In silico screening, synthesis, and antimalarial evaluation of PABA substituted 1,3,5-triazine derivatives as Pf-DHFR inhibitors.

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 These PABA-substituted 1,3,5-triazine compounds could be exploited to develop a new class of Pf-DHFR inhibitors as a lead candidate.

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