In vitro and in silico assessment of bioactivity properties and pharmacokinetic studies of new 3,5-disubstituted-1,2,4-triazoles

• Published in: Journal of molecular structure 2023-03, Vol.1275, p.134720, Article 134720
• Main Authors: Amjad, Hira, Abbasi, Muhammad Athar, Siddiqui, Sabahat Zahra, Iqbal, Javed, Rasool, Shahid, Ashraf, Muhammad, Hussain, Safdar, Shah, Syed Adnan Ali, Imran, Syahrul, Shahid, Muhammad, Rasool, Arslan, Rehman, Muhammad Tjammal, Rehman, Aziz ur
• Format: Article
• Language: English
• Subjects: 1,2,4-Triazole; ADMET; Biofilm inhibition; Enzyme inhibition; Piperidine; Sulfonamide
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2022.134720

•Multistep synthesis resulted heterocyclic derivatives.•One compound potent inhibitor of AChE & BChE and seven of urease.•Biofilm formation revealed a few antibacterial agents.•Low toxicity revealed by hemolysis, drug-likeness by ADMET and binding by molecular docking. The synthesis of new, more potent, with the least side effects and economical drugs is essential for the modern world. In search of such drug candidates, a biologically important moiety 1,2,4-triazole was introduced to bioactive piperidine to acquire a list of compounds, 8a-8n, with subtle structural variation. These compounds were synthesized from 4-chlorobenzene sulfonyl chloride (1) and piperidine-4-carboxylate (2) through a multistep synthesis of 5-{1-[(4-chlorophenyl)sulfonyl]-4-piperidinyl}-4-ethyl-4H-1,2,4-triazol-3-thiol (6) bearing bioactive moieties. The molecular structures were confirmed through FTIR, 1HNMR and 13CNMR. The in vitro enzyme inhibition potential of compounds was analyzed against acetyl cholinesterase (AChE), butyryl cholinesterase (BChE) and urease enzymes. Compound 8b bearing 2-chlorobenzyl group was the most active inhibitor of AChE and 8a bearing benzyl group of BChE with IC50 values (µM) of 32.43±0.53 and 68.14±0.34, respectively. Compounds 8k (IC50 1.78±0.12 µM), 8c (IC50 2.32±0.15 µM), 8a (IC50 3.09±0.42 µM), 8d (IC50 4.78±0.73 µM), 8f (IC50 6.58±0.91µM), 8h (IC50 11.25±1.12 µM), 8i (IC50 14.83±1.37 µM) and 8l (IC50 28.85±2.37 µM) were found potent inhibitors against the urease enzyme as compared with standard thiourea. Structure activity relationship (SAR) studies for urease inhibition displayed that compounds bearing n-propyl group (8k), 3,4-dichlorobenzyl group (8c), un-substituted benzyl group (8a) and 4-chlorobenzyl group (8d) were the most potent ones. Molecular docking studies showed that the compounds with aromatic substitution were better drug candidates in general. Antibacterial activity as determined by biofilm method showed some molecules active against gram positive bacteria. The hemolytic activity much inferred about the toxicity level of synthesized compounds. The chemo-informatics investigations including physicochemical properties and ADMET revealed that the most of the molecules had potential drug-likeness properties. Further work is required on the derivatization of the active compounds into more active ones as ‘lead’ compounds and is in progress. [Display omitted]