Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities

Levaique, Helene and Pamlard, Olivier and Apel, Cecile and Bignon, Jerome and Arriola, Margaux and Kuhner, Robin and Awang, Khalijah and Loiseau, Philippe M. and Litaudon, Marc and Pomel, Sebastien (2021) Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities. Molecules, 26 (6). ISSN 1420-3049, DOI

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Leishmaniasis is a vector-borne disease caused by the protozoan parasite Leishmania found in tropical and sub-tropical areas, affecting 12 million people around the world. Only few treatments are available against this disease and all of them present issues of toxicity and/or resistance. In this context, the development of new antileishmanial drugs specifically directed against a therapeutic target appears to be a promising strategy. The GDP-Mannose Pyrophosphorylase (GDP-MP) has been previously shown to be an attractive therapeutic target in Leishmania. In this study, a chemical library of 5000 compounds was screened on both L. infantum (LiGDP-MP) and human (hGDP-MP) GDP-MPs. From this screening, oncostemonol D was found to be active on both GDP-MPs at the micromolar level. Ten alkyl-resorcinol derivatives, of which oncostemonols E and J (2 and 3) were described for the first time from nature, were then evaluated on both enzymes as well as on L. infantum axenic and intramacrophage amastigotes. From this evaluation, compounds 1 and 3 inhibited both GDP-MPs at the micromolar level, and compound 9 displayed a three-times lower IC50 on LiGDP-MP, at 11 mu M, than on hGDP-MP. As they displayed mild activities on the parasite, these compounds need to be further pharmacomodulated in order to improve their affinity and specificity to the target as well as their antileishmanial activity.

Item Type: Article
Funders: French National Research Agency (ANR) [ANR-10-LABX-25-01]
Uncontrolled Keywords: Leishmania; Therapeutic target; GDP-Mannose pyrophosphorylase; Natural products; alkyl-resorcinol
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Divisions: Faculty of Science > Department of Chemistry
Depositing User: Ms Zaharah Ramly
Date Deposited: 09 Jun 2022 05:54
Last Modified: 09 Jun 2022 05:54

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