TY - JOUR
T1 - Sterol 14α-Demethylase Structure-Based Optimization of Drug Candidates for Human Infections with the Protozoan Trypanosomatidae
AU - Friggeri, Laura
AU - Hargrove, Tatiana Y.
AU - Rachakonda, Girish
AU - Blobaum, Anna L.
AU - Fisher, Paxtyn
AU - De Oliveira, Gabriel Melo
AU - Da Silva, Cristiane França
AU - Soeiro, Maria De Nazaré C.
AU - Nes, W. David
AU - Lindsley, Craig W.
AU - Villalta, Fernando
AU - Guengerich, F. Peter
AU - Lepesheva, Galina I.
N1 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/12/13
Y1 - 2018/12/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85058147150&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.8b01671
DO - 10.1021/acs.jmedchem.8b01671
M3 - Article
C2 - 30451500
AN - SCOPUS:85058147150
VL - 61
SP - 10910
EP - 10921
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 23
ER -