Design, synthesis and evaluation of novel carboline-triazole hybrids as promising antimalarial agents

A series of twenty-four carboline-triazole derivatives were synthesized using a molecular hybridization approach and evaluated for their antimalarial activity against Plasmodium parasites. Ten compounds exhibited strong in vitro antimalarial activity against both chloroquine-sensitive Pf3D7 and chloroquine-resistant PfK1 strains, with IC₅₀ values ranging from 0.21 to 0.98 μM and 0.32-0.82 μM, respectively. Among them, compound 15k demonstrated significant in vivo antimalarial activity against P. yoelii N67 in Swiss mice. Notably, compounds 15e, 15f, and 15k also inhibited P. berghei liver stage development with IC₅₀ values ranging from 4.81 to 7.58 μM. Evaluation of in vitro pharmacokinetic parameters revealed that the synthesized carboline-triazole conjugate 15k fulfils the criteria for orally active drug development. These findings highlight the potential of this scaffold as a promising framework for the development of antimalarial agents.