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A Novel Hybrid of Chloroquine and Primaquine Linked by Gold(I): Multitarget and Multiphase Antiplasmodial Agent
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-24 , DOI: 10.1002/cmdc.202000653 Caroline de Souza Pereira 1 , Helenita Costa Quadros 2 , Diogo Rodrigo Magalhaes Moreira 2 , William Castro 3 , Romulo Ivisson Santos De Deus Da Silva 2 , Milena Botelho Pereira Soares 2 , Diana Fontinha 4 , Miguel Prudêncio 4 , Vinicius Schmitz 1 , Hélio F Dos Santos 1 , Mathieu Gendrot 5, 6, 7 , Isabelle Fonta 5, 6, 7, 8 , Joel Mosnier 5, 6, 7, 8 , Bruno Pradines 5, 6, 7, 8 , Maribel Navarro 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-11-24 , DOI: 10.1002/cmdc.202000653 Caroline de Souza Pereira 1 , Helenita Costa Quadros 2 , Diogo Rodrigo Magalhaes Moreira 2 , William Castro 3 , Romulo Ivisson Santos De Deus Da Silva 2 , Milena Botelho Pereira Soares 2 , Diana Fontinha 4 , Miguel Prudêncio 4 , Vinicius Schmitz 1 , Hélio F Dos Santos 1 , Mathieu Gendrot 5, 6, 7 , Isabelle Fonta 5, 6, 7, 8 , Joel Mosnier 5, 6, 7, 8 , Bruno Pradines 5, 6, 7, 8 , Maribel Navarro 1
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Plasmodium parasites kill 435 000 people around the world every year due to unavailable vaccines, a limited arsenal of antimalarial drugs, delayed treatment, and the reduced clinical effectiveness of current practices caused by drug resistance. Therefore, there is an urgent need to discover and develop new antiplasmodial candidates. In this work, we present a novel strategy to develop a multitarget metallic hybrid antimalarial agent with possible dual efficacy in both sexual and asexual erythrocytic stages. A hybrid of antimalarial drugs (chloroquine and primaquine) linked by gold(I) was synthesized and characterized by spectroscopic and analytical techniques. The CQPQ‐gold(I) hybrid molecule affects essential parasite targets, it inhibits β‐hematin formation and interacts moderately with the DNA minor groove. Its interaction with PfTrxR was also examined in computational modeling studies. The CQPQ‐gold(I) hybrid displayed an excellent in vitro antimalarial activity against the blood‐stage of Plasmodium falciparum and liver‐stage of Plasmodium berghei and efficacy in vivo against P. berghei, thereby demonstrating its multiple‐stage antiplasmodial activity. This metallic hybrid is a promising chemotherapeutic agent that could act in the treatment, prevention, and transmission of malaria.
中文翻译：
一种由金连接的氯喹和伯氨喹的新型杂交物（I）：多靶点和多相抗疟原虫剂
疟原虫由于无法获得疫苗、抗疟药物库有限、治疗延迟以及耐药性导致当前做法的临床有效性降低，寄生虫在全世界每年造成 435 000 人死亡。因此，迫切需要发现和开发新的抗疟原虫候选物。在这项工作中，我们提出了一种新策略来开发一种多靶点金属混合抗疟剂，在有性和无性红细胞阶段可能具有双重功效。合成了一种由金 (I) 连接的抗疟药物（氯喹和伯氨喹）的混合物，并通过光谱和分析技术进行了表征。CQPQ-gold(I) 杂合分子影响重要的寄生虫靶标，它抑制 β-血红素形成并与 DNA 小沟适度相互作用。在计算建模研究中也检查了它与 PfTrxR 的相互作用。CQPQ-gold(I) 混合体表现出优异的体外抗疟原虫血液阶段和伯氏疟原虫肝脏阶段的抗疟活性以及体内抗伯氏疟原虫的功效，从而证明其多阶段抗疟原虫活性。这种金属混合物是一种很有前途的化学治疗剂，可用于治疗、预防和传播疟疾。
更新日期：2020-11-24
中文翻译：
一种由金连接的氯喹和伯氨喹的新型杂交物（I）：多靶点和多相抗疟原虫剂
疟原虫由于无法获得疫苗、抗疟药物库有限、治疗延迟以及耐药性导致当前做法的临床有效性降低，寄生虫在全世界每年造成 435 000 人死亡。因此，迫切需要发现和开发新的抗疟原虫候选物。在这项工作中，我们提出了一种新策略来开发一种多靶点金属混合抗疟剂，在有性和无性红细胞阶段可能具有双重功效。合成了一种由金 (I) 连接的抗疟药物（氯喹和伯氨喹）的混合物，并通过光谱和分析技术进行了表征。CQPQ-gold(I) 杂合分子影响重要的寄生虫靶标，它抑制 β-血红素形成并与 DNA 小沟适度相互作用。在计算建模研究中也检查了它与 PfTrxR 的相互作用。CQPQ-gold(I) 混合体表现出优异的体外抗疟原虫血液阶段和伯氏疟原虫肝脏阶段的抗疟活性以及体内抗伯氏疟原虫的功效，从而证明其多阶段抗疟原虫活性。这种金属混合物是一种很有前途的化学治疗剂，可用于治疗、预防和传播疟疾。
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