دورية أكاديمية
أعرض في EDS

Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus.

التفاصيل البيبلوغرافية
العنوان: Discovery of novel 6-(piperidin-1-ylsulfonyl)-2H-chromenes targeting α-glucosidase, α-amylase, and PPAR-γ: Design, synthesis, virtual screening, and anti-diabetic activity for type 2 diabetes mellitus.
المؤلفون: Thabet HK; Department of Chemistry, College of Sciences and Arts, Northern Border University, Rafha 91911, Saudi Arabia. Electronic address: Hamdy.salem@nbu.edu.sa., Abusaif MS; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt., Imran M; Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia., Helal MH; Department of Chemistry, College of Sciences and Arts, Northern Border University, Rafha 91911, Saudi Arabia., Alaqel SI; Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia., Alshehri A; Department of Pharmacology and Toxicology, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia; Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, King Faisal Road, Dammam 31441, Saudi Arabia., Mohd AA; Department of Pharmacology and Toxicology, College of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia., Ammar YA; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt., Ragab A; Department of Chemistry, Faculty of Science (Boys), Al-Azhar University, Nasr City, Cairo 11884, Egypt. Electronic address: ahmed_ragab@azhar.edu.eg.
المصدر: Computational biology and chemistry [Comput Biol Chem] 2024 Aug; Vol. 111, pp. 108097. Date of Electronic Publication: 2024 May 17.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: England NLM ID: 101157394 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-928X (Electronic) Linking ISSN: 14769271 NLM ISO Abbreviation: Comput Biol Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier
Original Publication: Oxford : Pergamon, c2003-
مواضيع طبية MeSH: PPAR gamma*/metabolism , PPAR gamma*/antagonists & inhibitors , Benzopyrans*/chemistry , Benzopyrans*/pharmacology , Benzopyrans*/chemical synthesis , Hypoglycemic Agents*/chemistry , Hypoglycemic Agents*/pharmacology , Hypoglycemic Agents*/chemical synthesis , alpha-Glucosidases*/metabolism , Diabetes Mellitus, Type 2*/drug therapy , Diabetes Mellitus, Type 2*/metabolism , Glycoside Hydrolase Inhibitors*/pharmacology , Glycoside Hydrolase Inhibitors*/chemistry , Glycoside Hydrolase Inhibitors*/chemical synthesis , alpha-Amylases*/antagonists & inhibitors , alpha-Amylases*/metabolism , Drug Design*, Humans ; Structure-Activity Relationship ; Molecular Structure ; Molecular Docking Simulation ; Drug Evaluation, Preclinical ; Drug Discovery ; Dose-Response Relationship, Drug
مستخلص: A new series of 2H-chromene-based sulfonamide derivatives 3-12 has been synthesized and characterized using different spectroscopic techniques. The synthesized 2H-chromenes were synthesized by reacting activated methylene with 5-(piperidin-1-ylsulfonyl)salicylaldehyde through one-step condensation followed by intramolecular cyclization. Virtual screening of the designed molecules on α-glucosidase enzymes (PDB: 3W37 and 3A4A) exhibited good binding affinity suggesting that these derivatives may be potential α-glucosidase inhibitors. In-vitro α-glucosidase activity was conducted firstly at 100 µg/mL, and the results demonstrated good inhibitory potency with values ranging from 90.6% to 96.3% compared to IP = 95.8% for Acarbose. Furthermore, the IC 50 values were determined, and the designed derivatives exhibited inhibitory potency less than 11 µg/mL. Surprisingly, two chromene derivatives 6 and 10 showed the highest potency with IC 50 values of 0.975 ± 0.04 and 0.584 ± 0.02 µg/mL, respectively, compared to Acarbose (IC 50 = 0.805 ± 0.03 µg/mL). Moreover, our work was extended to evaluate the in-vitro α-amylase and PPAR-γ activity as additional targets for diabetic activity. The results exhibited moderate activity on α-amylase and potency as PPAR-γ agonist making it a multiplet antidiabetic target. The most active 2H-chromenes 6 and 10 exhibited significant activity to PPAR-γ with IC 50 values of 3.453 ± 0.14 and 4.653 ± 0.04 µg/mL compared to Pioglitazone (IC 50 = 4.884±0.29 µg/mL) indicating that these derivatives improve insulin sensitivity by stimulating the production of small insulin-sensitive adipocytes. In-silico ADME profile analysis indicated compliance with Lipinski's and Veber's rules with excellent oral bioavailability properties. Finally, the docking simulation was conducted to explain the expected binding mode and binding affinity.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
فهرسة مساهمة: Keywords: 6-sulfonamide-2H-chromenes; ADME prediction; Diabetes mellitus; Molecular docking simulation; Structural activity relationship (SAR)
المشرفين على المادة: 0 (PPAR gamma)
0 (Benzopyrans)
0 (Hypoglycemic Agents)
EC 3.2.1.20 (alpha-Glucosidases)
0 (Glycoside Hydrolase Inhibitors)
EC 3.2.1.1 (alpha-Amylases)
تواريخ الأحداث: Date Created: 20240521 Date Completed: 20240617 Latest Revision: 20240702
رمز التحديث: 20240702
DOI: 10.1016/j.compbiolchem.2024.108097
PMID: 38772048
قاعدة البيانات: MEDLINE
الوصف
تدمد:1476-928X
DOI:10.1016/j.compbiolchem.2024.108097