Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India.
Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Dibrugarh, Assam, India.
J Biochem Mol Toxicol. 2021 Sep;35(9):e22860. doi: 10.1002/jbt.22860. Epub 2021 Jul 27.
The present manuscript deals with the development of novel p-aminobenzoic acid (PABA) associated 1,3,5-triazine derivatives as antimalarial agents. The molecules were developed via microwave-assisted synthesis and structures of compounds were ascertained via numerous analytical and spectroscopic techniques. The synthesized compounds were also subjected to ADMET analysis. In a docking analysis, the title compounds showed high and diverse binding affinities towards wild (-162.45 to -369.38 kcal/mol) and quadruple mutant (-165.36 to -209.47 kcal/mol) Pf-DHFR-TS via interacting with Phe58, Arg59, Ser111, Ile112, Phe116. The in vitro antimalarial activity suggested that compounds 4e, 4b, and 4h showed IC ranging from 4.18 to 8.66 μg/ml against the chloroquine-sensitive (3D7) strain of Plasmodium falciparum. Moreover, compounds 4g, 4b, 4e, and 4c showed IC ranging from 8.12 to 12.09 μg/ml against chloroquine-resistant (Dd2) strain. In conclusion, our study demonstrated the development of hybrid PABA substituted 1,3,5-triazines as a novel class of Pf-DHFR inhibitor for antimalarial drug discovery.
本手稿涉及新型对氨基苯甲酸（PABA）相关 1,3,5-三嗪衍生物作为抗疟药物的开发。这些分子是通过微波辅助合成得到的，通过多种分析和光谱技术确定了化合物的结构。合成的化合物还进行了 ADMET 分析。在对接分析中，标题化合物对野生型（-162.45 至-369.38 kcal/mol）和四重突变型（-165.36 至-209.47 kcal/mol）Pf-DHFR-TS 表现出高且多样化的结合亲和力，通过与 Phe58、Arg59、Ser111、Ile112 和 Phe116 相互作用。体外抗疟活性表明，化合物 4e、4b 和 4h 对氯喹敏感（3D7）株疟原虫的 IC 范围为 4.18 至 8.66 μg/ml。此外，化合物 4g、4b、4e 和 4c 对氯喹耐药（Dd2）株的 IC 范围为 8.12 至 12.09 μg/ml。总之，我们的研究表明，杂合 PABA 取代的 1,3,5-三嗪作为一种新型 Pf-DHFR 抑制剂可用于抗疟药物发现。
