ABSTRACT
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.
Subject(s)
Glycoside Hydrolase Inhibitors/chemical synthesis , Indoles/chemistry , alpha-Amylases/metabolism , Binding Sites , Catalytic Domain , Glycoside Hydrolase Inhibitors/chemistry , Glycoside Hydrolase Inhibitors/metabolism , Indoles/chemical synthesis , Indoles/metabolism , Inhibitory Concentration 50 , Molecular Docking Simulation , Structure-Activity Relationship , alpha-Amylases/antagonists & inhibitorsABSTRACT
Novel sulfonamides having oxadiazole ring were synthesized by multistep reaction and evaluated to check in vitro ß-glucuronidase inhibitory activity. Luckily, except compound 13, all compounds were found to demonstrate good inhibitory activity in the range of IC50=2.40±0.01-58.06±1.60µM when compared to the standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25µM). Structure activity relationship was also presented. However, in order to ensure the SAR as well as the molecular interactions of compounds with the active site of enzyme, molecular docking studies on most active compounds 19, 16, 4 and 6 was carried out. All derivatives were fully characterized by 1H NMR, 13C NMR and EI-MS spectroscopic techniques. CHN analysis was also presented.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glucuronidase/antagonists & inhibitors , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Sulfonamides/chemistry , Sulfonamides/pharmacology , Enzyme Inhibitors/chemical synthesis , Glucuronidase/metabolism , Humans , Molecular Docking Simulation , Oxadiazoles/chemical synthesis , Structure-Activity Relationship , Sulfonamides/chemical synthesisABSTRACT
Natural products are the main source of motivation to design and synthesize new molecules for drug development. Designing new molecules against ß-glucuronidase inhibitory is utmost essential. In this study indole analogs (1-35) were synthesized, characterized using various spectroscopic techniques including 1H NMR and EI-MS and evaluated for their ß-glucuronidase inhibitory activity. Most compounds were identified as potent inhibitors for the enzyme with IC50 values ranging between 0.50 and 53.40µM, with reference to standard d-saccharic acid 1,4-lactone (IC50=48.4±1.25µM). Structure-activity relationship had been also established. The results obtained from docking studies for the most active compound 10 showed that hydrogen bond donor features as well as hydrogen bonding with (Oε1) of nucleophilic residue Glu540 is believed to be the most importance interaction in the inhibition activity. It was also observed that hydroxyl at fourth position of benzylidene ring acts as a hydrogen bond donor and interacts with hydroxyl (OH) on the side chain of catalysis residue Tyr508. The enzyme-ligand complexed were being stabilized through electrostatic π-anion interaction with acid-base catalyst Glu451 (3.96Å) and thus preventing Glu451 from functioning as proton donor residue.
Subject(s)
Glucuronidase/antagonists & inhibitors , Glycoproteins/pharmacology , Indoles/pharmacology , Dose-Response Relationship, Drug , Glucuronidase/metabolism , Glycoproteins/chemical synthesis , Glycoproteins/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Structure-Activity RelationshipABSTRACT
Compounds 1-25 showed varying degree of antileishmanial activities with IC50 values ranging between 1.95 and 88.56 µM. Compounds 2, 10, and 11 (IC50=3.29±0.07 µM, 1.95±0.04 µM, and 2.49±0.03 µM, respectively) were found to be more active than standard pentamidine (IC50=5.09±0.04 µM). Compounds 7 (IC50=7.64±0.1 µM), 8 (IC50=13.17±0.46 µM), 18 (IC50=13.15±0.02 µM), and 24 (IC50=15.65±0.41 µM) exhibited good activities. Compounds 1, 3, 4, 5, 9, 12, 15, 18, and 19 were found to be moderately active. Compounds 13, 14, 16, 17, 20-25 showed weak activities with IC50 values ranging between 57 and 88 µM.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Hydrazones/chemistry , Antiprotozoal Agents/chemistry , Antiprotozoal Agents/pharmacology , Drug Evaluation, Preclinical , Hydrazones/chemical synthesis , Hydrazones/pharmacology , Leishmania/drug effects , Pentamidine/chemistry , Structure-Activity RelationshipABSTRACT
Phenolic Schiff bases are known for their diverse biological activities and ability to scavenge free radicals. To elucidate (1) the structure-antioxidant activity relationship of a series of thirty synthetic derivatives of 2-methoxybezohydrazide phenolic Schiff bases and (2) to determine the major mechanism involved in free radical scavenging, we used density functional theory calculations (B3P86/6-31+(d,p)) within polarizable continuum model. The results showed the importance of the bond dissociation enthalpies (BDEs) related to the first and second (BDEd) hydrogen atom transfer (intrinsic parameters) for rationalizing the antioxidant activity. In addition to the number of OH groups, the presence of a bromine substituent plays an interesting role in modulating the antioxidant activity. Theoretical thermodynamic and kinetic studies demonstrated that the free radical scavenging by these Schiff bases mainly proceeds through proton-coupled electron transfer rather than sequential proton loss electron transfer, the latter mechanism being only feasible at relatively high pH.