Iodine-mediated 2,5-di(aryl/heteroaryl)-1,3,4-oxadiazoles: synthesis, and in vitro and in silico studies of anticancer and antifungal properties
Recent studies have highlighted the 1,3,4-oxadiazole scaffold as an important pharmacophore present in numerous biologically active molecules and therapeutic agents. In continuation of our interest in biologically active heterocyclic compounds, we report the synthesis of a series of novel 2,5-di(aryl/heteroaryl)-1,3,4-oxadiazoles using molecular iodine (1.0 equiv.) under basic conditions. The synthesized compounds were evaluated for in vitro anticancer and antifungal activities together with comprehensive computational investigations. Cytotoxicity studies against normal HEK-293 cells and the cancer cell lines DU145, HepG2, and B16–F10 demonstrated diverse activity profiles, with compounds 9b and 9g exhibiting the most favourable cytotoxic activity and selectivity, while compound 9r showed moderate activity. Antifungal evaluation of the nineteen synthesized derivatives against Alternaria solani (MTCC-2101), Pyricularia oryzae (MTCC-1477), Helminthosporium solani (MTCC-1899), and Fusarium oxysporum (MTCC-2087) revealed a limited, strain-dependent antifungal activity against selected fungal strains. ADME and drug-likeness analyses, using Erlotinib as a reference, indicated acceptable physicochemical and pharmacokinetic characteristics for the synthesized compounds. Comparative molecular docking studies against human DNA topoisomerase IIα (TOP2A), histone deacetylase 2 (HDAC2), and thymidine phosphorylase demonstrated favourable binding interactions, particularly for compounds 9b and 9g. Subsequent 200 ns molecular dynamics simulations, MM-GBSA binding free-energy calculations, and free energy landscape analyses consistently supported the stability of the corresponding protein–ligand complexes and identified TOP2A and HDAC2 as the most plausible molecular targets underlying the observed cytotoxic activity. Collectively, the integrated experimental and computational findings identify 9b and 9g as promising lead 1,3,4-oxadiazole derivatives for further development as anticancer agents.