Histone methyltransferase inhibitors are orally bioavailable, fast-acting molecules with activity against different species causing malaria in humans.

Abstract:

:Current antimalarials are under continuous threat due to the relentless development of drug resistance by malaria parasites. We previously reported promising in vitro parasite-killing activity with the histone methyltransferase inhibitor BIX-01294 and its analogue TM2-115. Here, we further characterize these diaminoquinazolines for in vitro and in vivo efficacy and pharmacokinetic properties to prioritize and direct compound development. BIX-01294 and TM2-115 displayed potent in vitro activity, with 50% inhibitory concentrations (IC50s) of <50 nM against drug-sensitive laboratory strains and multidrug-resistant field isolates, including artemisinin-refractory Plasmodium falciparum isolates. Activities against ex vivo clinical isolates of both P. falciparum and Plasmodium vivax were similar, with potencies of 300 to 400 nM. Sexual-stage gametocyte inhibition occurs at micromolar levels; however, mature gametocyte progression to gamete formation is inhibited at submicromolar concentrations. Parasite reduction ratio analysis confirms a high asexual-stage rate of killing. Both compounds examined displayed oral efficacy in in vivo mouse models of Plasmodium berghei and P. falciparum infection. The discovery of a rapid and broadly acting antimalarial compound class targeting blood stage infection, including transmission stage parasites, and effective against multiple malaria-causing species reveals the diaminoquinazoline scaffold to be a very promising lead for development into greatly needed novel therapies to control malaria.

authors

Malmquist NA,Sundriyal S,Caron J,Chen P,Witkowski B,Menard D,Suwanarusk R,Renia L,Nosten F,Jiménez-Díaz MB,Angulo-Barturen I,Santos Martínez M,Ferrer S,Sanz LM,Gamo FJ,Wittlin S,Duffy S,Avery VM,Ruecker A,Delves MJ

doi

10.1128/AAC.04419-14

subject

Has Abstract

pub_date

2015-02-01 00:00:00

pages

950-9

issue

2

eissn

0066-4804

issn

1098-6596

pii

AAC.04419-14

journal_volume

59

pub_type

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