Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
PLoS One. 2012;7(5):e37259. doi: 10.1371/journal.pone.0037259. Epub 2012 May 23.
Chloroquine (CQ) is a cost effective antimalarial drug with a relatively good safety profile (or therapeutic index). However, CQ is no longer used alone to treat patients with Plasmodium falciparum due to the emergence and spread of CQ-resistant strains, also reported for P. vivax. Despite CQ resistance, novel drug candidates based on the structure of CQ continue to be considered, as in the present work. One CQ analog was synthesized as monoquinoline (MAQ) and compared with a previously synthesized bisquinoline (BAQ), both tested against P. falciparum in vitro and against P. berghei in mice, then evaluated in vitro for their cytotoxicity and ability to inhibit hemozoin formation. Their interactions with residues present in the NADH binding site of P falciparum lactate dehydrogenase were evaluated using docking analysis software. Both compounds were active in the nanomolar range evaluated through the HRPII and hypoxanthine tests. MAQ and BAQ derivatives were not toxic, and both compounds significantly inhibited hemozoin formation, in a dose-dependent manner. MAQ had a higher selectivity index than BAQ and both compounds were weak PfLDH inhibitors, a result previously reported also for CQ. Taken together, the two CQ analogues represent promising molecules which seem to act in a crucial point for the parasite, inhibiting hemozoin formation.
氯喹（CQ）是一种具有相对良好安全性（或治疗指数）的廉价抗疟药物。然而，由于疟原虫对 CQ 耐药株的出现和传播，CQ 已不再单独用于治疗恶性疟原虫感染的患者，间日疟原虫也有报道。尽管存在 CQ 耐药性，但仍在继续考虑基于 CQ 结构的新型候选药物，如本工作所述。我们合成了一种单喹啉（MAQ）作为 CQ 的类似物，并与之前合成的双喹啉（BAQ）进行了比较，两者均在体外针对恶性疟原虫进行了测试，并在小鼠体内针对疟原虫进行了测试，然后在体外评估了它们的细胞毒性和抑制血红素形成的能力。使用对接分析软件评估了它们与恶性疟原虫乳酸脱氢酶 NADH 结合位点中存在的残基的相互作用。通过 HRPII 和次黄嘌呤试验评估，这两种化合物在纳米摩尔范围内均具有活性。MAQ 和 BAQ 衍生物均无毒性，且均能以剂量依赖的方式显著抑制血红素形成。MAQ 的选择性指数高于 BAQ，且这两种化合物均为弱 PfLDH 抑制剂，这一结果之前也有报道。综上所述，这两种 CQ 类似物代表了有前途的分子，它们似乎在寄生虫的一个关键部位发挥作用，抑制血红素形成。
