Synthesis and Antimicrobial Evaluation of Novel Oxopyrimido1,2–apyrimidine Derivatives

This study details the efficient synthesis and antimicrobial evaluation of a novel series of oxopyrimido1,2-apyrimidine derivatives. The synthetic pathway commenced with the preparation of a key chalcone intermediate, 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one, via a Claisen-Schmidt condensation of 4-chlorobenzaldehyde and acetophenone. This chalcone was subsequently cyclized with guanidine nitrate under basic conditions to yield the pivotal dihydropyrimidin-2-amine precursor. The core pyrimidopyrimidine scaffold was constructed through a Michael addition reaction, where the dihydropyrimidin-2-amine was reacted with ethyl 2-cyano-3,3-bis(methylthio)acrylate. This crucial step afforded the central intermediate, 2-(4-chlorophenyl)-8-(methylthio)-6-oxo-4-phenyl-1,6,9,9a-tetrahydro-2H-pyrimido1,2-apyrimidine-7-carbonitrile, which features a reactive methylthio group. This group served as a versatile handle for further functionalization, allowing for the synthesis of a diverse library of ten new analogues through nucleophilic substitution with various aromatic amines, phenols, and active methylene compounds. The structures of all synthesized compounds were unequivocally confirmed using modern spectroscopic techniques, including IR, ¹H NMR, ¹³C NMR, and mass spectrometry. The entire compound library was screened for in vitro antibacterial and antifungal activities. The results were promising, with several derivatives exhibiting significant growth inhibition against strains of Escherichia coli, Bacillus subtilis, Aspergillus niger, and Aspergillus flavus, showcasing their potential as leads for new antimicrobial agents.