Background: Novel drug development against malaria parasite over old conventional antimalarial
drugs is essential due to rapid and indiscriminate use of drugs, which led to the emergence of resistant
Methods: In this study, previously reported triazole-amino acid hybrids (13-18) are explored against
Plasmodium falciparum as antimalarial agents. Among six compounds, 15 and 18 exhibited antimalarial
activity against P. falciparum with insignificant hemolytic activity and cytotoxicity towards HepG2
mammalian cells. In molecular docking studies, both compounds bind into the active site of PfFP-2 and
block its accessibility to the substrate that leads to the inhibition of target protein further supported by
in vitro analysis.
Results: Antimalarial half-maximal inhibitory concentration (IC50) of 15 and 18 compounds were found
to be 9.26 μM and 20.62 μM, respectively. Blood stage specific studies showed that compounds, 15 and
18 are effective at late trophozoite stage and block egress pathway of parasites. Decreased level of free
monomeric heme was found in a dose dependent manner after the treatment with compounds 15 and 18,
which was further evidenced by the reduction in percent of hemoglobin hydrolysis. Compounds 15 and
18 hindered hemoglobin degradation via intra- and extracellular cysteine protease falcipain-2 (PfFP-2)
inhibitory activity both in in vitro and in vivo in P. falciparum.
Conclusion: We report antimalarial potential of triazole-amino acid hybrids and their role in the inhibition
of cysteine protease PfFP-2 as its mechanistic aspect.