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

© 2022 Elsevier Masson SAS. All rights reserved.
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 (PfHsp90). 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 (Pf3D7) and CQ-resistant (PfDd2, PfK1, and Pf7G8). P. falciparum strains. The most active compound, harmiquine 32, displayed single-digit nanomolar IC50 value against Pf3D7 (IC50 = 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 PfHsp90, which would explain their increased activity against the CQ-resistant Plasmodium strains. These results establish harmiquins as valuable antiplasmodial hits for future optimization.
The authors acknowledge the financial support by the Croatian Science Foundation (research project UIP-2017-05-5160), University of Zagreb (support for 2020), and Fundação para a Ciência e Tecnologia (grant 02/SAICT/2017/29550). This work has been supported in part by project Strengthening the scientific research and innovation capacities of the Faculty of Pharmacy and Biochemistry, University of Zagreb (FarmInova; project number KK.01.1.1.02.0021), financed from the European Regional Development Fund, Operational Program Competitiveness and Cohesion for the period 2014–2020. T.T. and R.V. would like to thank the Zagreb University Computing Centre (SRCE) for granting computational resources on the ISABELLA cluster. T.T. and R.V. would like to thank the Zagreb University Computing Centre (SRCE) for granting computational resources on the ISABELLA cluster.