De Souza Pereira Caroline, Quadros Helenita Costa, Aboagye Samuel Yaw, Fontinha Diana, D'Alessandro Sarah, Byrne Margaret Elizabeth, Gendrot Mathieu, Fonta Isabelle, Mosnier Joel, Moreira Diogo Rodrigo M, Basilico Nicoletta, Williams David L, Prudêncio Miguel, Pradines Bruno, Navarro Maribel
Laboratório de Química Bioinorgânica e Catálise, Departamento de Química, Universidade Federal de Juiz de Fora, Juiz de Fora 36036-900, Brazil.
Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador 40296-710, Brazil.
Pharmaceutics. 2022 Jun 12;14(6):1251. doi: 10.3390/pharmaceutics14061251.
Hybrid-based drugs linked through a transition metal constitute an emerging concept for intervention. To advance the drug design concept and enhance the therapeutic potential of this class of drugs, we developed a novel hybrid composed of quinolinic ligands amodiaquine (AQ) and primaquine (PQ) linked by gold(I), named [AuAQPQ]PF. This compound demonstrated potent and efficacious antiplasmodial activity against multiple stages of the life cycle. The source of this activity was thoroughly investigated by comparing parasite susceptibility to the hybrid's components, the annotation of structure-activity relationships and studies of the mechanism of action. The activity of [AuAQPQ]PF for the parasite's asexual blood stages was influenced by the presence of AQ, while its activity against gametocytes and pre-erythrocytic parasites was influenced by both quinolinic components. Moreover, the coordination of ligands to gold(I) was found to be essential for the enhancement of potency, as suggested by the observation that a combination of quinolinic ligands does not reproduce the antimalarial potency and efficacy as observed for the metallic hybrid. Our results indicate that this gold(I) hybrid compound presents a dual mechanism of action by inhibiting the beta-hematin formation and enzymatic activity of thioredoxin reductases. Overall, our findings support the potential of transition metals as a dual chemical linker and an antiplasmodial payload for the development of hybrid-based drugs.
通过过渡金属连接的基于杂化的药物构成了一种新兴的干预概念。为了推进药物设计理念并增强这类药物的治疗潜力，我们开发了一种新型杂化物，它由通过金（I）连接的喹啉配体氨酚喹（AQ）和伯氨喹（PQ）组成，名为[AuAQPQ]PF。该化合物对疟原虫生命周期的多个阶段都表现出强效且有效的抗疟活性。通过比较寄生虫对杂化物各成分的敏感性、结构 - 活性关系的注释以及作用机制的研究，对这种活性的来源进行了深入研究。[AuAQPQ]PF对寄生虫无性血液阶段的活性受AQ的存在影响，而其对配子体和前体红细胞期寄生虫的活性则受两种喹啉成分的影响。此外，正如观察到喹啉配体的组合不能重现金属杂化物所观察到的抗疟效力和功效所表明的那样，发现配体与金（I）的配位对于增强效力至关重要。我们的结果表明，这种金（I）杂化化合物通过抑制β-血红素的形成和硫氧还蛋白还原酶的酶活性呈现出双重作用机制。总体而言，我们的研究结果支持了过渡金属作为双重化学连接体和抗疟有效载荷在基于杂化的药物开发中的潜力。
