Synthesis and <i>in Silico</i> Studies of Some New 1,2,3‐Triazolyltetrazole Bearing Indazole Derivatives as Potent Antimicrobial Agents

Abstract

Abstract 1,2,3‐Triazole and tetrazole derivatives bearing pyrrolidines are found to exhibit notable biological activity and have become useful scaffolds in medicinal chemistry for application in lead discovery and optimization. Novel indazole bearing 1,2,3‐triazolyltetrazoles were designed as potential antimicrobial candidates. The structure of duel heterocyclics was validated by a spectroscopic technique of infrared (IR), nuclear magnetic resonance ( 1 H and 13 C NMR), and mass spectral data. Compounds 4b , 4c , 4d , and 4h were found to have a stronger antibacterial effect against Gram‐positive ( S. aureus, B. subtilis, M. Luteus ) and Gram‐negative ( E. coli , P. aeruginosa ) microorganisms with MICs ranging from 5±0.03–18±0.02 μM, respectively. Moreover, scaffolds 4a , 4h showed potent antifungal activity against A. flavus , M. gypsuem strains with MIC values of 10±0.02, 11±0.01 μM, which are similar activity that of the standard Itraconazole (MIC=8±0.02, 10±0.01 μM). The binding mode for compound 4 inside the catalytic pocket of S. aureus complexed with nicotinamide adenine dinucleotide phosphate and trimethoprim and produced a network of hydrophobic and hydrophilic interactions (3FRE). From in silico results, 4b demonstrated highly stable hydrogen binding amino acids Leu62(X) [N18…O, 2.47 Å], Arg44(X) [N17…N, 3.11 Å], Thr96(X) [N10…OG1, 3.05 Å], Gly94(X) [F7…N, 2.82 Å], and Gly43(X) [F7…N, 2.90 Å], which are plays a crucial role in ensuring efficient binding of the ligand in a crystal structure of antibacterial receptor. Furthermore, the physicochemical and ADME filtration molecular properties, estimation of toxicity, and bioactivity scores of these novel scaffolds were evaluated by using SwissADME and ADMETlab2.0 online protocols. Thus, the significant antimicrobial activity of indazole linked to duel heterocyclic compounds can be used for development of new antimicrobial agents with further modifications.