DNA促旋酶和拓扑异构酶IV显示出作为抗菌药物靶标的巨大潜力。近几十年来,已经确定了各种类型的小分子抑制剂;然而,没有一个在市场上有效。第一次,我们开发了一系列二丙烯酸亚甲基/席夫碱杂种(5a-k)作为靶向DNA促旋酶和拓扑异构酶IV的抗菌剂。结果表明,新靶点5f-k对革兰氏阳性和革兰氏阴性细菌具有显著的抗菌活性,功效范围为标准环丙沙星水平的75%至115%。化合物5h与其他测试化合物相比显示出最大的功效,对金黄色葡萄球菌的最小抑制浓度(MIC)值为0.030、0.065和0.060μg/mL,大肠杆菌,还有铜绿假单胞菌.5h对枯草芽孢杆菌的MIC值为0.050μg/mL,比环丙沙星的效力低五倍.最有效的抗菌衍生物5f的抑制作用,5h,5i,和5k对大肠杆菌DNA促旋酶进行评估。测试化合物对大肠杆菌DNA促旋酶具有抑制作用,IC50值范围为92至112nM。这些结果表明,5F,5h,5i,5k比参考新生霉素更有效,其IC50值为170nM。化合物5f,5h,5i,和5k进行针对大肠杆菌拓扑异构酶IV的额外评估。化合物5h和5i,在抑制大肠杆菌促旋酶方面具有最高的功效,还显示了对拓扑异构酶IV的有希望的效果。化合物5h和5i的IC50值为3.50µM和5.80µM,分别。这些结果比新生霉素的IC50值11μM低得多,也更有效。对接研究证明了化合物5h作为大肠杆菌DNA促旋酶和拓扑异构酶IV的有效双重抑制剂的潜力,ADMET分析显示了抗菌药物开发的有希望的药代动力学特征。
DNA gyrase and
topoisomerase IV show great potential as targets for antibacterial medicines. In recent decades, various categories of small molecule inhibitors have been identified; however, none have been effective in the market. For the first time, we developed a series of disalicylic acid methylene/Schiff bases hybrids (5a-k) to act as antibacterial agents targeting DNA gyrase and
topoisomerase IV. The findings indicated that the new targets 5f-k exhibited significant antibacterial activity against Gram-positive and Gram-negative bacteria, with efficacy ranging from 75% to 115% of the standard ciprofloxacin levels. Compound 5h demonstrated the greatest efficacy compared to the other compounds tested, with minimum inhibitory concentration (MIC) values of 0.030, 0.065, and 0.060 μg/mL against S. aureus, E. coli, and P. aeruginosa. 5h had a MIC value of 0.050 μg/mL against B. subtilis, which is five times less potent than ciprofloxacin. The inhibitory efficacy of the most potent antibacterial derivatives 5f, 5h, 5i, and 5k against E. coli DNA gyrase was assessed. The tested compounds demonstrated inhibitory effects on E. coli DNA gyrase, with IC50 values ranging from 92 to 112 nM. These results indicate that 5f, 5h, 5i, and 5k are more effective than the reference novobiocin, which had an IC50 value of 170 nM. Compounds 5f, 5h, 5i, and 5k were subjected to additional assessment against E. coli
topoisomerase IV. Compounds 5h and 5i, which have the highest efficacy in inhibiting E. coli gyrase, also demonstrated promising effects on
topoisomerase IV. Compounds 5h and 5i exhibit IC50 values of 3.50 µM and 5.80 µM, respectively. These results are much lower and more potent than novobiocin\'s IC50 value of 11 µM. Docking studies demonstrate the potential of compound 5h as an effective dual inhibitor against E. coli DNA gyrase and
topoisomerase IV, with ADMET analysis indicating promising pharmacokinetic profiles for antibacterial drug development.