Morigi Rita, Esposito Daniele, Calvaresi Matteo, Marforio Tainah Dorina, Gentilomi Giovanna Angela, Bonvicini Francesca, Locatelli Alessandra
Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
Department of Chemistry "Giacomo Ciamician", Alma Mater Studiorum-University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
Antibiotics (Basel). 2024 Oct 19;13(10):992. doi: 10.3390/antibiotics13100992.
In the present study, a series of isatin bis-imidathiazole hybrids was designed and synthesized to develop a new class of heterocyclic compounds with improved antimicrobial activity against pathogens responsible for hospital- and community-acquired infections. A remarkable inhibitory activity against was demonstrated for a subset of compounds (range: 13.8-90.1 µM) in the absence of toxicity towards epithelial cells and human red blood cells. The best performing derivative was further investigated to measure its anti-biofilm potential and its effectiveness against methicillin-resistant strains. A structure-activity relationship study of the synthesized molecules led to the recognition of some important structural requirements for the observed antibacterial activity. Molecular docking followed by molecular dynamics (MD) simulations identified the binding site of the active compound FtsZ, a key protein in bacterial cell division, and the mechanism of action, i.e., the inhibition of its polymerization. The overall results may pave the way for a further rational development of isatin hybrids as FtsZ inhibitors, with a broader spectrum of activity against human pathogens and higher potency.
在本研究中，设计并合成了一系列异吲哚酮双咪唑噻唑杂化物，以开发一类新型杂环化合物，其对引起医院获得性感染和社区获得性感染的病原体具有更强的抗菌活性。在对上皮细胞和人类红细胞无毒性的情况下，部分化合物（范围：13.8 - 90.1 μM）表现出显著的抑制活性。对性能最佳的衍生物进一步研究，以测定其抗生物膜潜力及其对耐甲氧西林菌株的有效性。对合成分子的构效关系研究揭示了观察到的抗菌活性的一些重要结构要求。分子对接随后进行分子动力学（MD）模拟，确定了活性化合物FtsZ（细菌细胞分裂中的关键蛋白）的结合位点以及作用机制，即抑制其聚合。总体结果可能为进一步合理开发作为FtsZ抑制剂的异吲哚酮杂化物铺平道路，使其对人类病原体具有更广泛的活性谱和更高的效力。
