Tetrazolo[1,5-c]quinazolines as anti-Klebsiella pneumoniae scaffolds: Bridging in vitro activity and multi-target docking prediction.

Abstract

The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a significant challenge in antimicrobial chemotherapy, with mortality rates reaching 50% in bloodstream infections. Building on prior disk diffusion evidence of K. pneumoniae inhibition by N-acetamide tetrazoloquinazoline compounds and a cross-series analysis of >60 published derivatives across seven structural subclasses, this study presents the first MIC-quantified antibacterial evaluation against a clinically isolated, multidrug-resistant K. pneumoniae strain. Twenty-one synthetic tetrazolo[1,5-c]quinazoline derivatives were evaluated, with molecular docking performed against five bacterial enzyme targets: FabI (fatty acid synthesis), MurA (cell wall biosynthesis), DNA gyrase (DNA replication), KPC-2 (β-lactam resistance), and LpxC (lipopolysaccharide synthesis). Two compounds demonstrated antibacterial activity, both with MIC values of 64 mg/L: the thiol derivative 63sh (315 μM) and 2-chlorobenzyl acetamide 102 (166 μM). No inhibition was observed against Escherichia coli or Staphylococcus aureus at concentrations up to 512 mg/L. Computational docking against five bacterial enzyme targets revealed FabI enoyl-ACP reductase as the most favorable binding target. Under conventional medicinal chemistry criteria, MIC values of 64 mg/L correspond to hit-level rather than lead-level potency; substantial structural optimization is required before preclinical consideration. In silico ADMET profiling (admetSAR3.0) indicates that the computationally favored but experimentally inactive/weak compounds (96, 97, 109, 112) possess lower predicted membrane permeability (Caco-2: -5.07 to -5.41 vs. -4.36 to -4.98 log nm/s) and higher P-glycoprotein inhibition probabilities (0.741-0.795), consistent with impaired membrane permeation as the primary mechanistic explanation for this discordance.