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Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae.

Abstract：

:Sterol 14α-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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Friggeri L,Hargrove TY,Rachakonda G,Blobaum AL,Fisher P,de Oliveira GM,da Silva CF,Soeiro MNC,Nes WD,Lindsley CW,Villalta F,Guengerich FP,Lepesheva GI

doi

10.1021/acs.jmedchem.8b01671

subject

Has Abstract

pub_date

2018-12-13 00:00:00

pages

10910-10921

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

61

pub_type

杂志文章

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