Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes

Okombo, J., Kiara, S. M., Abdirahman, A., Mwai, L., Ohuma, E., Borrmann, S., Nzila, A. and Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 (2013) 'Antimalarial activity of isoquine against Kenyan Plasmodium falciparum clinical isolates and association with polymorphisms in pfcrt and pfmdr1 genes'. Journal of Antimicrobial Chemotherapy, Vol 68, Issue 4, pp. 786-788.

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Abstract

Background

The use of amodiaquine in prophylaxis is associated with serious toxicity, resulting from its metabolic conversion into a reactive quinone-imine metabolite by the hepatic cytochrome P450. To circumvent this toxicity, several amodiaquine analogues that lack the potential to form a quinone-imine derivative, while retaining antimalarial activity, have been designed. Isoquine is one of these promising molecules that has already reached Phase I clinical trials in humans.

Methods

We analysed the in vitro activity of isoquine against 62 Plasmodium falciparum isolates collected in Kenya and the association of this activity with polymorphisms in pfcrt and pfmdr1 genes.

Results

The median concentration of isoquine that inhibited 50% of parasite growth (IC50) was 9 nM, compared with 56 nM chloroquine, 8 nM amodiaquine, 10 nM desethylamodiaquine, 69 nM lumefantrine and 1 nM dihydroartemisinin. Isoquine activity was correlated with polymorphisms in pfcrt at codon 76, but not in pfmdr1 at codon 86.

Conclusions

The high activity of isoquine against field isolates, including chloroquine-resistant isolates, with IC50 <10 nM, warrants its further development as an antimalarial.

Item Type:	Article
Subjects:	QU Biochemistry > Genetics > QU 470 Genetic structures QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QW Microbiology and Immunology > QW 45 Microbial drug resistance. General or not elsewhere classified. QX Parasitology > Protozoa > QX 135 Plasmodia
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI):	https://doi.org/10.1093/jac/dks471
Depositing User:	Lynn Roberts-Maloney
Date Deposited:	05 Mar 2015 13:00
Last Modified:	06 Feb 2018 13:09
URI:	https://archive.lstmed.ac.uk/id/eprint/4984

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