DESIGN, SYNTHESIS, MOLECULAR DOCKING, ADME PREDICTION, AND BIOLOGICAL EVALUATION OF PYRIMIDINE-2-THIOL DERIVATIVES

Abstract

The growing problem of antimicrobial resistance has created a need for new agents; a new class of pyrimidine derivatives was synthesized, and their biological potential was determined by in vitro and in silico analyses. Pyrimidine derivatives were designed and synthesized in the wet lab. The Structures of the compounds were confirmed by IR, 1H, 13C NMR, and CHN analysis. The synthesized compounds were further evaluated through molecular docking against alpha glycerophosphate oxidase, in silico ADME prediction, antimicrobial assay by agar well diffusion and minimum inhibitory concentration (MIC) assays, antioxidant activity using the DPPH method, and in vitro anticancer evaluation against the MDA-MB-231 human breast cancer cell line using the sulforhodamine B (SRB) assay. The ADME analysis indicated that most compounds possessed favourable drug-like properties, with good predicted oral absorption and compliance with Lipinski's rule of five. Antimicrobial studies demonstrated concentration-dependent activity. Among the tested compounds, M5 displayed the strongest antibacterial activity, while C9, M5, C11, and M3 showed the lowest MIC values (7.8125–31.25 µg/ml). In the antioxidant assay, derivatives containing electron-donating substituents exhibited better free radical scavenging activity than the remaining compounds. In addition, M4 showed the highest antiproliferative activity against MDA-MB-231 cells with a GI₅₀ value of 5 µM, followed by M1 (GI₅₀ = 8 µM). These findings identify this scaffold as a promising lead for the further development of a multifunctional therapeutic agent.