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Synthesis of new generation of harmiquins, harmine and chloroquine hybrids as potential antiplasmodial agents

Malaria is an infectious disease caused by Plasmodium parasites. In 2020 there was an estimate of 241 million malaria cases and 627 000 deaths. Linking two or more bioactive moieties into a single molecule represents molecular hybridisation, a strategy to combat emerging multidrug-resistant Plasmodium strains. Harmiquins represent hybrids of chloroquine, an inhibitor of heme polymerization, and harmine, capable of binding to P. falciparum heat shock protein 90. Here we present the synthesis of novel harmiquins as potential antiplasmodial agents. A series of amide/triazole linked compounds composed of harmine and chloroquine were synthesized together with their precursors. The compounds were prepared by using standard synthetic procedures. Synthesis of harmiquins required the synthesis of their bulding blocks which were all obtained in multiple reaction steps. Amide type harmiquins (1, 2a-c) were synthesised by coupling reaction of 7- chloroquinoline-based carboxylic acid and β- carboline-based amines using T3P as a coupling agent and TEA as a base. Triazole type harmiquins (3, 4a-c) were obtained by Cu(I)-catalysed cycloaddition from 7-chloroquinoline-based azides and β-carboline-based alkynes. We have successfully prepared a series of 8 novel amide/triazole harmiquins with various substituents at O-6 and O-7 position of the β- carboline ring in moderate to good yields. All of the synthesized compounds were characterized by the standard analytical and spectroscopic methods (IR, MS, 13C and 1H NMR), their melting points were determined and were uncorrected. The antiplasmodial activity of harmiquins will be evaluated against the erythrocytic and hepatic stage of the Plasmodium life cycle.

malaria, harmine, chloroquine, click chemistry, coupling reactions

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