Programa de Pós-Graduação Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, UFRJ, Av. Carlos Chagas, 373 - bl. K, 2° andar, sala 35 - Prédio do Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil.
Programa de Pós-Graduação Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, UFRJ, Av. Carlos Chagas, 373 - bl. K, 2° andar, sala 35 - Prédio do Centro de Ciências da Saúde, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-902, Brazil; Departamento de Síntese Orgânica, Instituto de Tecnologia em Fármacos - Farmanguinhos - Fiocruz, Rua Sizenando Nabuco, 100 Manguinhos, Rio de Janeiro, RJ 21041-250, Brazil; Faculdade de Farmácia Universidade Iguaçu-UNIG, Av. Abílio Augusto Távora, 2134, Nova Iguaçu, RJ 26275-580, Brazil.
Bioorg Med Chem. 2019 Mar 15;27(6):1002-1008. doi: 10.1016/j.bmc.2019.01.044. Epub 2019 Feb 2.
Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quinolines based on the structures of mefloquine ((2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol) and amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) using ring bioisosteric replacement and molecular hybridization of the functional groups. The compounds were evaluated in vitro against Plasmodium falciparum and in vivo in mice infected with P. berghei. All derivatives presented anti-P. falciparum activity with IC values ranging from 0.083 to 33.0 µM. The compound with the best anti-P. falciparum activity was N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (12) which showed an IC of 0.083 µM. The three most active compounds were selected for antimalarial activity tests against P. berghei-infected mice. Compound 12 was the most active on the 5th day after infection, reducing parasitemia by 66%, which is consistent with its in vitro activity. This is an important result as 12, a simpler molecule than mefloquine, does not contain the stereogenic center, and consequently, its synthesis in the laboratory is easier and less expensive. This system proved promising for the design of potential antimalarial compounds.
疟疾仍然是全球主要的公共卫生问题，它导致了高发病率和死亡率。目前已经发现对抗疟药物的耐药性，急需新的药物。在这项研究中，我们基于甲氟喹（（2,8-双（三氟甲基）喹啉-4-基）（哌啶-2-基）甲醇）和阿莫地喹（4-（（7-氯喹啉-4-基）氨基）-2-（（二乙氨基）甲基）苯酚）的结构，通过环生物等排替代和官能团的分子杂交设计并合成了十七种新型喹啉。这些化合物在体外对恶性疟原虫进行了评估，并在感染疟原虫的小鼠体内进行了评估。所有衍生物均具有抗疟原虫活性，IC值范围为 0.083 至 33.0µM。具有最佳抗疟原虫活性的化合物是 N-（5-甲基-4H-1,2,4-三唑-3-基）-2,8-双（三氟甲基）喹啉-4-胺（12），其 IC 值为 0.083µM。选择三种最有效的化合物进行抗疟原虫活性测试，测试针对感染疟原虫的小鼠。化合物 12 在感染后第 5 天最为活跃，将寄生虫血症减少了 66%，这与其体外活性一致。这是一个重要的结果，因为 12 比甲氟喹更简单，不包含手性中心，因此，其在实验室中的合成更容易且成本更低。该系统为设计潜在的抗疟化合物提供了有希望的结果。
