Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, Brazil.
Departamento de Química Orgânica, Instituto de Química, Universidade Federal Fluminense, Rua Outeiro São João Batista, Niterói 24020-141, Rio de Janeiro, Brazil.
Molecules. 2021 Jan 15;26(2):423. doi: 10.3390/molecules26020423.
Chagas disease (CD) still represents a serious public health problem in Latin America, even after more than 100 years of its discovery. Clinical treatments (nifurtimox and benznidazole) are considered inadequate, especially because of undesirable side effects and low efficacy in the chronic stages of the disease, highlighting the urgency for discovering new effective and safe drugs. A small library of compounds (- and -) was designed based on the structural optimization of a Hit compound derived from 1,4-naphthoquinones (C2) previously identified. The biological activity, structure-activity relationship (SAR), and the in silico physicochemical profiles of the naphthoquinone derivatives were analyzed. Most modifications resulted in increased trypanocidal activity but some substitutions also increased toxicity. The data reinforce the importance of the chlorine atom in the thiophenol benzene ring for trypanocidal activity, highlighting which exhibit a drug-likeness profile, as a promising compound against . SAR analysis also revealed as cliff generator in the structure-activity similarity map (SAS maps). However, compounds C2 and were unable to reduce parasite load, and did not prevent mouse mortality in acute infection. Phenotypic screening and computational analysis have provided relevant information to advance the optimization and design of new 1,4-naphthoquinone derivatives with a better pharmacological profile.
恰加斯病（CD）在发现一百多年后，仍然是拉丁美洲严重的公共卫生问题。临床治疗药物（硝呋替莫和苯硝唑）被认为效果不佳，尤其是因为在疾病的慢性阶段存在不良副作用和低疗效，这凸显了迫切需要发现新的有效和安全药物。在以前鉴定的来源于 1,4-萘醌的命中化合物（C2）的结构优化基础上，设计了一个化合物库（-和-）。分析了萘醌衍生物的生物活性、构效关系（SAR）和计算物理化学特征。大多数修饰导致杀锥虫活性增加，但有些取代也增加了毒性。这些数据强调了在噻吩苯环中氯原子对杀锥虫活性的重要性，突出了一些化合物表现出类药性特征，是一种有前途的针对的药物。SAR 分析还表明，化合物 C2 和 是结构活性相似性图（SAS 图）中的悬崖生成剂。然而，化合物 C2 和 无法降低寄生虫负荷，也无法预防急性感染时的小鼠死亡。表型筛选和计算分析为优化和设计具有更好药理特性的新型 1,4-萘醌衍生物提供了相关信息。
