Design, Synthesis, Antimicrobial Activity and Molecular Docking of New 1,2,4-Triazepine, 1,3,4,6-Oxatriazepine and Pyridazino[1,2-a] Pyrimidine Derivatives

Background: Recently, compounds such as pyrimidine, pyridazine, 1,2,4-triazepine, 1,3,4,6-oxatriazepine, pyridazino[1,2-a]pyrimidine, and pyridazino[1,2-c] pyrimidine, as well as their derivatives, have attracted attention due to their diverse biological activities. Objective: This study focuses on the synthesis of new heterocyclic compounds that feature a seven-membered ring, including pyridazinopyrimido[2,1-c] [1,2,4]triazepine-tetraones (4), pyridazinopyrimidotriazepine-triones (5–8), aminopyri-dazinopyrimido[2,1-c][1,2,4]triazepine-tetraone (9), and 6-amino-8-imino-pyridazino pyrimido[2,1-c] [1,2,4]triazepine-trione (10). These new compounds were synthesized starting from 1-(4-oxo-1,4-dihydropyrimidine)-1,2-dihydropyridazine-3,6-dione (3) and were then evaluated for their antimicrobial activity. Methods: A new series of pyridazino[1,2-a]pyrimido[2,1-c][1,2,4]triazepines and 1,3,4,6-oxatriazepines were synthesized using modern techniques and advanced technology, achieving yields between 72% and 90%. Results: All new compounds were confirmed through IR, ¹H NMR, ¹³C NMR, and mass spectroscopy (MS) and tested for in vitro antimicrobial activity. Compounds (8-10) exhibited excellent antimicrobial activity. Computational analysis provided a comprehensive evaluation of the broad-spectrum inhibitory potential of four lead compounds (6, 8, 9, and 10) against key microbial and fungal targets. These compounds demonstrated consistently superior binding affinities compared to control drugs cefotaxime and nystatin across a range of enzymes essential for pathogen viability and virulence. Conclusions: The structure–activity relationship (SAR) study established a correlation between the tested compounds and their antimicrobial activity. Molecular docking analysis indicated that the in silico results strongly suggest that compounds (6, 8, 9, and 10) are promising multi-target agents capable of disrupting essential bacterial processes and critical fungal pathways, making them excellent candidates for the development of novel antimicrobial therapeutics. These consistent findings support the conclusion that both practical and theoretical studies of the new compounds align with their antimicrobial effectiveness.