A multicomponent reaction to design antimalarial pyridyl-indole derivatives: Synthesis, biological activities and...

Using fragment-based design strategy, new pyridyl-indole hybrids 4a-y and indole intermediates 3a-e were synthesized using multicomponent one pot reaction. The synthesized compounds were subjected to screening for antimalarial activity against chloroquine sensitive (D6) and chloroquine resistant (W2) strains of Plasmodium falciparum. Several compounds exhibited antimalarial activity with IC₅₀ values in the range of 1.47-9.23 μM, and 1.16-7.66 μM, for D6 and W2 strains, respectively. Compounds 4a, 4k and 4u showed the highest selectivity index among all the tested compounds (S.I. ranged 3.8-10). Binding interactions between the active antimalarial compounds and the active site of quadruple mutant Plasmodium falciparum dihydrofolate reductase enzyme have been investigated using molecular docking analysis.