Laboratorio de Sintese de Farmacos, Instituto de Tecnologia em Farmacos, Farmanguinhos - FIOCRUZ, Fundacao Oswaldo Cruz. Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, 21041-250, Brazil; Programa de Pós-Graduação em Química, PGQu Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Instituto de Física de São Carlos, Universidade de São Paulo, Av. João Dagnone, 1.100, Jd. Santa Angelina, São Carlos, SP, Brazil.
Eur J Med Chem. 2021 Jan 1;209:112941. doi: 10.1016/j.ejmech.2020.112941. Epub 2020 Oct 21.
In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti-P. falciparum activity, with IC values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5-a]pyrimidine derivatives were more potent than the pyrazolo[1,5-a]pyrimidine and quinoline analogues. Compounds 20, 21, 23 and 24 were the most potent inhibitors, with IC values in the range of 0.030-0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5-a]pyrimidine derivatives inhibited PfDHODH activity in the low micromolar to low nanomolar range (IC values of 0.08-1.3 μM) and did not show significant inhibition against the HsDHODH homologue (0-30% at 50 μM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5-a]pyrimidine derivatives to PfDHODH, and the highest interaction affinities for the PfDHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF, R = F; IC = 0.086 μM), 21 (R = CF; R = CH; IC = 0.032 μM), 23, (R = CF, R = CF; IC = 0.030 μM) and 24 (R = CF, 2-naphthyl; IC = 0.050 μM) and the most active inhibitor against PfDHODH 19 (R = CF, R = Cl; IC = 0.08 μM - PfDHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the PfDHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5-a]pyrimidine derivatives.
在这项工作中，我们设计并合成了 35 种新的三唑并嘧啶、吡唑并嘧啶和喹啉衍生物，作为疟原虫抑制剂（3D7 株）。其中 30 种化合物具有抗疟原虫活性，IC 值范围为 0.030 至 9.1 μM。[1,2,4]三唑并[1,5-a]嘧啶衍生物比吡唑并[1,5-a]嘧啶和喹啉类似物更有效。化合物 20、21、23 和 24 是最有效的抑制剂，IC 值范围为 0.030-0.086 μM，与氯喹相当。此外，这些化合物具有选择性，对人肝癌细胞系 HepG2 没有细胞毒性。所有[1,2,4]三唑并[1,5-a]嘧啶衍生物均能在低微摩尔至低纳摩尔范围内抑制 PfDHODH 活性（IC 值为 0.08-1.3 μM），并且对 HsDHODH 同源物没有明显抑制作用（在 50 μM 时为 0-30%）。分子对接研究表明了[1,2,4]三唑并[1,5-a]嘧啶衍生物与 PfDHODH 的结合模式，与体外实验评价结果一致，这些化合物对 PfDHODH 酶的最高相互亲和力。因此，对疟原虫寄生虫最有效的化合物是 20（R = CF，R = F；IC = 0.086 μM）、21（R = CF；R = CH；IC = 0.032 μM）、23（R = CF，R = CF；IC = 0.030 μM）和 24（R = CF，2-萘基；IC = 0.050 μM），对 PfDHODH 最有效的抑制剂是 19（R = CF，R = Cl；IC = 0.08 μM-PfDHODH），它们作为抗疟药物发现的新先导化合物脱颖而出。这些化合物对疟原虫的体外活性强，对 PfDHODH 酶的选择性抑制强烈表明，这是一系列新型[1,2,4]三唑并[1,5-a]嘧啶衍生物的作用机制。
