Antimalarial activity of Malaria Box Compounds against Plasmodium falciparum clinical isolates

Jersley D Chirawurah,Felix Ansah,Prince B Nyarko,Samuel Duodu,Yaw Aniweh,Gordon A Awandare

doi:10.1016/j.ijpddr.2017.10.005

Jersley D Chirawurah, Felix Ansah + Show 4 more

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https://doi.org/10.1016/j.ijpddr.2017.10.005

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Abstract

Malaria remains a major cause of childhood deaths in resource-limited settings. In the absence of an effective vaccine, drugs and other interventions have played very significant roles in combating the scourge of malaria. The recent reports of resistance to artemisinin necessitate the need for new antimalarial drugs with novel mechanisms of action. Towards the development of new, affordable and easily accessible antimalarial drugs for endemic regions, the Medicines for Malaria Venture (MMV) assembled a total of 400 active antimalarial compounds called the Malaria Box. The potency and the efficacy of the Malaria Box Compounds have been determined mainly using laboratory strains of P. falciparum.This study investigated the potency of twenty compounds from the Malaria Box against four clinical isolates from Ghana, using optimized in vitro growth inhibitory assays. Seven out of the 20 compounds screened had 50% inhibitory concentration (IC50) below 500 nM. The most active among the selected compounds was MMV006087 (average IC50 of 30.79 nM). Variations in the potency of the Malaria Box Compounds were observed between P. falciparum clinical isolates and Dd2 strain. We also investigated the sensitivity of the clinical isolates to chloroquine and artesunate. The N093 clinical isolate was found to be resistant to chloroquine but showed high sensitivity to artesunate.The results underscore the importance of including clinical isolates with different drug-resistant backgrounds, in addition to laboratory strains, in validating potential compounds during antimalarial compound screening programs.

Highlights

Plasmodium falciparum related malaria is still a major threat to health systems in resource-limited settings
This study investigated the potency of twenty compounds from the Malaria Box against four clinical isolates from Ghana, using optimized in vitro growth inhibitory assays
A subset of 20 Malaria Box Compounds (Table 1) that have been found to be potent against laboratory strains of P. falciparum (Fong et al, 2015; Tiwari et al, 2016; Van Voorhis et al, 2016) were selected and evaluated against four clinical isolates of P. falciparum (N093, A160, A156 and K239)

Summary

Introduction

Plasmodium falciparum related malaria is still a major threat to health systems in resource-limited settings. The emergence of resistant parasites to antimalarial drugs such as chloroquine (Moore and Lanier, 1961; Payne, 1987), sulfadoxine and pyrimethamine (Hurwitz, 1981) over the years, led to the recommendation for the use of artemisinin and artemisinin-based combination therapies (ACT), as first-line drugs for the treatment of malaria in all endemic regions (Smithuis et al, 2004; Valecha et al, 2010; WHO, 2001). The recent emergence of ACT resistant Plasmodium falciparum strains in South-East Asia (Ashley et al, 2014; Dondorp et al, 2009; Noedl et al, 2008; Yeung et al, 2009), calls for new sets of antimalarial drugs with novel mechanisms of action

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