2-（喹啉-4-基氧基）乙酰胺对药物敏感和耐药结核分枝杆菌菌株均有活性。
2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains.
作者信息
Pissinate Kenia, Villela Anne Drumond, Rodrigues-Junior Valnês, Giacobbo Bruno Couto, Grams Estêvão Silveira, Abbadi Bruno Lopes, Trindade Rogério Valim, Roesler Nery Laura, Bonan Carla Denise, Back Davi Fernando, Campos Maria Martha, Basso Luiz Augusto, Santos Diógenes Santiago, Machado Pablo
机构信息
Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul , 90619-900 Porto Alegre, RS, Brazil.
Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil; Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, 90619-900 Porto Alegre, RS, Brazil.
出版信息
ACS Med Chem Lett. 2016 Jan 11;7(3):235-9. doi: 10.1021/acsmedchemlett.5b00324. eCollection 2016 Mar 10.
2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
2-（喹啉-4-基氧基）乙酰胺已被描述为结核分枝杆菌生长的强效体外抑制剂。在此，对先导化合物进行了进一步的化学修饰，得到了高效抗结核药物，其最低抑菌浓度（MIC）值低至0.05μM。此外，合成的化合物对耐药菌株具有活性，对Vero和HaCat细胞无明显毒性（IC50≥20μM）。此外，2-（喹啉-4-基氧基）乙酰胺在感染的巨噬细胞中对杆菌表现出细胞内活性，其作用类似于利福平，药物相互作用风险低，在1和5μM浓度下对斑马鱼（Danio rerio）无心脏毒性迹象。因此，这些数据表明这类化合物可能为未来的开发提供候选药物，有望为结核病治疗提供药物替代品。
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