Design, Synthesis, and Antibacterial Evaluation of Pyrido[2,3-d]Pyrimidine and Pyrido[3,2-e]Pyrimido[1,2-c]Pyrimidine Derivatives

A new series of N-substituted pyrido2,3-dpyrimidines and pyrido[3,2-e]pyrimido[1,2-c]pyrimidine derivatives were synthesized. The synthesis was initiated from pyridopyrimidin-4(3H)-one derivatives which were prepared via a tandem Pinner/Dimroth rearrangement in the presence of phosphoryl chloride. Its N-substituted derivatives were prepared after treatment of chloro-derivative with a series of amines, and then some of these derivatives underwent cyclization to give the tricyclic derivatives. The fused pyridopyrimidopyrimidines were obtained via the reaction of amino compound with malonates derivatives. Most of these compounds were evaluated for their antibacterial activity. The structures of the synthesized compounds were confirmed by elemental analysis and spectroscopic techniques (IR, NMR, and EI-MS). Several derivatives, particularly compounds 5b, 5c, 5f, 6, 7, and 14a, exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria, with minimum inhibitory concentration (MIC) values ranging from 0.48 to 3.91 μg/mL. Notably, tricyclic derivatives demonstrated enhanced efficacy, suggesting a promising scaffold for the development of new antibacterial agents.