Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities
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 con...
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my.um.eprints.343642022-06-09T05:54:32Z http://eprints.um.edu.my/34364/ Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities Levaique, Helene Pamlard, Olivier Apel, Cecile Bignon, Jerome Arriola, Margaux Kuhner, Robin Awang, Khalijah Loiseau, Philippe M. Litaudon, Marc Pomel, Sebastien QD Chemistry QH301 Biology 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. MDPI 2021-03 Article PeerReviewed 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 https://doi.org/10.3390/molecules26061551 <https://doi.org/10.3390/molecules26061551>. 10.3390/molecules26061551 |
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QD Chemistry QH301 Biology Levaique, Helene Pamlard, Olivier Apel, Cecile Bignon, Jerome Arriola, Margaux Kuhner, Robin Awang, Khalijah Loiseau, Philippe M. Litaudon, Marc Pomel, Sebastien Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
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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. |
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Article |
author |
Levaique, Helene Pamlard, Olivier Apel, Cecile Bignon, Jerome Arriola, Margaux Kuhner, Robin Awang, Khalijah Loiseau, Philippe M. Litaudon, Marc Pomel, Sebastien |
author_facet |
Levaique, Helene Pamlard, Olivier Apel, Cecile Bignon, Jerome Arriola, Margaux Kuhner, Robin Awang, Khalijah Loiseau, Philippe M. Litaudon, Marc Pomel, Sebastien |
author_sort |
Levaique, Helene |
title |
Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
title_short |
Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
title_full |
Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
title_fullStr |
Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
title_full_unstemmed |
Alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
title_sort |
alkyl-resorcinol derivatives as inhibitors of gdp-mannose pyrophosphorylase with antileishmanial activities |
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MDPI |
publishDate |
2021 |
url |
http://eprints.um.edu.my/34364/ |
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1735570302873632768 |
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13.160551 |