Instituto de Química, Universidade Federal do Rio Grande do Sul, Porto Alegre, CP 91501-970, RS, Brazil.
Instituto Gonçalo Moniz, FIOCRUZ, Salvador, CEP 40296-710, BA, Brazil.
Chemistry. 2023 Oct 2;29(55):e202301642. doi: 10.1002/chem.202301642. Epub 2023 Aug 18.
Malaria is the one of the deadliest infectious diseases worldwide. Chemically, quinolines are excellent ligands for metal coordination and are deployed as drugs for malaria treatment. There is a growing body of evidence indicating that metal complexes can be conjugated with antimalarial quinolines to be used as chemical tools to overcome the disadvantages of quinolines, improving their bioactive speciation, cellular distribution, and subsequently broadening the spectrum of activity to multiple stages of the complex Plasmodium life cycle. In this study, four novel complexes of ruthenium(II)- and gold(I)-containing amodiaquine (AQ) were synthesized, and a careful chemical characterization revealed the precise coordination site of AQ to the metals. Their speciation in solution was investigated, demonstrating the stability of the quinoline-metal bond. Ru - and Au -AQ complexes were demonstrated to be potent and efficacious in inhibiting parasite growth in multiple stages of the Plasmodium life cycle as assayed in vitro and in vivo. These properties could be attributed to the ability of the metal-AQ complexes to reproduce the suppression of heme detoxification induced by AQ, while also inhibiting other processes in the parasite life cycle; this can be attributed to the action of the metallic species. Altogether, these findings indicate that metal coordination with antimalarial quinolines is a potential chemical tool for drug design and discovery in malaria and other infectious diseases susceptible to quinoline treatment.
疟疾是全球最致命的传染病之一。从化学角度来看，喹啉类化合物是金属配位的优秀配体，并被用作治疗疟疾的药物。越来越多的证据表明，金属配合物可以与抗疟喹啉结合，用作克服喹啉缺点的化学工具，提高其生物活性形态、细胞分布，从而扩大活性谱，作用于疟原虫生命周期的多个阶段。在这项研究中，合成了四种新型的含钌(II)和金(I)的阿莫地喹（AQ）配合物，并通过仔细的化学表征揭示了 AQ 与金属的精确配位位置。研究了它们在溶液中的形态，证明了喹啉-金属键的稳定性。研究表明，Ru-AQ 和 Au-AQ 配合物在体外和体内都能有效地抑制疟原虫生命周期的多个阶段的寄生虫生长，具有强大的功效。这些特性可以归因于金属-AQ 配合物能够重现 AQ 诱导的血红素解毒抑制，同时抑制寄生虫生命周期中的其他过程；这可以归因于金属物种的作用。总的来说，这些发现表明，金属与抗疟喹啉的配位是设计和发现抗疟疾和其他易受喹啉治疗的传染病的潜在化学工具。
