Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents

Title:Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents

Volume: 21 Issue: 21

Author(s): Paulo Fernando da Silva Santos-Júnior, Martine Schmitt, João Xavier de Araújo-Júnior and Edeildo Ferreira da Silva-Júnior*

Affiliation:

• Chemistry and Biotechnology Institute, Federal University of Alagoas, Campus A.C. Simões, Lourival Melo Mota Avenue, Maceió57072-970,Brazil

Keywords: Drug discovery, Sterol 14α-demethylase, Trypanosomatidae, Leishmaniasis, HAT, Trypanosomiasis.

Abstract: Trypanosomatidae family belongs to the Kinetoplastida order, which consists of obligatory parasites that affect plants and all classes of vertebrates, especially humans and insects. Among the heteroxenic parasites, Leishmania spp., Trypanosoma cruzi, and T. brucei are protozoa of most significant interest for medicinal chemistry, being etiological agents of Leishmaniasis, Chagas, and Sleep Sickness diseases, respectively. Currently, inefficient pharmacotherapy, especially in chronic phases and low selectivity towards parasite/host cells, justifies the need to discover new drugs to treat them effectively. Among other targets, the sterol 14α-demethylase (CYP51), an enzyme responsible for ergosterol's biosynthesis in Trypanosomatidae parasites, has received more attention in the development of new bioactive compounds. In this context, antifungal ravuconazole proved to be the most promising drug among this class against T. cruzi, being used in combined therapy with Bnz in clinic trials. Non-antifungal inhibitors, such as VFV and VNF, have shown promising results against T. cruzi and T.brucei, respectively, being tested in Bnz-combined therapies. Among the experimental studies involving azoles, compound (15) was found to be the most promising derivative, displaying an IC50 value of 0.002 μM against amastigotes from T. cruzi, in addition to being non-toxic and highly selective towards TcCYP51 (< 25 nM). Interestingly, imidazole analog (16) was active against infectious forms of these three parasites, demonstrating Ki values of 0.17, 0.02, and 0.36 nM for CYP51 from T. cruzi, T. brucei, and L. infantum. Finally, this review will address promising inhibitors targeting sterol 14α-demethylase (CYP51) from Trypanosomatidae parasites, highlighting SAR studies, interactions with this target, and recent contributions and advances in the field, as well.

Cite this article as:

da Silva Santos-Júnior Fernando Paulo , Schmitt Martine , de Araújo-Júnior Xavier João and da Silva-Júnior Ferreira Edeildo*, Sterol 14α-Demethylase from Trypanosomatidae Parasites as a Promising Target for Designing New Antiparasitic Agents, Current Topics in Medicinal Chemistry 2021; 21 (21) . https://dx.doi.org/10.2174/1568026621666210303144448