New piperidinyl heterocyclic azoles acquired through Li(I)-catalyzed reactions: Anti-enzymatic, ADME and computational studies

Abstract

A biological impact of the fused heterocyclic rings as anti-enzymatic agents was explored through experimental, theoretical and computational studies. The targeted hybrids of 1,2,4-triazole (8a–q) were synthesized through multistep protocol. Initially, the carboxylate 3 was synthesized through stirring of 4-chlorobenzenesulfonyl chloride (1) and 4-(ethoxycarbonyl)piperidine (2) at room temperature. Carboxylate was converted into carbohydrazide 4, which was refluxed with phenyl isothiocyanate and KOH to synthesize 1,2,4-triazole (6) through the formation of an intermediate hydrazinecarbothioamide (5). A series of alkyl/aralkyl halides (7a–q) were stirred at room temperature with compound 6 in the presence of Li(I) catalyst to avail the targeted library of hybrids (8a–q). All the designed hybrids were screened for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), urease, hemolysis and biofilm inhibition potential and were found active with variable potential against all the evaluations. The best compound for AChE inhibition was 8c having 89.24 ± 0.78 % inhibition at 0.5 mM with IC50 16.43 ± 0.62 µM, while the best against BChE was 8 g with 87.25 ± 0.47 % inhibition and IC50 31.42 ± 0.34 µM. The whole series of compounds remained potent inhibitors against urease enzyme with better potential as compared to standard thiourea. The potent compounds of the series were 8o and 8i with IC50 values of 1.32 ± 1.03 µM and 1.38 ± 0.34 µM, respectively. Half of the whole library of compounds (8a–q) possessed outstanding biofilm inhibition potential against the tested bacterial strains and confirmed themselves as better anti-microbial agents. The compounds were also screened for hemolytic activity and results exhibited medium to excellent hemolytic activity. The compound 8b showed the least toxicity among the synthesized compounds, 8a–q. The computational studies of all the synthesized compounds were also carried out to elaborate the binding forces of synthesized compounds with the active sites of enzymes to establish SAR. In silico data supported the in vitro profiles. Further work is suggested for in vivo studies of the most of compounds in search for their anti-cholinesterase and anti-urease potential. Work is in progress on these lines.