Cargando…

Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases

Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regul...

Descripción completa

Detalles Bibliográficos
Autores principales: Afzal, Saira, al-Rashida, Mariya, Hameed, Abdul, Pelletier, Julie, Sévigny, Jean, Iqbal, Jamshed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734281/
https://www.ncbi.nlm.nih.gov/pubmed/33328992
http://dx.doi.org/10.3389/fphar.2020.585876
_version_ 1783622441997697024
author Afzal, Saira
al-Rashida, Mariya
Hameed, Abdul
Pelletier, Julie
Sévigny, Jean
Iqbal, Jamshed
author_facet Afzal, Saira
al-Rashida, Mariya
Hameed, Abdul
Pelletier, Julie
Sévigny, Jean
Iqbal, Jamshed
author_sort Afzal, Saira
collection PubMed
description Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC(50) values in lower micromolar range, these include compounds 8b (IC(50) = 0.29 ± 0.02 µM), 8e (IC(50) = 0.15 ± 0.009 µM), 8f (IC(50) = 0.24 ± 0.01 µM) and 8l (IC(50) = 0.30 ± 0.03 µM). Similarly, compound 8k (IC(50) = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC(50) = 0.19 ± 0.02 µM) and 8m (IC(50) = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion.
format Online
Article
Text
id pubmed-7734281
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-77342812020-12-15 Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases Afzal, Saira al-Rashida, Mariya Hameed, Abdul Pelletier, Julie Sévigny, Jean Iqbal, Jamshed Front Pharmacol Original Research Ectonucleoside triphosphate diphosphohydrolases (NTPDases) are ectoenzymes that play an important role in the hydrolysis of nucleoside triphosphate and diphosphate to nucleoside monophosphate. NTPDase1, -2, -3 and -8 are the membrane bound members of this enzyme family that are responsible for regulating the levels of nucleotides in extracellular environment. However, the pathophysiological functions of these enzymes are not fully understood due to lack of potent and selective NTPDase inhibitors. Herein, a series of oxoindolin hydrazine carbothioamide derivatives is synthesized and screened for NTPDase inhibitory activity. Four compounds were identified as selective inhibitors of h-NTPDase1 having IC(50) values in lower micromolar range, these include compounds 8b (IC(50) = 0.29 ± 0.02 µM), 8e (IC(50) = 0.15 ± 0.009 µM), 8f (IC(50) = 0.24 ± 0.01 µM) and 8l (IC(50) = 0.30 ± 0.03 µM). Similarly, compound 8k (IC(50) = 0.16 ± 0.01 µM) was found to be a selective h-NTPDase2 inhibitor. In case of h-NTPDase3, most potent inhibitors were compounds 8c (IC(50) = 0.19 ± 0.02 µM) and 8m (IC(50) = 0.38 ± 0.03 µM). Since NTPDase3 has been reported to be associated with the regulation of insulin secretion, we evaluated our synthesized NTPDase3 inhibitors for their ability to stimulate insulin secretion in isolated mice islets. Promising results were obtained showing that compound 8m potently stimulated insulin secretion without affecting the NTPDase3 gene expression. Molecular docking studies of the most potent compounds were also carried out to rationalize binding site interactions. Hence, these compounds are useful tools to study the role of NTPDase3 in insulin secretion. Frontiers Media S.A. 2020-11-30 /pmc/articles/PMC7734281/ /pubmed/33328992 http://dx.doi.org/10.3389/fphar.2020.585876 Text en Copyright © 2020 Iqbal, Afzal, al-Rashida, Hameed, Pelletier and Sévigny http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Original Research
Afzal, Saira
al-Rashida, Mariya
Hameed, Abdul
Pelletier, Julie
Sévigny, Jean
Iqbal, Jamshed
Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title_full Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title_fullStr Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title_full_unstemmed Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title_short Functionalized Oxoindolin Hydrazine Carbothioamide Derivatives as Highly Potent Inhibitors of Nucleoside Triphosphate Diphosphohydrolases
title_sort functionalized oxoindolin hydrazine carbothioamide derivatives as highly potent inhibitors of nucleoside triphosphate diphosphohydrolases
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734281/
https://www.ncbi.nlm.nih.gov/pubmed/33328992
http://dx.doi.org/10.3389/fphar.2020.585876
work_keys_str_mv AT afzalsaira functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases
AT alrashidamariya functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases
AT hameedabdul functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases
AT pelletierjulie functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases
AT sevignyjean functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases
AT iqbaljamshed functionalizedoxoindolinhydrazinecarbothioamidederivativesashighlypotentinhibitorsofnucleosidetriphosphatediphosphohydrolases