Quinoline-2-carboxamide-phenylacetamide hybrids as preliminary antimicrobial and cytotoxic hits: Synthesis, biological screening, molecular docking, and in silico ADMET profiling.

In this work, novel quinoline-2-carboxamide-phenylacetamide hybrids 23a-d were designed, synthesised, and evaluated through antimicrobial and breast cancer-cell cytotoxicity screening. The compounds showed moderate antimicrobial activity against methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Candida albicans, with compound 23b showing the lowest MIC values of 0.125 and 0.039 mg/mL against MRSA and P. aeruginosa, respectively. Cytotoxicity screening against MCF-7 and MDA-MB-231 breast cancer cell lines identified compound 23d as the most active member of the series against MCF-7 cells, with an IC₅₀ of 6.249 ± 0.30 µg/mL, corresponding to 14.55 ± 0.70 µM using the molecular weight applied in this study. Molar comparison showed that the activity profile was cell-line dependent: 23d displayed a lower molar IC₅₀ than cisplatin against MCF-7 under the assay conditions used, whereas cisplatin remained more potent against MDA-MB-231 cells. Molecular docking against activated CDC42-associated kinase 1 (ACK1) suggested that 23d can adopt a favourable predicted binding pose within the ACK1 ATP-binding pocket, with a GlideScore of - 8.112 kcal/mol compared with - 9.651 kcal/mol for the co-crystallised inhibitor. However, docking alone cannot confirm ACK1 inhibition or establish the mechanism of cytotoxicity. Because non-cancerous-cell cytotoxicity was not performed, cancer-cell selectivity remains unresolved and selectivity indices could not be calculated. Accordingly, compounds 23a-d are presented as preliminary antimicrobial and cytotoxic hits requiring further optimisation, analytical validation, non-cancerous-cell cytotoxicity testing, and mechanistic confirmation.