INVESTIGATION OF ISOXAZOLE-1,3,4-OXADIAZOLE HYBRIDS AS ANTIMYCOBACTERIAL AGENTS - A PILOT STUDY

Abstract

Given the rising number of cases of both latent and drug-resistant tuberculosis, there is an urgent need for thedevelopment of novel, potent compounds capable of combating this global health threat1. In medicinalchemistry, heterocycles play a crucial role and are frequently incorporated into the molecular design aimed atdiscovering new biologically active agents. Among them, 1,3,4-oxadiazole and isoxazole scaffolds arewell-established for their antimycobacterial potential.2In this study, we report the design and synthesis of a pilot series of eighteen hybrid molecules combining bothisoxazole and 1,3,4-oxadiazole cores, with the goal of identifying a lead compound exhibiting significantantimycobacterial activity. The synthetic route involved a three main steps: (1) synthesis of ethyl5-formylisoxazole-3-carboxylate; (2) condensation with a variety of hydrazides to afford hydrazide-hydrazoneintermediates; and (3) oxidative cyclization of these intermediates to form the 1,3,4-oxadiazole ring, carried outvia two methodologies using either [bis(trifluoroacetoxy)iodo]benzene or iodine.All final compounds were evaluated for their antimycobacterial, antibacterial, and antifungal activities. Theresults revealed selective antimycobacterial activity across the series, with minimal or no effect against bacterialand fungal strains. Among the synthesized derivatives, compound 1, ethyl5-(5-(4-(dimethylamino)phenyl)-1,3,4-oxadiazol-2-yl)isoxazole-3-carboxylate, emerged as the mostpotent candidate, with minimum inhibitory concentration of 1 µM against Mycobacterium tuberculosis H37Rv.However, its ester functionality limits its drug-likeness profile. To address this issue, compound 1 was selectedfor further structural optimization, beginning with hydrolysis of the ester moiety followed by functionalization ofthe resulting carboxylic acid. These modifications are currently ongoing.