DEVELOPMENT AND SYNTHESIS OF NEW TINIDAZOLE-BASED NITRONE DERIVATIVES: STRUCTURAL CHARACTERIZATION AND IN VITRO BIOLOGICAL EVALUATION

Abstract

Objective: The rapid emergence of multi-drug resistant (MDR) bacterial pathogens has intensified the search for novel antimicrobial scaffolds. This study reports the design, synthesis, and biological evaluation of a new series of nitrone derivatives based on the Tinidazole scaffold. Methods: A library of compounds (M1–M3) was synthesized via the condensation of various aryl-substituted benzaldehydes with tinidazole-derived hydroxylamine intermediates. The molecular structures and stereochemical configurations of the synthesized hybrids were rigorously confirmed using spectral characterization techniques, including FT-IR, 1H NMR, 13C NMR, and Mass Spectrometry, which consistently indicated the formation of the stable (Z)-isomeric form. Results: The in vitro biological evaluation revealed that these nitrone derivatives possess potent broad-spectrum antibacterial activity against Gram-positive (Staphylococcus aureus) and Gram-negative (Klebsiella pneumoniae) clinical isolates. Notably, compounds M1 (4-F), M2 (H), and M3 (4-Br) exhibited exceptional zones of inhibition (ZOI) ranging from 41 to 46 mm at the highest concentrations, significantly outperforming the standard drug (ST), which reached a maximum ZOI of 22 mm. Furthermore, the compounds demonstrated significant antioxidant potential in the DPPH radical scavenging assay. Novelty: The Structure-Activity Relationship (SAR) analysis suggests that the electronic and lipophilic modulation of the aryl-substituted nitrone framework, particularly with halogenated substituents, plays a pivotal role in enhancing membrane permeability and bactericidal efficacy. These findings position tinidazole-based nitrones as highly promising candidates for the development of next-generation antimicrobial agents to combat resistant pathogens.