Autor: Chasák, J.; Brulíková, L.*
Název práce v češtině: Squaramidy: Nové antituberkulotické přípravky účinné i proti BDQ-resistentním kmenům
Název práce v angličtině: Squaramides: New Antituberculosis Agents Effective Against BDQ-Resistant Strains
Klíčová slova v češtině: squaramidy, tuberkulóza, rezistence
Klíčová slova v angličtině:squaramides, tuberculosis, resistance
Abstrakt česky: Tuberkulóza je infekční onemocnění způsobované M. tuberculosis. I přes usilovnou prevenci je toto onemocnění stále problémem s globálním dopadem. Jsou proto potřeba nové látky s mimořádnou antimykobakteriální aktivitou a novými mechanismy účinku. V průběhu několika posledních let jsme připravili více než 60 cílových squaramidů, které působí jako inhibitory mykobakteriální ATP synthasy. Podařilo se nám identifikovat místo účinku těchto látek a pomocí molekulárního dokování racionaliovat jejich návrh. Pro jejich přípravu bylo také vyvinutou hned několik syntetických metodologií.
Abstrakt anglicky: Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, still remains a serious health issue with global impact. Despite significant efforts in prevention, TB continues to pose a serious threat. Therefore, there is a pressing need for novel chemical scaffolds displaying potent antimycobacterial properties and novel modes of action. In response to this challenge, we focused our attention on squaramides as potential inhibitors of mycobacterial ATP synthase.
Over the years, we synthesized more than 60 squaramide derivatives and evaluated their in vitro biological activity. This broad compound library enabled us to systematically analyse the structural features contributing to their efficacy. Additionally, in silico testing allowed us to rationalize these structural insights. Notably, we successfully identified the binding site of squaramides on the mycobacterial ATP synthase. They specifically bind to subunit a of the mycobacterial enzyme (Fig. 1). This key discovery facilitated the interpretation of our computational assays, streamlining the process of designing potentially active molecules. Also crucial in this context was the discovery that the binding site of squaramides on the target enzyme differs from that of bedaquiline (BDQ), the first approved inhibitor of mycobacterial ATP synthase. Consequently, squaramides exhibit activity even against BDQ-resistant strains of M. tuberculosis.
Armed with this structural understanding, we were able to rationally design new series of compounds. However, the synthesis of these derivatives presented challenges due to their structural complexity and the necessity of introducing aromatic substituents crucial for their biological activity. Consequently, we suggested multiple synthetic strategies over time to achieve successful compound synthesis. Specifically, we employed different approaches involving Friedel-Crafts-type reactions, reaction with organolithium salts, and ultimately, Liebeskind-Srogl cross-coupling reaction to effectively introduce the desired aromatic substituents onto the squaramide scaffold.
Jazyk v originále: angličtina
Publikace abstraktu: –
Forma prezentace: oral communication
Název konference: Blue Danube Ph.D. Symposium
Místo konání: virtual symposium
Datum konání: 5th June
Rok konání: 2024
Způsob financování: JG_2019_00; IGA_PrF_2022_022; IGA_PrF_2023_020; IGA_PrF_2024_028