Rational Design and Synthesis of Benzothiophene–Quinoxaline–Oxadiazole Conjugates Targeting Bacterial and Fungal Pathogens

Abstract

The escalating threat of antimicrobial resistance demands new therapeutic agents. This study reports the synthesis, characterization, and biological evaluation of novel benzothiophene–quinoxaline–oxadiazole hybrids. The core framework was constructed via phase‐transfer catalysis to yield compound 1a , which underwent ring‐opening to form 1c , while additional Schiff bases were cyclized into 1,3,4‐oxadiazoles using copper triflate (Cu(OTf) 2 ) in the presence of potassium carbonate in DMF. All structures were confirmed by NMR, IR, and HRMS. Biological screening revealed that antimicrobial activity is highly structure‐dependent. Notably, oxadiazole formation in 1a dramatically enhanced broad‐spectrum antibacterial potency, rivaling streptomycin. Structure–activity analysis identified chlorine substitution as favorable for gram‐negative activity, whereas electron‐donating groups were detrimental. Several derivatives also exhibited significant antifungal effects, with compounds 1a, 1b, 3a , 3b , 4a , and 4b demonstrating MIC values against Rhizopus microporus and Aspergillus oryzae comparable or superior to fluconazole. These findings establish the oxadiazole‐linked scaffold, particularly lead compound 1a , as a promising foundation for developing safe and effective antimicrobial agents.