3-Iodo-4-aminoquinoline derivative sensitises resistant strains of Plasmodium falciparum to chloroquine

• Synthesis and characterisation of novel chloroquine (CQ) derivative, i.e. 3-iodo-CQ, modified at the third position of 4-aminoquinoline moiety.
• 3-Iodo-CQ inhibits the proliferation of CQ-sensitive and -resistant Plasmodium falciparum, likely by reducing β-haematin formation.
• 3-Iodo-CQ synergises with CQ to inhibit the proliferation of CQ-resistant P. falciparum isolates.
• Modification of the third position of aminoquinoline unlocks huge potential to generate novel quinoline-based drugs.

Chloroquine (CQ), the first cost-effective synthetic antimalarial, is rendered ineffective in malaria-endemic regions owing to the rise and spread of CQ-resistant Plasmodium falciparum. In this report, we show that a halogen derivative of CQ, namely 3-iodo-CQ, inhibits the proliferation of CQ-sensitive and -resistant P. falciparum in a verapamil-insensitive manner. Similar to CQ, the antimalarial activity of 3-iodo-CQ is likely due to its inhibition of β-haematin formation. Interestingly, the presence of non-inhibitory concentrations of 3-iodo-CQ potentiated the antiproliferative activity of CQ against CQ-resistant strains or P. falciparum transfectants expressing wild-type or mutant P. falciparum CQ resistance transporter (PfCRT) (C2GC03 or C4Dd2, respectively). These findings demonstrate that halogenation of the third position of 4-aminoquinoline, with a simple one-step reaction from CQ, generates a novel derivative that is active against CQ-sensitive and -resistant P. falciparum, possibly by inhibiting the activity of mutant PfCRT.

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