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Design, synthesis, and evaluation of new 2-(quinoline-4-yloxy)acetamide-based antituberculosis agents.
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.ejmech.2020.112179 Ana Flávia Borsoi 1 , Josiane Delgado Paz 2 , Bruno Lopes Abbadi 3 , Fernanda Souza Macchi 2 , Nathalia Sperotto 1 , Kenia Pissinate 3 , Raoní S Rambo 3 , Alessandro Silva Ramos 3 , Diana Machado 4 , Miguel Viveiros 4 , Cristiano Valim Bizarro 2 , Luiz Augusto Basso 5 , Pablo Machado 2
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-02-21 , DOI: 10.1016/j.ejmech.2020.112179 Ana Flávia Borsoi 1 , Josiane Delgado Paz 2 , Bruno Lopes Abbadi 3 , Fernanda Souza Macchi 2 , Nathalia Sperotto 1 , Kenia Pissinate 3 , Raoní S Rambo 3 , Alessandro Silva Ramos 3 , Diana Machado 4 , Miguel Viveiros 4 , Cristiano Valim Bizarro 2 , Luiz Augusto Basso 5 , Pablo Machado 2
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Using a classical molecular simplification approach, a series of 36 quinolines were synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (M. tuberculosis) growth. Structure-activity relationship (SAR) studies leaded to potent antitubercular agents, with minimum inhibitory concentration (MIC) values as low as 0.3 μM against M. tuberculosis H37Rv reference strain. Furthermore, the lead compounds were active against multidrug-resistant strains, without cross-resistance with some first- and second-line drugs. Testing the molecules against a spontaneous mutant strain containing a single mutation in the qcrB gene (T313A) indicated that the synthesized quinolines targeted the cytochrome bc1 complex. In addition, leading compounds were devoid of apparent toxicity to HepG2 and Vero cells and showed moderate elimination rates in human liver S9 fractions. Finally, the selected structures inhibited M. tuberculosis growth in a macrophage model of tuberculosis infection. Taken together, these data indicate that this class of compounds may furnish candidates for the future development of antituberculosis drugs.
中文翻译：
设计，合成和评估新型的基于2-（喹啉-4-基氧基）乙酰胺的抗结核药。
使用经典的分子简化方法，合成了36种喹啉系列，并作为结核分枝杆菌（M. tuberculosis）生长的体外抑制剂进行了评估。结构-活性关系（SAR）研究导致了有效的抗结核药，针对结核分枝杆菌H37Rv参考菌株的最低抑菌浓度（MIC）值低至0.3μM。此外，先导化合物对多药耐药菌株具有活性，而与某些一线和二线药物没有交叉耐药性。对分子进行抗qcrB基因中单个突变的自发突变菌株的测试（T313A），表明合成的喹啉靶向细胞色素bc1复合物。此外，前体化合物对HepG2和Vero细胞没有明显的毒性，并且在人肝S9组分中显示出中等的消除率。最后，在结核感染的巨噬细胞模型中，选定的结构抑制了结核分枝杆菌的生长。综合来看，这些数据表明这类化合物可能为抗结核药物的未来发展提供候选。
更新日期：2020-02-21
中文翻译：
设计，合成和评估新型的基于2-（喹啉-4-基氧基）乙酰胺的抗结核药。
使用经典的分子简化方法，合成了36种喹啉系列，并作为结核分枝杆菌（M. tuberculosis）生长的体外抑制剂进行了评估。结构-活性关系（SAR）研究导致了有效的抗结核药，针对结核分枝杆菌H37Rv参考菌株的最低抑菌浓度（MIC）值低至0.3μM。此外，先导化合物对多药耐药菌株具有活性，而与某些一线和二线药物没有交叉耐药性。对分子进行抗qcrB基因中单个突变的自发突变菌株的测试（T313A），表明合成的喹啉靶向细胞色素bc1复合物。此外，前体化合物对HepG2和Vero细胞没有明显的毒性，并且在人肝S9组分中显示出中等的消除率。最后，在结核感染的巨噬细胞模型中，选定的结构抑制了结核分枝杆菌的生长。综合来看，这些数据表明这类化合物可能为抗结核药物的未来发展提供候选。
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