Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents

Malaria remains one of the major health problems worldwide. The lack of an effective vaccine and the increasing resistance of Plasmodium to the approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmiquins represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e. , a chloroquine (CQ) scaffold, known to inhibit heme polymerization and a β-carboline ring capable of binding to P. falciparum heat shock protein 90 ( Pf Hsp90). Here we present their synthesis, evaluation of biological activity and potential mechanism of action. The synthesized hybrids differed in the type of linker employed (triazole ring or amide bond) and in the position of the substitution on the β-carboline core of harmine. The antiplasmodial activity of harmiquins was evaluated against the erythrocytic stage of the Plasmodium life cycle, and their cytotoxic effect was tested on HepG2 cells. The results showed that harmiquins exerted remarkable activity against both CQ-sensitive ( Pf 3D7) and CQ-resistant ( Pf Dd2, Pf K1, and Pf 7G8). P. falciparum strains. The most active compound, harmiquine 32 , displayed single-digit nanomolar IC 50 value against Pf 3D7 (IC 50 = 2.0 ± 0.3 nM). Importantly, it also showed significantly higher activity than CQ against the resistant Plasmodium strains and had a very high selectivity index (4450). Harmiquins may act through the inhibition of heme polymerization and binding to the ATP binding site of the Pf Hsp90, which would explain their increased activity against the CQ-resistant Plasmodium strains. These results establish harmiquins as valuable antiplasmodial hits for future optimization. • Harmiquins represent hybrids of harmine and chloroquine scaffolds. • High activity against erythrocytic stage of both sensitive and resistant P. falciparum strains. • Cytotoxicity study revealed remarkable selectivity of the most active harmiquine 32 . • Harmiquins may act through inhibition of heme polymerization and binding to Pf Hsp90.