da Rochaa David R, de Souza Alessandra M T, de Souza Ana Carolina G, Castro Helena C, Rodrigues Carlos R, Menna-Barreto Rubem F S, de Castro Solange L, Ferreira Vitor F
Departamento de Quimica Organica, Instituto de Quimica,UFF, 24020-150, Niteroi, RJ, Brazil.
Med Chem. 2014;10(6):564-70. doi: 10.2174/1573406410666131229151303.
The available treatment for the prevention and cure of Chagas disease, caused by the protozoan Trypanosoma cruzi, is still unsatisfactory. Thus, there is an urgent need to develop new drugs. In the last few years, our research group has focused on finding a new chemical entity able to target the infectious bloodstream trypomastigotes. In this study, we assayed 16 β-lapachone analogous with modifications in the pyran and aromatic ring to find a new prototype with high trypanocidal activity. Interestingly, two ortho-naphthoquinones presented the best trypanocidal profile (8c and 8d with an IC50/24 h of 26.9 ± 1.3 and 23.5 ± 2.5 μM, respectively), which were 4 to 17 times more effective than β-lapachone (391.5 ± 16.5 μM) and the standard drug benznidazole (103.6 ± 0.6 μM). The introduction of a hydroxyl group on the compounds' aromatic ring modulated their biological profile by increasing their activity not only for cancer cells (MDAMB435), as previously described in literature, but also against T. cruzi. The Structure-Activity Relationship (SAR) study indicated that this introduction modulated HOMO and MEP parameters, improving the trypanocidal activity.
由原生动物克氏锥虫引起的恰加斯病，目前可用的预防和治疗方法仍不尽人意。因此，迫切需要开发新药。在过去几年中，我们的研究小组致力于寻找一种能够靶向感染性血流锥鞭毛体的新化学实体。在本研究中，我们对16种在吡喃环和芳香环上有修饰的β-拉帕醌类似物进行了测定，以寻找具有高杀锥虫活性的新原型。有趣的是，两种邻萘醌表现出最佳的杀锥虫特性（8c和8d的24小时半数抑制浓度分别为26.9±1.3和23.5±2.5μM），其效力比β-拉帕醌（391.5±16.5μM）和标准药物苯硝唑（103.6±0.6μM）高4至17倍。在化合物的芳香环上引入羟基不仅如文献中先前所述增加了它们对癌细胞（MDAMB435）的活性，还调节了它们的生物学特性，使其对克氏锥虫也有活性。构效关系（SAR）研究表明，这种引入调节了最高占据分子轨道（HOMO）和分子静电势（MEP）参数，提高了杀锥虫活性。
