Synthesis of novel bithiazole–pyrazole hybrid compounds linked via carbohydrazide and their antimicrobial SAR evaluation​

Journal of Molecular Chemistry

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A novel series of N′-((5-substituted-3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)-5-isobutyl-[2,2′-bithiazole]-4-carbohydrazide derivatives (11a to 11j) was synthesized via a stepwise condensation strategy. The structures were confirmed using ¹H NMR, ¹³C NMR, FTIR, LC-MS, and elemental analysis, with HPLC confirming ≥95% purity. All compounds were evaluated for antimicrobial activity against Gram-positive (S. aureus, S. pyogenes), Gram-negative (E. coli, P. aeruginosa), and fungal strains (C. albicans, A. clavatus, A. niger) using the agar well diffusion method. Compounds 11b (phenoxy) and 11j (2-nitrophenoxy) exhibited the highest activity, with zones of inhibition up to 2.2 mm. Structure activity relationship (SAR) analysis revealed that ortho substituted electron withdrawing groups and flexible phenoxy moieties enhance hydrogen bonding and – interactions with microbial targets, while para-substitutions reduced potency. Molecular docking studies confirmed favorable binding energies and interactions with key bacterial and fungal protein residues, correlating with experimental activity. Preliminary cytotoxicity assays indicated low toxicity (IC₅₀ > 80 µM), yielding a high selectivity index (>44). Overall, these findings highlight 11b and 11j as promising lead compounds for broad-spectrum antimicrobial development.