School of Pharmaceutical Sciences , Nanjing Tech University , No. 30 South Puzhu Road , Nanjing 211816 , People's Republic of China.
Medicinal Chemistry , Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus) , 381 Royal Parade , Parkville , Victoria 3052 , Australia.
J Med Chem. 2019 Mar 14;62(5):2485-2498. doi: 10.1021/acs.jmedchem.8b01799. Epub 2019 Mar 5.
A series of 3,3'-disubstituted 5,5'-bi(1,2,4-triazine) derivatives was synthesized and screened against the erythrocytic stage of Plasmodium falciparum 3D7 line. The most potent dimer, 6k, with an IC (50% inhibitory concentration) of 0.008 μM, had high in vitro potency against P. falciparum lines resistant to chloroquine (W2, IC = 0.0047 ± 0.0011 μM) and artemisinin (MRA1240, IC = 0.0086 ± 0.0010 μM). Excellent ex vivo potency of 6k was shown against clinical field isolates of both P. falciparum (IC = 0.022-0.034 μM) and Plasmodium vivax (IC = 0.0093-0.031 μM) from the blood of outpatients with uncomplicated malaria. Despite 6k being cleared relatively rapidly in mice, it suppressed parasitemia in the Peters 4-day test, with a mean ED value (50% effective dose) of 1.47 mg kg day following oral administration. The disubstituted triazine dimer 6k represents a new class of orally available antimalarial compounds of considerable interest for further development.
一系列 3,3'-二取代的 5,5'-双(1,2,4-三嗪)衍生物被合成并针对恶性疟原虫 3D7 系的红细胞阶段进行了筛选。最有效的二聚体 6k，IC （半抑制浓度）为 0.008 μM，对氯喹（W2，IC = 0.0047 ± 0.0011 μM）和青蒿素（MRA1240，IC = 0.0086 ± 0.0010 μM）耐药的恶性疟原虫系具有高体外活性。6k 对来自无并发症疟疾门诊患者血液中的恶性疟原虫（IC = 0.022-0.034 μM）和间日疟原虫（IC = 0.0093-0.031 μM）的临床分离株也表现出极好的体外活性。尽管 6k 在小鼠体内清除速度相对较快，但它在 Peters 4 天试验中抑制了寄生虫血症，口服给药后，平均 ED 值（50%有效剂量）为 1.47 mg kg day。二取代三嗪二聚体 6k 代表了一类新的具有口服活性的抗疟化合物，具有很大的开发潜力。
