Sroor Farid M, El-Sayed Ahmed F, Abdelraof Mohamed
Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt.
Microbial Genetics Department, Biotechnology Research Institute, National Research Centre, Giza, Egypt.
Drug Dev Res. 2025 May;86(3):e70096. doi: 10.1002/ddr.70096.
A new series of biologically active benzo[4,5]imidazo[1,2-a]pyrimidine derivatives containing different substitutions such as thiophene, pyridine, pyrrole, and 3,4-dimethoxyphenyl at carbon 2 and, phenyl-pyrrolidinyl, -morpholinyl, -piperidinyl at carbon 4 were synthesized. The treatment of chalcone derivatives 5-16 with 2-aminobenzimidazole in DMF and drops of TEA afforded the targeted benzo[4,5]imidazo[1,2-a]pyrimidine derivatives (18-29) in good to excellent yields. These compounds were tested to evaluate their antimicrobial activity against different microbial pathogens such as Aspergillus niger, Candida albicans, Staphylococcus aureus and Salmonella typhimurium. Potently compounds 19 and 23 were contributed in a broad-spectrum inhibition process against all tested pathogens with lower MIC values ranging between 10 and 60 µg/mL. Furthermore, the efficiency of the potent compounds to inhibit the biofilm formation was moderately detected by compounds 18, 19 and 23. This study investigated the antimicrobial potential of synthesized compounds through experimental and computational approaches. Compounds 18, 19, 23, 25, and 28 demonstrated strong binding affinities to antimicrobial target proteins (1AD4, 2SIL, 4ZA5, and 5TZ1), suggesting their ability to inhibit key enzymes via diverse molecular interactions. Computational ADMET profiling confirmed their compliance with Lipinski's rules, indicating favorable drug-like properties. Molecular dynamics simulations further validated the stability of complexes formed by compounds 19 and 28, with stable RMSD values (0.17-0.45 nm), low RMSF fluctuations (0.10-0.7 nm), and consistent structural compactness (Rg: 1.45-1.75 nm). Solvent exposure (SASA: 120-220 nm²) varied across complexes. These results highlight the compounds' potential as promising candidates for antimicrobial drug development, warranting further preclinical exploration.
合成了一系列新的具有生物活性的苯并[4,5]咪唑并[1,2 - a]嘧啶衍生物，这些衍生物在碳2位含有不同的取代基，如噻吩、吡啶、吡咯和3,4 - 二甲氧基苯基，在碳4位含有苯基 - 吡咯烷基、吗啉基、哌啶基。在DMF中用2 - 氨基苯并咪唑和几滴TEA处理查尔酮衍生物5 - 16，以良好至优异的产率得到了目标苯并[4,5]咪唑并[1,2 - a]嘧啶衍生物（18 - 29）。测试了这些化合物对不同微生物病原体的抗菌活性，如黑曲霉、白色念珠菌、金黄色葡萄球菌和鼠伤寒沙门氏菌。高效的化合物19和23在对所有测试病原体的广谱抑制过程中发挥作用，其较低的最低抑菌浓度（MIC）值在10至60μg/mL之间。此外，化合物18、19和23适度检测到了高效化合物抑制生物膜形成的效率。本研究通过实验和计算方法研究了合成化合物的抗菌潜力。化合物18、19、23、25和28对抗菌靶蛋白（1AD4、2SIL、4ZA5和5TZ1）表现出很强的结合亲和力，表明它们能够通过多种分子相互作用抑制关键酶。计算的ADMET分析证实它们符合Lipinski规则，表明具有良好的类药物性质。分子动力学模拟进一步验证了化合物19和28形成的复合物的稳定性，其具有稳定的均方根偏差（RMSD）值（0.17 - 0.45nm）、低均方根波动（RMSF）（0.10 - 0.7nm）和一致的结构紧凑性（Rg：1.45 - 1.75nm）。不同复合物的溶剂可及表面积（SASA：120 - 220nm²）有所不同。这些结果突出了这些化合物作为抗菌药物开发有前景的候选物的潜力，值得进一步的临床前探索。
