Síntese e Avaliação de Atividade Antimicrobiana de Hidrazonas e 1,3,4-oxadiazóis

Abstract

Over the years, bacteria have developed increasingly sophisticated mechanisms to circumvent the effects of antimicrobial agents, leading to the continuous emergence of resistant strains that surpass even the most advanced antibiotics. Global health indicators highlight infectious diseases as one of the top ten threats to public health worldwide, drawing the attention of organizations such as the World Health Organization (WHO), the European Union, the National Health Surveillance Agency (ANVISA), the National Health Council (CNS), and the Centers for Disease Control and Prevention (CDC). In response, the WHO, through the Global Action Plan on Antimicrobial Resistance, has established the development of new drugs and antibacterial strategies as a global priority to combat antimicrobial resistance. Estimates indicate that, in 2019, approximately 1.27 million deaths worldwide were attributed to infections caused by resistant microorganisms. Moreover, projections suggest that this number could rise to 10 million by 2050 if no significant actions are taken to mitigate antimicrobial resistance. In the context of drug discovery, hydrazones and their derivatives have gained considerable attention due to their chemical properties and biological activities. These compounds not only serve as crucial intermediates in the synthesis of various heterocyclic systems but also exhibit noteworthy biological activities. In this study, commercially available aldehydes were utilized as precursors for the synthesis of N-acylhydrazones and 1,3,4-oxadiazoles to evaluate the antimicrobial activity of the obtained compounds, thereby expanding the understanding of their properties and potential applications. The synthetic route for oxadiazole production involved two steps. Initially, six N-acylhydrazones were synthesized through the reaction of 3-hydroxybenzaldehyde and salicylaldehyde with 4-fluorophenyl, 4-chlorophenyl, and 4-bromophenyl hydrazides under reflux in ethanol, yielding quantitative products. These N-acylhydrazones were then subjected to an intramolecular cyclization reaction with acetic anhydride at 100°C to afford six novel oxadiazoles, with yields ranging from 16% to 50%. The structures of all substances were confirmed by Nuclear Magnetic Resonance (NMR) spectroscopy techniques. The antimicrobial activity of the synthesized compounds was assessed using the broth microdilution assay. All N-acylydrazones exhibited weak antibiotic activity against Staphylococcus aureus and Escherichia coli. Among the oxadiazoles, only compound 6A demonstrated moderate activity against S. aureus, whereas the remaining oxadiazoles showed weak activity against both S. aureus and E. coli.