Synthesis, Antimicrobial Evolution, Defibrillation Threshold Studies, Docking Studies, Silico Admet Analysis and PER-Metabolism Study of Some New Dihydropyrmidine Derivatives

Abstract

Dihydropyrimidinone and dihydropyrimidine derivatives are reported to possess broad biological activities. Many synthetic samples have been studied as antibacterial, antiviral, and anticancer agents. We decided to synthesize novel compounds of new pyrimidine derivatives. The present work involves the synthesis of new dihydropyridine derivatives. The starting vanillin, compound (1) was used as the key intermediate to prepare the 5-acetyl-4-(4-hydroxy-3-methoxyphenyl)-6-methyl pyrimidine-2(1H)-one(2),Ethyl 4-(4-hydroxy-3-methoxyphenyl)-6-methyl-2-oxo-1,2-dihydropyrimidine-5-carboxylate (3), 4-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetrahydro quinazoline-2(1H)-one (4), respectively, through the reaction with urea and acetylacetone or ethyl acetoacetate or cyclohexanone but 4-(4-hydroxy-3-methoxyphenyl)-5,6,7,8-tetrahydro quinazoline-2(1H)-thione (5) reacted with thiourea and cyclohexanone. FTIR,1H-NMRand13C-NMR spectroscopy characterized all the synthesized compounds. The synthesized derivatives were screened for their in vitro, antibacterial activity against two gram-positive bacteria: Bacillus subtilis, and Staphylococcus aureus and two gram-negative bacteria: Klebsiella pneumonia and Salmonella typhi and the results showed that most of them have good antibacterial activity. While their antifungal activity against three fungi species: (Aspergillus fumigates, Aspergillus niger, and Rhizopus), revealed that compounds (1-5) displayed the most potent antifungal activity. Density functional theory ( DFT) calculations for the synthesized compounds (1-5) were conducted, using a molecular structure with optimized geometry. Highest occupied molecular orbital/lowest unoccupied molecular orbital energies and structures are demonstrated. The antimicrobial activity indicates that compounds 3 and 4 are the most active than the compounds 2 and 5. Molecular docking revealed that compounds (4) and (5), with cyclohexyl groups are important to block the active centers of glucose -6-phosphate synthase in the bacteria and fungi.