Novel tetrazolyl-1,2,3-triazole derivatives as potent antimicrobial targets: design, synthesis and molecular docking techniques

The main objective of this study is to produce novel triazoles-loaded tetrazoles, which are crucial in the development of prospective therapeutic agents in medicinal chemistry. Recent investigations have found a wide range of uses for these derivatives, and they are prospective lead molecules for the synthesis of substances with enormous therapeutic utility for various diseases, especially for bacterial therapy. New series of 1,2,3-triazole derivatives have been synthesized from methyl (2S,4S)-4-azido-1-(2,4-difluoro-3-methylbenzoyl)pyrrolidine-2-carboxylate (<b>5</b>) using a well-established click reaction that has several advantages to afford a novel heterocyclic compound based on tetrazole moieties. The structures of the new compounds were ascertained by spectral means (IR, NMR: ¹H and ¹³C) and mass spectrum. All the synthesized compounds were assessed <i>in vitro</i> antimicrobial activity against Gram-+ve (<i>S. pyogenes</i>, <i>S. aureus</i> and <i>B. subtilis</i>), Gram-negative (<i>E. coli</i> and <i>P. aeruginosa</i>) bacterial and fungal strains <i>A. flavus</i> and <i>C. albicans</i>. The prepared compounds <b>7b</b> and<b>7f</b> proved to have strong impact on <i>S. aureus</i> and <i>S. pyogenes</i> strains with MICs of 2.5 µg/mL and 1.5 µg/mL respectively. Among the tested compounds, hybrids <b>7b</b>, <b>7f</b>, <b>7h</b>, and <b>7i</b> exhibited exceptional antifungal susceptibilities against <i>C. albicans</i> with zone of inhibition 25 ± 0.2, 30 ± 0.3, 30 ± 0.1, and 28 ± 0.2 mm respectively, which is stronger than fluconazole (28 ± 0.1 mm). The capacity of ligand <b>7f</b> to form a stable compound on the active site of <i>S. aureus</i> complex with DNA Gyrase (2XCT) was confirmed by docking studies using amino acids Ala233(A), Arg234(A), Gly283(A), Ser286(A), Lys52(A), His280(A), Gly51(A), His282(A) and Val246(A). Furthermore, the physicochemical and ADME (absorption, distribution, metabolism, and excretion) filtration molecular properties, estimation of toxicity, and bioactivity scores of these scaffolds were evaluated.