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Hit, Lead & Candidate Discovery A variety of novel 2‐(methyl/phenyl)‐3‐(4‐(5‐substituted‐1,3,4‐oxadiazol‐2‐yl)phenyl) quinazolin‐4(3H)‐ones have been synthesized by treating 3‐(4‐(5‐mercapto‐1,3,4‐oxadiazol‐2‐yl)phenyl)‐2‐(methyl/phenyl)‐quinazolin‐4(3H)‐one with a variety of secondary amines. Graph theoretical analysis was used in identification of drug target that is, NMDAR (N‐methyl‐d‐aspartate receptors). The observed reports of in silico modeling and ligand based toxicity, metabolism prediction studies were encouraging us to synthesize of title compounds and evaluate their antiepileptic effects. The title compounds were tested for its antiepileptic potency by MES and scPTZ model. Rotorod test is used to assess its neurotoxicity. In the preliminary test it was found that in MES test, analogs 6d, 6e, 6f, and 6l were potent; whereas in scPTZ test analogs 6d, 6e, 6f, and 6k displayed potent antiepileptic activity. Additionally these five derivatives were tested in rats orally at a dose of 30 mg/kg and found that compounds 2‐methyl‐3‐(4‐(5‐morpholino‐1,3,4‐oxadiazol‐2‐yl)phenyl)quinazolin‐4(3H)‐one 6e and 2‐methyl‐3‐(4‐(5‐(piperidin‐1‐yl)‐1,3,4‐oxadiazol‐2‐yl)phenyl)quinazolin‐4(3H)‐one 6f exhibited superior activity than reference Phenytoin. In MES test, these derivatives 6e and 6f showed activity at 30 mg/kg i.p. dose after 0.5 hr and 4.0 hr. In scPTZ test these derivatives 6e and 6f showed activity at 100 and 300 mg/kg i.p. dose after 0.5 hr and 4.0 hr, respectively. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Small organic molecules were found to be effective inhibitors of BACE-1 enzyme. • Tetrahydrobenzo[ b ]pyrans were targeted for the BACE-1 enzyme in docking studies. • Those compounds were synthesized in the lab and characterized using spectral data. • The synthesized compounds were subjected for in-vitro studies against the enzyme. • One compound with code KVB-5 (4e) was showing IC50 value at nanomolar concentration. Abstract β -Secretase (BACE1) has been broadly documented as one of the possible therapeutic targets for the treatment of Alzheimer's disease. In this paper, we report the synthesis and the for β -secretase (BACE-1) inhibitory activity of new series of tetrahydrobenzo [ b ] pyran derivatives. One-pot synthesis of tetrahydrobenzo [ b ] pyrans was carried out by condensing aromatic aldehyde, malononitrile and 1,3-cyclohexanedione using ionic liquid 1-butyl-3-methyl imidazolium chloride ([bmIm]Cl−) in aqueous alcohol media. The addition of alcohol and water in the ratio of 1:2 keeps all the reactants in solution which facilitates the reaction and makes the product formation very easy. The synthesized compounds were subjected to BACE1 inhibition assay and six compounds, 4d, 4e, 4f, 4h, 4i, and 4p have shown significant IC 50 values at micromolar level. Among these six active compounds, 4e was a potential inhibitor with its IC 50 value in nanomolar range. All the synthesized compounds were docked onto the active site of β -Secretase enzyme. [ABSTRACT FROM AUTHOR]

The reaction of a multi‐substituted pyrazole 1 with aryl or heteroaryl aldehydes and active methylene compounds afford unexpected pyrazolo[1,5‐a]pyridine derivatives 4(a‐k). Mechanism for this unexpected reaction involving reactivity of the active methylene moiety with a neighboring endocyclic NH group is proposed and structure has been established by the NMR and single crystal X‐ray diffraction studies. Moreover, all the newly synthesized compounds were tested for their anticancer activity against sixty human cell lines at NCI. Among all the compounds, three scaffolds 4d, 4 h and 4k showed enhancement in anticancer activity in comparison with remaining synthesized compounds. Interestingly compound 4k was found to highly active even at a five dose concentration. The IC50 values were determined against two cell lines MCF‐7 and HepG2, the results obtained have shown promising effects against cancer cell lines. Further, the molecular docking studies revealed that substituted pyrazolo[1,5‐a]pyridine derivatives are good candidates in the medicinal field. Multi‐substituted pyrazole (1) with aryl or heteroaryl aldehydes and active methylene compounds afford unexpected pyrazolo[1,5‐a]pyridine derivatives 4(a–k). Moreover, all the newly synthesized compounds were tested for their anticancer activityagainst sixty human cell lines at NCI. Threes scaffolds (4 d), (4 h) and (4 k) showed enhancement in anticancer activity in comparison with remaining synthesized compounds. Further, the molecular docking studies revealed that substituted pyrazolo[1,5‐a]pyridinederivativesare good candidates in the medicinal field. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is still a demanding worldwide health problem and mycobacterium tuberculosis (MTB) remains one of the most toxic human pathogens. In pursuit of searching new antitubercular and antimicrobial agents, substituted coumarin and phenyl‐1,2,4‐triazolidine‐3‐thiones 4a‐i and 5a‐e have been synthesized and evaluated for their antitubercular and antimicrobial activities. Most of the Substituted coumarin and phenyl‐1,2,4‐triazolidine‐3‐thiones showed promising activity against Mycobacterium tuberculosis (H37Rv). The title compounds have exhibited excellent in vitro antibacterial activity against the S.aureus, Bacillus sps and E.coli with the values of low MIC ranging from of 0.4 to 1.6 μg/mL. In vitro antifungal activity shown that the compounds 4a‐i and 5a‐e are excellent antifungal agents against Candida albicans, Aspergillus flavus, Aspergillus niger and Aspergillus fumigate fungal stains with the values of low minimum inhibitory concentrations (MIC) ranging from 0.4 to 6.25 μg/mL. Molecular docking study was performed for all the synthesized compounds with E.coli as antibacterial and Mycobacterium tuberculosis DprE1 as antituberculosis. In pursuit of searching new antitubercular and antimicrobial agents, coumarin and phenyl‐1,2,4‐triazolidine‐3‐thiones 4a‐i and 5a‐e have been synthesized and evaluated for their antitubercular and antimicrobial activities. Most of the coumarin and phenyl‐1,2,4‐triazolidine‐3‐thiones showed promising activity against Mycobacterium tuberculosis (H37Rv). The compounds have exhibited excellent in vitro antibacterial activity against the S.aureus, Bacillus sps and E.coli. Antifungal activity shown that the compounds 4a‐i and 5a‐e are excellent antifungal agents against fungal strains. Molecular docking study was performed for all the compounds. [ABSTRACT FROM AUTHOR]

Our recent research interest regarding synthesis of bioactive furanocoumarin derivatives, we have developed pyridinium yield assisted synthesis of 2,3‐dihydrofuran coumarin derivatives via, multicomponent one step reaction with excellent yield. All compounds 4(a–p) and 6(a–b) were screened for their in vitro antimicrobial, Anti‐inflammatory and cytotoxicity activity. The activity results demonstrated that, synthesized compounds are selective against both Gram positive bacterial strains B.subtilis, S.aureus and inactive against Gram negative bacterial strains E.coli, P.aeruginosa. Similarly, compounds are highly potent against both fungal strains C.albicans and C.tropicalis over standard drugs Fuconazole. The anti‐inflammatory activity was examined using egg albumin protein denaturation and Human red blood cell membrane stabilization methods; in both methods anti‐inflammatory results are highly promising. Compounds 4 a, 4 b, 4 d and 4 o exhibited potential cytotoxic activity against lung cancer cell lines with IC50 value ranging from 0.29 to 0.35 μM. Identifying the active antimicrobial and anti‐inflammatory agent is as essential factor for the successful development of lead molecules in drug designing. Molecular docking study was performed for all the compounds and docking result reveals that compounds are possessing drug like property. Furanocoumarin derivatives are selectively active against Gram positive bacterial strains and are found to be highly potent antifungal agent. These compounds also showed promising activity against anti‐inflammatory and cytotoxic, based on these result, compounds are considered to be lead molecules in drug designing. Molecular docking study was performed for all the compounds and docking result reveals that, these compounds are possessing drug like property. [ABSTRACT FROM AUTHOR]

Abstract: Improvement of antifungal agents is a good solution to beat the drug‐resistance problems. In this context, a series of novel bis‐1,2,4‐triazolin‐3‐ones (5i‐t) were designed and synthesized by microwave irradiation (MWI), a convenient and efficient method. An effort was also made to get these bis‐1,2,4‐triazolin‐3‐ones (5i‐t) by one‐pot three‐component reaction (3CR) using 3‐aryl‐5‐methyl‐1,3,4‐oxadiazol‐2(3H)‐one (2a‐b), formamide and dibromo reagent (4c‐h) under microwave irradiation (MWI). In vitro antifungal activity was carried out against six pathogenic fungi. From the results it was observed that the newly synthesized bis‐1,2,4‐triazolin‐3‐ones (5i‐t) have shown excellent activity against all the tested pathogenic fungi with least MIC values in the range of 0.80 μg/ml to 0.20 μg/ml. Particularly, in comparison with the reference drug Fluconazole and mono‐1,2,4‐triazolin‐3‐ones (3a‐b) some of the bis‐1,2,4‐triazolin‐3‐ones (5i, 5j, 5 m, 5p and 5r) have shown broad spectrum of antifungal activity. Further, the molecular docking study has been performed for all the tested compounds with 14α‐demethylase (CYP51) as target enzyme and this study validated the experimental results. Thus, docking study has culminated in the identification of a new class of potent inhibitors of CYP51. The results provide significant information for the future design of more potent antifungal agents. [ABSTRACT FROM AUTHOR]

An efficient, high yields and rapid synthesis of N - tert -butyl-4-(4-substituted phenyl)-2-((substituted-2-oxo-2H-chromen-4-yl)methylthio)-6-oxo-1,6-dihydropyrimidine-5-carboxamide derivatives (4a–4j) under microwave-irradiation has been described. All the newly synthesized compounds (4a–4j) were characterized by elemental analysis and spectroscopic studies. The synthesised compounds (4a–4j) were evaluated for their antibacterial activity by agar-well diffusion method and anti-inflammatory activity by egg albumin denaturation method. The compound (4f) exhibits antibacterial effect with MIC–2.5 μg/mL against gram positive S. aureus bacterial strain compared to standard ciprofloxacin drug (MIC–10 μg/mL). The compound (4c) shows an inhibition of heat induced protein denaturation 75.42% at a concentration of 31.25 μg/ml and is almost ten times more active than compared to standard aceclofenac drug (5.50%). Molecular docking study has been performed for all the synthesized compounds with S. aureus dihydropteroate synthetase (DHPS) and results obtained are quite promising. [ABSTRACT FROM AUTHOR]

A novel series of 6-chloro-7-methyl-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives were synthesized. Structure of the newly synthesized compounds was established by their analytical and spectroscopic data. The title compounds were evaluated for their anticancer activity against human breast cancer (T-47D) and lung cancer (NCI-H226) cell lines. Effects of compounds on the cell morphology of these cell lines were studied. Among the series of compounds tested, 6-chloro-7-methyl-2-(4-((2-(piperidin-1-yl)ethylamino)methyl) phenyl)-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one [MTDP4(9)] exhibited good anticancer activity against both cell lines. Further, the binding interaction of [MTDP4(9)] with bovine serum albumin has been investigated by UV, fluorescence and molecular docking studies. [ABSTRACT FROM AUTHOR]

A series of novel 5-(1-aryl-3-(thiophen-2-yl)-1 H -pyrazol-4-yl)-1 H -tetrazoles 7 ( h-s ) were designed and synthesized. Structural characterization was done by spectral and single crystal X-ray studies. The intermolecular interactions of compound 7n were quantified and visualized using Hirshfeld surface analysis. Structures of newly synthesized compounds were docked into active site of COX-2 enzyme PDB: 1CX2 , 3.0 Å X-ray resolution and plausible binding modes were compared with standard drug Celecoxib . The results of molecular docking prompted the pharmacological studies for further optimization of identified selective inhibition. The compounds 7k , 7m , 7n , and 7q-s have shown excellent anti-inflammatory activity and compounds 7i , 7k , 7l , 7n , and 7s have exhibited anti-bacterial inhibitory potency in enzyme based assays. [ABSTRACT FROM AUTHOR]

A series of novel coumarin-theophylline hybrids were synthesized and examined for their anti-tubercular activity in vitro against Mycobacterium tuberculosis H 37 Rv, anti-microbial activity in vitro against gram-positive bacteria ( Staphylococcus aureus ) and gram-negative bacterias ( Escherichia coli , Salmonella typhi ) as well as fungi ( Candida albicans ). The compound ( 3a ) has shown excellent anti-tubercular activity with MIC of 0.12 μg/mL. Electron donating compounds ( 3a, 3f ) have displayed significant anti-microbial activity. The compounds have also been precisely elucidated using single crystal X-ray diffraction techniques. Molecular docking study has been performed against 4DQU enzyme of Mycobacterium tuberculosis showed good binding interactions and is in agreement with the in vitro results. [ABSTRACT FROM AUTHOR]

A green and efficient protocol has been developed and a series of coumarin based pyrano[3,2- c ]chromene derivatives ( 2 ) have been synthesized using multi-component reaction (MCR) approach. Unexpected 3-coumarinyl-3-pyrazolylpropanoic acids ( 3 ) and C 4 -C 4 chromenes ( 5 ) have been isolated instead of expected product 4 by the reaction of compound ( 2 ) in formic acid at 90 °C for about 4–5 h and at 130 °C for about 8–10 h respectively. Further, C 4 -C 4 chromenes ( 5 ) formation was confirmed by intramolecular cyclization of compounds ( 3 ). These compounds were screened for their biological activities and most of them exhibited promising antibacterial activity. The anti-inflammatory assay was evaluated against HRBC membrane stabilization method and the compounds exhibit excellent anti-inflammatory activity. Molecular docking study has been performed for all the synthesized compounds with Klebsiella pneumoni ae acetolactate synthase and results obtained are quite promising. [ABSTRACT FROM AUTHOR]

Substituted quinolines containing a 1,2,4-triazole moiety were synthesized using reported methods. The molecular docking studies support the experimental results that these compounds are active against A. fumigatus and C. albicans where N-myristoyl transferase (NMT) and dihydrofolate reductase (DHFR), respectively, are the target enzymes. The analogues that contain methoxy and chloro substituents exhibit the best antifungal activity. [ABSTRACT FROM AUTHOR]

We report herein, first ever synthesis of series of novel differently substituted quinoxalinyl chalcones using Claisen Schmidt condensation, its molecular docking studies, and potential to be good anti-microbial, anti-tubercular and anti-cancer agents. The antimicrobial studies were carried out against Staphylococcus aureus , Escherichia coli and Candida albicans using disc diffusion procedure. The selected chalcones were tested for anti-cancer and cytotoxicity activity against MCF-7 cancer cell line using MTT assay method. All the synthesized compounds were screened for in vitro anti-tubercular screening against MtbH37RV strains by Alamar blue dye method. These results were compared with molecular docking studies carried out on Mycobacterium tuberculosis enzyme enoyl ACP reductase using Surflex-Dock program that is interfaced with Sybyl-X 2.0. SAR analysis for antimicrobial and antitubercular activity has also been proposed. [ABSTRACT FROM AUTHOR]

Transition metal coordination complexes of Co(II), Ni(II), Cu(II) and Zn(II) with a newly designed ligand, 2-(2-(1H-benzo[d]imidazol-2-yl)hydrazono)propan-1-ol have been synthesized and characterized using various spectro-analytical techniques. The molecular structures of Co(II), Cu(II) and Zn(II) complexes are determined by single-crystal X-ray diffraction method. The metal to ligand stoichiometry has been found to be 1:2 in the case of Cobalt(II), Nickel(II) and Zinc(II) whereas 1:1 in the case of Copper(II) complex. The newly synthesized ligand and complexes have been assessed for their growth inhibiting potencies against H37Rv strain of Mycobacterium tuberculosis . The copper and cobalt complexes have emerged to be potent in vitro growth inhibitors of H37Rv. All the complexes are inhibiting the growth of other tested common microbial flora to a significantly lesser extent, making them selective towards H37Rv in the preliminary analysis. The consensus scores obtained by the docking studies of the molecules to the target protein enoyl acyl carrier protein reductase of M. tuberculosis H37Rv are in good agreement with the obtained MIC values. [ABSTRACT FROM AUTHOR]

In this study, drug target was identified using KEGG database and network analysis through Cytoscape software. Designed series of novel benzimidazoles were taken along with reference standard Flibanserin for insilico modeling. The novel 4-(1 H-benzo[ d]imidazol-2-yl)- N-(substituted phenyl)-4-oxobutanamide ( 3a-j) analogs were synthesized and evaluated for their antidepressant activity. Reaction of 4-(1 H-benzo[ d]imidazol-2-yl)-4-oxobutanoic acid ( 1) with 4-(1 H-benzo [ d] imidazol-2-yl)-4-oxobutanoyl chloride ( 2) furnished novel 4-(1 H-benzo [ d] imidazol-2-yl)- N-(substituted phenyl)-4-oxobutanamide ( 3a-j). All the newly synthesized compounds were characterized by IR, 1H- NMR, and mass spectral analysis. The antidepressant activities of synthesized derivatives were compared with standard drug clomipramine at a dose level of 20 mg/kg. Among the derivatives tested, most of the compounds were found to have potent activity against depression. The high level of activity was shown by the compounds 3d, 3e, 3i, and it significantly reduced the duration of immobility time at the dose level of 50 mg/kg. [ABSTRACT FROM AUTHOR]

A new series of 2,5 and 1,5-regioisomers of the tetrazolyl group viz ., 3-[(5-benzyl/benzylthio-2 H -tetrazol-2-yl) methyl]-2-chloro-6-substituted quinoline 6h-q and 3-[(5-benzyl/benzylthio-1 H -tetrazol-1-yl) methyl]-2-chloro-6-substituted quinolines 7h-q were synthesized. Docking studies of all these compounds with DNA as target using PDB: 1AU5 and 453D revealed that the compounds 6h and 6i act as covalent cross linker on the DNA helix of the former and intercalate the latter both with higher C score values. Another set of docking studies in the active pocket of dihydrofolate reductase and N -myristoyl transferase as targets to assess antifungal activity revealed that compounds 6k , 6l , 6p and 7q (with bromo and fluro substituents) showcases different binding modes and hydrogen bonding. Further, the compounds were screened for anticancer activity (primary cytotoxicity) against NCI-60 Human tumor cell line at a single high dose (10 −5 M) concentration assay. Among the tested compounds, 6h has shown 99.28% of GI against Melanoma (SK-MEL-5) and compound 6i has shown 97.56% of GI against Breast Cancer (T-47D) . Further, in vitro antifungal assay against A. fumigatus and C. albicans for these compounds 6h-q and 7h-q revealed potential to moderate activities as compared to the standard. [ABSTRACT FROM AUTHOR]

A green, eco-friendly and efficient protocol has been developed and synthesized a series of coumarin based pyrano[2,3- c ]pyrazole derivatives ( 3 ) by multi-component reaction (MCR). Unexpected 3-coumarinyl-3-pyrazolylpropanoic acids ( 4 ) have been isolated by the reaction of compound ( 3 ) in acidic conditions. Further, intramolecular cyclization of compounds ( 4 ) leads to C 4 C 4 chromons ( 9 ) and these compounds were screened for their biological activities using array of techniques. Most of the compounds exhibited promising antibacterial activity, in particular Gram-positive bacteria. The anti-inflammatory assay was evaluated against protein denaturation as well as HRBC membrane stabilization methods and compounds exhibit excellent anti-inflammatory activity in both methods. Molecular docking study has been performed for all the synthesized compounds with S. aureus dihydropteroate synthetase (DHPS) and results obtained are quite promising. [ABSTRACT FROM AUTHOR]

[Display omitted] • Coumarin-TZD (TZD11-TZD18) were designed and synthesized for glucose uptake activity. • All the compounds displayed good safety profile in HEK-293 cell lines. • All the compounds are docked to the active site of PPARγ (PDB ID: 3CS8). • Computational toxicity and silico studies was done for them. Thiazolidinedione (TZD) based medications have demonstrated to enhance the insulin sensitivity control, hyperglycemia, and lipid metabolism in patients with type 2 diabetes. Hence, in this study, a new series of novel coumarin-4-yl-1,2,3-triazol-4-yl-methyl-thiazolidine-2,4-diones (TZD1-TZD18) were synthesized via copper (I)-catalyzed azide-alkyne cycloaddition " Click Chemistry". The synthesized compounds were evaluated for their glucose uptake assay and in vitro cytotoxicity against HEK-293 (human embryonic kidney) cells which were compared with the standard drug Pioglitazone. Further, molecular docking analysis of these compounds was carried out to explain the in vitro results with PPARγ (PDB ID: 3CS8) and to better understand the bonding interactions with the target protein. The outcomes of in vitro assessment, molecular docking, and pharmacokinetics of the title compounds were revealed to be highly correlated. Interestingly, the compounds TZD4, TZD10, TZD14 and TZD16 were most efficient in lowering the blood glucose level compared with standard drug. [ABSTRACT FROM AUTHOR]

In this study, a series of novel scaffold-based 3-(((substituted phenyl)amino)methyl)-2- methylquinazolin-4(3H)-one compounds, 3a-3r, was synthesized, characterized, and screened for its in vitro activity against the H37Ra strain of Mycobacterium tuberculosis. A number of analogs were found to have highly potent anti-tuberculosis activity. Compound 3m in particular had potent activity equal to that of the standard anti-tuberculosis drug rifampicin. New leads can be generated with the model developed in this study and this model will be optimized with the eventual goal of preparing new anti-tuberculosis agents. [ABSTRACT FROM AUTHOR]

• Simple synthetic procedures were employed to synthesize new triazole bridged bi-heterocycles. • Synthesized scaffolds were assessed for their in vitro antitubercular, antioxidant, cytotoxic and superoxide dismutase enzyme activities. • The scaffolds were proven to be potential anti-TB agents. • Molecular docking studies with DprE1 enzyme shown similar interaction of compounds as that of FDO ligand. • The scaffolds may be considered for in vivo use as lead drug. In search of new potent molecules against tuberculosis, 3,4-dihydro-2(1H)-quinolinone based 1,2,3-triazoles were synthesized efficiently by means of click chemistry and their structures were confirmed by spectral data. Among the synthesized twelve novel molecules, seven are hybrid of 3,4-dihydro-2(1H)-quinolinone, 1,2,3–1H-triazole nucleus with different coumarin derivatives and in remaining molecules coumarin is replaced by alkyl, aryl, and pyranose derivatives. Among the synthesized compounds, eight were screened for anti-TB activity against H37Rv strain and found to have good inhibition activity with lower MIC values (2.7–10.6 µM). Compound 6 h with (6-(acetoxymethyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate) substitution is most active against MTB. Further their antioxidant activity was assessed using DPPH assay and the compounds have shown moderate to low activity compared to standard ascorbic acid. The cytotoxicity of the synthesised compounds against lung cancer cell lines exhibited good to moderate activity and do not induce significant toxicity. In Superoxide dismutase(SOD) enzyme activity studies some of the compounds exhibited promising activity. The interactions of the molecules were studied against DprE1 protein of MTB through molecular docking. [Display omitted] [ABSTRACT FROM AUTHOR]

• Novel coumarin-thioether conjugates were synthesised and characterised. • The synthesised compounds are assessed for in vitro anti-TB activity (H 37 Rv strain). • Compound 6b (MIC = 0.39 µg/mL) was twofold more active than Rifampin (0.8 µg/mL). • Compounds 6b and 6f possessed low level of cytotoxicity against Vero cells. • Molecular docking study revealed higher C-score values that supports the findings. In this work, we report a series of 4-(2,6-dimethylphenyl)thio)methyl)-2H-chromen-2-one conjugates as promising leads to treat tuberculosis. Spectroscopic and other analytical methods were used to validate the synthesised compounds. The compounds were assessed for in vitro anti-tubercular activity with the H 37 Rv strain of Mycobacterium tuberculosis. Further, cytotoxicity studies were performed using Vero cells. Most of the synthesised conjugates were effective and displayed notable activity with MIC values in the range 0.39–12.5 µg/mL.The most diligent compound 6b (MIC = 0.39 µg/mL) was twofold more active than standard anti-TB drug Rifampin (0.8 µg/mL) and was comparable to Isoniazid (0.1 µg/mL). Compound 6f also displayed exemplary activity (MIC 0.78 µg/mL). Both compounds 6b and 6f possessed low levels of cytotoxicity, Molecular docking evaluation of the synthesised conjugates and 4DQU ligand demonstrated that the synthesised conjugates had higher C-score values that further supports the obtained results. It indicates compound 6b and 6f are promising lead compounds in search of novel antitubercular drug-like molecules. [Display omitted] [ABSTRACT FROM AUTHOR]

A series of mono and bis -triazole coumarin hybrids 6a–u and 9a–f respectively have been synthesized using 4-(azidomethyl)-2 H -chromen-2-ones 5a–i and aryl propargyl ethers 2a–c/8 employing Click chemistry modified protocol for Azide-Alkyne cycloadditions(CuAAC). Anti-tubercular screening showed moderate activity for mono aryloxy compounds 6a–u with MIC 50–100 μg/mL, whereas the bis compounds 9a–f were more effective with MICs between 0.2 and 12.5 μg/mL. Molecular modeling and 3D-QSAR measurements using CoMFA and Topomer CoMFA further supported the observed results. The bis compound 9b showed excellent activity with MIC value as low as 0.2 μg/mL. [ABSTRACT FROM AUTHOR]

• Novel quinoline containing 3-piperazin-1-yl-benzo[ d ]isothiazole and 3-piperidin-4-yl-benzo[ d ]isoxazoles were synthesized. • The single crystal XRD, DFT studies and in silico pharmacokinetic and toxicity parameters were done. • In vitro antimicrobial activity was analysed and correlated with energy difference in Frontier Molecular Orbitals. • Antimicrobial activity observed from in vitro assays and DFT studies were validated by Docking studies. Novel quinoline containing 3-piperazin-1-yl-benzo[ d ]isothiazole 4a and 4b and 3-piperidin-4-yl-benzo[ d ]isoxazole 5c were synthesized and characterized by spectral, single crystal XRD and DFT studies. Hirshfeld surface, electrostatic potential maps were obtained respectively from SCXRD and DFT studies. These compounds were analysed for in vitro antimicrobial activity and correlated with energy difference (ΔE) between HOMO and LUMO energy levels obtained from DFT and correlated with ΔE of standard drug to explain the activity. Further the antimicrobial activity was corroborated by docking against various target enzymes. The present work provided some hints for developing novel antimicrobial quinoline derivatives. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Total nine 1,3,4-oxadiazole-2-thiol derivatives (2a-2i) were synthesized. • The compounds had varying degree of enzyme inhibition for amylase and α-glucosidase. • In vitro studies indicate compounds 2b and 2g had better activity. • In vivo study indicates that 2b , 2g and 2i lowered glucose levels in the Drosophila. • 2b , 2g and 2i may be considered as potential drug candidates for further development. A hybrid molecule of different biologically active substances can improve affinity and efficiency compared to a standard drug. Hence based on this fact, we predict that a combination of fluorine, oxadiazole, sulfur, etc., may enhance α-glucosidase inhibition activity compared to a standard drug. A series of novel 5-(2,5-bis(2,2,2-trifluoroethoxy)phenyl)-1,3,4-oxadiazole-2-thiol derivatives (2a-2i) were synthesized and characterized using spectroscopic techniques such as 1HNMR and LC-MS. In order to evaluate its bioactivity, in vitro α-amylase and α-glycosidase inhibitory activity were performed. In vivo study was carried using a genetic model, Drosophila melanogaster, for assessing the antihyperglycemic effects. The compounds 2a-2i demonstrated α-amylase inhibitory activity in the range of IC 50 = 40.00–80.00 μg/ml as compare to standard acarbose (IC 50 = 34.71 μg/ml). Compounds 2a-2i demonstrated α-glucosidase inhibitory activity in the range of IC 50 = 46.01–81.65 μg/ml as compared to standard acarbose (IC 50 = 34.72 μg/ml). Docking studies on a target protein, N -terminal subunit of human Maltase-glucoamylase (PDB:2QMJ) was carried and the compounds were found to dock into the active site of the enzyme (Fig. 1). The predicted binding energies of the compounds were calculated. The in vitro studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. Whereas in vivo study indicates that 2b , 2g , and 2i could lower glucose levels in the Drosophila , but then 17–30% reduced capacity than acarbose and may be overcome by adjusting their dosage. The in vitro and in vivo studies indicate that compounds 2b and 2g had better activity among the synthesized compounds. This study has recognized that compounds like 2b , 2g , and 2i may be considered potential candidates for further developing a novel class of antidiabetic agents. [ABSTRACT FROM AUTHOR]

• Anticancer drugs have achieved great successes in recent years. • Designed and synthesized dipyrromethane-coumarin and porphyrin-coumarin Derivatives. • Dipyrromethane-coumarins and porphyrin-coumarins were screened for their anticancer activity at NCI-USA. • Among the synthesized series, two compounds were referred three time repeat analysis and three time recommended to Biological evaluation committee (BEC) in NCI. These two compounds are most prominent anticancer agents with GI 50 values <1. 0 µM. Coumarin analogues of dipyrromethane and porphyrin derivatives were synthesized and tested for their in-vitro anticancer activity at NCI (USA). Seven of the obtained compounds, 4-(di(1H-pyrrol-2-yl)methyl)-6-methoxy-2H-chromen-2-one (2c), 4-((1H-pyrrol-2-yl)(2H-pyrrol-2-ylidene)methyl)-6-methyl-2H-chromen-2-one (3a), 4-((1H-pyrrol-2-yl)(2H-pyrrol-2-ylidene)methyl)-6-chloro-2H-chromen-2-one (3d), Tetrahydro(6-methyl-coumarin) calix [4]pyrroles (4a), Tetrahydro(6-methoxy-coumarin) calix [4]pyrroles (4c), Tetra(6-methyl-coumarin) calix [4]pyrroles (5a) and Tetra(6-methoxy-coumarin) calix [4]pyrroles (5c) were screened for their antiproliferative activity against 60 human cancer cell lines. Among seven selected compounds, 2c, 3a, 4a and 4c showed remarkable activity with GI 50 values around 1. 0 μM (54 out of 60 cell lines) and <1. 0 μM (59 out of 60 cell lines) respectively. Interestingly, two compounds 2c and 4a have been subjected more than three times for repeat analysis against all the 60 cell lines and have been referred to Biological Evaluation Committee (BEC) for their advance study, among these two, compound 2c has been referred to BEC three times. Further, the ct-DNA interaction, absorptions and fluorescence quenching results of more active compounds 2c and 4a are quite promising. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel coumarin-4-yl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t are reported. • Microwave synthesis resulted shorter reaction times, excellent yields with high purity. • The reported compounds demonstrated high selectivity against COX-2. • All the compounds exhibited strong antioxidant activity. A modest, competent and green synthetic procedure for novel coumarinyl-1,3,4-oxadiazolyl-2-mercaptobenzoxazoles 8i-t has been reported. Analysis of the docked (PDB ID: 5IKR; A-Chain) poses of the compounds illustrated that they adopt identical conformations to the extremely selective COX-2 inhibitor. The biological outcomes as well as computational study suggested that the compounds originated to have elevated resemblance towards COX-2 enzyme than COX-1. The compounds 8i , 8l , 8q , 8r , 8s and 8t emerged as most potent and selective COX-2 inhibitors in contrast with Mefenamic acid. The selectivity index of 8l , 8n and 8r was respectively found to be 33.95, 20.25 and 24.98 which manifested their high selectivity against COX-2. Interestingly, the compounds which were active as COX-2 inhibitors were also active as antioxidant agents. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel quinoline and 1,2,4-triazole appended triazole derivatives were conceived. • Microwave synthesis resulted transitory reaction times, exceptional yields and purity. • The reported compounds proclaimed excellent anti-tubercular activity. • All the compounds exhibited exceptional antifungal activity. Quinolin-3-yl-methyl-1,2,3-triazolyl-1,2,4-triazol-3(4 H)-ones 8j-v were synthesized by click chemistry as an ultimate tactic where [3 + 2] cycloaddition of azides with terminal alkynes has been evolved. Herein, we are inclined to divulge the implication and prevalence of CuSO 4 ·5H 2 O and THF/water promoted [3 + 2] cycloaddition reactions. The foremost supremacy of this method are transitory reaction times, facile workup, excellent yields (88–92%) with exorbitant purity and regioselective single product formation both under conventional and microwave method. Docking studies illustrated strong binding interactions with enzyme InhA-D148G (PDB ID: 4DQU) by means of high C-score values. The anti-tubercular and antifungal screening of synthesized compounds proclaimed promising activity. The in vitro and in silico studies imply that these triazoles appended quinolines may acquire the ideal structural prerequisites for auxiliary expansion of novel therapeutic agents. [ABSTRACT FROM AUTHOR]

• Anticancer and anti-TB activity of novel coumarin-azaspiro conjugates (1a-1l). • 1f exhibited the most potent activity against MDA-MB-231cell line (IC 50 = 9.05 µM). • 1g showed most potent activity against A549 cell line (IC 50 = 7.05 µM). • 1c is found to be the hit candidate against MTBH 37 Rv strain with MIC 0.78 µg/mL. In this work, a series of new 8-[(substituted 2-oxo-2H-chromen-4-yl)methyl]-8-azaspiro[4.5]decane-7,9-dione derivatives (1a - 1l) is synthesized and characterized by 1H NMR, 13C NMR, FT-IR, GC-MS and elemental analysis. In addition, the structure of compound 1k has been elucidated using single crystal X-ray diffraction techniques. The synthesized compounds are screened for their anticancer and anti-TB activity. Preliminary anticancer results showed that compounds (1a - 1l) exhibit moderate to potent activity against MDA-MB-231, A549, HT-29 and Hela cancer cell lines. Compound 1f exhibited the most potent activity against MDA-MB-231cell line with IC 50 value of 9.05 µM concentration, compound 1g and 1h showed potent activity against A549 cell line with IC 50 value of 7.05 and 13.31 µM concentration respectively. Compound 1j showed good cytotoxicity against Hela cell line with IC 50 of 16.14 µM, whereas, compound 1l is found to be moderately active against HT-29 cell line with IC 50 of 18.07 µM. Anti-tubercular activity revealed that compound 1c, 1d, 1g, 1h and 1j have significant activity against MTBH 37 Rv strain with MIC 0.78, 1.56, 0.19, 0.39 and 0.78 µg/mL respectively. Further, to investigate the mechanism of anti-TB activity and detailed intermolecular interactions between the synthesized compounds, molecular docking studies are performed. [ABSTRACT FROM AUTHOR]

The enzymes MetAP-2 and NMT play a crucial role in the process of myristoylation of oncoproteins which is deregulated in many types of cancers. Execution of both these enzymes is considered as strategy for the intervention of various cancers and relative fungal infections, and hence the discovery of novel MetAP-2 and NMT inhibitors necessitate their high relevancy. In this investigation, we have synthesized a series of novel seven-membered triazolothiadiazepinyl quinolines 10(a – m) distinctively under microwave irradiation technique and identified as selective MetAP-2 and NMT inhibitors. Amongst the functionalized derivatives when evaluated for the in vitro antifungal assay, compounds 10b , 10c , 10e and 10f were considered promising due to notable inhibitory effects (MIC = 0.2 mg/mL) on Aspergillus fumigatus. Screening of the anticancer activity against NCI-60 Human tumor cell lines portrayed that conjugates 10b , 10c , 10e and 10f were found to be moderately effective against the Renal Cancer cell line UO-31. The data acquired from biological studies was further validated by molecular docking studies and pharmacokinetic evaluation. Image 1 • Microwave-assisted synthesis of triazolothiadiazepinyl quinolines was achieved. • Triazolothiadizepinylquinoline analogues were identified as MetAP-2/NMT inhibitors. • 10b , 10c , 10e & 10f exhibited anticancer activity on Renal Cancer cell line UO-31. • 10b , 10c , 10e & 10f are promising antifungals against Aspergillus fumigatus. • 10b , 10c , 10e & 10f exerted vital potency against MetAP-2/NMT verified by docking. [ABSTRACT FROM AUTHOR]

The objective of the research study was to develop and characterize a biodegradable, thermo and pH dual responsive Oxaliplatin-loaded chitosan-graft-poly-N-isopropylacrylamide (CS-g-PNIPAAm) co-polymeric nanoparticles as a tumor-targeting drug delivery system. CS-g-PNIPAAm co-polymers were synthesized, characterized and optimized its thermo and pH responsive properties for tumor microenvironment conditions. Optimized co-polymer could be efficiently loaded with Oxaliplatin in nanoparticle form, evaluated for their morphology (TEM), particle size, zeta potential, loading efficiency and drug content. In vitro drug release study at tumor microenvironment and physiological pH and temperature conditions. The in vitro drug release was optimal at above lower critical solution temperature (LCST) and tumor microenvironment pH when compared to physiological pH & temperature. MTT assay and fluorescence microscopic study showed that drug release and cell uptake was significantly enhanced in tumor microenvironment. In conclusion, the obtained nanoparticles appeared to be of great promise in tumor targeted drug delivery of oxaliplatin. [ABSTRACT FROM AUTHOR]

A wide range of mono- and bis-triazole coumarin hybrids are formed from chromene-2-one derivatives and propargyl ethers employing a Click chemistry modified protocol for Azide-Alkyne cycloadditions. [ABSTRACT FROM AUTHOR]