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Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis

A series of aminated- (1–9) and sulfonamide-containing diarylpentadienones (10–18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were nonassociated PAINS compounds. Th...

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Main Authors:	Maryam Aisyah, Abdullah, Lee, Yu-Ri, Siti Nurulhuda, Mastuki, Leong, Sze Wei, Wan Norhamidah, Wan Ibrahim, Muhammad Alif, Mohammad Latif, Aizi Nor Mazila, Ramli, Mohd F. F., Mohd Aluwi, Siti Munirah, Mohd Faudzi, Kim, Cheol-Hee
Format:	Article
Language:	English English
Published:	Academic Press Inc. 2020
Subjects:	TP Chemical technology
Online Access:	http://umpir.ump.edu.my/id/eprint/30212/1/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor.pdf http://umpir.ump.edu.my/id/eprint/30212/2/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor_FULL.pdf http://umpir.ump.edu.my/id/eprint/30212/ https://doi.org/10.1016/j.bioorg.2020.104277 https://doi.org/10.1016/j.bioorg.2020.104277
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spelling	my.ump.umpir.302122022-04-27T02:16:16Z http://umpir.ump.edu.my/id/eprint/30212/ Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis Maryam Aisyah, Abdullah Lee, Yu-Ri Siti Nurulhuda, Mastuki Leong, Sze Wei Wan Norhamidah, Wan Ibrahim Muhammad Alif, Mohammad Latif Aizi Nor Mazila, Ramli Mohd F. F., Mohd Aluwi Siti Munirah, Mohd Faudzi Kim, Cheol-Hee TP Chemical technology A series of aminated- (1–9) and sulfonamide-containing diarylpentadienones (10–18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were nonassociated PAINS compounds. The sulfonamide-containing series (compounds 10– 18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of αglucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients. Academic Press Inc. 2020-11 Article PeerReviewed pdf en http://umpir.ump.edu.my/id/eprint/30212/1/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor.pdf pdf en http://umpir.ump.edu.my/id/eprint/30212/2/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor_FULL.pdf Maryam Aisyah, Abdullah and Lee, Yu-Ri and Siti Nurulhuda, Mastuki and Leong, Sze Wei and Wan Norhamidah, Wan Ibrahim and Muhammad Alif, Mohammad Latif and Aizi Nor Mazila, Ramli and Mohd F. F., Mohd Aluwi and Siti Munirah, Mohd Faudzi and Kim, Cheol-Hee (2020) Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis. Bioorganic Chemistry, 104 (104277). pp. 1-15. ISSN 0045-2068 https://doi.org/10.1016/j.bioorg.2020.104277 https://doi.org/10.1016/j.bioorg.2020.104277
institution	Universiti Malaysia Pahang
building	UMP Library
collection	Institutional Repository
continent	Asia
country	Malaysia
content_provider	Universiti Malaysia Pahang
content_source	UMP Institutional Repository
url_provider	http://umpir.ump.edu.my/
language	English English
topic	TP Chemical technology
spellingShingle	TP Chemical technology Maryam Aisyah, Abdullah Lee, Yu-Ri Siti Nurulhuda, Mastuki Leong, Sze Wei Wan Norhamidah, Wan Ibrahim Muhammad Alif, Mohammad Latif Aizi Nor Mazila, Ramli Mohd F. F., Mohd Aluwi Siti Munirah, Mohd Faudzi Kim, Cheol-Hee Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
description	A series of aminated- (1–9) and sulfonamide-containing diarylpentadienones (10–18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were nonassociated PAINS compounds. The sulfonamide-containing series (compounds 10– 18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of αglucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.
format	Article
author	Maryam Aisyah, Abdullah Lee, Yu-Ri Siti Nurulhuda, Mastuki Leong, Sze Wei Wan Norhamidah, Wan Ibrahim Muhammad Alif, Mohammad Latif Aizi Nor Mazila, Ramli Mohd F. F., Mohd Aluwi Siti Munirah, Mohd Faudzi Kim, Cheol-Hee
author_facet	Maryam Aisyah, Abdullah Lee, Yu-Ri Siti Nurulhuda, Mastuki Leong, Sze Wei Wan Norhamidah, Wan Ibrahim Muhammad Alif, Mohammad Latif Aizi Nor Mazila, Ramli Mohd F. F., Mohd Aluwi Siti Munirah, Mohd Faudzi Kim, Cheol-Hee
author_sort	Maryam Aisyah, Abdullah
title	Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
title_short	Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
title_full	Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
title_fullStr	Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
title_full_unstemmed	Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
title_sort	development of diarylpentadienone analogues as alpha-glucosidase inhibitor: synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis
publisher	Academic Press Inc.
publishDate	2020
url	http://umpir.ump.edu.my/id/eprint/30212/1/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor.pdf http://umpir.ump.edu.my/id/eprint/30212/2/Development%20of%20diarylpentadienone%20analogues%20as%20alpha-glucosidase%20inhibitor_FULL.pdf http://umpir.ump.edu.my/id/eprint/30212/ https://doi.org/10.1016/j.bioorg.2020.104277 https://doi.org/10.1016/j.bioorg.2020.104277
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score	13.211869

Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis

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