RESUMEN
Triazole-based acetamides serve as important scaffolds for various pharmacologically active drugs. In the present work, structural hybrids of 1,2,4-triazole and acetamides were furnished by chemically modifying 2-(4-isobutylphenyl) propanoic acid (1). Target compounds 7a-f were produced in considerable yields (70-76%) by coupling the triazole of compound 1 with different electrophiles under different reaction conditions. These triazole-coupled acetamide derivatives were verified by physiochemical and spectroscopic (HRMS, FTIR, 13CNMR, and 1HNMR,) methods. The anti-liver carcinoma effects of all of the derivatives against a HepG2 cell line were investigated. Compound 7f, with two methyl moieties at the ortho-position, exhibited the highest anti-proliferative activity among all of the compounds with an IC50 value of 16.782 µg/mL. 7f, the most effective anti-cancer molecule, also had a very low toxicity of 1.190.02%. Molecular docking demonstrates that all of the compounds, especially 7f, have exhibited excellent binding affinities of -176.749 kcal/mol and -170.066 kcal/mol to c-kit tyrosine kinase and protein kinase B, respectively. Compound 7f is recognized as the most suitable drug pharmacophore for the treatment of hepatocellular carcinoma.
RESUMEN
Aim: To synthesize pyrrolopyridine-based thiazolotriazoles as a novel class of α-amylase and α-glucosidase inhibitors and to determine their enzymatic kinetics. Methodology: Pyrrolopyridine-based thiazolotriazole analogs (1-24) were synthesized and characterized through proton nuclear magnetic resonance, carbon-13 nuclear magnetic resonance and high-resolution electron ionization mass spectrometry. Results: All synthesized analogs displayed good inhibitory potential of α-amylase and α-glucosidase ranging 17.65-70.7 µM and 18.15-71.97 µM, respectively, compared with the reference drug, acarbose (11.98 µM and 12.79 µM). Analog 3 was the most potent among the synthesized analogs, having α-amylase and α-glucosidase inhibitory activity at 17.65 and 18.15 µM, respectively. The structure-activity relationship and binding modes of interactions between selected analogs were confirmed via docking and enzymatic kinetics studies. The compounds (1-24) were tested for cytotoxicity against the 3T3 mouse fibroblast cell line and were observed to be nontoxic.
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Diabetes Mellitus , Compuestos Heterocíclicos , Animales , Ratones , Simulación del Acoplamiento Molecular , alfa-Glucosidasas/metabolismo , Cinética , Inhibidores de Glicósido Hidrolasas/química , Relación Estructura-Actividad , alfa-Amilasas , Estructura MolecularRESUMEN
Usnic acid (UA) lately piqued the interest of researchers for its extraordinary biological characteristics, including anticancer activity. Here, the mechanism was clarified through network pharmacology,molecular docking and molecular dynamic simulation. Sixteen proteins were selected through network pharmacology study as they are probable to interact with UA. Out of these proteins, 13 were filtered from PPI network analysis based on their significance of interactions (p < 0.05). KEGG pathway analysis has also aided us in determining the three most significant protein targets for UA, which are BCL2, PI3KCA and PI3KCG. Therefore molecular docking and molecular dynamic (MD) simulations throughout 100 ns were performed for usnic acid onto the three proteins mentioned. However, UA's docking score in all proteins is lower than their co-crystalised ligand, especially for BCL2 (-36.5158 kcal/mol) and PI3KCA (-44.5995 kcal/mol) proteins. The only exception is PI3KCG which has comparable results with the co-crystallised ligand with (-41.9351 kcal/mol). Furthermore, MD simulation has also revealed that usnic acid does not stay fit in the protein throughout the simulation trajectory for PI3KCA protein evident from RMSF and RMSD plots. Nevertheless, it still poses good ability in inhibiting BCL2 and PI3KCG protein in MD simulation. In the end, usnic acid has exhibited good potential in the inhibition of PI3KCG proteins, rather than the other proteins mentioned. Thus further study on structural modification of usnic acid could enhance the ability of usnic acid in the inhibition of PI3KCG as anti-colorectal and anti-small cell lung cancer drug candidate.Communicated by Ramaswamy H. Sarma.
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Simulación de Dinámica Molecular , Farmacología en Red , Simulación del Acoplamiento Molecular , Ligandos , Proteínas Proto-Oncogénicas c-bcl-2RESUMEN
Since the first prevalence of COVID-19 in 2019, it still remains the most devastating pandemic throughout the world. The current research aimed to find potential natural products to inhibit the novel coronavirus and associated infection by MD simulation and network pharmacology approach. Molecular docking was performed for 39 natural products having potent anti-SARS-CoV activity. Five natural products showed high binding interaction with the viral main protease for the SARS-CoV-2 virus, where 3ß,12-diacetoxyabieta-6,8,11,13 tetraene showed stable binding in MD simulation until 100 ns. Both 3ß,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A targeted 11 common genes that are related to COVID-19 and interact with each other. Gene ontology development analysis further showed that all these 11 genes are attached to various biological processes. The KEGG pathway analysis also showed that the proteins that are targeted by 3ß,12-diacetoxyabieta-6,8,11,13 tetraene and tomentin A are associated with multiple pathways related to COVID-19 infection. Furthermore, the ADMET and MDS studies reveals 3ß,12-diacetoxyabieta-6,8,11,13 as the best-suited compound for oral drug delivery.Communicated by Ramaswamy H. Sarma.
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Productos Biológicos , COVID-19 , Humanos , SARS-CoV-2 , Simulación del Acoplamiento Molecular , Farmacología en Red , Productos Biológicos/farmacología , Simulación de Dinámica Molecular , Inhibidores de Proteasas/farmacologíaRESUMEN
Dengue hemorrhagic fever (DHF) is severe dengue with a hallmark of vascular leakage. ß-tryptase has been found to promote vascular leakage in DHF patients, which could be a potential target for DHF treatment. This study aims to develop a theoretical background for designing and selecting human ß-tryptase inhibitors through computational studies. Thirty-four α-keto-[1,2,3]-oxadiazoles scaffold-based compounds were used to generate 2D-QSAR models and for molecular docking studies with ß-tryptase (PDB Code 4A6L). In addition, molecular dynamics (MD) simulation and molecular mechanics generalised born surface area (MM-GBSA) analysis on the binding of the reported most active compound, compound 11e, towards ß-tryptase were performed. Finally, a structure-based pharmacophore model was generated. The selected 2D-QSAR models have statistically proven good models by internal and external validation as well as the y-randomization test. The docking results of compound 11e showed lower CDOCKER energy than the 4A6L co-crystallised ligand and a similar binding pattern as the 4A6L co-crystallised ligand. From molecular dynamics simulation, 4A6L in compound 11e bound state has RMSD below 2 Å throughout the 500 ns simulation, indicating the docked complex is stable. Besides, MM-GBSA analysis suggested the 4A6L-compound 11e docked complex (-66.04 Kcal/mol) is structurally as stable as the 4A6L-native ligand co-crystallized structure (-66.84 Kcal/mol). The best pharmacophore model identified features included hydrogen bond acceptor, ionic interaction, hydrophobic interaction, and aromatic ring, which contribute to the inhibitory potency of a compound. This study supplied insight and knowledge for developing novel chemical compounds with improved inhibition of ß-tryptase.Communicated by Ramaswamy H. Sarma.
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Simulación de Dinámica Molecular , Farmacóforo , Humanos , Simulación del Acoplamiento Molecular , Triptasas , Relación Estructura-Actividad Cuantitativa , Ligandos , Diseño de FármacosRESUMEN
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 inâ 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±0.10â µM, and similarly for butyrylcholinesterase with range IC50 values from 0.10±0.050â µM to 10.70±0.20â µM, respectively as compared to standard Donepezil inhibitor (IC50 =2.16±0.12â µM), (IC50 =4.5±0.11â µM).Among the series, the analogs with hydroxy group showed superior inhibitory potentials against acetylcholinesterase and butyrylcholinesterase enzymes. Therefore, analog 20 (IC50 =0.070±0.050â µM), (IC50 =0.10±0.050â 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±0.050â µM), (IC50 =0.20±0.050â 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±0.10â 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.
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Chalcona , Chalconas , Butirilcolinesterasa/metabolismo , Acetilcolinesterasa/metabolismo , Simulación del Acoplamiento Molecular , Benzaldehídos , Chalcona/química , Donepezilo , Inhibidores de la Colinesterasa/química , Relación Estructura-Actividad , Estructura MolecularRESUMEN
In search of potent urease inhibitor indole analogues (1-22) were synthesized and evaluated for their urease inhibitory potential. All analogues (1-22) showed a variable degree of inhibitory interaction potential having IC50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90 µM when compared with standard thiourea having IC50 value 21.86 ± 0.90 µM. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05 µM respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.
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Inhibidores Enzimáticos , Ureasa , Inhibidores Enzimáticos/química , Indoles , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Tiourea/química , Tiourea/metabolismoRESUMEN
The fungal transformations of ethynodiol diacetate (1) were investigated for the first-time using Botrytis cinerea, Trichothecium roseum, and R3-2 SP 17. The metabolites obtained are as following: 17α-Ethynyl-17ß-acetoxyestr-4-en-3-one-15ß-ol (2), 19-nor-17a-ethynyltestosterone (3), and 17α-ethynyl-3ß-hydroxy-17ß-acetoxyestr-4-ene (4). The new metabolite, 2 (IC50 = 104.8 µM), which has ketone group at C-3, and the ß-hydroxyl group at C-15, resulted in an almost equipotent strength with the parent compound (IC50 = 103.3 µM) against proliferation of SH-SY5Y cells. The previously reported biotransformed product, 3, showed almost equal strength to 1 against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.
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Diacetato de Etinodiol , Biotransformación , Botrytis , HypocrealesRESUMEN
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.
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Diabetes Mellitus Experimental/tratamiento farmacológico , Inhibidores de Glicósido Hidrolasas/farmacología , Hipoglucemiantes/farmacología , Indoles/farmacología , Simulación del Acoplamiento Molecular , Sulfonamidas/farmacología , alfa-Glucosidasas/metabolismo , Animales , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores de Glicósido Hidrolasas/síntesis química , Inhibidores de Glicósido Hidrolasas/química , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Indoles/síntesis química , Indoles/química , Estructura Molecular , Ratas , Ratas Wistar , Estreptozocina , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/químicaRESUMEN
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.
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Glicoproteínas , Hidrazonas , Indoles , Glucuronidasa/antagonistas & inhibidores , Glucuronidasa/química , Glicoproteínas/síntesis química , Glicoproteínas/química , Hidrazonas/síntesis química , Hidrazonas/química , Indoles/síntesis química , Indoles/química , Simulación del Acoplamiento MolecularRESUMEN
The fungal transformations of medroxyrogesterone (1) were investigated for the first time using Cunninghamella elegans, Trichothecium roseum, and Mucor plumbeus. The metabolites obtained are as following: 6ß, 20-dihydroxymedroxyprogesterone (2), 12ß-hydroxymedroxyprogesterone (3), 6ß, 11ß-dihydroxymedroxyprogesterone (4), 16ß-hydroxymedroxyprogesterone (5), 11α, 17-dihydroxy-6α-methylpregn-4-ene-3, 20-dione (6), 11-oxo-medroxyprogesterone (7), 6α-methyl-17α-hydroxypregn-1,4-diene-3,20-dione (8), and 6ß-hydroxymedroxyprogesterone (9), 15ß-hydroxymedroxyprogesterone (10), 6α-methyl-17α, 11ß-dihydroxy-5α-pregnan-3, 20-dione (11), 11ß-hydroxymedroxyprogesterone (12), and 11α, 20-dihydroxymedroxyprogesterone (13). Among all the microbial transformed products, the newly isolated biotransformed product 13 showed the most potent activity against proliferation of SH-SY5Y cells. Compounds 12, 5, 6, 9, 11, and 3 (in descending order of activity) also showed some extent of activity against SH-SY5Y tumour cell line. The never been reported biotransformed product, 2, showed the most potent inhibitory activity against acetylcholinesterase. Molecular modelling studies were carried out to understand the observed experimental activities, and also to obtain more information on the binding mode and the interactions between the biotransformed products, and enzyme.
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Proliferación Celular/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Medroxiprogesterona/farmacología , Animales , Biotransformación , Caenorhabditis elegans/metabolismo , Inhibidores de la Colinesterasa/química , Simulación por Computador , Cunninghamella/metabolismo , Hypocreales/metabolismo , Técnicas In Vitro , Medroxiprogesterona/química , Medroxiprogesterona/farmacocinética , Simulación del Acoplamiento Molecular , Análisis Espectral/métodosRESUMEN
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.
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Antiprotozoarios/farmacología , Disulfuros/farmacología , Leishmania/efectos de los fármacos , Antiprotozoarios/síntesis química , Antiprotozoarios/química , Disulfuros/química , Relación Dosis-Respuesta a Droga , Simulación del Acoplamiento Molecular , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Bases de Schiff/química , Bases de Schiff/farmacología , Relación Estructura-ActividadRESUMEN
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.
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Inhibidores de Glicósido Hidrolasas/química , Inhibidores de Glicósido Hidrolasas/síntesis química , Simulación del Acoplamiento Molecular , Tiourea , alfa-Glucosidasas/química , Relación Estructura-Actividad , Tiourea/análogos & derivados , Tiourea/síntesis química , Tiourea/químicaRESUMEN
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⯵M (SD standard deviation). When compared with the standard thiourea (IC50â¯=â¯21.40⯱â¯0.21⯵M). Among these derivatives, compounds 7 (IC50â¯=â¯0.29⯱â¯0.01), 9 (IC50â¯=â¯2.4⯱â¯0.05), 10 (IC50â¯=â¯2.25⯱â¯0.05) and 16 (IC50â¯=â¯0.12⯱â¯0.01) are better inhibitors of the urease compared with thiourea (IC50â¯=â¯21.40⯱â¯0.21⯵M). 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.
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Cumarinas/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Tiadiazoles/química , Ureasa/antagonistas & inhibidores , Células 3T3-L1 , Animales , Supervivencia Celular/efectos de los fármacos , Cumarinas/química , Cumarinas/metabolismo , Cumarinas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacología , Hepatocitos/efectos de los fármacos , Ratones , Simulación del Acoplamiento Molecular , Estructura Molecular , Ratas Wistar , Relación Estructura-ActividadRESUMEN
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.
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Antineoplásicos Fitogénicos/farmacología , Goniothalamus/química , Lactonas/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Lactonas/química , Lactonas/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/farmacologíaRESUMEN
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 (IC50â¯=â¯38.45⯱â¯0.80⯵M). 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 (IC50â¯=â¯38.45⯱â¯0.80⯵M). Here in the present study analog 4 (IC50â¯=â¯6.20⯱â¯0.30⯵M) 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.
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Diabetes Mellitus/tratamiento farmacológico , Simulación del Acoplamiento Molecular/métodos , Quinolinas/síntesis química , Humanos , Relación Estructura-ActividadRESUMEN
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⯵M, and hence were found to have excellent inhibitory potential in comparison to standard d-saccharic acid 1,4-lactone (IC50â¯=â¯48.4⯱â¯1.25⯵M). 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.
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Glicoproteínas/uso terapéutico , Simulación del Acoplamiento Molecular/métodos , Oxadiazoles/síntesis química , Glicoproteínas/farmacología , Oxadiazoles/químicaRESUMEN
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⯵M showed tremendously potent inhibition as compared to the standard pentamidine with IC50 value 7.02⯱â¯0.09⯵M. 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⯵M 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.
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Quinolinas/farmacología , Tiadiazoles/farmacología , Tripanocidas/farmacología , Dominio Catalítico , Leishmania donovani/química , Leishmania major/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Simulación del Acoplamiento Molecular , Estructura Molecular , Oxidorreductasas/química , Oxidorreductasas/metabolismo , Unión Proteica , Quinolinas/síntesis química , Quinolinas/metabolismo , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/metabolismo , Tripanocidas/síntesis química , Tripanocidas/metabolismoRESUMEN
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⯵M. 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.
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Diseño de Fármacos , Inhibidores Enzimáticos/química , Metano/química , Oxadiazoles/química , Timidina Fosforilasa/antagonistas & inhibidores , Sitios de Unión , Dominio Catalítico , Inhibidores Enzimáticos/metabolismo , Escherichia coli/enzimología , Humanos , Enlace de Hidrógeno , Simulación del Acoplamiento Molecular , Relación Estructura-Actividad , Timidina Fosforilasa/metabolismoRESUMEN
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⯵M when compared with standard acarbose having IC50 values 1.927⯱â¯0.17⯵M. 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.