Discovery of novel furo[2,3‐d]pyrimidin‐2‐one–1,3,4‐oxadiazole hybrid derivatives as dual antiviral and anticancer agents that induce apoptosis

A new series of furo[2,3‐d]pyrimidine–1,3,4‐oxadiazole hybrid derivatives were synthesized via an environmentally friendly, multistep synthetic tool and a one‐pot Songoashira‐heterocyclization protocol using, for the first time, nanostructured palladium pyrophosphate (Na2PdP2O7) as a heterogeneous catalyst. Compounds 9a–c exhibited broad‐spectrum activity with low micromolar EC50 values toward wild and mutant varicella‐zoster virus (VZV) strains. Compound 9b was up to threefold more potent than the reference drug acyclovir against thymidine kinase‐deficient VZV strains. Importantly, derivative 9b was not cytostatic at the maximum tested concentration (CC50 > 100 µM) and had an acceptable selectivity index value of up to 7.8. Moreover, all synthesized 1,3,4‐oxadiazole hybrids were evaluated for their cytotoxic activity in four human cancer cell lines: fibrosarcoma (HT‐1080), breast (MCF‐7 and MDA‐MB‐231), and lung carcinoma (A549). Data showed that compound 8f exhibits moderate cytotoxicity, with IC50 values ranging from 13.89 to 19.43 µM. Besides, compound 8f induced apoptosis through caspase 3/7 activation, cell death independently of the mitochondrial pathway, and cell cycle arrest in the S phase for HT1080 cells and the G1/M phase for A549 cells. Finally, the molecular docking study confirmed that the anticancer activity of the synthesized compounds is mediated by the activation of caspase 3. New furo[2,3‐d]pyrimidine–1,3,4‐oxadiazole hybrid derivatives were synthesized via a multistep synthetic tool and a one‐pot Songoashira‐heterocyclization protocol. Compounds 9a–c exhibited broad‐spectrum activity toward wild and mutant varicella‐zoster virus (VZV) strains. When evaluated for their cytotoxic activity in four human cancer cell lines, compound 8f exhibited moderate cytotoxicity (IC50 = 13.89–19.43 µM). The anticancer activity of the compounds is mediated by caspase 3 activation.