Abd El-Mawgoud Heba K, AboulMagd Asmaa M, Shaker Ahmed M M, Hemdan Magdy M, Hassaballah Aya I, Farag Paula S
Chemistry Department, Faculty of Women for Arts, Science and Education, Ain Shams University, Heliopolis, 11767 Cairo, Egypt.
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University (NUB), Beni-Suef, Egypt.
Bioorg Chem. 2025 Feb;155:108101. doi: 10.1016/j.bioorg.2024.108101. Epub 2025 Jan 8.
The escalating prevalence of antibiotic-resistant bacteria has led to a serious global public health problem; therefore, there is an urgent need for the development of structurally innovative antibacterial agents. In our study, different series of tetra-substituted thiophene derivatives were designed and synthesized by multi-component reactions (MCRs) in moderate to excellent yields. Some of the designed final compounds were synthesized by both microwave assisted method and traditional synthesis. Thirteen compounds were evaluated against antibiotic resistance bacteria ESKAPE, among which compounds 11, 13 and 17 showed the most potent inhibitory activities against multidrug-resistant Enterococcus faecalis with MIC (minimum inhibitory concentration) values as low as 15.62, 7.61 and 15.62 µg/mL, respectively. Two potent candidates 11 and 13 not only showed rapid bactericidal properties and impeded E. faecalis biofilm formation to effectually relieve the development of drug resistance, but also performed low toxicity toward human normal cells. Moreover, time dependent killing assay was performed that showed the reduction of the concentration of bacteria by 5.0 Log (CFU/mL) within 6 h, stronger than reference drug, ampicillin at the same concentration. Additionally, mechanistic investigation demonstrated that both compounds 11 and 13 could exert inhibitory activity against DHPS with IC value of 1.73 and 4.67 µM, respectively and against DNA gyrase enzyme with IC value of 0.07 and 0.04 µM, respectively. Moreover, the cytotoxic activity of the most active compound was crucial to be determined that showed IC value of 75.42 µM. Molecular docking indicated that the binding of both compounds 11 and 13 to DHPS and DNA gyrase enzymes could hinder their function. These results can provide novel structures of antibacterial drugs chemically different from currently known antibiotics and broaden prospects for the development of effective antibiotics against antibiotic-resistant bacteria.
抗生素耐药菌的日益流行已导致严重的全球公共卫生问题；因此，迫切需要开发结构创新的抗菌剂。在我们的研究中，通过多组分反应（MCRs）设计并合成了不同系列的四取代噻吩衍生物，产率适中至优异。一些设计的最终化合物通过微波辅助方法和传统合成方法合成。对13种化合物针对抗生素耐药菌ESKAPE进行了评估，其中化合物11、13和17对多重耐药粪肠球菌表现出最强的抑制活性，最低抑菌浓度（MIC）值分别低至15.62、7.61和15.62μg/mL。两种强效候选物11和13不仅表现出快速杀菌特性并阻碍粪肠球菌生物膜形成，从而有效缓解耐药性的发展，而且对人类正常细胞的毒性较低。此外，进行了时间依赖性杀菌试验，结果表明在6小时内细菌浓度降低了5.0 Log（CFU/mL），比相同浓度的参考药物氨苄西林更强。此外，机理研究表明，化合物11和13均可对二氢蝶酸合酶（DHPS）发挥抑制活性，IC值分别为1.73和4.67μM，对DNA促旋酶的IC值分别为0.07和0.04μM。此外，确定了最具活性化合物的细胞毒性活性，IC值为75.42μM。分子对接表明，化合物11和13与DHPS和DNA促旋酶的结合均可阻碍其功能。这些结果可以提供与目前已知抗生素化学结构不同的新型抗菌药物结构，并拓宽开发抗抗生素耐药菌有效抗生素的前景。
