Design, Synthesis and Bio‐Evaluation of Novel Chalcones Bridged with 1,3,4‐Oxadiazole Linkers: ADMET and Docking Analysis

Abstract

In this article, we prepared a novel series of 1,3,4‐oxadiazoles containing chalcone analogs via replacement of phthalazine which had increased antibacterial activity and the final compounds were confirmed by proton, carbon nuclear magnetic resonance spectroscopy, infrared and mass spectral analysis. Two sets of 1,3,4‐oxadiazoles like 2‐methyl‐5‐substitutedbenzylthio‐1,3,4‐oxadiazolyl‐4‐methylphthalazine‐2‐ones (3a–f), (E)‐substituted phenyl acryloylphenyl‐4‐methyl‐1‐oxophthalazine‐1,3,4‐oxadiazolylthioacetamides (5a–f) were designed, synthesized and evaluated for their in vitro antibacterial potency against different Gram‐(+ve), Gram‐(–ve) microorganisms and fungal strains. The synthesized 4‐methyl‐2‐{[5‐({[2‐(trifluoromethyl)phenyl]methyl}sulfanyl)‐1,3,4‐oxadiazol‐2‐yl]methyl}phthalazin‐1(2H)‐one (3c), 4‐methyl‐2‐[(5‐{[(4‐nitrophenyl)methyl]sulfanyl}‐1,3,4‐oxadiazol‐2‐yl)methyl]phthalazin‐1(2H)‐one (3d), N‐(4‐{(2E)‐3‐[2‐(dimethylamino)phenyl]prop‐2‐enoyl}phenyl)‐2‐({5‐[(4‐methyl‐1‐oxophthalazin‐2(1H)‐yl)methyl]‐1,3,4‐oxadiazol‐2‐yl}sulfanyl)acetamide (5d), and N‐{4‐[(2E)‐3‐(3‐hydroxy‐4‐methoxyphenyl)prop‐2‐enoyl]phenyl}‐2‐({5‐[(4‐methyl‐1‐oxophthalazin‐2(1H)‐yl)methyl]‐1,3,4‐oxadiazol‐2‐yl}sulfanyl)acetamide (5e) displayed improved activity with MICs 1.41, 0.87, 2.16, 0.89 μg/mL as compared to the standard drugs rifamycin, ciprofloxacin, fluconazole (MIC=1.52, 1.94, 3.02 μg/mL). The prepared compounds were also analyzed with better target binding towards bacterial bioavailability, 5e exhibited highest bonds with amino acids ArgA45, LysA20, LysA17, ArgA171, AspA49, IleA14, HisA18 and having docking energy −8.68 Kcal/mol and dissociation constant 432.48 nM, respectively. These compounds were further evaluated for their ADMET and physicochemical properties by using SwissADME.

New triazole based oxadiazolo/thiadiazolo–phthalazines as potent antimycobacterial agents: Design, synthesis, molecular modelling and in silico ADMET profiles

“…Absorption, distribution, metabolism, excretion and toxicology (ADMET) studies were performed to know how well the drug is absorbed, supplied, broken down, and eliminated determines how efficient it is in the body. The online tools such as SwissADME and ADMETlab2.0 were used to forecast how closely a chemical substance resembles a drug and what effects it has on the body [50] . Lipophilicity determines how well it acts like as drug.…”

“…The online tools such as SwissADME and ADMETlab2.0 were used to forecast how closely a chemical substance resembles a drug and what effects it has on the body. [50] Lipophilicity determines how well it acts like as drug. The primary physicochemical features investigated in this investigations include molecular weight, HBD (hydrogen bond donors), HBA (hydrogen bond acceptors), lipophilicity (logp o/w ), number of rings, rotatable bonds, polar surface area, and synthetic accessibility attributes.…”

Synthesis, antimicrobial activity, and in silico studies of fluoroquinolones bearing 1,3,4‐oxadiazolyl‐triazole derivatives

“…HCl and the resulting precipitate was collected and recrystallized from EtOH to give white solid 1 (92%). Furthermore, the treatment of 1-ethyl-6-fluoro-3-(5-mercapto-1,3,4-oxadiazol-2-yl)-7-(piperazin-1-yl)quinolin-4(1H)one 1 (0.0047 mol) with hydrazine hydrate (0.007 mol) under refluxedfor 6 h to give 3-(4-amino-5-mercapto-4H-1,-2,4-triazol-3-yl)-1-ethyl-6-fluoro-7-(piperazin-1-yl)quinolin-4 (1H)-one (2) as light yellow crystals (87%) [49]. To a solution of 1,2,4-triazole 2 (0.003 mol) was reacted with 2-bromo-4 0 -substituted acetophen-1-one (0.004 mol) in the presence of absolute ethanol (18 mL) and the reaction was refluxed for 6.5-8 h to yielded the key intermediates 1-ethyl-6-fluoro-3-substitutedphenyl-7H- [1,2,4]triazolo [3,4b][1,3,4]thiadiazin-3-yl)-7-(piperazin-1-yl)quinolin-4(1H)one 3a-f, respectively [50].…”

New Fluoroquinolone‐1,2,4‐triazoles as Potent Antibacterial Agents: Design, Synthesis, Docking Studies and in Silico ADME Profiles

“…The investigation of active sites in molecules was provided by molecular descriptive analysis, including molecular docking and SwissADMET. [29,30] The lipophilicity parameter, which determines the solubility of drug candidate molecules in different body fluids, is related to the behavior of the molecule in the biological environment and its ADMET profile. In this study, we have applied extensive molecular modelling utilising DNA Topoisomerases as the target to understand the binding mode, and key active site interactions (hydrogen bonding, Π -Π, cation-Π, and σσ) of the ligands to estimate their binding affinity of 3RAE protein.…”

“…By combining molecular interactions and biochemical activity with molecular level analyses, the structure‐activity relationship was optimised. The investigation of active sites in molecules was provided by molecular descriptive analysis, including molecular docking and SwissADMET [29,30] . The lipophilicity parameter, which determines the solubility of drug candidate molecules in different body fluids, is related to the behavior of the molecule in the biological environment and its ADMET profile.…”