Novel Pyridopyrimidine-Based Compounds: Design, Synthesis and Cytotoxic Evaluation

Abstract

In this study, fifteen novel pyrido[2,3-d]pyrimidine derivatives (11a-o) were successfully designed, synthesized and characterized using spectroscopic techniques. The synthesized compounds were evaluated for their anticancer activity against three human cancer cell lines: MDA-MB-231 (breast cancer), HeLa (cervical cancer) and MCF-7 (breast cancer). The MTT assay results revealed that while some compounds exhibited low to moderate activity, the majority demonstrated potent anticancer effects, with pyrido[2,3-d]pyrimidine derivatives standing out as particularly effective. Among the synthesized compounds, compound 11m featuring a pyrido[2,3-d]pyrimidine core fused with an 8-bis(4-fluorophenyl)-4-oxo-2-phenyl moiety, exhibited the most potent cytotoxic activity. It displayed IC₅₀ values of 1.29 ± 0.18 µM, 1.34 ± 0.02 µM and 1.57 ± 0.12 µM against MDA-MB-231, HeLa and MCF-7 cell lines, respectively. Similarly, compound 11e containing a pyrido[2,3-d]pyrimidine scaffold fused with a 5-amino-8-(3-chlorophenyl)-N-(4-fluorophenyl)-4-oxo-2-phenyl moiety, also demonstrated significant anticancer activity, with IC₅₀ values of 1.42 ± 0.12 µM, 1.54 ± 0.13 µM and 1.85 ± 0.23 µM against the same cell lines. The potent activity of compounds 11m and 11e highlights the importance of pyrido[2,3-d]pyrimidine core and the strategic incorporation of electron-withdrawing substituents, such as fluoro and chloro groups, in enhancing anticancer efficacy. These findings suggest that these compounds could serve as promising lead candidates for further development as multifunctional anticancer agents. Future studies should focus on optimizing their structural features, evaluating their mechanisms of action and assessing their in vivo efficacy and safety profiles to advance their potential as therapeutic agents for cancer treatment.