Synthesis and computational investigation of novel 2-mercaptoimidazolones as dual antimicrobial and anti-proliferative agents with potential multitargeting kinase inhibitory activity

Anticancer drug therapy-induced immunosuppression increases the incidence of treatment-resistant infectious diseases in cancer patients. Combining antibacterial and anticancer capabilities into a single medication can potentially enhance the treatment outcomes. In this light, the current study focused on developing innovative 5-arylidene-3-phenyl-2-thioimidazolones 1a-e and evaluated them as antimicrobial candidates against a panel of Gram-positive and Gram-negative bacterial and fungal isolates. Compounds 1e and 2d exhibited the most potent microbial activity, with MIC values ranging from 24 ± 0.5 to 12 ± 0.20 µg/ml in comparison with streptomycin and cycloheximide as reference standards. Using the colon cancer cell line (HCT 116) as a representative example, the novel compounds were assessed as anticancer agents. Compounds 1e and 2d appeared to be the most effective candidates, with IC₅₀ values of 7.25 ± 1.03 and 44.3 ± 3.28 µg/ml, respectively, when compared to doxorubicin (IC₅₀ = 4.12 ± 0.50 µg/ml). Therefore, we extended the anticancer study of both 1e and 3b to include the other three cancer cells, PC3, A549, and MCF-7, and the normal Vero cell line. 1e was the most effective anticancer compound, exhibiting IC₅₀ values ranging from 5.2 ± 0.09 to 8.1 ± 0.11 µg/mL and demonstrating a promising safety profile against the BJ1 normal cell line. In vitro enzyme screening assay of 1e against CDK-2, EGFR, HER-2, and VEGFR-2 enzymes investigated its promising multitargeting inhibiting activity (IC₅₀ = 0.314 ± 0.031, 0.183 ± 0.014, 0.197 ± 0.024, and 0.235 ± 0.028 µM, respectively). A molecular docking study was carried out to discover the probable interactions of compound 1e with the active sites of the assessed kinases. Additionally, in silico ADMET studies were carried out for 1e, which represented its good oral absorption, good drug-likeness characteristics, and low toxicity risks.