Ultrasound-assisted synthesis of new triazole-thiazole hybrids: Molecular modeling, anticancer, and antiviral activities

A series of triazole-thiazole hybrids 3, 4, and 5 were synthesized by applying ultrasonic irradiation methodology to the reactions of triazolyl-3-oxo-N-phenylpropanethioamides 2a or 2b with ethyl chloroacetate, chloroacetone, and/or 3-chloroacetylacetone. Density functional theory (DFT) exploration of the produced hybrids disclosed bent configurations. Also, the frontier molecular orbital (FMO) diagrams designated that the thioamide conjugates 2a-b have coincided configurations, whereas the phenylthiazolyl hybrids 3a-b, 4a-b, and 5a-b have alternative structures of their highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). In addition, the cytotoxic activities of the newly synthesized hybrids towards some cancer cell lines have been evaluated. The hybrids 5a and 5b showed the strongest cell-killing potential, especially against MCF-7 (IC₅₀ = 3.07±0.14 and 2.19±0.23 µM, respectively). While hybrids 3a and 3b had strong inhibitory effects on HepG2 cells (IC₅₀ = 2.08±0.39 and 2.77±0.24 µM, respectively). Furthermore, the antiviral efficacy against the highly infectious avian influenza H5N1 virus in Madin-Darby canine kidney cells (MDCK) cells was assessed using a plaque reduction test. The results showed that hybrids 4a and 5a have the best antiviral activity, stopping viruses completely at doses that don’t damage cells, which is the same as amantadine. Also, the binding affinities of synthesized hybrids were explored through a molecular docking study, which indicated that hybrid 5a exhibited the highest docking score, specifically bonded to CYS47. Also, the pharmacokinetic parameters of these conjugates were estimated using the SwissADME online program to simulate their drug-likeness and potential pharmacokinetic profiles, where hybrid 5a exhibited one Lipinski violation, while hybrid 5b showed two violations and a lower bioavailability score = 0.17.