由于微生物对抗生素的抗性的增加,开发新的抗微生物剂已经成为必需。评估了所有新的金刚烷衍生物对6种MDR临床病原分离株的抗菌活性。结果表明,13个化合物具有从有效到良好的活性。其中,五个衍生物(6,7,9,14a,和14b)显示了与环丙沙星(CIP)和氟康唑(FCA)相比,对所测试的不同分离株的有效活性(细菌的MIC<0.25µg/ml,真菌的MIC<8µg/ml)。此外,基于(MBC和MFC)和时间杀灭试验,强效金刚烷具有杀菌和杀真菌作用。活性最强的金刚烷衍生物7和14b对细菌和真菌分离株表现出ΣFIC≤0.5与CIP和FCA的协同作用。此外,对于测试的衍生物没有出现拮抗作用。此外,DNA促旋酶和拓扑异构酶IV酶与化合物6,7,9,14a,和14b使用体外生化测定和基于凝胶的DNA超螺旋抑制方法表现出有效的抗微生物活性。DNA促旋酶和拓扑异构酶IV酶的活性在化合物7和10.14µM和13.28µM的情况下显示出6.20µM和9.40µM的抑制活性(IC50)。分别。令人惊讶的是,将化合物7暴露于γ辐射灭菌并增加其活性。最后,计算机分析预测,活性最强的衍生物具有良好的药物相似性和安全性。此外,分子对接和量子化学研究揭示了活性位点内部的几个重要相互作用,并显示了活性所必需的结构特征。
Developing novel antimicrobial agents has become a necessitate due to the increasing rate of microbial resistance to antibiotics. All the newly adamantane derivatives were evaluated for their antimicrobial activities against six MDR clinical pathogenic isolates. The results exhibited that 13 compounds have from potent to good activity. Among those, five derivatives (6, 7, 9, 14a, and 14b) displayed the potent activities against the different isolates tested (MIC < 0.25 µg/ml with bacteria and <8 µg/ml with fungi) compared with Ciprofloxacin (CIP) and Fluconazole (FCA). Additionally, the potent adamantanes showed bactericidal and fungicidal effects based on (MBCs and MFCs) and the time-kill assay. The most active adamantane derivatives 7 and 14b exhibited a synergistic effect of ΣFIC ≤ 0.5 with CIP and FCA against the bacterial and fungal isolates. Moreover, no antagonistic effect appeared for the tested derivatives. Additionally, the interaction of DNA gyrase and topoisomerase IV enzymes with the compounds 6, 7, 9, 14a, and 14b exhibited potent antimicrobial activity using in vitro biochemical assays and gel-based DNA-supercoiling inhibition method. The activity of DNA gyrase and topoisomerase IV enzymes showed inhibitory activity (IC50 ) of 6.20 µM and 9.40 µM with compound 7 and 10.14 µM and 13.28 µM with compound 14b, respectively. Surprisingly, exposing compound 7 to gamma irradiation sterilized and increased its activity. Finally, the in-silico analysis predicted that the most active derivatives had good drug-likeness and safe properties. Besides, molecular docking and quantum chemical studies revealed several important interactions inside the active sites and showed the structural features necessary for activity.