Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 23, Pages 10910-10921Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b01671
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Funding
- National Institutes of Health [GM067871]
- Fundacao Carlos Chagas Filho de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologic (CNPq)
- Fundacao Oswaldo Cruz, Instituto Oswaldo Cruz
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Sterol 14 alpha-demethylases (CYP51) are cytochrome P450 enzymes essential for sterol biosynthesis in eukaryotes and therapeutic targets for antifungal azoles. Multiple attempts to repurpose antifungals for treatment of human infections with protozoa (Trypanosomatidae) have been undertaken, yet so far none of them have revealed sufficient efficacy. VNI and its derivative VFV are two potent experimental inhibitors of Trypanosomatidae CYP51, effective in vivo against Chagas disease, visceral leishmaniasis, and sleeping sickness and currently under consideration as antiprotozoal drug candidates. However, VNI is less potent against Leishmania and drug-resistant strains of Trypanosoma cruzi and VFV, while displaying a broader spectrum of antiprotozoal activity, and is metabolically less stable. In this work we have designed, synthesized, and characterized a set of close analogues and identified two new compounds (7 and 9) that exceed VNI/VFV in their spectra of antiprotozoal activity, microsomal stability, and pharmacokinetics (tissue distribution in particular) and, like VNI/VFV, reveal no acute toxicity.
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