Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites.
作者： Alexios N. Matralis , Adnan Malik , Maria Penzo , Inmaculada Moreno , Maria J. Almela
DOI: 10.1021/ACS.JMEDCHEM.9B01099
关键词:
摘要: One of the attractive properties artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, unique benefits these medicines are now compromised by prolonged parasite clearance times and increasing frequency treatment failures, attributed to increased tolerance Plasmodium falciparum artemisinin. This emerging artemisinin resistance threatens undermine effectiveness antimalarial combination therapies. Herein, we describe medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading identification novel chemical entities with very potent, similar artemisinins, potency against asexual blood stages that cause disease, activity gametocyte activation required for transmission. Furthermore, confirm selective PKG inhibitors have slow speed kill, while chemoproteomic analysis suggests first time serine/arginine 2 (SRPK2) targeting as strategy developing compounds properties.
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