dc.contributor.author |
Sundriyal, Sandeep |
|
dc.date.accessioned |
2024-01-17T04:36:50Z |
|
dc.date.available |
2024-01-17T04:36:50Z |
|
dc.date.issued |
2015-01 |
|
dc.identifier.uri |
https://journals.asm.org/doi/full/10.1128/aac.04419-14 |
|
dc.identifier.uri |
http://dspace.bits-pilani.ac.in:8080/jspui/xmlui/handle/123456789/13850 |
|
dc.description.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. |
en_US |
dc.language.iso |
en |
en_US |
dc.publisher |
ASM Journals |
en_US |
dc.subject |
Pharmacy |
en_US |
dc.subject |
Histone |
en_US |
dc.subject |
Methyltransferase Inhibitors |
en_US |
dc.subject |
Malaria parasite |
en_US |
dc.title |
Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans |
en_US |
dc.type |
Article |
en_US |