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

AI Article Synopsis

  • Sterol 14α-demethylases (CYP51) are important cytochrome P450 enzymes targeted by antifungal azoles, crucial for sterol biosynthesis in eukaryotes.
  • Efforts to use existing antifungals for treating protozoan infections have been largely unsuccessful, with new experimental inhibitors VNI and VFV showing promise against diseases like Chagas and leishmaniasis but with limited effectiveness against certain strains.
  • Researchers have created and tested new analogues of these compounds, discovering two new ones that outperform VNI and VFV in terms of effectiveness, stability, and safety in tissue distribution.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467724PMC
http://dx.doi.org/10.1021/acs.jmedchem.8b01671DOI Listing

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