Synthesis and Molecular Docking of New Bis-Thiazolidinone-Based Chalcone Analogs as Effective Inhibitors of Acetylcholinesterase and Butyrylcholinesterase.

This work reports the convenient strategy for the synthesis of bis-thiazolidinone based chalcone analogs (1-20) from readily available thiosemicarbazide hydrochloride, ammonium thiocyanate and benzaldehyde. All the newly afforded bis-thiazolidinone based chalcone analogs (1-20) were screened in vitro for their acetylcholinesterase and butyrylcholinesterase inhibition profile. It was noteworthy, that all the synthetic analogs (except analogs 10, 12 and 14, which are found to be inactive) showed moderate to good inhibitory potentials on screening against acetylcholinesterase having range of inhibitory with IC50 values from 0.070±0.050 to 7.60±0.10 µM, and similarly for butyrylcholinesterase with range IC50 values from 0.10±0.050 µM to 10.70±0.20 µM, respectively as compared to standard Donepezil inhibitor (IC50 =2.16±0.12 µM), (IC50 =4.5±0.11 µM).Among the series, the analogs with hydroxy group showed superior inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes. Therefore, analog 20 (IC50 =0.070±0.050 µM), (IC50 =0.10±0.050 µM) bearing trihydroxy substitutions on ortho-, meta- and para-position of both rings A and B was found to be the most active inhibitor of acetylcholinesterase and butyrylcholinesterase enzymes among the current synthesized series (1-23). Analog 19 (IC50 =0.15±0.050 µM), (IC50 =0.20±0.050 µM) bearing dihydroxy substitutions on ortho- and meta-position of both ring A and ring B was identified as the second most potent inhibitor against both these enzymes. Interestingly, the compound (16) (IC50 =1.50±0.10 µM against AChE) has a better selectivity index (2.60) than standard Donepezil drug (2.083) for AChE over BuChE. The different types of spectroscopic techniques such as HR-EI-MS, 1 H- and 13 C- NMR were used to confirm the structure of all the newly synthetics analogs. To find structure-activity relationship, molecular docking studies were carried out to understand the binding mode of active inhibitors with active site of enzymes and results supported the experimental data.

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.

Synthesis, ß-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids.

The ß-glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising ß-glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane (1-30) were synthesized and evaluated for in vitro ß-glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC50 = 0.50-46.5 µM) than standard D-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the ß-glucuronidase and displayed significant binding interactions with essential residues.

Synthesis of symmetrical bis-Schiff base-disulfide hybrids as highly effective anti-leishmanial agents.

Leishmaniasis has affected a wider part of population around the globe. Most often, the existing regiments to battle against leishmaniasis are inadequate and limited. In our ongoing efforts to develop new leishmanicidal agents, we have synthesized a series of novel and symmetrical bis-Schiff base-disulfide hybrids 1-27. Intermediate disulfide was synthesized from corresponding 2-aminothiol followed by reacting the coupled adduct with various aromatic aldehydes. All these compounds showed outstanding inhibition when compared with standard (Table 1). Out of twenty seven analogues, twenty two analogues i.e. 1-5, 7-13, 17-21, 23-27 analogues showed excellent inhibitory potential with EC50 values ranging from 0.010 ± 0.00 to 0.096 ± 0.01 µM while five compounds i.e. 6, 14-16, and 22 showed good inhibitory potential with EC50 values ranging from 0.10 ± 0.00 to 0.137 ± 0.01 µM when compared with the standard Amphotericin B. Structure-activity relationship has been established while molecular docking studies were performed to pin the binding interaction of active molecules. This study will help to develop new antileishmanial lead compounds.

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.

Synthesis of oxadiazole-coupled-thiadiazole derivatives as a potent ß-glucuronidase inhibitors and their molecular docking study.

A new series of oxadiazole with thiadiazole moiety (6-27) were synthesized, characterized by different spectroscopic techniques and evaluated for ß-glucuronidase inhibitory potential. Sixteen analogs such as 6, 7, 8, 9, 10, 12, 13, 14, 17, 18, 20, 23, 24, 25, 26 and 27 showed IC50 values in the range of 0.96 ±â€¯0.01 to 46.46 ±â€¯1.10 µM, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC50 = 48.4 ±â€¯1.25 µM). Two analogs such as 16 and 19 showed moderate inhibitory potential while analogs 11, 15, 21 and 22 were found inactive. Our study identifies new series of potent ß-glucuronidase inhibitors for further investigation. Structure activity relationships were established for all compounds which showed that the activity is varied due to different substituents on benzene ring. The interaction of the compounds with enzyme active site were confirmed with the help of docking studies, which reveals that the electron withdrawing group and hydroxy group make the molecules more favorable for enzyme inhibition.

Goniolanceolatins A-H, Cytotoxic Bis-styryllactones from Goniothalamus lanceolatus.

Eight new bis-styryllactones, goniolanceolatins A-H (1-8), possessing a rare α,ß-unsaturated δ-lactone moiety with a (6S)-configuration, were isolated from the CH2Cl2 extract of the stembark and roots of Goniothalamus lanceolatus Miq., a plant endemic to Malaysia. Absolute structures were established through extensive 1D- and 2D-NMR data analysis, in combination with electronic dichroism (ECD) data. All of the isolates were evaluated for their cytotoxicity against human lung and colorectal cancer cell lines. Compounds 2 and 4 showed cytotoxicity, with IC50 values ranging from 2.3 to 4.2 µM, and were inactive toward human noncancerous lung and colorectal cells. Compounds 1, 3, 6, 7, and 8 showed moderate to weak cytotoxicity. Docking studies of compounds 2 and 4 showed that they bind with EGFR tyrosine kinase and cyclin-dependent kinase 2 through hydrogen bonding interactions with the important amino acids, including Lys721, Met769, Asn818, Arg157, Ile10, and Glu12.

Design, synthesis, in vitro evaluation, molecular docking and ADME properties studies of hybrid bis-coumarin with thiadiazole as a new inhibitor of Urease.

Hybrid bis-coumarin derivatives 1-18 were synthesized and evaluated for their in vitro urease inhibitory potential. All compounds showed outstanding urease inhibitory potential with IC50 value (The half maximal inhibitory concentration) ranging in between 0.12 SD 0.01 and 38.04 SD 0.63 µM (SD standard deviation). When compared with the standard thiourea (IC50 = 21.40 ±â€¯0.21 µM). Among these derivatives, compounds 7 (IC50 = 0.29 ±â€¯0.01), 9 (IC50 = 2.4 ±â€¯0.05), 10 (IC50 = 2.25 ±â€¯0.05) and 16 (IC50 = 0.12 ±â€¯0.01) are better inhibitors of the urease compared with thiourea (IC50 = 21.40 ±â€¯0.21 µM). To find structure-activity relationship molecular docking as well as absorption, distribution, metabolism, and excretion (ADME) studies were also performed. Various spectroscopic techniques like 1H NMR, 13C NMR, and EI-MS were used for characterization of all synthesized analogs. All compounds were tested for cytotoxicity and found non-toxic.

Synthesis of novel quinoline-based thiadiazole, evaluation of their antileishmanial potential and molecular docking studies.

New series of quinoline-based thiadiazole analogs (1-20) were synthesized, characterized by EI-MS, 1H NMR and 13C NMR. All synthesized compounds were subjected to their antileishmanial potential. Sixteen analogs 1-10, 12, 13, 16, 17, 18 and 19 with IC50 values in the range of 0.04 ±â€¯0.01 to 5.60 ±â€¯0.21 µM showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02 ±â€¯0.09 µM. Analogs 11, 14, 15 and 20 with IC50 8.20 ±â€¯0.35, 9.20 ±â€¯0.40, 7.20 ±â€¯0.20 and 9.60 ±â€¯0.40 µM respectively showed good inhibition when compared with the standard. Structure-activity relationships have been also established for all compounds. Molecular docking studies were performed to determine the binding interaction of the compounds with the active site target.

Synthesis of Novel Triazinoindole-Based Thiourea Hybrid: A Study on α-Glucosidase Inhibitors and Their Molecular Docking.

A new class of triazinoindole-bearing thiosemicarbazides (1-25) was synthesized and evaluated for α-glucosidase inhibitory potential. All synthesized analogs exhibited excellent inhibitory potential, with IC50 values ranging from 1.30 ± 0.01 to 35.80 ± 0.80 µM when compared to standard acarbose (an IC50 value of 38.60 ± 0.20 µM). Among the series, analogs 1 and 23 were found to be the most potent, with IC50 values of 1.30 ± 0.05 and 1.30 ± 0.01 µM, respectively. The structure-activity relationship (SAR) was mainly based upon bringing about different substituents on the phenyl rings. To confirm the binding interactions, a molecular docking study was performed.

Rational design of bis-indolylmethane-oxadiazole hybrids as inhibitors of thymidine phosphorylase.

Inhibition of Thymidine phosphorylase (TP) is continuously studied for the design and development of new drugs for the treatment of neoplastic diseases. As a part of our effort to identify TP inhibitors, we performed a structure-based virtual screening (SBVS) of our compound collection. Based on the insights gained from structures of virtual screening hits, a scaffold was designed using 1,3,4-oxadiazole as the basic structural feature and SAR studies were carried out for the optimization of this scaffold. Twenty-five novel bis-indole linked 1,3,4-oxadiazoles (7-31) were designed, synthesized and tested in vitro against E. coli TP (EcTP). Compound 7 emerged as potent TP inhibitor with an IC50 value of 3.50 ±â€¯0.01 µM. Docking studies were carried out using GOLD software on thymidine phosphorylase from human (hTP) and E. coli (EcTP). Various hydrogen bonding, hydrophobic interactions, and π-π stacking were observed between designed molecules and the active site amino acid residues of the studied enzymes.

Synthesis: Small library of hybrid scaffolds of benzothiazole having hydrazone and evaluation of their ß-glucuronidase activity.

Due to the great biological importance of ß-glucuronidase inhibitors, here in this study, we have synthesized a library of novel benzothiazole derivatives (1-30), characterized by different spectroscopic methods and evaluated for ß-glucuronidase inhibitory potential. Among the series sixteen compounds i.e.1-6, 8, 9, 11, 14, 15, 20-23 and 26 showed outstanding inhibitory potential with IC50 value ranging in between 16.50 ±â€¯0.26 and 59.45 ±â€¯1.12 when compared with standard d-Saccharic acid 1,4-lactone (48.4 ±â€¯1.25 µM). Except compound 8 and 23 all active analogs showed better potential than the standard. Structure activity relationship has been established.

Oxindole based oxadiazole hybrid analogs: Novel α-glucosidase inhibitors.

Inhibition of α-glucosidase is an effective strategy for controlling post-prandial hyperglycemia in diabetic patients. Beside these α-glucosidase inhibitors has been also used as anti-obesity and anti-viral drugs. Keeping in view the greater importance of α-glucosidase inhibitors here in this study we are presenting oxindole based oxadiazoles hybrid analogs (1-20) synthesis, characterized by different spectroscopic techniques including 1H NMR and EI-MS and their α-glucosidase inhibitory activity. All compounds were found potent inhibitors for the enzyme with IC50 values ranging between 1.25 ±â€¯0.05 and 268.36 ±â€¯4.22 µM when compared with the standard drug acarbose having IC50 value 895.09 ±â€¯2.04 µM. Our study identifies novel series of potent α-glucosidase inhibitors and further investigation on this may led to the lead compounds. A structure activity relationship has been established for all compounds. The interactions of the active compounds and enzyme active site were established with the help of molecular docking 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, α-glucosidase inhibition and molecular docking study of coumarin based derivatives.

We have synthesized seventeen Coumarin based derivatives (1-17), characterized by 1HNMR, 13CNMR and EI-MS and evaluated for α-glucosidase inhibitory potential. Among the series, all derivatives exhibited outstanding α-glucosidase inhibition with IC50 values ranging between 1.10 ±â€¯0.01 and 36.46 ±â€¯0.70 µM when compared with the standard inhibitor acarbose having IC50 value 39.45 ±â€¯0.10 µM. The most potent derivative among the series is derivative 3 having IC50 value 1.10 ±â€¯0.01 µM, which are many folds better than the standard acarbose. The structure activity relationship (SAR) was mainly based upon by bring about difference of substituent's on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.

Synthesis, α-amylase inhibitory potential and molecular docking study of indole derivatives.

In search of potent α-amylase inhibitor we have synthesized eighteen indole analogs (1-18), characterized by NMR and HR-EIMS and screened for α-amylase inhibitory activity. All analogs exhibited a variable degree of α-amylase inhibition with IC50 values ranging between 2.031 ±â€¯0.11 and 2.633 ±â€¯0.05 µM when compared with standard acarbose having IC50 values 1.927 ±â€¯0.17 µM. All compounds showed good α-amylase inhibition. Compound 14 was found to be the most potent analog among the series. Structure-activity relationship has been established for all compounds mainly based on bringing about the difference of substituents on phenyl ring. To understand the binding interaction of the most active analogs molecular docking study was performed.

Synthesis, in vitro α-glucosidase inhibitory potential and molecular docking study of thiadiazole analogs.

α-Glucosidase is a catabolic enzyme that regulates the body's plasma glucose levels by providing energy sources to maintain healthy functioning. 2-Amino-thiadiazole (1-13) and 2-amino-thiadiazole based Schiff bases (14-22) were synthesized, characterized by 1H NMR and HREI-MS and screened for α-glucosidase inhibitory activity. All twenty-two (22) analogs exhibit varied degree of α-glucosidase inhibitory potential with IC50 values ranging between 2.30 ±â€¯0.1 to 38.30 ±â€¯0.7 µM, when compare with standard drug acarbose having IC50 value of 39.60 ±â€¯0.70 µM. Among the series eight derivatives 1, 2, 6, 7, 14, 17, 19 and 20 showed outstanding α-glucosidase inhibitory potential with IC50 values of 3.30 ±â€¯0.1, 5.80 ±â€¯0.2, 2.30 ±â€¯0.1, 2.70 ±â€¯0.1, 2.30 ±â€¯0.1, 5.50 ±â€¯0.1, 4.70 ±â€¯0.2, and 5.50 ±â€¯0.2 µM respectively, which is many fold better than the standard drug acarbose. The remaining analogs showed good to excellent α-glucosidase inhibition. Structure activity relationship has been established for all compounds. The binding interactions of these compounds were confirmed through molecular docking.

Synthesis and biological evaluation of indole derivatives as α-amylase inhibitor.

A series of twenty indole hydrazone analogs (1-21) were synthesized, characterized by different spectroscopic techniques such as 1H NMR and EI-MS, and screened for α-amylase inhibitory activity. All analogs showed a variable degree of α-amylase inhibition with IC50 values ranging between 1.66 and 2.65µM. Nine compounds that are 1 (2.23±0.01µM), 8 (2.44±0.12µM), 10 (1.92±0.12µM), 12 (2.49±0.17µM), 13 (1.66±0.09µM), 17 (2.25±0.1µM), 18 (1.87±0.25µM), 20 (1.83±0.63µM), and 19 (1.97±0.02µM) showed potent α-amylase inhibition when compared with the standard acarbose (1.05±0.29µM). Other analogs showed good to moderate α-amylase inhibition. The structure activity relationship is mainly focusing on difference of substituents on phenyl part. Molecular docking studies were carried out to understand the binding interaction of the most active compounds.

Molecular hybridization conceded exceptionally potent quinolinyl-oxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: In silico validation and SAR studies.

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover a novel series of compounds 6-23 based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal potential. The most potent compound (23, IC50=0.10±0.001µM) among the series was found ∼70 times more lethal than the standard drug. The current series 6-23 conceded in the development of fourteen (14) extraordinarily active compounds against leishmaniasis. In silico analysis were also performed to probe the mode of action while all the compounds structure were established by NMR and Mass spectral analysis.

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.