Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Parasitology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India.
Bioorg Med Chem. 2014 Jul 15;22(14):3573-86. doi: 10.1016/j.bmc.2014.05.024. Epub 2014 May 20.
Emergence and spread of multidrug resistant strains of Plasmodium falciparum has severely limited the antimalarial chemotherapeutic options. In order to overcome the obstacle, a set of new side-chain modified 4-aminoquinolines were synthesized and screened against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of P. falciparum. The key feature of the designed molecules is the use of methylpiperazine linked α, β(3)- and γ-amino acids to generate novel side chain modified 4-aminoquinoline analogues. Among the evaluated compounds, 20c and 30 were found more potent than CQ against K1 and displayed a four-fold and a three-fold higher activity respectively, with a good selectivity index (SI=5846 and 11,350). All synthesized compounds had resistance index between 1.06 and >14.13 as against 47.2 for chloroquine. Biophysical studies suggested that this series of compounds act on heme polymerization target.
疟原虫多药耐药株的出现和传播严重限制了抗疟化学疗法的选择。为了克服这一障碍，我们合成了一组新的侧链修饰的 4-氨基喹啉，并对氯喹敏感（3D7）和氯喹耐药（K1）株疟原虫进行了筛选。设计分子的关键特征是使用甲基哌嗪连接α，β（3）-和γ-氨基酸，以生成新型侧链修饰的 4-氨基喹啉类似物。在所评估的化合物中，化合物 20c 和 30 对 K1 的活性均强于 CQ，其活性分别提高了四倍和三倍，具有良好的选择性指数（SI=5846 和 11350）。所有合成的化合物的耐药指数在 1.06 到>14.13 之间，而氯喹的耐药指数为 47.2。生物物理研究表明，该系列化合物作用于血红素聚合靶标。
