Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, 786004, Assam, India.
Regional Medical Research Centre, Indian Council of Medical Research (ICMR), Dibrugarh, 786001, Assam, India.
Exp Parasitol. 2023 Jul;250:108546. doi: 10.1016/j.exppara.2023.108546. Epub 2023 May 19.
Drug resistance in malaria parasites necessitates the development of new antimalarial drugs with unique mechanisms of action. In the present research work, the PABA conjugated 1,3,5-triazine derivatives were designed as an antimalarial agent.
In this present work, a library of two hundred-seven compounds was prepared in twelve different series such as [4A (1-23), 4B(1-22), 4C(1-21), 4D(1-20), 4E(1-19), 4F(1-18), 4G(1-17), 4H(1-16), 4I(1-15), 4J(1-13), 4K(1-12) and 4L(1-11) ] respectively using different primary and secondary aliphatic and aromatic amines. Ten compounds were ultimately selected through in silico screening. They were synthesized by conventional and microwave-assisted methods followed by in vitro antimalarial evaluations performed in chloroquine-sensitive (3D7) and resistant (DD2) strains of P. falciparum.
The docking results showed that compound 4C(11) had good binding interaction with Phe116, Met55 (-464.70 kcal/mol) and Phe116, Ser111 (-432.60 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf-DHFR. Furthermore, in vitro, antimalarial activity results indicated that compound 4C(11) showed potent antimalarial activity against chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2) strain of P. falciparum along with IC (14.90 μg mL) and (8.30 μg mL).
These PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.
疟原虫的耐药性要求开发具有独特作用机制的新抗疟药物。在本研究工作中，设计了 PABA 共轭 1,3,5-三嗪衍生物作为抗疟药物。
在本工作中，使用不同的伯胺和仲胺，分别在十二种不同的系列中制备了 207 种化合物的库，如[4A(1-23)、4B(1-22)、4C(1-21)、4D(1-20)、4E(1-19)、4F(1-18)、4G(1-17)、4H(1-16)、4I(1-15)、4J(1-13)、4K(1-12)和 4L(1-11)]。通过计算机筛选，最终选择了十种化合物。它们通过常规和微波辅助方法合成，并在氯喹敏感(3D7)和氯喹耐药(DD2)株的体外抗疟活性评估中进行了评估。
对接结果表明，化合物 4C(11)与 Pf-DHFR 的野生型(1J3I)和四突变型(1J3K)具有良好的结合相互作用，与 Phe116、Met55(-464.70kcal/mol)和 Phe116、Ser111(-432.60kcal/mol)结合。此外，在体外，抗疟活性结果表明，化合物 4C(11)对氯喹敏感(3D7)和氯喹耐药(Dd2)株的疟原虫具有很强的抗疟活性，IC(14.90μg mL)和(8.30μg mL)。
这些 PABA 取代的 1,3,5-三嗪化合物可用于开发一类新的 Pf-DHFR 抑制剂作为候选药物。
