Synthesis and evaluation of novel 1, 2, 4-substituted triazoles for urease and anti-proliferative activity.

1,2,4-triazoles are a major group of heterocyclic compounds. In the current work, a concise library of such triazoles synthesized through a multistep protocol. The synthesis involved hydrazinolysis of ethyl-2-(p-Cl-phenoxy) acetate followed by reflux with phenyl isothiocyanate to yield the intermediate 2-[2-(p-Cl-phenoxy)acetyl)-N-phenyl-hydrazinecarbothioamide. This intermediate was then cyclized to form 5-[p-(Cl-phenoxy)-methyl]-4-phenyl-4H-1,2,4-triazole-3-thiol (the parent moiety) at alkaline pH. In parallel, 3-bromopropionyl bromide was reacted with a series of phenylamines to yield N-(substituted-phenyl)bromopropanamides. In the final step, N-substitution of 5-[p-(Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-thiol was carried out with N-(substituted-phenyl)bromopropanamides to give desired library of 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(substituted-phenyl) propan-amides (8a-l). The prepared moieties were identified via IR, NMR, & EIMS and evaluated for urease and anti-proliferative activities. 3-[5-[(p-Cl-phenoxy)-methyl]-4- phenyl-4H-1,2,4-triazole-3-ylthio]-N-(3-methyl-phenyl)propanamide 8k, was found to be most prominent hit as urease inhibitor (IC50= 42.57± 0.13 µM) using thiourea as standard (IC50= 21.25±0.15µM). The interaction of 8k with urease were studied using docking studies. Anti-proliferative activity results showed 8k as promising candidates and rest of the synthesized derivatives were found to be moderately anti-proliferative. Molecular docking results also displayed 8k, 8h, and 8c as potential hits for further study.

Evaluation and docking of indole sulfonamide as a potent inhibitor of α-glucosidase enzyme in streptozotocin -induced diabetic albino wistar rats.

We have synthesized new hybrid class of indole bearing sulfonamide scaffolds (1-17) as α-glucosidase inhibitors. All scaffolds were found to be active except scaffold 17 and exhibited IC50 values ranging from 1.60 to 51.20 µM in comparison with standard acarbose (IC50 = 42.45 µM). Among the synthesized hybrid class scaffolds 16 was the most potent analogue with IC50 value 1.60 µM, showing many folds better potency as compared to standard acarbose. Whereas, synthesized scaffolds 1-15 showed good α-glucosidase inhibitory potential. Based on α-glucosidase inhibitory effect, Scaffold 16 was chosen due to highest activity in vitro for further evaluation of antidiabetic activity in Streptozotocin induced diabetic rats. The Scaffold 16 exhibited significant antidiabetic activity. All analogues were characterized through 1H, 13CNMR and HR MS. Structure-activity relationship of synthesized analogues was established and confirmed through molecular docking study.

Indole acrylonitriles as potential anti-hyperglycemic agents: Synthesis, α-glucosidase inhibitory activity and molecular docking studies.

One of the most prevailing metabolic disorder diabetes mellitus has become the global health issue that has to be addressed and cured. Different marketed drugs have been made available for the treatment of diabetes but there is still a need of introducing new therapeutic agents that are economical and have lesser or no side effects. The current study deals with the synthesis of indole acrylonitriles (3-23) and the evaluation of these compounds for their potential for α-glucosidase inhibition. The structures of these synthetic molecules were deduced by using different spectroscopic techniques. Acarbose (IC50 = 2.91 ± 0.02 µM) was used as standard in this study and the synthetic molecules (3-23) have shown promising α-glucosidase inhibitory activity. Compounds 4, 8, 10, 11, 14, 18, and 21 displayed superior inhibition of α-glucosidase enzyme in the range of (IC50 = 0.53 ± 0.01-1.36 ± 0.04 µM) as compared to the standard acarbose. Compound 10 (IC50 = 0.53 ± 0.01 µM) was the most effective inhibitor of this library and displayed many folds enhanced activity in contrast to the standard. Molecular docking of synthetic compounds was performed to verify the binding interactions of ligand with the active site of enzyme. This study had identified a number of potential α-glucosidase inhibitors that can be used for further research to identify a potent therapeutic agent against diabetes.

Syntheses, in vitro α-amylase and α-glucosidase dual inhibitory activities of 4-amino-1,2,4-triazole derivatives their molecular docking and kinetic studies.

Thirty-three 4-amino-1,2,4-triazole derivatives 1-33 were synthesized by reacting 4-amino-1,2,4-triazole with a variety of benzaldehydes. The synthetic molecules were characterized via1H NMR and EI-MS spectroscopic techniques and evaluated for their anti-hyperglycemic potential. Compounds 1-33 exhibited good to moderate in vitro α-amylase and α-glucosidase inhibitory activities in the range of IC50 values 2.01 ± 0.03-6.44 ± 0.16 and 2.09 ± 0.08-6.54 ± 0.10 µM as compared to the standard acarbose (IC50 = 1.92 ± 0.17 µM) and (IC50 = 1.99 ± 0.07 µM), respectively. The limited structure-activity relationship suggested that different substitutions on aryl part of the synthetic compounds are responsible for variable activity. Kinetic study predicted that compounds 1-33 followed mixed and non-competitive type of inhibitions against α-amylase and α-glucosidase enzymes, respectively. In silico studies revealed that both triazole and aryl ring along with different substitutions were playing an important role in the binding interactions of inhibitors within the enzyme pocket. The synthetic molecules were found to have dual inhibitory potential against both enzymes thus they may serve as lead candidates for the drug development and research in the future studies.

Synthesis of quinoline derivatives as diabetic II inhibitors and molecular docking studies.

In searchof the potenttherapeutic agent as an α-glucosidase inhibitor, we have synthesized twenty-five analogs (1-25) of quinoline-based Schiff bases as an inhibitoragainst α-glucosidase enzyme under positive control acarbose (IC50 = 38.45 ±â€¯0.80 µM). From the activity profile it was foundthat analogs 1, 2, 3, 4, 11, 12 and 20with IC50values 12.40 ±â€¯0.40, 9.40 ±â€¯0.30, 14.10 ±â€¯0.40, 6.20 ±â€¯0.30, 14.40 ±â€¯0.40, 7.40 ±â€¯0.20 and 13.20 ±â€¯0.40 µMrespectively showed most potent inhibition among the series even than standard drug acarbose (IC50 = 38.45 ±â€¯0.80 µM). Here in the present study analog 4 (IC50 = 6.20 ±â€¯0.30 µM) was found with many folds better α-glucosidase inhibitory activity than the reference drug. Eight analogs like 5, 7, 8, 16, 17, 22, 24 and 25 among the whole series displayed less than 50% inhibition. The substituents effects on phenyl ring thereby superficially established through SAR study. Binding interactions of analogs and the active site of ligands proteins were confirmed through molecular docking study. Spectroscopic techniques like 1H NMR, 13C NMR and ESIMS were used for characterization.

2,5-Disubstituted thiadiazoles as potent ß-glucuronidase inhibitors; Synthesis, in vitro and in silico studies.

Twenty-five thiadiazole derivatives 1-25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against ß-glucuronidase enzyme. Most of the compounds including 1 (IC50 = 26.05 ±â€¯0.60 µM), 2 (IC50 = 42.53 ±â€¯0.80 µM), 4 (IC50 = 38.74 ±â€¯0.70 µM), 5 (IC50 = 9.30 ±â€¯0.29 µM), 6 (IC50 = 6.74 ±â€¯0.26 µM), 7 (IC50 = 18.40 ±â€¯0.66 µM), and 15 (IC50 = 18.10 ±â€¯0.53 µM) exhibited superior activity potential than the standard d-saccharic acid-1,4-lactone (IC50 = 48.4 ±â€¯1.25 µM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.

Schiff bases of tryptamine as potent inhibitors of nucleoside triphosphate diphosphohydrolases (NTPDases): Structure-activity relationship.

Overexpression of NTPDases leads to a number of pathological situations such as thrombosis, and cancer. Thus, effective inhibitors are required to combat these pathological situations. Different classes of NTPDase inhibitors are reported so far including nucleotides and their derivatives, sulfonated dyes such as reactive blue 2, suramin and its derivatives, and polyoxomatalates (POMs). Suramin is a well-known and potent NTPDase inhibitor, nonetheless, a range of side effects are also associated with it. Reactive blue 2 also had non-specific side effects that become apparent at high concentrations. In addition, most of the NTPDase inhibitors are high molecular weight compounds, always required tedious chemical steps to synthesize. Hence, there is still need to explore novel, low molecular weight, easy to synthesize, and potent NTPDase inhibitors. Keeping in mind the known NTPDase inhibitors with imine functionality and nitrogen heterocycles, Schiff bases of tryptamine, 1-26, were synthesized and characterized by spectroscopic techniques such as EI-MS, HREI-MS, 1H-, and 13C NMR. All the synthetic compounds were evaluated for the inhibitory avidity against activities of three major isoforms of NTPDases: NTPDase-1, NTPDase-3, and NTPDase-8. Cumulatively, eighteen compounds were found to show potent inhibition (Ki = 0.0200-0.350 µM) of NTPDase-1, twelve (Ki = 0.071-1.060 µM) of NTPDase-3, and fifteen compounds inhibited (Ki = 0.0700-4.03 µM) NTPDase-8 activity. As a comparison, the Kis of the standard inhibitor suramin were 1.260 ±â€¯0.007, 6.39 ±â€¯0.89 and 1.180 ±â€¯0.002 µM, respectively. Kinetic studies were performed on lead compounds (6, 5, and 21) with human (h-) NTPDase-1, -3, and -8, and Lineweaver-Burk plot analysis showed that they were all competitive inhibitors. In silico study was conducted on compound 6 that showed the highest level of inhibition of NTPDase-1 to understand the binding mode in the active site of the enzyme.

Chalcones and bis-chalcones: As potential α-amylase inhibitors; synthesis, in vitro screening, and molecular modelling studies.

Despite of a diverse range of biological activities associated with chalcones and bis-chalcones, they are still neglected by the medicinal chemist for their possible α-amylase inhibitory activity. So, the current study is based on the evaluation of this class for the identification of new leads as α-amylase inhibitors. For that purpose, a library of substituted chalcones 1-13 and bis-chalcones 14-18 were synthesized and characterized by spectroscopic techniques EI-MS and 1H NMR. CHN analysis was carried out and found in agreement with the calculated values. All compounds were evaluated for in vitro α-amylase inhibitory activity and demonstrated good activities in the range of IC50 = 1.25 ±â€¯1.05-2.40 ±â€¯0.09 µM as compared to the standard acarbose (IC50 = 1.04 ±â€¯0.3 µM). Limited structure-activity relationship (SAR) was established by considering the effect of different groups attached to aryl rings on varying inhibitory activity. SMe group in chalcones and OMe group in bis-chalcones were found more influential on the activity than other groups. However, in order to predict the involvement of different groups in the binding interactions with the active site of α-amylase enzyme, in silico studies were also conducted.

Synthetic nicotinic/isonicotinic thiosemicarbazides: In vitro urease inhibitory activities and molecular docking studies.

Nicotinic and isonicotinic thiosemicarbazide or hydrazine carbothioamides 3-27 were synthesized and the structures of synthetic compounds were elucidated by various spectroscopic techniques such as EI-MS, 1H-, and 13C NMR. Synthetic derivatives were evaluated for their urease inhibitory activity which revealed that except few all derivatives demonstrated excellent inhibition in the range of IC50 values of 1.21-51.42 µM as compared to the standard thiourea (IC50 = 21.25 ±â€¯0.13 µM). Among the twenty-five synthetic derivatives nineteen 1-5, 7, 8, 10, 12, 14-18, 20-22, 24-27 were found to be more active showing IC50 values between 1.13 and 19.74 µM showing superior activity than the standard. Limited structure-activity relationship demonstrated that the positions of substituent as well as position of nitrogen in pyridine ring are very important for inhibitory activity of this class of compound. To verify these interpretations, in silico study was also performed. A good correlation was obtained between the biological evaluation of active compounds and docking study.

Synthesis, and In Vitro and In Silico α-Glucosidase Inhibitory Studies of 5-Chloro-2-Aryl Benzo[d]thiazoles.

Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (1-25) were synthesized and evaluated for their α-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC50 values between 22.1 ±â€¯0.9 and 136.2 ±â€¯5.7 µM, when compared with standard acarbose (IC50 = 840 ±â€¯1.73 µM). The most potent compounds 4, 9, and 10 showed IC50 values in the range of 22.1 ±â€¯0.9 to 25.6 ±â€¯1.5 µM. Compounds 2, 5, 11, and 19 showed IC50 values within the range of 40.2 ±â€¯0.5 to 60.9 ±â€¯2.0 µM. Compounds 1 and 3 were also found to be good inhibitors with IC50 values 136.2 ±â€¯5.7 and 104.8 ±â€¯9.9 µM, respectively. Their activities were compared with α-glucosidase inhibitor drug acarbose (standard) (IC50 = 840 ±â€¯1.73 µM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of α-glucosidase enzyme. All the active compounds (1-5, 9-11, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC50 = 0.80 ±â€¯0.12 µM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies.

Synthesis, molecular docking study and thymidine phosphorylase inhibitory activity of 3-formylcoumarin derivatives.

Thymidine phosphorylase (TP) over expression plays role in several pathological conditions, such as rheumatoid arthritis, chronic inflammatory diseases, psoriasis, and tumor angiogenesis. The inhibitor of this enzyme plays an important role in preventing the serious threat due to over expression of TP. In this regard, a series of seventeenanalogs of 3-formylcoumarin (1-17) were synthesized, characterized by 1HNMR and EI-MS and screened for thymidine phosphorylaseinhibitory activity. All analogs showed a variable degree of thymidine phosphorylase inhibition with IC50 values ranging between 0.90 ±â€¯0.01 and 53.50 ±â€¯1.20 µM when compared with the standard inhibitor 7-Deazaxanthine having IC50 value 38.68 ±â€¯1.12 µM. Among the series, fifteenanalogs such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 16 and 17 showed excellent inhibition which is many folds better than the standard 7-Deazaxanthine whiletwo analogs 13 and 14 showed good inhibition. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituents on phenyl ring. Molecular docking study was carried out to understand the binding interaction of the most active analogs.

Synthesis and study of the α-amylase inhibitory potential of thiadiazole quinoline derivatives.

α-Amylase is a target for type-2 diabetes mellitus treatment. However, small molecule inhibitors of α-amylase are currently scarce. In the course of developing small molecule α-amylase inhibitors, we designed and synthesized thiadiazole quinoline analogs (1-30), characterized by different spectroscopic techniques such as 1HNMR and EI-MS and screened for α-amylase inhibitory potential. Thirteen analogs 1, 2, 3, 4, 5, 6, 22, 23, 25, 26, 27, 28 and 30 showed outstanding α-amylase inhibitory potential with IC50 values ranges between 0.002±0.60 and 42.31±0.17µM which is many folds better than standard acarbose having IC50 value 53.02±0.12µM. Eleven analogs 7, 9, 10, 11, 12, 14, 15, 17, 18, 19 and 24 showed good to moderate inhibitory potential while seven analogs 8, 13, 16, 20, 21 and 29 were found inactive. Our study identifies novel series of potent α-amylase inhibitors for further investigation. Structure activity relationship has been established.

Synthesis, structure-activity relationships studies of benzoxazinone derivatives as α-chymotrypsin inhibitors.

A series of benzoxazinones 1-28 were synthesized via reaction of anthranilic acid with various substituted benzoyl chlorides in the presence of triethylamine in chloroform. Compounds 1-18 showed a good inhibition of α-chymotrypsin with IC50±SEM values between 6.5 and 341.1µM. Preliminary structure-activity relationships studies indicated that the presence of substituents on benzene ring reduces the inhibitory potential of benzoxazinone. Also the increased inhibitory potential due to fluoro group at phenyl substituent was observed followed by chloro and bromo substituents. Compounds with strong electron donating or withdrawing groups on phenyl substituent, showed a good inhibitory potential at ortho>meta>para position. Kinetics studies showed diverse types of inhibition, except uncompetitive-type inhibition. The Ki values ranged between 4.7 and 341.2µM. Interestingly, most of these compounds were non-cytotoxic to 3T3 cell line at 30µM, except compounds 6, 14 and 15. Competitive inhibitors of chymotrypsin are like to inhibit other α-chymotrypsin-like serine proteases due to structural and functional similarities between them. The inhibitors identified during the current study deserve to be further studied for their therapeutic potential against abnormalities mediated by chymotrypsin or other serine protease.

Facile synthesis of novel substituted aryl-thiazole (SAT) analogs via one-pot multi-component reaction as potent cytotoxic agents against cancer cell lines.

In this study, twenty-five (25) substituted aryl thiazoles (SAT) 1-25 were synthesized, and their in vitro cytotoxicity was evaluated against four cancer cell lines, MCF-7 (ER+ve breast), MDA-MB-231 (ER-ve breast), HCT116 (colorectal) and HeLa (cervical). The activity was compared with the standard anticancer drug doxorubicin (IC50=1.56±0.05µM). Among them, compounds 1, 4-8, and 19 were found to be toxic to all four cancer cell lines (IC50 values 5.37±0.56-46.72±1.80µM). Compound 20 was selectively active against MCF7 breast cancer cells with IC50 of 40.21±4.15µM, whereas compound 19 was active against MCF7 and HeLa cells with IC50 of 46.72±1.8, and 19.86±0.11µM, respectively. These results suggest that substituted aryl thiazoles 1 and 4 deserve to be further investigated in vivo as anticancer leads.

3D-QSAR CoMFA studies on bis-coumarine analogues as urease inhibitors: a strategic design in anti-urease agents.

A 3D-QSAR study has been performed on thirty (30) bis-coumarine derivatives to correlate their chemical structures with their observed urease inhibitory activity. Due to the absence of information on their active mechanism, comparative molecular field analysis (CoMFA) was used in the study. Two different properties: steric, electrostatic, assumed to cover the major contributions to ligand binding, were used to generate the 3D-QSAR model. Significant cross-validated correlation coefficients q(2) (0.558) and r(2) (0.992) for CoMFA were obtained, indicating the statistical significance of this class of compounds. The red electrostatic contour map highlighting those portion of compounds which may be interacting with nickel metal center in the active site of urease; while the blue contour map indicates positively charged groups in the ligands have improved biological activity and thus lower the IC(50)s. The steric contour map shows that bulkier substitutions at the 'R' position are detrimental to ligand receptor interaction. Actual urease inhibitory activities of this class and the predicted values were in good agreement with the experimental results. Moreover, from the contour maps, the key features vital to ligand binding have been identified, which are important for us to trace the important properties and gain insight into the potential mechanisms of intermolecular interactions between the ligand and receptor.