muscle ratio of >6 was depicted in biodistribution and SPECT imaging studies in U-87 MG xenograft model nude mice.
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- 2017
10. Modified benzoxazolone (ABO-AA) based single photon emission computed tomography (SPECT) probes for 18 kDa translocator protein
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Pooja Srivastava, Pravir Kumar, Dipti Kakkar, and Anjani K. Tiwari
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Lipopolysaccharides ,Lung Diseases ,Male ,Biodistribution ,Stereochemistry ,Protein Data Bank (RCSB PDB) ,Single-photon emission computed tomography ,Scintigraphy ,03 medical and health sciences ,chemistry.chemical_compound ,Radioligand Assay ,0302 clinical medicine ,Receptors, GABA ,Drug Discovery ,medicine ,Translocator protein ,Animals ,Humans ,Fluorescent Dyes ,chemistry.chemical_classification ,Inflammation ,Tomography, Emission-Computed, Single-Photon ,Benzoxazoles ,Mice, Inbred BALB C ,medicine.diagnostic_test ,biology ,Chemistry ,Technetium ,A549 Cells ,030220 oncology & carcinogenesis ,Lipophilicity ,biology.protein ,Propionate ,Rabbits ,030217 neurology & neurosurgery ,Acetamide - Abstract
Acetamidobenzoxazolone (ABO) has been modified to ABO-AA, 2-(2-(5-bromo/chloro benzoxazolone)acetamide)-3-(1H-indol-3-yl)propionate to improve pharmacokinetics and lipophilicity (log p = 2.04). The final compound was synthesized in better yield and in fewer steps than previously reported MBIP-Br (70% vs. 62%). Computational docking confirmed binding of MBIP-Cl with translocator protein (TSPO) as well as with mutant TSPO (-8.99 for PDB: 4RYQ and -9.30 for PDB: 4UC1, respectively). Ex-vivo biodistribution and scintigraphy showed that 99m Tc-MBIP-Cl is better than 99m Tc-MBIP-Br in terms of uptake in TSPO-rich organs and release kinetics 0-120 min postinjection. At 15 min, uptake was 2.75-fold (12.91%ID/g vs. 4.69%ID/g) in lung and seven-fold (5.16%ID/g vs. 0.72%ID/g) in heart for 99m Tc-MBIP-Cl compared to that of 99m Tc-MBIP-Br which gives warrant to utilize this single photon emission computed tomography agent in higher animals.
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- 2019
11. Synthesis and biological evaluation of modified laminin peptide (N2S2-KDP) with enhanced affinity for neuronal growth and targeted molecular imaging (SPECT)
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Roger Strömberg, Aruna Kaushik, Puja Panwar Hazari, Ankur Kaul, Anjani K. Tiwari, Sweta Singh, Meenakshi Saklani, Raunak Varshney, Anil K. Mishra, and Rashi Mathur
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chemistry.chemical_classification ,Neurite ,biology ,010405 organic chemistry ,Organic Chemistry ,Peptide ,01 natural sciences ,Biochemistry ,0104 chemical sciences ,Amino acid ,Cell biology ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Laminin ,Cell culture ,Drug Discovery ,Peptide synthesis ,biology.protein ,Isoleucine ,Receptor ,Molecular Biology - Abstract
An analog of γ1 laminin (RDIAEIIKDI) decapeptide has been used to augment neuronal survival and regeneration after injuries, during aging and other CNS disorder. As a prime synthetic peptide, KDI, is responsible for the neurite outgrowth of human embryonic neurons. In this study, we have designed, modified a KDI derivative and synthesized by replacing isoleucine (I) with Pro (P) amino acid at C-terminal to enhance its potency towards neurite growth. -Cys-Gly-Cys (-CGC) N2S2 motif was also incorporated in the present design for peptide radiolabeling. The modified peptide showed a better binding with the desired 3T1M receptor for neurite growth. The peptide was synthesized using solid phase peptide synthesis and Fmoc-strategy with more than 80% yield. The receptor binding studies of 99mTc-N2S2-KDP in Neuro2A cell lines showed Kd value in 31 nM range and the complex showed appreciable brain uptake in mice. The results on human SH-SY5Y indicate that the unlabeled N2S2-KDP may perhaps be useful for neurite growth in neurodegenerative disorder.
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- 2021
12. Lanthanide (Ln3+) complexes of bifunctional chelate: Synthesis, physicochemical study and interaction with human serum albumin (HSA)
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Ramendra Pratap, Deepika Singh, Anjani K. Tiwari, Anil Mishra, Pooja, Vinay Singh, and Swati Aggarwal
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Quenching (fluorescence) ,Chemistry ,Hydrogen bond ,Ligand ,Potentiometric titration ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,Human serum albumin ,01 natural sciences ,Medicinal chemistry ,Binding constant ,Atomic and Molecular Physics, and Optics ,0104 chemical sciences ,Analytical Chemistry ,chemistry.chemical_compound ,Amide ,medicine ,Carboxylate ,0210 nano-technology ,Instrumentation ,Spectroscopy ,medicine.drug - Abstract
Bifunctional chelate EDTA-bis amide (N,N′-bis (tyramide)ethylenediamine-N,N′-diacetic acid) that has ability to mimic natural amino acids was synthesized and analyzed by various spectroscopic techniques. The physicochemical studies were performed to calculate the various thermodynamic and kinetic parameters for the synthesized poly-amino carboxylate ligand. The two protonation constant (pka's = 3.460 and 6.722) of the prepared ligand and stability constants (log KML's = 15.8, 18.1, 16.2, 18.4, 17.5, 18.9, 13.6 and 12.8) of the complexes formed with Ce3+, Sm3+, Eu3+, Gd3+, Tb3+, Lu3+, Zn2+ and Cu2+ were determined by potentiometric titration using 0.1 M Me4NOH as non-aqueous base. The formation kinetics of [EuEDTA-TA2]+ and [CeEDTA-TA2]+ was studied and the rate constants were found to be 2.95 × 10–5 s−1 and 4.414 × 10–5 s−1respectively including the exchange reaction of [EuEDTA-TA2]+ with Zn2+ and Cu2+ spectrophotometrically. The Eu(III) complex of EDTA(TA)2 gives three emission bands at 480 nm, 540 nm and 610 nm (λmax = 270 nm, excitation) which shows efficacy of the ligand as an optical imaging agent. Molecular docking studies with Human Serum Albumin (HSA: PDB 1E78 ) showed binding pattern with the residues Arg218, Arg222, Lys195 and Lys444 in sub domain II A of site I via hydrogen bond and identifies the ligand-HSA interaction and specific insight for transportation to the target sites. Subsequently, fluorescence spectroscopy was performed at λex = 350 nm binding constant for HSA was 5.847 × 104 M−1 which showed effective quenching effect.
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- 2021
13. Comparative evaluation of Bis(thiosemicarbazone)- Biotin and Met-ac-TE3A for tumor imaging
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Anil K. Mishra, Bachcha Singh, Gauri Shukla, Sweta Singh, Anjani K. Tiwari, Raunak Varshney, Narmada Bag, and R. Mathur
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Diagnostic Imaging ,Serum ,Thiosemicarbazones ,Biodistribution ,Biotin ,Mice, Nude ,Nanotechnology ,02 engineering and technology ,Acetates ,030218 nuclear medicine & medical imaging ,Analytical Chemistry ,Heterocyclic Compounds, 1-Ring ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Tissue Distribution ,Instrumentation ,Semicarbazone ,Spectroscopy ,chemistry.chemical_classification ,Ligand ,Hydrogen-Ion Concentration ,021001 nanoscience & nanotechnology ,Atomic and Molecular Physics, and Optics ,In vitro ,Amino acid ,chemistry ,Potentiometry ,Biological Assay ,Rabbits ,Protons ,Radiopharmaceuticals ,0210 nano-technology ,Ex vivo ,Nuclear chemistry - Abstract
2,2',2″-(11-(2-((4-mercapto-1-methoxy-1-oxobutan-2-yl)amino)-2-oxoethyl)-1,4,8,11-tetraaza cyclotetradecane-1,4,8-triyl)triacetic acid, Met-ac-TE3A and (E)-N-methyl-2-((E)-3-(2-(2-(5-((3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)hydrazinecarbono-thioyl)hydrazonobutan-2-ylidene)hydrazinecarbothioamide, Bis(thiosemicarbazone)- Biotin were synthesized and evaluated for imaging application. The pharmacokinetics of these ligands were determined by tracer methods. In vitro human serum stability of (99m)Tc Met-ac-TE3A/(99m)Tc Bis(thiosemicarbazone)-Biotin after 24h was found to be 96.5% and 97.0% respectively. Blood kinetics of both ligands in normal rabbits showed biphasic clearance pattern. Ex vivo biodistribution study revealed significant initial tumor uptake and high tumor/muscles ratio which is a pre-requisite condition for a ligand to work as SPECT-radiopharmaceutical for tumor imaging.
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- 2016
14. Design, synthesis and biological evaluation of methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate: TSPO ligand for SPECT
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Ankur Kaul, Himanshu Ojha, Pooja Srivastava, Pravir Kumar, and Anjani K. Tiwari
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0301 basic medicine ,Indole test ,Biodistribution ,Ligand ,Hydrochloride ,Stereochemistry ,General Chemical Engineering ,Protein Data Bank (RCSB PDB) ,General Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Column chromatography ,chemistry ,Docking (molecular) ,Pharmacophore - Abstract
The translator protein (TSPO, 18 kDa), a transmembrane mitochondrial protein, has been explored as an important biomarker by researchers because of its involvement in inflammation, immune modulation and cell proliferation. Recently, our group has explored a modified benzoxazolone derivative for diagnostic applications that has overcome few problems of first and second generation TSPO PET ligands. In this study, a new skeleton acetamidobenzoxazolone–indole, a conjugation of two TSPO pharmacophoric moieties benzoxazolone and indole, has been designed, synthesized and evaluated for TSPO targeting for SPECT. The methyl-2-(2-(5-bromo benzoxazolone)acetamido)-3-(1H-indol-3-yl)propanoate (MBIP) ligand was designed on the basis of pharmacophore modeling done on benzoxazolone based TSPO ligands which was then validated computationally for TSPO binding through docking studies (PDB ID: 4RYO, 4RYQ, and 4UC1) which showed a comparable Glide Gscore as compared to known ligands like PK11195, PBR28, and FGIN-127. MBIP was synthesized by amidation reaction of 2-(5-bromo-benzoxazolone)acetic acid with tryptophan methyl ester hydrochloride (yield 62%). The compound was synthesized and characterized using spectroscopic techniques like 1H-NMR, 13C-NMR, and mass spectroscopy. Purification was carried out by column chromatography and analytical HPLC (purity > 97%). The purified compound was labelled with 99mTc (radiochemical yield > 96%). The radiolabelled compound showed >94% stability in solution and >91% stability in serum after 24 h indicating the stable nature of the radio complex. A biodistribution study on BALB/c mice showed uptake of 99mTc-MBIP in TSPO rich organs and appropriate pharmacokinetics of excretion and release for a SPECT agent. Further evaluation of the 99mTc-MBIP may prove it as a potential candidate for TSPO targeting using SPECT.
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- 2016
15. Design, synthesis and relaxation studies of triazole linked gadolinium(<scp>iii</scp>)–DO3A-BT-bistriazaspirodecanone as a potential MRI contrast agent
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Raunak Varshney, Anil K. Mishra, S. Senthil Kumaran, Sandhya Rangaswamy, Swarndeep K. Sethi, Marilyn Daisy Milton, and Anjani K. Tiwari
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010405 organic chemistry ,Stereochemistry ,MRI contrast agent ,Gadolinium ,Potentiometric titration ,Triazole ,chemistry.chemical_element ,General Chemistry ,010403 inorganic & nuclear chemistry ,01 natural sciences ,Combinatorial chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,Click chemistry ,Moiety ,MTT assay ,Conjugate - Abstract
Magnetic resonance imaging (MRI) is a diagnostic and research technique widely used in clinical research. We describe here a novel and facile synthesis of a bisconjugated triazaspirodecanone moiety using ‘click chemistry’ as a key step in the synthesis of a triazole based macrocyclic MRI contrast agent. A bivalent approach has been applied to conjugate two triazole rings and triazaspirodecanone moieties across a four carbon spaced linker which is finally conjugated to DO3A to yield the desired MRI contrast agent, DO3A-bis(triazole-triazaspirodecanone), in an overall yield of 70%. All the intermediates and the final compounds have been characterized by NMR and mass spectrometry. In vitro experiments include cytotoxicity (MTT assay) and relaxivity studies. The potentiometric titration of a gadolinium loaded complex displayed strong selectivity for Gd3+ over physiological metal ions such as Zn2+ and Cu2+. IC50 values obtained from the MTT assay indicate the suitability of the synthesized conjugate as a safe diagnostic agent. The longitudinal relaxivity of DO3A-bis(triazole-triazaspirodecanone) was found to be 18.6 mM−1 s−1, which shows that the synthesized conjugate is a suitable MRI contrast agent.
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- 2016
16. Evaluation of methionine and tryptophan derivatised vehicles: Met-ac-TE3A/Trp-ac-TE3A for tumor imaging
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Raunak Varshney, B. Singh, Rashi Mathur, Puja Panwar Hazari, Anjani K. Tiwari, Anil K. Mishra, and Sweta Singh
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chemistry.chemical_classification ,Biodistribution ,Chromatography ,Methionine ,General Chemical Engineering ,Kinetics ,Tryptophan ,General Chemistry ,In vitro ,Amino acid ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,Biochemistry ,Chemical stability - Abstract
Two novel amino acid (methionine and tryptophan) appended 1,4,8,11-tetraazacyclotetradecane triacetate (TE3A) compounds Met-ac-TE3A and Trp-ac-TE3A were synthesized and evaluated for imaging applications. The pharmacokinetics of these compounds was analyzed by 99mTc labeled tracer methods. In vitro human serum stability of 99mTc labeled Met-ac-TE3A/Trp-ac-TE3A was found to be 96.5% and 96.0% after 24 h respectively. Blood kinetics of both the labeled probes on normal rabbits showed biphasic clearance. The tumor (EAT cell line) grafted in balb/c mice were readily identifiable in the gamma images. Biodistribution revealed significant tumor uptake and good contrast in the EAT tumor bearing mice and also showed high tumor/muscles ratio which is a requisite condition to work as SPECT-radiopharmaceutical for tumor imaging. To look its future applicability for therapy using M+2 and M+3 metal ions, we performed thermodynamic stability constants of complexes derived from Met-ac-TE3A and Trp-ac-TE3A with CuII and LnIII metal ions.
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- 2015
17. Design, synthesis and biological evaluation of coumarin coupled nitroimidazoles as potential imaging agents
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Mohan Paul S. Ishar, Ankur Kaul, Nisha Saini, Raunak Varshney, Anil K. Mishra, and Anjani K. Tiwari
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Biodistribution ,Nitroimidazole ,medicine.diagnostic_test ,Stereochemistry ,General Chemical Engineering ,General Chemistry ,Coumarin ,Molecular biology ,In vitro ,Flow cytometry ,chemistry.chemical_compound ,chemistry ,In vivo ,Cell culture ,medicine ,Pimonidazole - Abstract
Solid tumors contain regions of hypoxia in comparison to normal tissues. The nitroimidazoles have shown great promise for targeting different types of cancers. The present work involves the design, syntheses, and in vitro and in vivo investigations of hypoxia targeted nitroimidazole radioconjugates (2NIHC and 4NIHC). Flow cytometry analysis showed that the normoxic–hypoxic mean fluorescence of 2NIHC is 10 fold greater than that of 4NIHC and much higher than that of the well-known pimonidazole hypoxia marker. Furthermore, molecular modeling studies of these ligands with CK2α revealed that 2NIHC is a more potential CK2α inhibitor due to π–π interactions and H-bonding with Val116, Glu114, Asp175, Asn161 and His160 in the active pockets of the target. Radio labeling yields for both the complexes with 99mTc were >98%. Biodistribution in EAT tumor bearing mice demonstrated rapid clearance of 99mTc-2NIHC and high T/M ratio (3.57% ID/g) as compared to 99mTc-4NIHC (2.05% ID/g) at 4 h. IC50 values of both ligands were estimated by MTS in different cell lines in addition to tumor regression studies.
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- 2015
18. Novel pyridinium oximes: synthesis, molecular docking and in vitro reactivation studies
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Anjani K. Tiwari, Swati Aggarwal, Gurmeet Singh, A. K. Mishra, Pooja Pooja, Ramendra Pratap, and Vijay Kumar
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Paraoxon ,Stereochemistry ,General Chemical Engineering ,Ligand binding assay ,Protein Data Bank (RCSB PDB) ,General Chemistry ,Oxime ,In vitro ,chemistry.chemical_compound ,chemistry ,medicine ,Molecule ,Pyridinium ,Linker ,medicine.drug - Abstract
A computational approach has been attempted for the screening of 4-pyridoxinium (4P) ring based reactivators for paraoxon inhibited AChE. The oxime molecules were designed with the common 4P skeleton and varying the carbon linkers. Initially, the AChE binding capability was assessed by molecular docking with PDB:2WHP and 3ZLV, which showed important interactions with Ser298, Try124 and Trp286. These computational results were validated by an in vitro AChE binding assay, which showed binding affinities in the range of 10–90%. Finally, reactivation potency was calculated as % reactivation on paraoxon inhibited eelAChE in the concentration range of 10−5 to 10−7 M. It was observed that introduction of an aliphatic linker attached to 4-pyridoxime has a high binding affinity and hence, may act as a good reactivator as compared to the aromatic pyridoximes.
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- 2015
19. [18F]FPBMP: – a potential new positron emission tomography radioligand for imaging of translocator protein (18 kDa) in peripheral organs of rats
- Author
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Lin Xie, Tomoteru Yamasaki, Akiko Hatori, Katsushi Kumata, Ming-Rong Zhang, Joji Yui, Masayuki Fujinaga, Anjani K. Tiwari, Yoko Shimoda, and Yiding Zhang
- Subjects
Kidney ,Biodistribution ,medicine.diagnostic_test ,biology ,General Chemical Engineering ,Metabolite ,General Chemistry ,Pharmacology ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,Pharmacokinetics ,Positron emission tomography ,medicine ,Radioligand ,Translocator protein ,biology.protein ,Ex vivo - Abstract
The five transmembrane translocator protein (18 kDa, TSPO) is abundantly expressed in the mitochondria of activated microglia (brain) and peripheral tissues, including those of the heart, lung and kidney. We recently developed the 18F-labelled molecule 2-[5-(4-[18F]fluoropropyloxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([18F]FPBMP) as a novel positron emission tomography (PET) radioligand for imaging TSPO. In this study, we have evaluated the pharmacokinetics of this radioligand based on its biodistribution in mice, as well as the results of PET and metabolite studies in rats. The specificity of [18F]FPBMP towards TSPO was assessed by blocking experiments involving the intravenous injection of 1 mg kg−1 of unlabeled PK11195. A metabolite study was performed in the plasma and peripheral organs of rats by HPLC methods. The ex vivo biodistribution of [18F]FPBMP in mice showed a high uptake of radioactivity in TSPO enriched peripheral organs, especially in the lung, heart and kidney. The in vivo biodistribution of this compound was evaluated through PET summation images of rats 1–10, 10–20, 20–30 and 50–60 min after the injection of the radioligand. The TSPO-enriched organs, including the heart, kidney and lung, were clearly visualized. Pre-treatment with TSPO-specific PK11195 minimized the uptake of [18F]FPBMP in the TSPO-enriched tissues, thereby confirming its selectivity for TSPO. Metabolite analysis in rats confirmed the presence of [18F]FPBMP in the heart, lung and kidney up to 60 min. In summary, these data demonstrate that [18F]FPBMP is a suitable PET ligand for the imaging of TSPO in peripheral tissues.
- Published
- 2015
20. Comparison of BTSE-RGD with DOTA-RGD as a potential imaging agent for tumors
- Author
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Krishna Chutani, Puja Panwar, Raunak Varshney, Neelam Yadav, B. Singh, Rashi Mathur, Anil K. Mishra, Shivani Singh, Anjani K. Tiwari, and Sweta Singh
- Subjects
Biodistribution ,Chemistry ,Stereochemistry ,General Chemical Engineering ,General Chemistry ,High-performance liquid chromatography ,Imaging agent ,chemistry.chemical_compound ,Peptide synthesis ,DOTA ,Specific activity ,Chelation ,Nuclear chemistry ,Conjugate - Abstract
RGD and its analogues are very important compounds and can be used as potential tumor-targeting agents. Bisthiosemicarbazone-conjugated RGD (BTSE-RGD) and DOTA-RGD were prepared using a chemical strategy based on peptide synthesis and chemoselective ligations. BTSE-RGD comprises two domains, the first a tumour selective domain and the other a chelating vehicle, for conjugation of radioisotopes. Both compounds were synthesized and labelled with 99mTc and radiochemically analysed by HPLC. The stability of the radioconjugate in the presence of human serum was checked at 37 °C up to 8 h. Labelling yield of 96.8 ± 0.32% was obtained, which corresponds to a specific activity in the range of 36–89 MBq μmol−1 for BTSE-RGD. The BTSE-RGD conjugate was examined in vitro for its ability to bind with the αvβ3 receptor. The functionalized BTSE-RGD displayed a binding affinity toward αvβ3 integrin (31.9 ± 6.8 nM) many-fold better than DOTA-RGD. 99mTc-BTSE-RGD showed a slower distribution half-life (T1/2α) and elimination half-life (T1/2β) of 65 ± 0.001 min and 21 h 15 min ± 0.001 min, respectively, in comparison to 99mTc-DOTA-RGD, with T1/2α of 18 ± 0.001 min and T1/2β of 9 h 10 min ± 0.005 min. Biodistribution study showed better tumor-to-muscle ratio for BTSE-RGD, which reaches maximum around 3.5 (% ID) in 2 h, while for DOTA-RGD the maximum was 13.60 at 24 h.
- Published
- 2015
21. Block Copolymer Based Nanoparticles for Theranostic Intervention of Cervical Cancer: Synthesis, Pharmacokinetics, and in Vitro/in Vivo Evaluation in HeLa Xenograft Models
- Author
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Surendra Singh, Dipti Kakkar, Yogesh Rai, Anant Narayan Bhatt, Anjani K. Tiwari, Shweta Dumoga, and Anil K. Mishra
- Subjects
Biodistribution ,Materials science ,Mice, Nude ,Uterine Cervical Neoplasms ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Theranostic Nanomedicine ,Polyethylene Glycols ,HeLa ,chemistry.chemical_compound ,Mice ,medicine ,Animals ,Humans ,General Materials Science ,Tissue Distribution ,Cytotoxicity ,Drug Carriers ,biology ,technology, industry, and agriculture ,Glutamic acid ,021001 nanoscience & nanotechnology ,biology.organism_classification ,medicine.disease ,Hemolysis ,0104 chemical sciences ,Biochemistry ,chemistry ,Apoptosis ,Cancer research ,Heterografts ,Nanoparticles ,Female ,Rabbits ,0210 nano-technology ,Ethylene glycol ,Folate targeting ,HeLa Cells - Abstract
Polymer-based nanoparticles have proven to be viable carriers of therapeutic agents. In this study, we have developed nanoparticles (NPs) from polypeptide-polyethylene glycol based triblock and diblock copolymers. The synthesized block copolymers poly(ethylene glycol)-b-poly(glutamic acid)-b-poly(ethylene glycol) (GEG) and poly(ethylene glycol)-b-poly(glutamic acid) (EG) conjugated with folic acid for targeting specificity (EGFA) have been used to encapsulate methotrexate (MTX) to form M-GEG and M-EGFA NPs aimed at passive and active targeting of cervical carcinoma. In-vitro SRB cytotoxicity and hemolysis assays revealed that these NPs were cytocompatible to healthy human cells and hemocompatible to human RBCs. Cellular uptake by FACS demonstrated their prompt internalization by human cervical carcinoma (HeLa) cells and points toward an apoptotic mechanism of cell kill as confirmed by AO/EB staining as well as histological analysis of explanted HeLa tumors. Pharmacokinetics and biodistribution studies were performed in New Zealand albino rabbits and HeLa xenografted Athymic mice models, respectively, by radiolabeling these NPs with
- Published
- 2017
22. In silicothermodynamics stability change analysis involved in BH4responsive mutations in phenylalanine hydroxylase: QM/MM and MD simulations analysis
- Author
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Kumar, Anjani K. Tiwari, Milton, A. K. Mishra, and Nidhi Chadha
- Subjects
Protein Folding ,Phenylalanine hydroxylase ,In silico ,Mutant ,Mutation, Missense ,Phenylalanine ,Molecular Dynamics Simulation ,Protein Structure, Secondary ,QM/MM ,Hydroxylation ,chemistry.chemical_compound ,Structural Biology ,Catalytic Domain ,medicine ,Humans ,Molecular Biology ,Genetics ,chemistry.chemical_classification ,biology ,Chemistry ,Phenylalanine Hydroxylase ,General Medicine ,Tetrahydrobiopterin ,Biopterin ,Enzyme ,Biochemistry ,biology.protein ,Quantum Theory ,Thermodynamics ,medicine.drug - Abstract
The mammalian tetrahydrobiopterin (BH4)-dependent phenylalanine hydroxylases (PAH), involved in important metabolic pathways of phenylalanine, belong to non-heme iron-containing aromatic acid hydroxylases' enzyme (AAH) family. AAHs utilize BH4 as protein co-factor and thus promote hydroxylation reactions of their substrates. Any alterations in BH4 -mediated AAH's pathway or mutations in these enzymes are responsible for various disorders, and thus highlights the importance of mutational analysis to assess the effect on their biosynthetic pathways. Our present studies are aimed at single-site mutations in PAH that lead to thermodynamic stability change upon folding and further validation of designed non-reduced BH2 designed co-factors. We have presented single-site mutational analysis of PAH where single-site mutations have been identified from known literature. Further, in silico studies with the PAH, in silico mutant PAH, and crystallized known mutant A313T forms, involved QM/MM and Molecular Dynamics (MD) simulations analysis. The modified co-factor A showed high affinity with PAH and all mutant PAH with high G-score of -14.851. The best pose high affinity co-factor A subjected to QM/MM optimization which leads to square-pyramidal coordination of non-heme active site. The structural and energetic information obtained from the production phase of 20 ns MD simulation of co-factor-metalloprotein complex results helped to understand the binding mode and involvement of three molecules throughout the reaction pathways' catalysis of PAH. The free energies of binding (dG) of A were found to be -68.181 kcal/mol and -72.249 for 1DMW and 1TDW for A313T mutant. Binding of Co-factor A do not perturb the coordination environment of iron at the active site which resides in 2-Histdine and 1-Glutamate triad, and may enhance the percentage response towards co-factor-mediated therapy.
- Published
- 2014
23. Investigation for the Interaction of Tyramine-Based Anthraquinone Analogue with Human Serum Albumin by Optical Spectroscopic Technique
- Author
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Gurmeet Singh, Swati Aggarwal, Nidhi Chadha, Anjani K. Tiwari, Pooja Srivastava, Anil K. Mishra, and Vikas Kumar
- Subjects
Pharmacology ,Anthraquinone Analogue ,Molecular model ,Stereochemistry ,Chemistry ,Organic Chemistry ,Human serum albumin ,Biochemistry ,Binding constant ,Fluorescence ,Anthraquinone ,Fluorescence spectroscopy ,chemistry.chemical_compound ,Drug Discovery ,medicine ,Molecular Medicine ,HOMO/LUMO ,medicine.drug - Abstract
A newly synthesized anthraquinone derivative 'N-(2-methylanthraquinone)-4-(2-aminoethyl) phenol' (Tyan) were characterized as a fluorophore from photophysical analysis by measuring the UV-Vis absorptive (λ(ex) = 325 nm) and fluorescence emitive (λ(em) = 660 nm) values. Density functional theory additionally supported the spectroscopic data by modulation of highest occupied molecular orbital rather than lowest unoccupied molecular orbital due to the affect of tyramine moiety present in Tyan. The pharmacological importance of Tyan was evaluated by molecular docking with human serum albumin. The molecular docking of the Tyan was performed with the crystal structure of human serum albumin (PDB entry 1E78), which shows binding in all the three domains of human serum albumin corresponding to -7.74 as the GScore. Moreover, the interactions of human serum albumin with Tyan were assessed employing fluorescence spectroscopy under simulative physiological conditions, and the binding constant for the interaction at 25 °C was found to be 0.6 × 10(3)/M.
- Published
- 2012
24. Design, Synthesis, and Antimycobacterial Property of PEG-bis(INH) Conjugates
- Author
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Krishna Chuttani, Anil Mishra, Anjani K. Tiwari, Anupama Datta, Alka Khanna, Dipti Kakkar, and Harpal Singh
- Subjects
Pharmacology ,Biodistribution ,Polymer-drug conjugates ,medicine.drug_class ,Organic Chemistry ,Isoniazid ,bacterial infections and mycoses ,Antimycobacterial ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,PEG ratio ,medicine ,Molecular Medicine ,Organic chemistry ,MTT assay ,Cytotoxicity ,Ethylene glycol ,medicine.drug ,Nuclear chemistry - Abstract
Poly(ethylene glycol) derivatives of isoniazid with varying molecular weight of poly(ethylene glycol) were designed as antimycobacterial agents. Poly(ethylene glycol)-diacrylate of three different molecular weights (MW 258, 575, and 700) was conjugated with isoniazid by the Michael addition approach. The poly(ethylene glycol)-bis(isoniazid) conjugates thus obtained were completely characterized by FT-IR, (1)H and (13)C NMR, and ESI-MS spectroscopic techniques. Comparative MTT assay of the poly(ethylene glycol)-bis(isoniazid) conjugates showed much lower cytotoxicity than the neat isoniazid. MIC studies on Mycobaterium tuberculosis H37Rv showed potential antimycobacterial activity than the free isoniazid on a molar basis. The poly(ethylene glycol)-bis(isoniazid) conjugates were successfully radiolabeled with 99m-Technetium with more than 97% efficiency and stability to assess their in vivo fate. The (99m)Tc labeled poly(ethylene glycol)-bis(isoniazid) conjugates showed higher blood retention time in New Zealand rabbits which increased with increasing molecular weight of poly(ethylene glycol). Biodistribution studies in infection-induced murine models (BALB/c mice) showed significant retention of these conjugates at the site of infection for 72 h. The results of this study illustrate the potential utility of the PEGylated isoniazid conjugates as long circulating carriers for improved antitubercular drug therapy.
- Published
- 2012
25. Synthesis of Oxovanadium(IV) Schiff base Complexes derived from C-substituted Diamines and Pyridoxal-5-Phosphate as Antitumor Agents
- Author
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Anand Kumar Pandey, Anjani K. Tiwari, Anil K. Mishra, Sudhir Chandna, Shubhra Chaturvedi, Bilikere S. Dwarakanath, and Puja Panwar Hazari
- Subjects
Pharmacology ,Schiff base ,Guanine ,Stereochemistry ,Organic Chemistry ,Conjugated system ,Biochemistry ,Transplantation ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Molecular Medicine ,Chelation ,Pyridoxal phosphate ,Bifunctional ,DNA - Abstract
Oxovanadium (IV) complexes of N,N'-bispyridoxyl-5, 5'-bis (phosphate) ethylenediimine (L1) and N,N'-bis(pyridoxyl)-5,5'-bis(phosphate)-1''-(p-nitrobenzyl)ethylenediimine (L2) were synthesized by condensation of optically active C-substituted diamines and pyridoxal-5-phosphate. Oxovanadium (IV) complexes derived from L1 and L2 were evaluated as DNA cleavage agent (cleavage of supercoiled plasmid pBR322 DNA). Interestingly, both the oxovanadium (IV) complexes exhibited DNA nuclease activity, and the extent of oxidation of DNA by these vanadyl complexes was superior to VOSO(4) . The significant reduction in primary tumor and increased delay in tumor growth of 15 days was seen in the tumor regression analysis with oxovanadium (IV) complex of L1. With the preliminary studies performed with the pyridoxal-5-phosphate -based salen derivatives including the cytotoxicity and tumor regression, it is evident that the salen bifunctional chelating agent has obtained therapeutic potential if conjugated to a gene-specific targeting molecule for the oxidation of guanine residue.
- Published
- 2012
26. Kinetics of Formation for Lanthanide (III) Complexes of DTPA-(Me-Trp)2 used as Imaging Agent
- Author
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Deepa Sinha, Dipti Kakkar, Anupama Datta, Anil K. Mishra, and Anjani K. Tiwari
- Subjects
Pharmacology ,Lanthanide ,Chemistry ,Ligand ,MRI contrast agent ,Organic Chemistry ,Analytical chemistry ,Protonation ,Nuclear magnetic resonance spectroscopy ,Biochemistry ,chemistry.chemical_compound ,Reaction rate constant ,Ionic strength ,Amide ,Drug Discovery ,Molecular Medicine ,Nuclear chemistry - Abstract
Diethlenetriamine-N,N,N'N''N''-pentaacetic acid (DTPA)-bis (amide) analogs have been synthesized and evaluated as a potential biomedical imaging agents. Imaging and biodistribution studies were performed in mice that showed a significant accumulation of DTPA analogs in brain. The stability and protonation constants of the complexes formed between the ligand [DTPA-(Me-Trp)(2)] and Gd(3+), Eu(3+), and Cu(2+) have been determined by pH potentiometry (Gd(3+), Eu(3+)) and spectrophotometry (Cu(2+)) at 25 °C and at constant ionic strength maintained by 0.10 M KCl. The kinetic inertness of Gd [DTPA-(Me-Trp)(2)] was characterized by the rates of exchange reactions with Zn(2+) and Eu(3+). In the Eu(3+) exchange, a second-order [H(+)] dependence was found for the pseudo-first-order rate constant [k(0) = (4.5 ± 1.2) × 10(-6)/s; k(1) = 0.58 ± 0.1 /M/s, k(2) = (6.6 ± 0.2) × 10(4) /M(2)/s, k(3) = (4.8 ± 0.8) × 10(-4) /M/s]. In the Eu(3+) exchange, at pH
- Published
- 2011
27. Quantitative Structure Activity Relationship Study of 2,4,6-Trisubstituted-s-triazine Derivatives as Antimalarial Inhibitors of Plasmodium Falciparum Dihydrofolate Reductase
- Author
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Rita Kakkar, Himanshu Ojha, Anjani K. Tiwari, Mallika Pathak, and Pragya Gahlot
- Subjects
Pharmacology ,Quantitative structure–activity relationship ,Correlation coefficient ,biology ,Stereochemistry ,Organic Chemistry ,Quantitative structure ,Plasmodium falciparum ,biology.organism_classification ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Molecular descriptor ,Drug Discovery ,Dihydrofolate reductase ,biology.protein ,Molecular Medicine ,Molecule ,Triazine - Abstract
This study presents a quantitative structure activity relationships (QSAR) study on a pool of 19 bio-active s-triazine compounds. Molecular descriptors, kappa {¹κ}, chi {³χ}, x component of the dipole moment (μ(x) ), Coulson charge (q(N) ) on the nitrogen atom sandwiched between the two substituted carbons of the triazine ring, and total energy (E(T) ) obtained from AM1 calculations provide valuable information and have a significant role in the assessment of dihydrofolate reductase (DHFR) inhibitory activity of the compounds. By using the Genetic Function Approach (GFA) technique, five QSAR models have been drawn up with the help of these calculated descriptors and DHFR inhibitory activity data of the molecules. Among the obtained QSAR models presented in the study, statistically the most significant one is a four-parameter linear equation with the Lack-of-Fit value 0.5624, squared correlation coefficient R² value of 0.7697, and the squared cross-validated correlation coefficient R²(CV) value of 0.6469. The results are discussed in light of the main factors that influence the DHFR inhibitory activity.
- Published
- 2010
28. Design, Synthesis, and In Vitro Antiproliferative Activity of Benzimidazole Analogues for Radiopharmaceutical Efficacy
- Author
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Himanshu Ojha, Sweta Singh, Bachcha Singh, Anil K. Mishra, Anjani K. Tiwari, and Nitin Kumar
- Subjects
Male ,Cancer Research ,Benzimidazole ,Biodistribution ,Quantitative structure–activity relationship ,Lung Neoplasms ,Reducing agent ,Pharmacology ,Ligands ,Mice ,Structure-Activity Relationship ,chemistry.chemical_compound ,Tumor Cells, Cultured ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Mice, Inbred BALB C ,Molecular Structure ,Brain ,Prostatic Neoplasms ,Heart ,Organotechnetium Compounds ,General Medicine ,Stannous Tartrate ,Combinatorial chemistry ,In vitro ,Liver ,Oncology ,chemistry ,Design synthesis ,Drug Design ,Proton NMR ,Benzimidazoles ,Radiopharmaceuticals - Abstract
The synthesis of eight ligands by using 2-amino benzimidazole with different mono/bis aldehydes is described herein. The final products were characterized by spectral techniques such as FT-IR, (1)H NMR, and EI-Mass. The structure-activity relationships of the benzimidazole derivatives are also reported. Studies on the complexation of the ligands with (99m)Tc were optimized by using stannous tartrate as reducing agent under various reaction conditions. The radiochemical stability wasor=95% for all the complexes, and they were to be stable for 12-14 hours in serum. Most of the ligands showed fast blood clearance. Biodistribution studies of the (99m)Tc complexes of these ligands showed no significant uptake in the brain or in the heart, and the clearance was mainly through the hepatobiliary system. Among the eight compounds evaluated for their antiproliferative activity in vitro, L(8) produced good activity against the cancer cell lines A549 and PC-3.
- Published
- 2010
29. 99mTc-DTPA-Amino Acids Conjugate as Specific SPECT Pharmaceuticals for Tumor Imaging
- Author
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Shubhra Chaturvedi, Deepa Sinha, Krishna Chuttani, Gauri Shukla, Anil K. Mishra, Anjani K. Tiwari, and Harish Chandra
- Subjects
Biodistribution ,Stereochemistry ,Biochemistry ,5-Hydroxytryptophan ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Amide ,Drug Discovery ,Animals ,Humans ,Tissue Distribution ,Amino Acids ,Carcinoma, Ehrlich Tumor ,Tomography, Emission-Computed, Single-Photon ,Pharmacology ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Chemistry ,Organic Chemistry ,Radiochemistry ,Tryptophan ,Pentetic Acid ,Condensation reaction ,Amino acid ,Yield (chemistry) ,Technetium Tc 99m Pentetate ,Molecular Medicine ,Rabbits ,Radiopharmaceuticals ,Conjugate - Abstract
(99m)Tc-Diethylene triamine pentaacetic acid-bis (amide) conjugates have been synthesized and evaluated as a potential radiopharmaceutical for tumor imaging. The compounds were synthesized by the condensation reaction of DTPA bis(anhydride) with different l-amino acids (methyl tryptophan, and 5-hydroxy tryptophan) and were characterized on the basis of IR, NMR, and Mass spectroscopy. (99m)Tc-labeled compounds were found stable for about 24 h under physiological conditions with more than 95% radiolabeling yield. Blood kinetic studies of all these complexes showed a bi-exponential pattern as well as quick wash out from the blood circulation. The biological t(1/2)(F) and t(1/2)(S) were found to be 20 +/- 0.001 min for DTPA-(Me-Trp)(2) and 18 +/- 0.001 min for DTPA-(5HT)(2) and t(1/2) (slow) 5 h 45 min +/- 0.001, 5 h 30 +/- 0.001 min for DTPA-(Me-Trp)(2), and DTPA-(5HT)(2), respectively. Imaging and biodistribution studies were performed in mice bearing Ehrlich ascites tumor (EAT) tumors in right thigh. Radioconjugate derived from l-5-hydroxytryptophan exhibited remarkable localization at tumor site; whereas radiotracer derived from l-methyl tryptophan shows relatively less accumulation at the tumor site. Tumor-to-muscles ratios were 5.07 +/- 0.001, and 4.2 +/- 0.001 at 1 and 4 h for (99m)Tc-DTPA-(Me trp)(2) and 4.97 +/- 0.001 and 5.8 +/- 0.001 at 1 and 4 h after postinjection for (99m)Tc-DTPA-(5HT)(2), respectively. The preliminary results with these amino acid based ligands are encouraging to carrying out further in vivo experiments for targeted tumor imaging.
- Published
- 2009
30. Synthesis and Assessment of 99mTc Chelate-Conjugated Alendronate for Development of Specific Radiopharmaceuticals
- Author
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Deepa Sinha, Rakesh Srivastava, Hairsh Cahndra, Anil K. Mishra, Anjani K. Tiwari, and Gauri Shukla
- Subjects
Cancer Research ,Biodistribution ,Indoles ,Spectrophotometry, Infrared ,Bone and Bones ,Cell Line ,Mice ,chemistry.chemical_compound ,Liquid chromatography–mass spectrometry ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Chelation ,Radionuclide Imaging ,Pharmacology ,Indole test ,Mice, Inbred BALB C ,Chromatography ,Alendronate ,business.industry ,Chemistry ,Technetium ,General Medicine ,Condensation reaction ,Solvent ,Oncology ,Specific activity ,Rabbits ,Radiopharmaceuticals ,Nuclear medicine ,business ,Derivative (chemistry) - Abstract
Indole-based alendronate (AI) was derived from the condensation reaction of indole 3-carboxaldehyde with sodium alendronate (ALN) and was characterized by various spectroscopic methods (e.g., ultraviolet, fourier-transform-infrared, and liquid chromatography mass spectrometry). The AI was labeled with (99m)Tc and radiochemical purity was above 97%, which was ascertained by instant thin-layer chromatography, using different solvent conditions, with a specific activity 2-5 mCi/mg. The receptor ligand assay on human bone cell line Soas-2 showed K(D) = 0.55 nM. The derivative (AI) was stable, which was determined under physiologic conditions up to 24 hours The blood kinetic study showed a biexponential pattern as well as quick wash-out from the circulation with varying biologic t(1/2)(F) and t(1/2)(S). Excellent-quality radio images were recorded of bone, showing a rapid clearance of background activity, at an early visualization at 1.5 hours. The excretory pathway of the derivative was through the kidneys, which was evidenced by biodistribution studies. Thus, the newly synthesized derivative can be considered as a specific bone-seeking agent.
- Published
- 2009
31. Synthesis and pharmacological study of novel pyrido-quinazolone analogues as anti-fungal, antibacterial, and anticancer agents
- Author
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Aruna Bajpai, Anjani K. Tiwari, Pushpa Mishra, A. K. Mishra, Vinay Singh, R. K. Sharma, and Vinay Kumar Pandey
- Subjects
Staphylococcus aureus ,Antifungal Agents ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Anti fungal ,Antineoplastic Agents ,Adenocarcinoma ,Biochemistry ,Chemical synthesis ,Structure-Activity Relationship ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Drug Discovery ,Humans ,Structure–activity relationship ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Antibacterial agent ,Molecular Structure ,Chemistry ,Organic Chemistry ,In vitro ,Anti-Bacterial Agents ,Klebsiella pneumoniae ,Aspergillus ,Pseudomonas aeruginosa ,Quinazolines ,Lactam ,Molecular Medicine - Abstract
A versatile method for novel pyrido-quinazolones was described here and tested for anti-fungal, antibacterial, and anticancerous activities. These synthesized compounds were characterized on the basis of spectroscopic techniques and evaluated for specific radiopharmaceuticals. Preliminary radiolabeling results with (99m)Tc and biological evaluation studies showed promising results for further evaluation in vivo. The efficiency of labeling was more than 98% and complexes were stable for about 18 h at 25 degrees C in the presence of serum.
- Published
- 2006
32. Synthesis and evaluation of new (18)F-labelled acetamidobenzoxazolone-based radioligands for imaging of the translocator protein (18 kDa, TSPO) in the brain
- Author
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Akiko Hatori, Bin Ji, Anjani K. Tiwari, Joji Yui, Ming-Rong Zhang, Feng Wang, Masayuki Fujinaga, Kazunori Kawamura, Yoko Shimoda, Tomoteru Yamasaki, Katsushi Kumata, Anil K. Mishra, Masanao Ogawa, and Lin Xie
- Subjects
Male ,Models, Molecular ,Biodistribution ,Fluorine Radioisotopes ,Stereochemistry ,Metabolite ,Biochemistry ,Brain Ischemia ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,In vivo ,Translocator protein ,Animals ,Physical and Theoretical Chemistry ,Benzoxazoles ,biology ,Organic Chemistry ,Brain ,Receptors, GABA-A ,In vitro ,Rats ,chemistry ,Docking (molecular) ,Positron-Emission Tomography ,biology.protein ,Specific activity ,Pharmacophore ,Carrier Proteins - Abstract
The visualization of the activated microglia/TSPO is one of the main aspects of neuroimaging. Here we describe two new (18)F-labelled molecules, 2-[5-(4-[(18)F]fluoroethoxyphenyl)- ([(18)F]2) and 2-[5-(4-[(18)F]fluoropropyloxyphenyl)- ([(18)F]3) -2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide as novel PET ligands for imaging the translocator protein (18 kDa, TSPO) in the brain. The three-D pharmacophore evaluation and docking studies suggested their high affinity for the TSPO and in vitro binding assays of the TSPO showed binding affinities 6.6 ± 0.7 nM and 16.7 ± 2.5 nM for 2 and 3, respectively. The radiochemical yields for [(18)F]2 and [(18)F]3 were found to be 22 ± 4% (n = 8) and 5 ± 2% (n = 5), respectively at EOB. The radiochemical purity for both was found ≥98% and the specific activity was in the range of 98-364 GBq μmol(-1) at EOS. In vitro autoradiography with an ischemic rat brain showed significantly increased binding on the ipsilateral side compared to the contralateral side. The specificity of [(18)F]2 and [(18)F]3 for binding TSPO was confirmed using the TSPO ligands PK11195 and MBMP. The biodistribution patterns of both PET ligands were evaluated in normal mice by 1 h dynamic PET imaging. In the brain, regional radioactivity reached the maximum very rapidly within 0-4 min for both ligands, similar to (R)[(11)C]PK11195. The metabolite study of [(18)F]2 also favoured a more favourable profile for quantification in comparison to (R)[(11)C]PK11195. In summary, these data indicated that [(18)F]2 and [(18)F]3 have good potential to work as PET ligands, therefore there are merits to use these radioligands for the in vivo evaluation in animal models to see their efficacy in the living brain.
- Published
- 2014
33. Studies for development of novel quinazolinones: new biomarker for EGFR
- Author
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Swati Aggarwal, Gurmeet Singh, Pooja Pooja, Anil K. Mishra, Deepa Sinha, Anjani K. Tiwari, and Ankur Kaul
- Subjects
Cell Survival ,Protein Data Bank (RCSB PDB) ,Antineoplastic Agents ,Pharmacology ,Analytical Chemistry ,chemistry.chemical_compound ,Animals ,Tissue Distribution ,Viability assay ,Instrumentation ,IC50 ,Quinazolinone ,Spectroscopy ,ADME ,Quinazolinones ,Mice, Inbred BALB C ,Egfr inhibition ,Affinity Labels ,Atomic and Molecular Physics, and Optics ,In vitro ,ErbB Receptors ,Molecular Docking Simulation ,Biochemistry ,chemistry ,Docking (molecular) ,MCF-7 Cells ,Rabbits - Abstract
The binding capabilities of a series of novel quinazolinone molecules were established and stated in a comprehensive computational methodology as well as by in vitro analysis. The main focus of this work was to achieve more insight of the interactions with crystal structure of PDB ID: 1M17 and predict their binding mode to EGFR. Three molecules were screened for further examination, which were synthesized and characterized using spectroscopic techniques. The persuasive affinity of these molecules towards EGFR inhibition (IC50 for QT=45nM) was established and validated from specific kinase assay including the cell viability spectrophotometric assay (QT=12nM). Drug likeliness property were also considered by analysing, the ADME of these molecules by using scintigraphic techniques. The result showed antitumour activity of QT (4.17 tumour/muscle at 4h). Further photo physical properties were also analysed to see in vitro HSA binding to QT.
- Published
- 2014
34. Oxime-dipeptides as anticholinesterase, reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA, dynamics simulations and DFT analysis
- Author
-
Kumar, A. K. Mishra, Anjani K. Tiwari, Milton, Nidhi Chadha, and Sangeeta Lal
- Subjects
Cholinesterase Reactivators ,Stereochemistry ,Protein Data Bank (RCSB PDB) ,Ligands ,Serine ,chemistry.chemical_compound ,Structural Biology ,Catalytic Domain ,Catalytic triad ,Oximes ,Molecular Biology ,Binding selectivity ,Binding Sites ,Molecular Structure ,Chemistry ,Hydrogen bond ,Hydrogen Bonding ,General Medicine ,Dipeptides ,Oxime ,Acetylcholinesterase ,Protein Structure, Tertiary ,Molecular Docking Simulation ,Kinetics ,Docking (molecular) ,Biocatalysis ,Cholinesterase Inhibitors ,Hydrophobic and Hydrophilic Interactions ,Algorithms ,Protein Binding - Abstract
Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer's disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with π-π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore -10.801 and MM-GBSA free energy -34.89 kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin-serine adduct has been investigated by the DFT approach at the vacuum MO6/6-311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.
- Published
- 2014
35. Bis(methylpyridine)-EDTA derivative as a potential ligand for PET imaging: synthesis, complexation, and biological evaluation
- Author
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Swati Aggarwal, Anjani K. Tiwari, Vikas Kumar, Anil K. Mishra, Pooja Singh, Ramendra Pratap, and Krishna Chuttani
- Subjects
Biodistribution ,Stereochemistry ,Pyridines ,Metal ions in aqueous solution ,Contrast Media ,Gallium ,Ligands ,Biochemistry ,chemistry.chemical_compound ,Mice ,Coordination Complexes ,Drug Discovery ,Pyridine ,medicine ,Animals ,Humans ,Tissue Distribution ,Edetic Acid ,Serum Albumin ,Pharmacology ,Mice, Inbred BALB C ,Chemistry ,Organic Chemistry ,Hydrogen Bonding ,Ligand (biochemistry) ,Human serum albumin ,Binding constant ,Kinetics ,Stability constants of complexes ,Positron-Emission Tomography ,Lipophilicity ,Molecular Medicine ,Rabbits ,Nuclear chemistry ,medicine.drug ,Protein Binding - Abstract
A novel transitional metal ligand derivatized from EDTA-conjugated 2-amino-4-methyl pyridine, an acyclic vehicle (EDTA-Mepy2 ) was designed, synthesized, and characterized for PET imaging with ⁶⁸Ga. The drug likeliness and appropriate lipophilicity were first analyzed by molecular docking studies which shows interactive property of ligand with serum albumin protein (HSA: PDB 1E78), at Lys199, Arg257, and His242 residues, which make it more appropriate in transportation as a specific ligand for PET imaging. As a confirmation, binding constant of the ligand with human serum albumin was calculated at λex = 350 nm which was found to be 4.9 × 10³ m⁻¹. The pharmacokinetics of (68) Ga-EDTA-Mepy2 was analyzed by blood kinetics (t(1/2) slow: 3 h 56 min and t(1/2) fast: 32 min) and biodistribution (maximum % ID/g was found in kidney at 1 h). Further the capability of this ligand was analyzed as optical marker also, by recording λex = 380 nm, RFU = 8000; 710 nm, RFU = 1000 units at fixed λem = 280 nm. Additionally, in physiological conditions where its stability was calculated, suggests 15-20 times selectivity over the endogenously present metal ions (KG aL /KZ nL = 14.3, KG aL /KC uL = 18.1).
- Published
- 2014
36. Synthesis, biological evaluation and molecular docking studies of high-affinity bone targeting N,N(') -bis (alendronate) diethylenetriamene-N,N'-triacetic acid: a bifunctional bone scintigraphy agent
- Author
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Nidhi Chadha, Deepa Sinha, Anil K. Mishra, Krishna Chuttani, and Anjani K. Tiwari
- Subjects
Biodistribution ,Geranylgeranyl pyrophosphate ,Stereochemistry ,medicine.medical_treatment ,Acetates ,Biochemistry ,Bone and Bones ,Cell Line ,chemistry.chemical_compound ,Mice ,Farnesyl diphosphate synthase ,Drug Discovery ,medicine ,Animals ,Humans ,Tissue Distribution ,Pharmacology ,Mice, Inbred BALB C ,biology ,medicine.diagnostic_test ,Organic Chemistry ,Bisphosphonate ,Molecular Docking Simulation ,Bone scintigraphy ,chemistry ,Docking (molecular) ,biology.protein ,Osteocalcin ,Molecular Medicine ,Rabbits ,Conjugate ,Half-Life - Abstract
A bisphosphonate derivative DTPA-bis(alendronate) conjugate has been synthesized and evaluated as potential radiopharmaceutical for bone imaging. The compound was synthesized by the covalent coupling of DTPA-bis(anhydride) with alendronate and was char-acterized on the basis of IR, NMR and mass spectroscopy. It was labelled with (99m) Tc with 96% efficacy and was found stable for about 24 h under physiological conditions. Blood kinetic studies of (99m) Tc DTPA-bis(alendronate) showed a biexponential pattern as well as quick washout from the blood circulation. The biological t1/2 (F) and t1/2 (S) were found to be 50 min ± 0.001 and 6 h 30 min ± 0.005, respectively. Imaging and biodistribution studies showed a significant accumulation of (99m) Tc DTPA-bis(alendronate) conjugate at bone site. Bone-to-muscles ratios were 12.08 ± 0.001 at 1 h, 45.33 ± 0.001 at 4 h and 35.83 ± 0.001 at 24 h after post-injection, respectively. The receptor binding of the (99m) Tc-DTPA-bis (alendronate) was established on human bone cell line (Soas-2) revealed KD = 0.86 nm. The preliminary result of the (99m) Tc-DTPA-bis(alendronate) is encouraging to carrying out further in vivo experiment for targeted bone imaging because of good-bone-to-normal-organ contrast. Further docking analysis with molecular targets, farnesyl diphosphate synthase, geranylgeranyl pyrophosphate and osteocalcin revealed the high affinity of -17.419 and thus represents strong potential of bone-imaging agent.
- Published
- 2013
37. Synthesis, conjugation and relaxation studies of gadolinium(III)-4-benzothiazol-2-yl-phenylamine as a potential brain specific MR contrast agent
- Author
-
Anil K. Mishra, Anjani K. Tiwari, Nisha Saini, Raunak Varshney, Mohan Paul S. Ishar, Michèle Allard, and Ankur Kaul
- Subjects
Stereochemistry ,Gadolinium ,Potentiometric titration ,chemistry.chemical_element ,Contrast Media ,Medicinal chemistry ,Inorganic Chemistry ,chemistry.chemical_compound ,Transmetalation ,Heterocyclic Compounds, 1-Ring ,Mice ,Cyclen ,Drug Stability ,In vivo ,Coordination Complexes ,DOTA ,Animals ,Humans ,Tissue Distribution ,Benzothiazoles ,Radionuclide Imaging ,Mice, Inbred BALB C ,Aniline Compounds ,Brain ,Technetium ,Ligand (biochemistry) ,Magnetic Resonance Imaging ,chemistry ,Stability constants of complexes ,Blood-Brain Barrier - Abstract
Magnetic resonance (MR) imaging is widely used in clinical research to map the structural and functional organization of the brain. We have designed and synthesized a Gd-based specific MR contrast agent that binds to regions in the brain. The presented compound {4-[(4-benzothiazol-2-yl-phenylcarbamoyl)-methyl]-7,10-bis-carboxymethyl-1,4,7,10-tetraazacyclododec-1-yl} acetic acid (DO3A-BT) was synthesized by conjugating the chloroacetylated product of 4-benzothiazol-2-yl-phenylamine with a trisubstituted cyclen. The lanthanide complex (Ln-DO3A-BT) was evaluated in vitro for both MR (Gd-DO3A-BT) and optical (Eu-DO3A-BT) imaging applications. The complex Gd-DO3A-BT displays a relaxivity of r1 = 4.18 mM(-1) s(-1) at 4.7 T which is 1.2 times greater than Dotarem and significantly higher than the brain specific MR contrast agent Luxol Fast Blue (LFB). The protonation constant of the ligand (pKa1 = 9.91, pKa2 = 8.22, pKa3 = 5.01) and the stability constant of the complex formed between Gd(III), Eu(III) and Ca(II) and ligand DO3A-BT (log βGdL = 18.4, log βEuL = 18.3, log βZn2L = 7.1, log βCa2L = 6.3) were recorded by potentiometric titration. The constants reflect the high stability of the ligand with lanthanides compared with endogenous metal ions. The transmetalation stability of Gd-DO3A-BT toward Zn proved to be excellent with a rate constant of 3.07 × 10(-5) s(-1) which is in line with other tetraazatetraacetic acid (DOTA)-monoamide complexes. The hydration number (q) was found to be 0.92, and is calculated from the difference in the luminescence lifetime of Eu-DO3A-BT in H2O and D2O solutions to determine the coordination state of this complex. The in vivo biodistribution of (99m)Tc-DO3A-BT in BALB/c mice showed a brain uptake of 1.2% ID g(-1) at 2 min post injection when injected with mannitol which disrupts the blood-brain-barrier (BBB) due to osmotic shock. In vitro binding on the brain homogenate revealed a high uptake by the neuronal/glial cells for in vivo applications.
- Published
- 2013
38. Synthesis and biological evaluation of newly designed phosphonate based bone-seeking agent
- Author
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Anil K. Mishra, Anjani K. Tiwari, Krishna Chuttani, Pooja Srivastava, and Nidhi Chadha
- Subjects
Models, Molecular ,Stereochemistry ,Protein Data Bank (RCSB PDB) ,Gallium Radioisotopes ,Ligands ,Bone and Bones ,chemistry.chemical_compound ,Heterocyclic Compounds, 1-Ring ,Mice ,Organophosphorus Compounds ,Drug Discovery ,Animals ,Chelation ,Tissue Distribution ,Bifunctional ,Radionuclide Imaging ,Biological evaluation ,Chelating Agents ,Pharmacology ,Mice, Inbred BALB C ,biology ,Molecular Structure ,Organic Chemistry ,General Medicine ,Organotechnetium Compounds ,Ligand (biochemistry) ,Phosphonate ,chemistry ,Stability constants of complexes ,Organ Specificity ,Drug Design ,Osteocalcin ,biology.protein ,Rabbits ,Radiopharmaceuticals ,Nuclear chemistry - Abstract
A cyclic tetraaza based bifunctional triphosphonate ligand 10-(2-aminoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenephosphonic acid) (DO3MP-EA) was synthesized as bone-seeking theranostic agent. The compound was characterized by spectroscopic techniques and labelled with 99m Tc with more than 97% purity. Blood clearance of 99mTc labelled compound a quick wash out from the circulation. The compound was excreted mainly via kidneys and accumulation of 99m Tc-DO3MP-EA in bone was 9.53 ± 1.06% of injected dose per gram of bone at 1 h. The preliminary CADD analysis confirms the efficacy of DO3MP-EA (G Score −7.005) as better binding agent for osteocalcin (pdb 1Q8H) rather than other known clinical agents. Subsequently stability constant of chelate with Ga(III) was found to be 18.6 which confirms its efficacy as 68 Ga labelled PET radiopharmaceutical for bone.
- Published
- 2012
39. Spectroscopic interaction of a coumarin derivative with bovine serum albumin
- Author
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Anjani K. Tiwari, Rajeev Sindhu, Mudassir M. Husain, and Lokesh C. Mishra
- Subjects
Pharmacology ,Cancer Research ,Quenching (fluorescence) ,biology ,Serum Albumin, Bovine ,General Medicine ,Coumarin ,Photochemistry ,Fluorescence ,Binding constant ,Fluorescence spectroscopy ,chemistry.chemical_compound ,Spectrometry, Fluorescence ,Oncology ,chemistry ,Coumarins ,biology.protein ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Cattle ,Bovine serum albumin ,Binding site ,Lead compound ,Cell Proliferation - Abstract
The absorption and fluorescence spectra of the 7-diethylamino-4-methyl coumarin (DAMC) in ethanol-water (1:9 v/v) solution at varying pH values were investigated. The interaction between DAMC and bovine serum albumin (BSA) was investigated by fluorescence spectroscopy. The Stern-Volmer quenching constant, the quenching rate constant of the bimolecular reaction (kq), the binding constant, and number of binding sites are mentioned but not calculated in the paper. Moreover, in a preliminary pharmacological study, DAMC not only remarkably increased cellular apoptosis in a concentration-dependent manner but also clearly induced A549 cell cycle arrest. Thus, these coumarin derivatives merit investigation as novel potential antitumor agents with further structural modification to produce an optimal lead compound and elucidate the detailed pharmacological mechanism.
- Published
- 2012
40. Polyethylene-glycolylated isoniazid conjugate for reduced toxicity and sustained release
- Author
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Anil K. Mishra, Krishnanand Mishra, Krishna Chuttani, Anjani K. Tiwari, Dipti Kakkar, Harpal Singh, and Raj Kumar
- Subjects
Drug ,Biodistribution ,Mice, Inbred BALB C ,Chromatography ,Chemistry ,media_common.quotation_subject ,Isoniazid ,Antitubercular Agents ,Pharmaceutical Science ,Biological activity ,Polyethylene glycol ,Polyethylene Glycols ,chemistry.chemical_compound ,Mice ,Biochemistry ,Delayed-Action Preparations ,medicine ,Animals ,MTT assay ,Rabbits ,Cytotoxicity ,medicine.drug ,media_common ,Conjugate - Abstract
Background: The antitubercular drug, isoniazid (INH), has been conjugated with a bifunctional polyethylene glycol derivative (MW 575) with the objective of designing a novel drug-delivery system that has reduced toxicity compared with the neat drug, without compromising its biological activity. The polyethylene glycol–bis(INH) conjugate was synthesized in high yield and was completely characterized by infrared, NMR and mass spectroscopies. Results: This conjugate was labeled with a 99mTc radionuclide with less than 95% labeling efficiency. MTT assay revealed lower cytotoxicity of the conjugate compared with INH. Blood kinetics in rabbits and biodistribution in mice compared the blood retention of the drug and its polymer conjugate and their uptake in various organs, respectively. Biodistribution and γ-scintigraphy in infection-induced animal models showed significantly high accumulation of the polymer–drug conjugate at the site of infection and retention for a long duration. Conclusion: This conjugate could prove to be a good lead molecule for infection diagnosis and therapy.
- Published
- 2012
41. Preclinical evaluation of DO3P-AME-DO3P: a polyazamacrocyclic methylene phosphonate for diagnosis and therapy of skeletal metastases
- Author
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Anjani K. Tiwari, Anupama Datta, Krishna Chuttani, Anil Mishra, Meganathan Thirumal, and Jyoti Tanwar
- Subjects
Pathology ,medicine.medical_specialty ,Biodistribution ,Kinetics ,Biomedical Engineering ,Pharmaceutical Science ,Bioengineering ,Bone Neoplasms ,Bone tissue ,chemistry.chemical_compound ,Mice ,Organophosphorus Compounds ,Osteoclast ,Spect imaging ,Acetamides ,medicine ,Animals ,Humans ,Methylene ,Cells, Cultured ,Pharmacology ,Mice, Inbred BALB C ,Molecular Structure ,Chemistry ,Organic Chemistry ,Organotechnetium Compounds ,Phosphonate ,In vitro ,medicine.anatomical_structure ,Models, Animal ,Rabbits ,Biotechnology ,Nuclear chemistry - Abstract
A phosphonate derivative 10'-bis(acetamido)-ethane-bis[1,4,7-tri(methylene phosphonic acid)-1,4,7,10-tetraazacyclododecane] (DO3P-AME-DO3P), was synthesized with 90% yield in high purity. It was labeled with (99m)Tc in 97.5% efficiency and specific activity of 112-250 MBq/μmol. The binding affinity of (99m)Tc-DO3P-AME-DO3P towards bone minerals was tested in vitro by using hydroxy apatite as a bone model with absorption of 93% during the first hour of the experiment. Receptor binding assay on human bone cell line SAOS-2 demonstrated K(d) value of 1.07 nM. Cell binding studies of DO3P-AME-DO3P on osteoblasts and osteoclasts cells performed in vitro displayed preferential affinity of the compound towards osteoclast (167.95 ± 3.56% dose/mg protein). The serum stability of (99m)Tc complex was found to be 96.8% after 24 h. Blood kinetics of (99m)Tc-DO3P-AME-DO3P performed on normal rabbits showed fast clearance with t(1/2)(F) = 15 min ± 0.014 min and t(1/2)(S) = 4 h 3 min ± 0.09 min. Biodistribution studies carried out in normal BALB/c mice showed bone-to-blood ratio of 20 and bone-to-muscle ratio of 33. The bone tissue demonstrated highest concentration of bound radioactivity with 10.73% ID/g at 1 h post injection. The protonation and stability constants were determined by pH-potentiometry titrations. The stability constants of DO3P-AME-DO3P with Lu(III), Sm(III), and Ho(III) were 19.7, 21.8, and 20.2 determined by "out of cell" method. The excellent bone seeking properties of DO3P-AME-DO3P make it a candidate of choice for SPECT imaging and preferential uptake of the compound in osteoclasts in comparison to osteoblasts; BMM and BMC can be used to understand the pathway of pathogenesis of osteoporosis and skeletal metastases.
- Published
- 2011
42. Design, synthesis, and fluorescence lifetime study of benzothiazole derivatives for imaging of amyloids
- Author
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Dipti Kakkar, Nisha Saini, Mukesh Chand, Nitin Kumar, Anjani K. Tiwari, and Anil K. Mishra
- Subjects
Cancer Research ,Quantitative structure–activity relationship ,Electrospray ,Biodistribution ,Reducing agent ,chemistry.chemical_element ,Quantitative Structure-Activity Relationship ,Plaque, Amyloid ,Technetium ,Fluorescence ,chemistry.chemical_compound ,Mice ,Alzheimer Disease ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Benzothiazoles ,Radionuclide Imaging ,Pharmacology ,Mice, Inbred BALB C ,Chromatography ,Amyloid beta-Peptides ,General Medicine ,Oncology ,chemistry ,Benzothiazole ,Isotope Labeling ,Proton NMR ,Rabbits ,Radiopharmaceuticals - Abstract
The imaging of the distribution of β-amyloid plaques in the brain is becoming an important diagnostic modality in Alzheimer's disease. The present study reports the synthesis of novel benzothiazole derivatives. The final products were characterized by spectral techniques such as FTIR, (1)H NMR, and electrospray ionization-mass spectrometry. The structure-activity relationship of these benzothiazole derivatives is also reported. The K(i) values of these derivatives were evaluated by competitive binding assay studies. The analogs were labeled with (99m)Tc for the potential diagnostic imaging of Alzheimer's disease using stannous chloride as a reducing agent. The radiochemical stability was found to be ≥ 90% for both the compounds and they were stable for 10-12 hours in human serum. Biodistribution studies of the (99m)Tc complex in normal mice were performed after intravenous injection through the tail vein. The data showed high initial brain uptakes at 2 minutes (2.2% ± 0.1% ID/g), and brain activities washed out to 0.3% ± 0.02% ID/g at 6 hours. In conclusion, benzothiazole derivatives showed excellent binding affinities for β-amyloid aggregates and high initial brain uptakes in normal mice.
- Published
- 2010
43. SAR of Cu (II) thiosemicarbazone complexes as hypoxic imaging agents: MM3 analysis and prediction of biologic properties
- Author
-
Himanshu Ojha, Anil K. Mishra, Anjani K. Tiwari, Nitin Kumar, Bachcha Singh, and Sweta Singh
- Subjects
Diagnostic Imaging ,Models, Molecular ,Thiosemicarbazones ,Cancer Research ,Quantitative structure–activity relationship ,chemistry.chemical_element ,Bioinformatics ,chemistry.chemical_compound ,Structure-Activity Relationship ,Computational chemistry ,Molecular descriptor ,Structure–activity relationship ,Humans ,Radiology, Nuclear Medicine and imaging ,Chelation ,HOMO/LUMO ,Semicarbazone ,Pharmacology ,General Medicine ,Copper ,Cell Hypoxia ,Partition coefficient ,Oxygen ,Oncology ,chemistry ,Copper Radioisotopes - Abstract
Copper(II) bis(thiosemicarbazone) are very useful for blood flow and hypoxic imaging. The aim of this study was to identify structure-activity relationships (SARs) within a series of analogues with different substitution patterns in the ligands, in order to design improved hypoxia imaging agents and elucidate hypoxia selectivity mechanisms. Genetic algorithms (GAs) were used to develop specific copper metal-ligand force field parameters for the MM3 force-field calculations. These new parameters produced results in good agreement with experiment and previously reported copper metal-ligand parameters. A successful quantitative SAR (QSAR) for predicting the several classes of Cu(II)-chelating ligands was built using a training set of 21 Cu(II) complexes. The QSAR exhibited a correlation between the predicted and experimental test set. The QSAR preformed with great accuracy; r(2) = 0.95 and q(2) = 0.90 utilizing a leave-one-out cross-validation with multiple linear regression analysis to find correlation between different calculated molecular descriptors of these complexes. The final QSAR mathematical models were found as the following: Log P = {3.01698 (+/-0.0590)} - LUMO {0.1248 (+/-0.068)} + MR {0.3219 (+/-0.086)} n = 21 |r| = 0.972 s = 0.188 F = 98.102 The resulting models could act as an efficient strategy for estimating the hypoxic conditions through imaging and provide some insights into the structural features related to the biological activity of these compounds.
- Published
- 2010
44. Disubstituted 4(3H) quinazolones: a novel class of antitumor agents
- Author
-
Vinay Kumar Singh, Rajbala Sharma, Rakesh Srivastava, Anjani K. Tiwari, Vikas Srivastava, Himanshu Sharma, and Anand Mohan Srivastava
- Subjects
Pharmacology ,Semicarbazide ,Stereochemistry ,Organic Chemistry ,Quantitative Structure-Activity Relationship ,Antineoplastic Agents ,Mass spectrometry ,Biochemistry ,Combinatorial chemistry ,chemistry.chemical_compound ,chemistry ,Nucleophile ,Cell Line, Tumor ,Neoplasms ,Drug Discovery ,Pyridine ,Anthranilic acid ,Quinazoline ,Quinazolines ,Molecular Medicine ,Moiety ,Humans ,Drug Screening Assays, Antitumor - Abstract
A series of disubstituted 4(3H) quinazolines were designed for potential application in tumors. Firstly, N-benzoyl anthranilic acid is formed, which undergoes cyclization in the presence of pyridine. Subsequently, nucleophilic attack by semicarbazide on the carbonyl carbon gives 2-substituted 3-carbamido 4(3H) quinazolones, which gives final compound with appropriate substitution. The final as well as intermediate products were confirmed by NMR, FT-IR, and mass spectrometry. In vitro toxicity was performed with different cell lines and showed that the connection of hydrophilic styryl to quinazoline moiety increases its efficacy.
- Published
- 2009
45. Effect of a novel series of benzothiazolo-quinazolones on epidermal growth factor receptor (EGFR) and biological evaluations
- Author
-
Anjani K. Tiwari, Vinay Singh, Gauri Shukla, Aruna Bajpai, Harish Chandra, and Anil K. Mishra
- Subjects
Microbial Sensitivity Tests ,Biochemistry ,Potassium carbonate ,Acetic acid ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Mice ,In vivo ,Potassium thiocyanate ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Epidermal growth factor receptor ,Benzothiazoles ,Pharmacology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Aromatic amine ,Technetium ,ErbB Receptors ,chemistry ,Benzothiazole ,Cell culture ,Isotope Labeling ,biology.protein ,Quinazolines ,Molecular Medicine - Abstract
A newly designed benzothiazolo-quinazolone series was synthesized by an aromatic amine and potassium thiocyanate in the presence of bromine in glacial acetic acid, and the final product was obtained by subsequent reaction with 5-arylamido/imidoalkyl-2-chlorobenzoic acid in the presence of potassium carbonate and further cyclization with sulphuric acid. A preliminary radiolabelling study with technetium shows a promising potential for further in vivo evaluation. Anti-bacterial, anti-viral and anti-tumor activities were evaluated for biological properties. Lead compounds are able to block epidermal growth factor receptor (EGFR) in human breast adenocarcinoma cell line, MCF-7.
- Published
- 2008
46. Polyethylene glycol conjugates of methotrexate and melphalan: synthesis, radiolabeling and biologic studies
- Author
-
Nitin Kumar, Anil K. Mishra, Deepa Sinha, Pushpa Mishra, Harish Chandra, Anjani K. Tiwari, and Gauri Shukla
- Subjects
Melphalan ,Cancer Research ,Polymers ,Antineoplastic Agents ,Polyethylene glycol ,Pharmacology ,Polyethylene Glycols ,chemistry.chemical_compound ,Mice ,Therapeutic index ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Radiology, Nuclear Medicine and imaging ,Tissue Distribution ,Dose-Response Relationship, Drug ,Chemistry ,Brain Neoplasms ,technology, industry, and agriculture ,General Medicine ,Glioma ,Polyethylene ,Hydrogen-Ion Concentration ,Kinetics ,Methotrexate ,Oncology ,PEGylation ,Drug carrier ,medicine.drug ,Conjugate - Abstract
Polyethylene glycols (PEGs) are potential drug carriers for humanizing the therapeutic index of anti-cancer agents. In this paper, we report on the modification of the anticancer drugs, methotrexate (MTX) and melphalan (L-PAM), covalently linked to PEGs for drug delivery. Conjugates of MTX and L-PAM were analyzed through different spectroscopic techniques. Both conjugates were labeled with (99m)Tc by the classical way, using reducing agents at a physiologic pH. Blood kinetic data revealed the biphasic pattern of clearance. Evaluation of the in vitro cytotoxicity of the drug polymer conjugates on the U87MG human glioma cell line revealed that the conjugates showed enhanced dose-dependent cytotoxicity.
- Published
- 2008
47. Synthesis, characterization and biological activity of Schiff base analogues of indole-3-carboxaldehyde
- Author
-
Deepa Sinha, Sweta Singh, Harish Chandra, Anjani K. Tiwari, Anil Mishra, Pushpa Mishra, and Gauri Shukla
- Subjects
Indoles ,Stereochemistry ,Glutamic Acid ,Chemical synthesis ,chemistry.chemical_compound ,Mice ,Valine ,Neoplasms ,Drug Discovery ,Aspartic acid ,Animals ,Humans ,Histidine ,Tissue Distribution ,Schiff Bases ,Antibacterial agent ,Pharmacology ,Indole test ,Schiff base ,Bacteria ,Chemistry ,Organic Chemistry ,Fungi ,Technetium ,General Medicine ,Thin-layer chromatography ,Rabbits ,Half-Life - Abstract
Eight novel heterocyclic Schiff bases derived from the condensation reactions of indole 3-carboxaldehyde with different l-amino acids (histidine, glutamic acid, aspartic acid, leucine, valine) as well as with some aminophenols, have been synthesized and characterized by various spectroscopic methods (IR, MS, (1)H NMR). Schiff base derivatives of indole 3-carboxaldehyde were labeled with (99m)Tc and radiochemical purity was above 97% which is ascertained by instant thin layer chromatography using different solvent conditions. Stability studies of all the derivatives of indole 3-carboxaldehyde was determined under physiological conditions and were stable for more than 24h. Blood clearance showed a quick wash out from the circulation and biological half life was found to be t((1/2))(F)=1h 15min; t((1/2))(S)=10h 05min. Excellent quality radioimages of tumor bearing mice were recorded showing rapid clearance of background activity, visualization of tumor at 3h and clearance from kidneys of histidine analogue which was further evidenced in biodistribution studies. Antimicrobial activity of these Schiff base compounds was evaluated against Bacillus subtilis, Pseudomonas fluorescence, Staphylococcus aureus, Aspergillus niger, Candida albicans and Trichophyton rubrum.
- Published
- 2007
48. Synthesis and evaluation of novel benzimidazole derivative [Bz-Im] and its radio/biological studies
- Author
-
Pushpa Mishra, Sweta Singh, Deepa Sinha, Anjani K. Tiwari, Vartika Singh, Aruna Bajpai, and Anil K. Mishra
- Subjects
Biodistribution ,Benzimidazole ,Antifungal Agents ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Biochemistry ,Chemical synthesis ,Cholecystokinin receptor ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,In vivo ,Drug Discovery ,medicine ,Animals ,Molecular Biology ,Organic Chemistry ,Biological activity ,Receptor antagonist ,In vitro ,Receptor, Cholecystokinin B ,chemistry ,Molecular Medicine ,Benzimidazoles ,Receptors, Cholecystokinin ,Aspergillus niger ,Rabbits ,Radiopharmaceuticals - Abstract
Two different benzimidazole analogues act as multimodal agent, first one as novel non-peptidic CCK-B receptor antagonist and similarly as potent anti-fungal agent, designated as [Bz-Im]. These compounds were synthesized and characterized by spectroscopic techniques such as FT-IR, NMR, EI-MS and also evaluated for specific radiopharmaceuticals. Preliminary radiolabeling results with (99m)Tc and biological evaluation studies showed promising results for further evaluation in vivo. The efficiency of labeling was more than 97% and complex was stable for about 12h at 30 degrees C in the presence of serum. Both ligands showed binding to most of the organs, known to express CCK receptors in biodistribution studies. Cholecystokinin (CCK(1) andCCK(2)) receptor binding affinities of these analogues are, IC(50), 0.942+/-0.107 for compound C and 0.665+/-0.211 for compound D in rat pancreatic acini. The anti-fungal activity has shown inhibitory activity against Aspergillus flavus and Aspergillus niger. These studies have provided a new template for further development of non-peptidic ligands for diagnostic and therapeutic purposes of diseases related with CCK receptors as well as anti-microbes.
- Published
- 2006
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