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Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists

New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide...

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Autores principales: El-Zahabi, Mohamed Ayman, Bamanie, Faida H., Ghareeb, Salah, Alshaeri, Heba K., Alasmari, Moudi M., Moustafa, Mohamed, Al-Marzooki, Zohair, Zayed, Mohamed F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455857/
https://www.ncbi.nlm.nih.gov/pubmed/36077003
http://dx.doi.org/10.3390/ijms23179605
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author El-Zahabi, Mohamed Ayman
Bamanie, Faida H.
Ghareeb, Salah
Alshaeri, Heba K.
Alasmari, Moudi M.
Moustafa, Mohamed
Al-Marzooki, Zohair
Zayed, Mohamed F.
author_facet El-Zahabi, Mohamed Ayman
Bamanie, Faida H.
Ghareeb, Salah
Alshaeri, Heba K.
Alasmari, Moudi M.
Moustafa, Mohamed
Al-Marzooki, Zohair
Zayed, Mohamed F.
author_sort El-Zahabi, Mohamed Ayman
collection PubMed
description New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile.
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spelling pubmed-94558572022-09-09 Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists El-Zahabi, Mohamed Ayman Bamanie, Faida H. Ghareeb, Salah Alshaeri, Heba K. Alasmari, Moudi M. Moustafa, Mohamed Al-Marzooki, Zohair Zayed, Mohamed F. Int J Mol Sci Article New quinazoline-sulfonylurea hybrids were prepared and examined for their in vivo anti-hyperglycemic activities in STZ-induced hyperglycemic rats using glibenclamide as a reference drug. Compounds VI-6-a, V, IV-4, VI-4-c, IV-6, VI-2-a, IV-1, and IV-2 were more potent than the reference glibenclamide. They induced significant reduction in the blood glucose levels of diabetic rats: 78.2, 73.9, 71.4, 67.3, 62, 60.7, 58.4, and 55.9%, respectively, while the reference glibenclamide had 55.4%. Compounds IV-1, VI-2-a, IV-2, V, and IV-6 showed more prolonged antidiabetic activity than glibenclamide. Moreover, molecular docking and pharmacokinetic studies were performed to examine binding modes of the prepared compounds against peroxisome proliferator-activated receptor gamma (PPARγ). The highest active compounds exhibited good binding affinity with high free energy of binding against PPARγ. In silico absorption, distribution, metabolism, elimination and toxicity (ADMET) studies were performed to investigate pharmacokinetics and safety of the synthesized compounds. They showed considerable human intestinal absorption with low toxicity profile. MDPI 2022-08-24 /pmc/articles/PMC9455857/ /pubmed/36077003 http://dx.doi.org/10.3390/ijms23179605 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
El-Zahabi, Mohamed Ayman
Bamanie, Faida H.
Ghareeb, Salah
Alshaeri, Heba K.
Alasmari, Moudi M.
Moustafa, Mohamed
Al-Marzooki, Zohair
Zayed, Mohamed F.
Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title_full Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title_fullStr Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title_full_unstemmed Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title_short Design, Synthesis, Molecular Modeling and Anti-Hyperglycemic Evaluation of Quinazoline-Sulfonylurea Hybrids as Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) and Sulfonylurea Receptor (SUR) Agonists
title_sort design, synthesis, molecular modeling and anti-hyperglycemic evaluation of quinazoline-sulfonylurea hybrids as peroxisome proliferator-activated receptor gamma (pparγ) and sulfonylurea receptor (sur) agonists
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9455857/
https://www.ncbi.nlm.nih.gov/pubmed/36077003
http://dx.doi.org/10.3390/ijms23179605
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