Abstract: Persistent infection with high-risk human papillomavirus (HPV) is a necessary cause of cervical cancer, and the viral E6 oncoprotein is a candidate target for small-molecule design. Five 3,4-dihydropyrimidinone derivatives (C1–C5) were designed on the Biginelli scaffold and modified by a Mannich-type reaction with benzamide, aniline, sulphadiazine, para-aminobenzoic acid (PABA) and 2-aminobenzothiazole, respectively. Drug-likeness and ADME properties were predicted with SwissADME, toxicity risks with OSIRIS Property Explorer, and binding to HPV16 E6 (PDB ID: 4GIZ) by molecular docking with PyRx/AutoDock. The top-ranked compound was tested against HeLa cells by the MTT assay. All five compounds showed no Lipinski violations, acceptable predicted ADME characteristics and no major predicted toxicity alerts. Docking scores were −7.3, −7.2, −7.8, −8.1 and −8.8 kcal/mol for C1–C5, respectively. The 2-aminobenzothiazole derivative C5 gave the most favorable score (−8.8 kcal/mol) and reduced HeLa cell viability in a concentration-dependent manner (IC50 36.01 µg/mL). As HeLa cells are HPV18-positive, this cytotoxicity cannot be attributed to inhibition of HPV16 E6; the docking result is predictive, and C5 is regarded as a candidate for further structural optimization and mechanistic testing in HPV16-positive cells.

Keywords: 3,4-dihydropyrimidinone; Mannich base; HPV16 E6; molecular docking; SwissADME; drug-likeness; toxicity prediction; PyRx; Auto Dock; in silico drug design.