作者
Boris Rodenko, Martin J Wanner, Abdulsalam AM Alkhaldi, Godwin U Ebiloma, Rebecca L Barnes, Marcel Kaiser, Reto Brun, Richard McCulloch, Gerrit-Jan Koomen, Harry P De Koning
发表日期
2015/11
期刊
Antimicrobial agents and chemotherapy
卷号
59
期号
11
页码范围
6708-6716
出版商
American Society for Microbiology
简介
The human and veterinary disease complex known as African trypanosomiasis continues to inflict significant global morbidity, mortality, and economic hardship. Drug resistance and toxic side effects of old drugs call for novel and unorthodox strategies for new and safe treatment options. We designed methyltriazenyl purine prodrugs to be rapidly and selectively internalized by the parasite, after which they disintegrate into a nontoxic and naturally occurring purine nucleobase, a simple triazene-stabilizing group, and the active toxin: a methyldiazonium cation capable of damaging DNA by alkylation. We identified 2-(3-acetyl-3-methyltriazen-1-yl)-6-hydroxypurine (compound 1) as a new lead compound, which showed submicromolar potency against Trypanosoma brucei, with a selectivity index of >500, and it demonstrated a curative effect in animal models of acute trypanosomiasis. We investigated the mechanism of …
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B Rodenko, MJ Wanner, AAM Alkhaldi, GU Ebiloma… - Antimicrobial agents and chemotherapy, 2015