Pyridazinone-based derivatives as anticancer agents endowed with anti-microbial activity: molecular design, synthesis, and biological investigationElectronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4md00481g

Cancer patients undergoing chemotherapy are highly susceptible to infections owing to their compromised immune system, which also promotes cancer progression through inflammation. Thus, this study aimed to develop novel chemotherapeutic agents with both anticancer and antimicrobial properties. A series of diarylurea derivatives based on pyridazinone scaffolds were designed, synthesized, and characterized as surrogates for sorafenib. The synthesized compounds were tested for their antimicrobial activity and screened against 60 cancer cell lines at the National Cancer Institute (NCI). Compound 10hexhibited potent antibacterial activity against Staphylococcus aureus(MIC = 16 μg mL−1), whereas compound 8gshowed significant antifungal activity against Candida albicans(MIC = 16 μg mL−1). Additionally, ten compounds were further evaluated for VEGFR-2 inhibition, with compound 17ashowing the best inhibitory activity. Compounds 8f, 10l, and 17ademonstrated significant anticancer activity against melanoma, NSCLC, prostate cancer, and colon cancer, with growth inhibition percentages (GI%) ranging from 62.21% to 100.14%. Compounds 10land 17awere selected for five-dose screening, displaying GI50values of 1.66–100 μM. Compound 10linduced G0–G1 phase cell cycle arrest in the A549/ATCC cell line, increasing the cell population from 85.41% to 90.86%. Gene expression analysis showed that compound 10lupregulated pro-apoptotic genes p53 and Bax and downregulated the anti-apoptotic gene Bcl-2. Molecular docking studies provided insights into the binding modes of the compounds to the VEGFR-2 enzyme. In conclusion, the pyridazinone-based diarylurea derivatives developed in this study show promise as dual-function antimicrobial and anticancer agents, warranting further investigation.