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Diabetes mellitus (DM), a chronic multifarious metabolic disorder resulting from impaired glucose homeostasis has become one of the most challenging diseases with severe life threat to public health. The inhibition of α-glucosidase, a key carbohydrate hydrolyzing enzyme, could serve as one of the effective methodology in both preventing and treating diabetes through controlling the postprandial glucose levels and suppressing postprandial hyperglycemia. In this context, three series of diamine-bridged bis-coumarinyl oxadiazole conjugates were designed and synthesized by one-pot multi-component methodology. The synthesized conjugates (4a–j, 5a–j, 6a–j) were evaluated as potential inhibitors of glucosidases. Compound 6f containing 4,4′-oxydianiline linker was identified as the lead and selective inhibitor of α-glucosidase enzyme with an IC50 value of 0.07 ± 0.001 μM (acarbose: IC50 = 38.2 ± 0.12 μM). This inhibition efficacy was ∼545-fold higher compared to the standard drug. Compound 6f was also emerged as the lead molecule against intestinal maltase-glucoamylase with good inhibition strength (IC50 = 0.04 ± 0.02 μM) compared to acarbose (IC50 = 0.06 ± 0.01 μM). Against β-glucosidase enzyme, compound 6 g was noted as the lead inhibitor with IC50 value of 0.08 ± 0.002 μM. Michaelis–Menten kinetic experiments were performed to explore the mechanism of inhibition. Molecular docking studies of the synthesized library of hybrid structures against glucosidase enzyme were performed to describe ligand-protein interactions at molecular level that provided an insight into the biological properties of the analyzed compounds. The results suggested that the inhibitors could be stabilized in the active site through the formation of multiple interactions with catalytic residues in a cooperative fashion. In addition, strong binding interactions of the compounds with the amino acid residues were effective for the successful identification of α-glucosidase inhibitors.

In the present study, we have designed and synthesized a Schiff base derivative 3 and characterized by FT-IR, 1H and 13C NMR spectroscopy. Single crystal X-ray diffraction and NMR studies were also performed. The synthetic compound was screened for its inhibitory potential against carbonic anhydrase II. The experimental results were validated by molecular docking and dynamic simulations of compound 3 in the active pocket of enzyme. Important binding interactions with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Moreover, supramolecular assembly of the title compound was analyzed by density functional theory (DFT) calculations. These studies rendered a more clear understanding for the demonstration of novel molecular mechanism involved in CA II inhibition by the synthesized compound.

Due to the immense importance of aryl indole nucleus, herein we report the palladium-catalyzed arylation of N-substituted 2-aryl indole utilizing Suzuki-Miyaura cross coupling methodology. The biological screening for cholinesterase inhibition of the resulted biaryl indole moieties was carried out to evaluate their pharmacological potential, expecting to involve the development of new therapeutics for various inflammatory, cardiovascular, gastrointestinal and neurological diseases. This research work also involved the use of utilization of microwave-assisted organic synthesis (MAOS) for the synthesis of Bischler-Möhlau indole which is further biarylated via palladium-catalyzed cross coupling reaction. All the synthetic compounds (3a-n) were tested for cholinesterase inhibition and exhibited high level of AChE inhibitory activities. Interestingly, compounds 3m and 3n were found to be dual inhibitors, however, remaining compound exhibited no inhibitory activity against BChE. The biological potential of the resulted compounds was explained on the basis of molecular docking studies, performed against AChE and BChE, exploring the probable binding modes of most potent inhibitors.

Fifteen N 4-benzyl-substituted isatin-3-thiosemicarbazones 5a–o were synthesized and evaluated for their urease and glycation inhibitory potential. Lemna aequinocitalis growth and Artemia salina assays were also done to determine their phytotoxic and toxic effects. All compounds are potent inhibitors of the urease enzyme, displaying inhibition [half maximal inhibitory concentration (IC50)=1.08±0.12–11.23±0.19 μm] superior to that of the reference inhibitor thiourea (IC50=22.3±1.12 μm). Compounds 5c, 5d, 5h, 5j,k are potent antiglycating agents, showing glycation inhibitory activity better than that of the reference inhibitor rutin (IC50 values 209.87±0.37–231.70±6.71 vs. 294.5±1.5 μm). In the phytotoxicity assay, 11 thiosemicarbazones 5a–d, 5g, 5h, 5j–l, 5n,o are active, demonstrating 5–100% growth inhibition of L. aequinocitalis at the highest tested concentrations (1000 or 500 μg/mL). In the brine shrimp (A. salina) lethality bioassay, three derivatives 5b, 5j and 5o are active with median lethal dose (LD50) values of 3.63×10−5, 2.90×10−5 and 2.31×10−4 m, respectively.

A new and efficient domino reaction of 3-chlorochromones with electron-rich aminoheterocycles was developed which allows for a convenient synthesis of a variety of pyrazolo[3,4-b]pyridines, pyrrolo[2,3-b]pyridines, pyrido[2,3-d]pyrimidines and benzofuro[3,2-b]pyridines. The products exhibit strong fluorescence. In addition, they exhibit significant ecto-5'-nucleotidase inhibition properties and cytotoxic behavior.

Objective: To determine inhibitory activity of methanolic leaf extract of Piper umbellatum and Persea americana (P. americana) (traditionally used in Cameroon against diabetes) on α -glucosidase, β -glucosidase, maltase-glucoamylase, aldose reductase and aldehyde reductase activities, enzymes involved in starch digestion or diabetic complications. Methods: The methanol extracts from Piper umbellatum and P. americana were prepared by maceration. To assess relative efficacy of these extracts, the determination of concentrations that were needed to inhibit 50% of enzyme activity was done, whereas, gas chromatography-mass spectrum was used to identify components from extracts that may be responsible for the activities. Results: The tested extracts strongly inhibited α -glucosidase, maltase-glucoamylase, aldose reductase and aldehyde reductase activities with IC50 ranging from (1.07 ± 0.03) to (31.77 ± 1.17) μg/mL. Among the tested extracts, P. americana was the most active against sensitive enzymes (IC50 of 1.07 ± 0.03 to 15.63 ± 1.23). But, none of the extracts showed interesting inhibitory effect against β -glucosidase as their percentage inhibitions were less than 16%. From gas chromatography-mass spectrum analysis, 10 and 8 compounds were identified in Piper umbellatum and P. americana extracts respectively, using NIST library 2014. Conclusions: Results of this study provide the scientific credential for a prospective usage of these plants to treat diabetes.

α-Glucosidase inhibitors have extensively been exploited for the effective management of type 2 diabetes and associated complications by significantly reducing the postprandial increase in glucose and plasma insulin levels. In this endeavour, we designed and synthesized a new series of coumarinyl iminothiazolidinone hybrid compounds (6a‒o) using a one-pot multi-component approach. The hybrid structures were accessed in good chemical yields. The synthesized compounds were tested for their glucosidase inhibitory efficacy using acarbose as a standard inhibitor (IC50 = 38.2 ± 0.12 µM). In-vitro analysis of the hybrid molecules identified several potential leads for the development of potent glucosidase inhibitors with IC50 values in the range of 0.09‒0.92 µM with compound 6g being the most potent drug candidate (IC50 = 0.09 ± 0.001 µM). Furthermore, compound 6f was identified as the lead inhibitor against maltase-glucoamylase with comparable inhibitory efficacy to acarbose with an IC50 value of 0.07 ± 0.016 µM. Binding interactions of potent compounds with the key residues in the active site of the glucosidase enzyme were revealed by molecular docking analysis. In summary, these new structural leads based on the hybrid pharmacophores could be developed as potential inhibitors of α-glucosidase for treating postprandial hyperglycemia.

Alkaline phosphatases are found in different living species and play crucial roles in various significant functions, such as hydrolyzing a variable spectrum of phosphate-containing physiological compounds, contributing to DNA synthesis, bone calcification, and attenuation of inflammation. They are homodimeric enzymes; each subunit contains one magnesium ion and two zinc ions crucial for the catalytic activity of the enzyme. Alkaline phosphatases exist in four distinct isoenzymes (placental, intestinal, germ cell, and tissue nonspecific alkaline phosphatases), which are expressed by four different genes; each one of them has distinguished functions. Any disturbance in the gene expression of alkaline phosphatase eventually induces serious disease conditions. Thus, the need to explore new lead inhibitors has increased recently. In this literature review, we aim to investigate the role of alkaline phosphatase in different diseases and physiological conditions and to study the structure-activity relationships of recently reported inhibitors. We focused on the lead compounds reported in the last 5 years (between 2015 and 2019).

We developed a simple and robust method for synthesis of 1,3-oxathiol-2-ylidene benzamides (4a–m) a sporadic class of heterocycles, by reacting freshly prepared aroyl isothiocyanates, with ethyl 2-chloroacetoacetate in presence of N-methylimidazole in dry acetonitrile. The synthesized compounds were explored for their inhibition against alkaline phosphatases and HeLa cancer cell lines. The results suggest that almost all the compounds possess good % inhibition against both enzymes, with compound 4m showing dual inhibition while 4g and 4i as potent and selective inhibitors of TNAP and c-IAP respectively. Structure activity relationship for the active members of series has been carried out based on molecular docking studies. The result of SAR shows the involvement of active inhibitors in H-bonding at various sites with different amino acid residues in addition to secondary metal ion interactions with Zn ions inside the active pocket of the enzyme. The π-π interactions between the 1,3-oxathiole ring and imidazole ring of His321 and His 317 further defines the dual mode of inhibition by compound 4m. These compounds also possess inhibition potential against cervical cell lines in the range of 2.42–69.03% with the maximum inhibition shown by the unsubstituted member 4a compared to the reference drug cisplatin.

Alkaline phosphatases are homodimeric protein enzymes which removes phosphates from several types of molecules. These catalyze the hydrolysis of monoesters in phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are a privileged class of heterocyclic compounds which may potentially serve as effective phosphatase inhibitors. In this regard, the present research paper reports the facile synthesis and characterization of substituted 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines with excellent yields. The synthesized compounds were tested for inhibitory potential against alkaline phosphatases. The compound 1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (5e) was found to be the most potent inhibitor of human tissue non-alkaline phosphatase in this group of molecules with an IC50 value of 1.09 ± 0.18 µM. The compound 1-(3,4-dimethoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (5d) exhibited selectivity and potency for human intestinal alkaline phosphatase with an IC50 value of 0.71 ± 0.02 µM. In addition, structure activity relationship and molecular docking studies were performed to evaluate their binding modes with the target site of alkaline phosphatase. The docking analysis revealed that the most active inhibitors showed the important interactions within the binding pockets of human intestinal alkaline phosphatase and human tissue non-alkaline phosphatase and may be responsible for the inhibitory activity of the compound towards the enzymes. Therefore, the screened thiazole derivatives provided an outstanding platform for further development of alkaline phosphatase inhibitors. Alkaline phosphatase assay revealed compound 5e (1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine) as the most active inhibitor of h-TNAP with an IC50 value of 1.09 ± 0.18 µM. Computational evaluation clearly depicts several interactions within the binding pockets of h-IAP and h-TNAP and maybe responsible for the inhibitory potential of the compound towards the enzymes.HighlightsThe synthesis of 1-(benzylidene) thiosemicarbazides 3(a-i) was performed by reacting thiosemicarbazide with substituted aromatic aldehydes 1(a-i).The synthesized 1-(benzylidene) thiosemicarbazides was cyclized with 1-chloropinacolone to obtain the respective 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i).The synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i) were successfully characterized using elemental analysis, FT-IR and multi nuclear NMR.Alkaline phosphatase assay and computational study was performed in favor of the synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i). The synthesis of 1-(benzylidene) thiosemicarbazides 3(a-i) was performed by reacting thiosemicarbazide with substituted aromatic aldehydes 1(a-i). The synthesized 1-(benzylidene) thiosemicarbazides was cyclized with 1-chloropinacolone to obtain the respective 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i). The synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i) were successfully characterized using elemental analysis, FT-IR and multi nuclear NMR. Alkaline phosphatase assay and computational study was performed in favor of the synthesized 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines 5(a-i). Communicated by Ramaswamy H. Sarma

Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors.

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH2, NHMe, or NMe2) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC50 ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.

A new series of sulfonate derivatives 1a–zk were synthesized and evaluated as inhibitors of nucleotide pyrophosphatases. Most of the compounds exhibited good to moderate inhibition towards NPP1, NPP2, and NPP3 isozymes. Compound 1m was a potent and selective inhibitor of NPP1 with an IC50 value of 0.387 ± 0.007 µM. However, the most potent inhibitor of NPP3 was found as 1x with an IC50 value of 0.214 ± 0.012 µM. In addition, compound 1e was the most active inhibitor of NPP2 with an IC50 value of 0.659 ± 0.007 µM. Docking studies of the most potent compounds were carried out, and the computational results supported the in vitro results.

The multifactorial nature of Parkinson's disease necessitates the development of new chemical entities with inherent ability to address key pathogenic processes. To this end, two series of new symmetrical 1,2- and 1,4-bis(2-aroyl/alkoylimino-5-(2-methoxy-2-oxoethylidene)-4-oxo-thiazolidin-3-yl)benzene derivatives (3a-g and 5a-e) were synthesized in good yields by the cyclization of 1,2- and 1,4-bis(N'-substituted thioureido)benzene intermediates with dimethyl acetylenedicarboxylate (DMAD) in methanol at ambient temperature. The bis-iminothiazolidinone compounds were investigated in vitro for their inhibition of monoamine oxidase (MAO-A & MAO-B) enzymes with the aim to identify new and distinct pharmacophores for the treatment of neurodegenerative disorders like Parkinson's disease. Most of the designed compounds exhibited good inhibitory efficacy against monoamine oxidases. Compound 5a was identified as the most potent inhibitor of MAO-A depicting an IC50 value of 0.001μM, a 4-fold stronger inhibitory strength compared to standard inhibitor (clorgyline: IC50=0.0045μM). Molecular docking studies provided insights into enzyme-inhibitor interactions and a rationale for the observed inhibition towards monoamine oxidases.

A series of fifteen N4-benzyl substituted 5-nitroisatin-3-thiosemicarbazones 5a–o was synthesized and evaluated for urease inhibitory, phytotoxic and cytotoxic influences. All the compounds proved to be highly potent inhibitors of the enzyme, showing inhibitory activity (IC50 = 0.87 ± 0.25–8.09 ± 0.23 μM) much better than the reference inhibitor, thiourea (IC50 = 22.3 ± 1.12 μM) and may thus act as persuasive leads for further studies. In phytotoxicity assay, twelve out of fifteen thiosemicarbazones tested i.e. 5a–e, 5g, 5i and 5k–o appeared to be active, exhibiting weak or non-significant (5–35%) growth inhibition at the highest tested concentrations (1000 or 500 μg/mL). In contrast, only one compound i.e. 5i was active in the brine shrimp (Artemia salina) lethality bioassay, demonstrating cytotoxic activity with LD50 value 2.55 × 10−5 M. Molecular docking studies of compounds 5a–o were also performed to identify their probable binding modes in the active site of the enzyme.

Two new series of pyrazolobenzothiazine-based carbothioamides (3a-o and 4a-o) were synthesized using saccharin as the starting material. The synthesized derivatives were investigated for their ability to inhibit monoamine oxidases (MAO). Compound 3b was found to be a very potent MAO-A inhibitor with an IC50 value of 0.003 ± 0.0007 μM, while compound 4d was the most effective inhibitor of MAO-B having an IC50 value of 0.02 ± 0.001 μM. Molecular docking studies were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. The synthetic and computational investigations in the current work suggested that these newly identified inhibitors may serve as a powerful starting point for the exploration and optimization of potential therapeutic agents targeting Parkinson's disease.

A series of new coumarin-triazolothiadiazine hybrid compounds (5a-j) was designed and synthesized by using the molecular hybridization concept. The cyclocondensation reaction involves the coumarinyl 4-amino-1,2,4-triazole and a range of bromo-acetophenones, delivering the desired products in good yields. The structures of the synthesized compounds were established on the basis of spectro-analytical data. The prepared compounds were evaluated against alkaline phosphatase (ALP) where compound 5j incorporating bis-coumarinyl motifs at the 3- and 6-positions of the heteroaromatic core turned out to be a potent inhibitor with an IC50 value of 1.15 ± 1.0 µM. The synthesized compounds were also tested against Leishmania major and 5h was the lead member with an IC50 value of 0.89 ± 0.08 μM. Anticancer activity was also determined using kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Compound 5i showed highest cytotoxic potential against H-157 cells with an IC50 value of 1.01 ± 0.12 μM, which is an improved inhibition compared to the standards (vincristine and cisplatin) used in this assay. Molecular docking studies were carried out on the synthesized library of coumarin-triazolothiadiazine hybrids against ALP. Almost all of the compounds showed strong interactions with the key residues of the active site of the receptor. In case of compounds 5a-c, 5h, and 5j, docking results positively complemented the experimental screening. These results provided substantial evidence for the further development of these compounds as potent inhibitors of ALP.

Fused diaza-heterocycles constitute the core structure of numerous bioactive natural products and effective therapeutic drugs. Among them, phthalazines have been recognized as remarkable structural leads in medicinal chemistry due to their wide application in pharmaceutical and agrochemical industries. Accessing such challenging pharmaceutical agents/drug candidates with high chemical complexity through synthetically efficient approaches remains an attractive goal in the contemporary medicinal chemistry and drug discovery arena. In this review, we focus on the recent developments in the synthetic routes towards the generation of phthalazine-based active pharmaceutical ingredients and their biological potential against various targets. The general reaction scope of these innovative and easily accessible strategies was emphasized focusing on the functional group tolerance, substrate and coupling partner compatibility/limitation, the choice of catalyst, and product diversification. These processes were also accompanied by the mechanistic insights where deemed appropriate to demonstrate meaningful information. Moreover, the rapid examination of the structure-activity relationship analyses around the phthalazine core enabled by the pharmacophore replacement/integration revealed the generation of robust, efficient, and more selective compounds with pronounced biological effects. A large variety of in silico methods and ADME profiling tools were also employed to provide a global appraisal of the pharmacokinetics profile of diaza-heterocycles. Thus, the discovery of new structural leads offers the promise of improving treatments for various tropical diseases such as tuberculosis, leishmaniasis, malaria, Chagas disease, among many others including various cancers, atherosclerosis, HIV, inflammatory, and cardiovascular diseases. We hope this review would serve as an informative collection of structurally diverse molecules enabling the generation of mature, high-quality, and innovative routes to support the drug discovery endeavors.

Ectonucleotidases are a broad family of ectoenzymes that play a crucial role in purinergic cell signaling. Ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) belong to this group and are important drug targets. In particular, NPP1 and NPP3 are known to be druggable targets for treatment of impaired calcification disorders (including pathological aortic calcification) and cancer, respectively. In this study, we investigated a series of sulfonate and sulfamate derivatives of benzofuran and benzothiophene as potent and selective inhibitors of NPP1 and NPP3. Compounds 1c, 1g, 1n, and 1s are the most active NPP1 inhibitors (IC50 values in the range 0.12–0.95 µM). Moreover, compounds 1e, 1f, 1j, and 1l are the most potent inhibitors of NPP3 (IC50 ranges from 0.12 to 0.95 µM). Compound 1d, 1f and 1t are highly selective inhibitors of NPP1 over NPP3, whereas compounds 1m and 1s are found to be highly selective towards NPP3 over NPP1. Structure-activity relationship (SAR) study has been discussed in detailed. With the aid of molecular docking studies, a common binding mode of these compounds and suramin (the standard inhibitor) was revealed, where the sulfonate group acts as a cation-binding moiety that comes in close contact with the zinc ion of the active site. Moreover, cytotoxic evaluation against MCF-7 and HT-29 cancer cell lines revealed that compound 1r is the most cytotoxic towards MCF-7 cell line with IC50 value of 0.19 µM. Compound 1r is more potent and selective against cancer cells than normal cells (WI-38) as compared to doxorubicin.

Poncirin, a natural flavanone glycoside present abundantly in many citrus fruits, contains an extensive range of biological activities. However, the antidiabetic mechanism of poncirin is unexplored yet. In this study, we examined the anti-diabetic prospective of poncirin by evaluating its ability to inhibit protein tyrosine phosphatase 1B (PTP1B), α-glucosidase, human recombinant AR (HRAR), rat lens aldose reductase (RLAR), and advanced glycation end-product (AGE) formation (IC50 = 7.76 ± 0.21, 21.31 ± 1.26, 3.56 ± 0.33, 11.91 ± 0.21, and 3.23 ± 0.09 µM, respectively). Kinetics data and docking studies showed the lowest binding energy and highest affinity for the mixed and competitive type of inhibitors of poncirin. Moreover, the molecular mechanisms underlying the antidiabetic outcomes of poncirin in insulin resistant C2C12 skeletal muscle cells were explored, which significantly increased glucose uptake and decreased the expression of PTP1B in C2C12 cells. Consequently, poncirin increased GLUT-4 expression level by activating the IRS-1/PI3K/Akt/GSK-3 signaling pathway. Moreover, poncirin (0.5–50 µM) remarkably inhibited the formation of fluorescent AGE, nonfluorescent CML, fructosamine, and β-cross amyloid structures in glucose-fructose-induced BSA glycation during 4 weeks of study. Poncirin also notably prevented protein oxidation demonstrated with decreasing the protein carbonyl and the consumption of protein thiol in the dose-dependent manner. The results clearly expressed the promising activity of poncirin for the therapy of diabetes and its related complications.

Design, synthesis and characterization of new trinary Benzocoumarin-Thiazoles-Azomethine derivatives having three bioactive scaffolds in a single structural unit were carried out. The newly synthesized molecules were investigated for the inhibitory activity on human tissue nonspecific alkaline phosphatase (h-TNAP) and human intestinal alkaline phosphatase (h-IAP) isozymes. All the tested compounds exhibited the potent inhibition profile on both isozymes of alkaline phosphatase i.e., h-TNAP and h-IAP. Molecular docking studies were performed to explore the putative binding mode of interactions of selective inhibitors. Moreover, the synthesized derivatives were evaluated against cervical cancer cell line, HeLa and a few compounds exhibited significant inhibition in the range of 21.0–69.7%. The derivatives can be potential and selective alkaline phosphatase inhibitors for future studies.

Owing to the desperate need of new drugs development to treat Alzheimer's ailment the synthesis of 1-aroyl-3-(5-(4-chlorophenyl)-1,2,4-triazole-3-thioneaminylthioureas (2–6) starting from (4-amino-5-(4-chlorophenyl)-4H-1,2,4-triazole-3-thiol) (1) and synthesis of 1-(3-(4-aminophenyl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-isobutylphenyl)propan-1-one (7–9) starting from 2-(4-isobutylphenyl)propanehydrazide (a) with the cyclization with substituted chalcones (c-e) was carried out. To check the biological potential of the synthesized compounds, all were subjected to acetylcholinesterase (AChE) and butrylcholinesterase (BChE) inhibition assays. The most potent and selective inhibitor for the acetylcholinesterase was compound 7 having an inhibitory concentration of 123 ± 51 nM, whereas, compound 6 was found as selective inhibitor of butyrylcholinesterase (BChE) with an IC50 value of 201 ± 80 nM. However, the compounds 1 and 2 were found as dual inhibitors i.e. active against both acetylcholinesterase as well as butyrylcholinesterase.

A series of oxadiazole-sulfonamide hybrids was synthesized through multistep reaction and for the formation of targeted thioethers 6(a-l), a much facile route was adopted through which S-alkylation was successfully carried out at room temperature. These novel thioethers 6(a-l) were later screened against aldehyde reductase (ALR1) and aldose reductase (ALR2). Beside the enzyme inhibition studies, the compounds were also tested against cervical cancer cell lines (HeLa). The results suggested the significant inhibition pattern towards ALR2, while few compounds were active against ALR1. The synthesized derivatives have shown weak to moderate cytotoxicity. The most potent inhibitors (6b, 6e, 6f and 6l) were selected for molecular docking studies and the binding interactions were reported.

A series of six compounds (1a-f) possessing pyridine-pyrazole-benzenethiourea or pyridine-pyrazole-benzenesulfonamide scaffold were synthesized. The target compounds were screened to evaluate their inhibitory effect on human nucleotide pyrophosphatase/phosphodiesterase 1 and −3 (ENPP1 and ENPP3) isoenzymes. Compounds 1c-e were the most potent inhibitors of ENPP1 with sub-micromolar IC50 values (0.69, 0.18, and 0.40 µM, respectively. Moreover, compound 1b was the most potent inhibitor of ENPP3 (IC50 = 0.21 µM). They were much more potent than the reference standard inhibitor, suramin (IC50 values against ENPP1 and −3 were 7.77 and 0.89 µM, respectively). Furthermore, all the six compounds were investigated for cytotoxic effect against cancerous cell lines (HeLa, MCF-7, and 1321N1) and normal cell line (BHK-21). Compound 1e was active against all the three cancer cell lines, however, showed preferential cytotoxicity against MCF-7 (IC50 = 16.05 µM), which is comparable to the potency of cisplatin. All the tested compounds exhibited low or negligible cytotoxic effect against the normal cells. They have the merit of superior selectivity towards cancer cells than normal cells compared to cisplatin. The relative selectivity and potency of the inhibitors was justified by molecular docking studies. All the docked structures showed considerable binding interactions with amino acids residues of active sites of ENPP isoenzymes.

With the aim to discover novel, efficient and selective inhibitors of human alkaline phosphatase and nucleotide pyrophosphatase enzymes, two new series of pyrazolyl pyrimidinetriones (PPTs) (6a–g) and thioxopyrimidinediones (PTPs) (6h–n) were synthesized in good chemical yields using Knoevenagel condensation reaction between pyrazole carbaldehydes (4a–g) and pharmacologically active N-alkylated pyrimidinetrione (5a) and thioxopyrimidinedione (5b). The inhibition potential of the synthesized hybrid compounds was evaluated against human alkaline phosphatase (h-TNAP and h-IAP) and ectonucleotidase (h-NPP1 and h-NPP3) enzymes. Most of the tested analogs were highly potent with a variable degree of inhibition depending on the functionalized hybrid structure. The detailed structure-activity relationship (SAR) of PPT and PTP derivatives suggested that the compound with unsubstituted phenyl ring from PPT series led to selective and potent inhibition (6a; IC50 = 0.33 ± 0.02 µM) of h-TNAP, whereas compound 6c selectively inhibited h-IAP isozyme with IC50 value of 0.86 ± 0.04 µM. Similarly, compounds 6b and 6h were identified as the lead scaffolds against h-NPP1 and h-NPP3, respectively. The probable binding modes for the most potent inhibitors were elucidated through molecular docking analysis. Structure-activity relationships, mechanism of action, cytotoxic effects and druglikeness properties are also discussed.

Background: Cancer is a far-reaching and lethal but curable disease. Researchers have investigated numerous anticancer agents with only a few commercially available effective drugs which are very costly. Objective: Herein, we report the synthesis , characterization and anti cancer assays of a series of novel dithiocarbamates derivatives. Methods: All compounds were synthesized from different secondary amines and substituted benzyl chlorides in a single step. The structures of newly synthesized dithiocarbamate derivatives were confirmed by spectroscopic techniques (IR, NMR and HR-MS). Results: The synthesized compounds showed a significant anti-proliferative effect in cancer cells (HeLa) with the maximum inhibitory activity of compound SHD-2 with an IC50 = 0.31 ± 0.09 μM. However, the same compound exhibited 19.2% inhibition towards Baby Hamster Kidney fibroblasts (BHK-21), normal cell lines. Moreover, quantification of cellular DNA by flow cytometry for the evaluation of pro-apoptotic activity in HeLa cells demonstrates that arrest in cell cycle along with apoptosis advance towards drug cytotoxicity. However, molecular docking studies of the potent compound suggested that it binds to the major groove of the DNA. Conclusion: The cytotoxic and pro-apoptotic potential of the potent inhibitor may be further investigated in the animal models to advance their anti-cancer prospective.

Here we report on the synthesis and structural characterization of the dithallium(III)-containing 30-tungsto -4-phosphate [Tl

Ethnopharmacological relevance Anthocleista vogelii Planch is a medicinal plant traditionally used in West Africa for the management and treatment of diabetes mellitus. Aim of the study To determine the antidiabetic activities of chloroform fraction (CF) of Anthocleista vogelii Planch root bark in rats with diet- and alloxan-induced obesity-diabetes. Materials and methods Inhibitory activities of CF against α-amylase and α-glucosidase activities were determined in vitro. Three weeks old rats were fed with high-fat diet for 9 weeks to induce obesity prior to further induction of diabetes using alloxan (150 mg/kg body weight, i.p.). Blood glucose levels and body weight were measured every 7 days throughout the experiment. Glucose tolerance was assessed in normal and CF-treated rats on day 21. Terminal blood samples were collected from sacrificed animals for the measurement of serum insulin levels. Pancreases were excised from treated and untreated animals for histopathological examination. Results LCMS/MS chromatographic profile of CF via positive and negative modes revealed 13 and 23 compounds respectively. Further analysis revealed quebrachitol (QCT), loganin, sweroside, oleoside 11-methyl ester and ferulic acid, which have been previously reported for their antidiabetic activities, as constituents of CF. CF inhibited activities of α-amylase (IC50 = 51.60 ± 0.92 µg/ml) and α-glucosidase (IC50 = 5.86 ± 0.97 µg/ml) in a dose-dependent manner. Treatment of animals with obesity-diabetes with 100 and 200 mg/kg CF significantly improved glucose tolerance (P Conclusions Antidiabetic activities of CF might be mediated via inhibition of α-amylase and α-glucosidase activities, elevation of serum insulin concentration, and enhancement of insulin and leptin sensitivity in obesity-diabetes rats. This study further substantiates the traditional use of A. vogelii in the management and treatment of diabetes in Africa and encourages further studies to investigate its mechanism of action.

The series of cobalt(III) complexes (1a–12a) with N,N,N′-trisubstituted acylthioureas were synthesized and characterized by FT-IR, and multinuclear (1H and 13C) NMR spectroscopy and LC–MS combined with elemental analysis. Crystal structure of cobalt(III) chelate of type Co(L-O, S)3 were determined by single crystal X-ray diffraction analysis. Complexes were adopted to have the octahedral geometry, where the fac-disposed N,N,N′-trisubstituted acylthioureas showed bidentate mode of coordination environment at cobalt centre defined by three O and three S donor atoms. The ligands are coordinated in a chelate fashion, forming three five-membered rings. The synthesized complexes were screened against Jack bean urease. In vitro anticancer activity against lung carcinoma (H-157), and kidney fibroblast (BHK-21) cell lines of the synthesized compounds were also studied and found them potent candidates for drugs. Cytotoxic results revealed that compound 10a was emerged as a leading member with an IC50 value of 0.75 ± 0.027 μM against H-157 cell lines. When synthesized compounds were tested for antileishmanial activity against the promastigote forms of Leishmania major, compound 4a was identified as the most potent and lead candidate showed highest inhibition with an IC50 value of 0.45 ± 0.053 μM.

A new series of thirty nine 5-trifluoromethoxy/fluoro/chloro-isatin 3-hydrazonothiazolines 5a–n, 6a–o and 7a–j were synthesized by cyclization of the corresponding intermediate N4-aryl-substituted isatin-3-thiosemicarbazones 3 (prepared by condensation of appropriate isatin 1 with appropriate N4-aryl-substituted 3-thiosemicarbazides 2) with 4-chlorophenacyl bromide 4 in absolute ethanol or ethanol–benzene mixture and screened for their cytotoxicity, phytotoxicity, antifungal and urease inhibitory potential. All the synthesized compounds were found to be almost inactive in a brine shrimp (Artemia salina) bioassay, demonstrating IC50 values > 1.62 × 10−4 to 2.17 × 10−4 M. In a phytotoxicity assay, out of thirty-nine compounds tested, six i.e. 5i, 6h, 6i, 6k, 7c and 7h proved to be active, showing weak or non-significant (5–30%) activity at the highest tested concentration (500 μg mL−1). Similarly, in antifungal assay, twenty-six compounds i.e. 5a, 5b, 5d–f, 5h–j, 5m, 6a, 6b, 6d, 6j, 6l–o, 7a, 7b and 7d–j were found to be active against one, two, or three selected fungal strains, exhibiting weak or non-significant inhibition (10–30%). Of these, 6d and 6o displayed a relatively better activity profile in terms of the number of organisms inhibited. On the other hand, in a urease inhibition bioassay, all the synthesized hydrazonothiazolines proved to be potent enzyme inhibitors, demonstrating inhibitory activity with IC50 values ranging from 3.70 ± 0.62 to 849 ± 2.26 μM. Compounds 5c, 5g–i, 5k, 5n, 6b, 6c, 6i, 6k, 6l, 6n, 6o, 7a, 7e, 7i and 7j were, however, found to be relatively very potent, displaying outstanding enzymatic activity (IC50 = 3.70 ± 0.62 to 20.9 ± 0.57 μM), even better than the reference inhibitor thiourea (IC50 = 22.3 ± 1.12 μM), and may thus act as valid leads for further studies. Molecular docking studies of the synthesized isatin–thiazolines 5a–n, 6a–o and 7a–j were also carried out to elucidate their relationship with the binding pockets of the enzyme. This study offers the first example of exhibition of urease inhibitory potential by isatin–thiazolines and as such provides a solid basis for further research on these compounds to develop more potent antiurease compounds of medicinal/agricultural interest.

Several isatin-3-thiosemicarbazones (a class of Schiff bases) from our earlier studies have been validated as promising cytotoxic agents and urease inhibitors. Also, a number of isatin-derived imines (Schiff bases) and their Cu(II) complexes have been reported in the literature to exhibit potential cytotoxic activity towards different cells. In view of this, a series of seven new 5-(un)-substituted isatin-derived bis-Schiff bases/ligands 3a–g and their Cu(II) complexes 5a–g were synthesized and evaluated for their cytotoxic and urease inhibitory activities. All the Schiff base ligands 3a–g proved to be active in sulforhodamine B (SRB) bioassay, displaying promising cytotoxic activity against lung carcinoma (H157) cells. Compound 3b was found to be the most potent inhibitor of H157 cells, exhibiting an IC50 value of 2.32 ± 0.11 μM. Similarly, all the metal complexes 5a–g proved to be active in this assay, demonstrating enhanced cytotoxic activity in each case, occurring as a result of coordination of the Schiff base ligands to the metal ion. Compound 5d proved to be the most potent inhibitor of H157 cells, showing cytotoxic activity comparable to that of the standard drug, vincristine (VCN) (IC50 = 1.29 ± 0.06 vs. 1.03 ± 0.04 μM). In the urease inhibition assay, all the synthesized Schiff base ligands except 3f proved to be highly potent enzyme inhibitors, displaying inhibitory activity even better than that of the reference inhibitor, thiourea (IC50 = 0.04 ± 0.004–5.86 ± 0.09 vs. 22.3 ± 1.12 μM), and thus may act as promising lead molecules for further studies. Molecular docking studies were also carried out for bis-Schiff bases 3a–g to elucidate their relationship with the binding pockets of the enzyme.

Alzheimer's disease is among the most widespread neurodegenerative disorder. Cholinesterases (ChEs) play an indispensable role in the control of cholinergic transmission and thus the acetylcholine level in the brain is enhanced by inhibition of ChEs. Coumarin linked thiourea derivatives were designed, synthesized and evaluated biologically in order to determine their inhibitory activity against acetylcholinesterases (AChE) and butyrylcholinesterases (BChE). The synthesized derivatives of coumarin linked thiourea compounds showed potential inhibitory activity against AChE and BChE. Among all the synthesized compounds, 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(3-chlorophenyl)thiourea (2e) was the most potent inhibitor against AChE with an IC50 value of 0.04±0.01μM, while 1-(2-Oxo-2H-chromene-3-carbonyl)-3-(2-methoxyphenyl)thiourea (2b) showed the most potent inhibitory activity with an IC50 value of 0.06±0.02μM against BChE. Molecular docking simulations were performed using the homology models of both cholinesterases in order to explore the probable binding modes of inhibitors. Results showed that the novel synthesized coumarin linked thiourea derivatives are potential candidates to develop for potent and efficacious acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors.

A series of fifteen N4-benzyl substituted 5-chloroisatin-3-thiosemicarbazones 5a–o were synthesized and screened mainly for their antiurease and antiglycation effects. Lemna aequinocitalis growth and Artemia salina assays were carried out to determine their phytotoxicity and cytotoxicity potential. All the compounds proved to be extremely effective urease inhibitors, demonstrating enzyme inhibition much better than the reference inhibitor, thiourea (IC50 values 1.31 ± 0.06 to 3.24 ± 0.15 vs. 22.3 ± 1.12 μM). On the other hand, eight out of fifteen compounds tested, i.e. 5b, 5c, 5h–k, 5m and 5n were found to be potent glycation inhibitors. Of these, five viz. 5c, 5h–j and 5n proved to be exceedingly efficient, displaying glycation inhibition greater than the reference inhibitor, rutin (IC50 values 114.51 ± 1.08 to 229.94 ± 3.40 vs. 294.5 ± 1.5 μM).

In this research work, we report the synthesis and biological evaluation of two new series of 1-benzyl-4-(benzylidenehydrazono)-3,4-dihydro-1H-benzo[c] [1,2]thiazine 2,2-dioxides and 1-benzyl-4-((1-phenylethylidene)hydrazono)-3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxides. The synthetic plan involves the mesylation of methyl anthranilate with subsequent N-benzylation of the product. The methyl 2-(N-benzylmethylsulfonamido)benzoate was subjected to cyclization reaction in the presence of sodium hydride to obtain 1-benzyl-1H-benzo[c][1,2]thiazin-4(3H)-one 2,2-dioxide which was treated with hydrazine hydrate to get corresponding hydrazone precursor. Finally, the titled compounds were obtained by reaction of hydrazone with various substituted aldehydes and ketones. The synthesized derivatives were subjected to carry out their inhibition activities against monoamine oxidases along with modelling investigations to evaluate their binding interactions and dynamic stability during the docking studies. The inhibition profile of potent compounds was found as competitive for both the isozymes. The compounds were more selective inhibitors of MAO-A as compared to MAO-B. Moreover, drug likeness profile of the derivatives was evaluated to have an additional insight into the physicochemical properties. The molecular dynamic simulations predicted the behaviour of amino acids with the active site residues.

N-[(4-methoxyphenyl)]-4-oxo-4-[oxy]butanamide was synthesized and characterized by various techniques like elemental analyses, FT-IR, NMR (1H, and 13C), mass spectrometry and single crystal X-ray structural analysis. The appearance of the OH peak of the carboxylic acid in the FT-IR and NMR spectra conform the formation of the compound. The molecular structure of the compound is stabilized by short intramolecular O–H⋯O hydrogen bonds within the molecule. The synthesized compound was screened for in vitro biological activities like antimicrobial, anticancer, antileishmanial activities as well as interaction with SS-DNA (Salmon sperm DNA). It shows good antimicrobial activity. The in vitro anticancer activity against lung carcinoma (H157) and Vero cell lines demonstrate that the synthesized compound has almost comparable activity to that of the standard anticancer drug, vincristine. The biological importance of the compound is that it has almost no effect (less than 26.7%) on the normal cell line, Vero cell line. It was also tested for antileishmanial activity against the promastigote form of leishmania major and obtained attractive result. It was also tested for urease inhibition and showed good inhibitory activity against jack bean urease (IC50 = 4.08 ± 2.54 μM). UV–Vis spectroscopic result reveals that the binding mode of interaction of the compound with SS-DNA is intercalative DNA interaction and the intercalative mode of interaction was further supported by viscometry.

A series of N,N,N'-trisubstituted thioureas (1-12) and their Ni(II) complexes (1a-12a) were synthesized and characterized by multinuclear ((1)H and (13)C) NMR, FT-IR spectroscopy and LC-MS techniques in combination with elemental analysis. The crystal structures of both ligands and Ni(II) chelates of type Ni(L-O, S)2 were determined by single crystal X-ray diffraction analysis. All the complexes were adopted to have square planar geometry, where the N,N,N'-trisubstituted thioureas showed bidentate mode of coordination at nickel centre through oxygen and sulfur atoms. The synthesized complexes were screened for potential inhibitors of Jack bean urease. Compounds 1a and 3a were observed as most potent inhibitors of urease exhibiting IC50 values of 1.17 ± 0.12 and 1.19 ± 0.41 µM, respectively. Cytotoxicity assay on lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell showed that compounds were significant anticancer agents. Additionally, the complexes were tested against Leishmania major and found to be potent antileishmanial agents.

In the design of new drugs, the hybridization approach might allow obtaining molecules with improved biological activity with respect to the corresponding lead compounds. Thus, adopting this approach, a new series of novel bis-coumarin–iminothiazole hybrids was designed, synthesized and tested for their biological action against alkaline phosphatase, leishmaniasis and cancerous cells. The structures of the synthesized hybrid compounds (5a–m) were characterized and established by using spectro-analytical data. The synthesized analogues were evaluated against alkaline phosphatase where compound 5j was emerged as a potent inhibitor with IC50 value of 1.38 ± 0.42 μM. This inhibitory efficacy is two-fold higher as compared to the standard inhibitor. The synthesized compounds were also assayed for their anti-leishmanial potential against Leishmania major and compound 5i was observed as the lead candidate with 70.4% inhibition. The prepared compounds also showed cytotoxic behavior against kidney fibroblast (BHK-21) and lung carcinoma (H-157) cancer cell lines. Molecular docking of the synthesized library of iminothiazole derivatives against ALP was performed to delineate ligand–protein interactions at molecular level which suggested that the major interacting residues in the binding sites of the proteins might have an instrumental role in the inhibition of enzyme's function. Our results inferred that compounds 5j–m may serve as potential surrogates for the development of potent inhibitors of ALP.

The present study reports the synthesis of Zn(II) complexes of tosyl sulfonamide derivatives obtained by the reaction of tosyl chloride with L-amino acids. The ligands and their complexes were characterized by IR, 1H and 13C-NMR, GC-MS, elemental analysis and X-ray crystallography in the case of NA3. All compounds were screened for their carbonic anhydrase inhibitory activities. Results demonstrated that complexes are stronger inhibitors of carbonic anhydrase compared to their parent ligands, which warrants further development of organometallics as active carbonic anhydrase inhibitors. Cytotoxicity assays on lung carcinoma (H-157) and kidney fibroblast (BHK-21) cancer cells demonstrated that compounds were potent anticancer agents. Additionally, the complexes were screened against promastigote forms of Leishmania major and found to be significant antileishmanial agents. Molecular docking studies were performed against bCA II enzymes to rationalize the inhibitory properties of these compounds. The identified inhibitors showed promise for the design of interesting pharmacological agents.

Three series of 4-hydroxy-N′-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9–11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N′-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.

A series of iminothiazolines (4a-j) featuring 2,4,5-trichlorophenyl moiety and aroyl/heteroaroyl substituents has been prepared from readily accessible thioureas. In-vitro screening against glucosidase enzymes showed highly specific inhibition of α-glucosidase with a marked dependence of the potency upon the nature of the aroyl/heteroaroyl substituents. The most potent representatives, bearing ortho-tolyl and bulky naphthyl groups displayed the highest inhibitory potential with IC50 value of 0.15±0.01µM compared to standard drug acarbose (IC50=38.2±0.12µM). Several other derivatives (4c, 4d, 4i and 4j) were also significantly powerful and selective inhibitors of α-glucosidase. Binding interactions of potent compounds 4b, 4c, 4h and 4i with α-glucosidase were explored by molecular docking simulation. These results clearly identified a new class of structural leads which can be further investigated for the development of promising α-glucosidase inhibitors for the prevention of diabetes mellitus.

In an effort to identify novel cholinesterase candidates for the treatment of Alzheimer’s disease (AD), a diverse array of potentially bioactive compounds including triazolothiadiazoles (4a–h and 5a–f) and triazolothiadiazines (6a–h) was obtained in good yields through the cyclocondensation reaction of 4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazole-3-thiol (3) with various substituted aryl/heteroaryl/aryloxy acids and phenacyl bromides, respectively. The structures of newly prepared compounds were confirmed by IR, 1H and 13C NMR spectroscopy and, in case of 4a, by single crystal X-ray diffraction analysis. The purity of the synthesized compounds was ascertained by elemental analysis. The newly synthesized conjugated heterocycles were screened for cholinesterase inhibitory activity against electric eel acetylcholinesterase (EeAChE) and horse serum butyrylcholinesterase (hBChE). Among the evaluated hybrids, several compounds were identified as potent inhibitors. Compounds 5b and 5d were most active with an IC50 value of 3.09 ± 0.154 and 11.3 ± 0.267 μM, respectively, against acetylcholinesterase, whereas 5b, 6a and 6g were most potent against butyrylcholinesterase, with an IC50 of 0.585 ± 0.154, 0.781 ± 0.213, and 1.09 ± 0.156 μM, respectively, compared to neostigmine and donepezil as standard drugs. The synthesized heteroaromatic compounds were also tested for their cytotoxic potential against lung carcinoma (H157) and vero cell lines. Among them, compound 6h exhibited highest antiproliferative activity against H157 cell lines, with IC50 value of 0.96 ± 0.43 μM at 1 mM concentration as compared to vincristine (IC50 = 1.03 ± 0.04 μM), standard drug used in this study.

Nitrogen-containing heterocycles are of particular interest and significant importance for the discovery of potent bioactive agents in pharmaceutical industry. The present study reports the synthesis of a library of new conjugated heterocycles including 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazoles (4a–g and 5a–e) and 3,6-disubstituted-1,2,4-triazolo-[3,4-b]-1,3,4-thiadiazines (6a–h), by cyclocondensation reaction of 4-amino-5-(pyridin-4-yl)-4H-1,2,4-triazole-3-thiol 3 with various substituted aromatic acids and phenacyl bromides, respectively. The structures of newly synthesized compounds were characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and in case of 4c by X-ray crystallographic analysis. Newly synthesized triazolothiadiazoles and thiadiazines were screened for acetyl- and butyryl-cholinesterases and alkaline phosphatase inhibition. Almost all of the compounds showed good to excellent activities against acetylcholinesterase more than the reference drugs. Compound 5d exhibited IC50 value 0.77 ± 0.08 μM against acetylcholinesterase and 4a showed IC50 9.57 ± 1.42 μM against butyrylcholinesterase. Among all the tested compounds, 4a also proved as excellent inhibitor of alkaline phosphatase with IC50 0.92 ± 0.03 μM. These heteroaromatic hybrid structures were also tested for their anticancer activity against lung carcinoma (H157) and kidney fibroblast (BHK-21) cell lines and leishmanias. Variable cell growth inhibitory activities were obtained and many compounds exhibit potent %inhibition.

A variety of 1-substituted-3-(3-aminosulfonylphenyl)thioureas (3a-k) and two new 1-aroyl-3-(4-aminosulfonylphenyl)thiourea derivatives (5a and 5b) were synthesized by reaction of 3-aminobenzenesulfonamide and 4-aminobenzenesulfonamide respectively with freshly prepared aroyl/heteroaryl isothiocyanates in dry acetonitrile. FTIR, H-1 NMR, C-13 NMR, GC-MS and elemental analyses data confirmed the assigned structures to the synthesized compounds. Further structure of compound (3g) was also confirmed by single crystal XRD analysis. The compounds were investigated as inhibitors of the bovine erythrocyte carbonic anhydrase isoform II (bCA II). The inhibition constants of these compounds against bCA II were in the range 0.011-17.1 mu M. Among the evaluated compounds, 1-substituted -3-(3-aminosulfonylphenyl)thiourea derivatives 3h and 5a were the most potent inhibitors with IC50 of 0.052 and 0.011 mu M, respectively. In silico docking and molecular dynamics simulation studies were performed against bCA II and human CA II enzymes to rationalize the inhibitory properties of these compounds.

A new series of raloxifene sulfonate/sulfamate derivatives were designed and synthesized. The target compounds were tested for inhibitory effect against nucleotide pyrophosphatase/phosphodiesterase-1 and -3 (NPP1 and NPP3) enzymes. Furthermore, all the ten target compounds were subjected to cytotoxic studies on various cancer cell lines, and the most potent derivatives were explored for their potency against these cancer cell lines as well as F180 fibroblasts to investigate the selectivity indexes. Compound 1f exerted the highest potency against HT-29 colon cancer cell line (IC50 = 1.4 μM) with 8.43-fold selectivity towards HT-29 than F180 fibroblasts. Compound 1f exerted sub-micromolar IC50 values against NPP1 and NPP3 (IC50 = 0.29 μM and 0.71 μM, respectively). The most potent inhibitors were docked in developed homology model of NPP1 and crystal structure of NPP3. All the docked analogues manifested remarkable interactions within the active pocket of NPP1 and NPP3.

This article demonstrates the synthesis and characterization of novel organotin(IV) carboxylate complexes and their medicinal applications. Metal complexes and organometallic compounds have growing importance in medicine, particularly in oncology. Organotin derivatives have caught much attention during the last two decades for their potential biocidal activities. In recent years several organotin compounds have been synthesized, some with interesting cytotoxic properties. Here we will focus on the relevance of organotin derivatives as very promising potential candidates in anticancer therapy. Ten new organotin(IV) complexes were synthesized and characterized by using FT-IR, NMR (1H, 13C and 119Sn), elemental analysis, mass spectrometry and single crystal X-ray techniques. The results of infrared spectroscopy of the sodium salt and complexes showed that the coordination took place through the oxygen atoms of the carboxylate group. Crystallographic data for complexes 1 and 3 showed that the tin has a distorted trigonal bipyramidal geometry with the three alkyl groups in the trigonal plane and the two oxygen atoms in the equatorial plane. In the case of complex 4 the geometry is tetrahedral due to the steric hindrance of the bulky phenyl groups. The compounds were screened for in vitro antiproliferative activity against lung carcinoma (H-157) and kidney fibroblast (BHK-21) cell lines and revealed significant anticancer activity. They were also tested for antileishmanial activity against the promastigote form of leishmania major and exhibited IC50 value 0.98 ± 0.06 μM (Compound 10) as compared to amphotericin B (IC50 value 0.29 ± 0.05 μM). The synthesized compounds act as a potent intercalator of SS-DNA and insert themselves into the nitrogenous bases of the DNA resulting in hypochromism and bathochromic shift.

Binding mode of potent inhibitor (green) & cognate ligand (pink) in the active site of MAO-B.

Background: Parkinson's disease (PD), a debilitating and progressive disorder, is among the most challenging and devastating neurodegenerative diseases predominantly affecting the people over 60 years of age. Objectives: To confront PD, an advanced and operational strategy is to design single chemical functionality able to control more than one target instantaneously. Methods: In this endeavor, for the exploration of new and efficient inhibitors of Parkinson's disease, we synthesized a series of quinoline carboxylic acids (3a‒j) and evaluated their in-vitro monoamine oxidase and cholinesterase inhibitory activities. The molecular docking and in silico studies of the most potent inhibitors were performed to identify the probable binding modes in the active site of the monoamine oxidase enzymes. Moreover, molecular properties were calculated to evaluate the drug-likeness of the compounds. Results: The biological evaluation results revealed that the tested compounds were highly potent against monoamine oxidase (A & B), 3c targeted the both isoforms of MAO with IC50 values of 0.51 ± 0.12 and 0.51 ± 0.03 µM, respectively. The tested compounds also demonstrated high and completely selective inhibitory action against acetylcholinesterase (AChE) with IC50 values ranging from 4.36 to 89.24 µM. Among the examined derivatives, 3i was recognized as the most potent inhibitor of AChE with an IC50 value of 4.36 ± 0.12 µM. Conclusions: The compounds appear to be promising inhibitors and could be used for the future development of drugs targeting neurodegenerative disorders.

A series of fifteen N