Academic Journal
Macromolecular scaffolds with nitrogen-sulfur motifs: Dual α-glucosidase and urease inhibition with molecular docking and mechanistic evaluation.
| Title: | Macromolecular scaffolds with nitrogen-sulfur motifs: Dual α-glucosidase and urease inhibition with molecular docking and mechanistic evaluation. |
|---|---|
| Authors: | Khan S; Department of Chemistry, Abbottabad University of Science and Technology, Abbottabad, 22500, Pakistan. Electronic address: shoaibkhanswati@gmail.com., Iqbal T; Department of Chemistry, Abbottabad University of Science and Technology, Abbottabad, 22500, Pakistan., Abass KS; Department of Physiology, Biochemistry, and Pharmacology, College of Veterinary Medicine, University of Kirkuk, Kirkuk, 36001, Iraq., Alzahrani E; Department of Chemistry, College of Science, Taif University, PO Box 11099, Taif, 21944, Saudi Arabia., Gomha SM; Department of Chemistry, Faculty of Science, Islamic University of Madinah, Madinah, 42351, Saudi Arabia., Zaki MEA; Department of Chemistry, Faculty of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, 11623, Saudi Arabia., Alshehri FF; Department of Medical Laboratories, College of Applied Medical Sciences, Ad Dawadimi, 17464, Shaqra University, Saudi Arabia., Al Shehri ZS; College of Applied Medical Sciences, Shaqra University, Aldawadmi, Saudi Arabia., Kashtoh H; Department of Biotechnology, Yeungnam University, Gyeongsan, 38541, Gyeongbuk, Republic of Korea. Electronic address: hamdy_kashtoh@ynu.ac.kr. |
| Source: | International journal of biological macromolecules [Int J Biol Macromol] 2025 Dec; Vol. 332 (Pt 1), pp. 148369. Date of Electronic Publication: 2025 Oct 19. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 7909578 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0003 (Electronic) Linking ISSN: 01418130 NLM ISO Abbreviation: Int J Biol Macromol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Amsterdam : Elsevier Original Publication: Guildford, Eng., IPC Science and Technology Press. |
| MeSH Terms: | Urease*/antagonists & inhibitors , Urease*/chemistry , Urease*/metabolism , alpha-Glucosidases*/chemistry , alpha-Glucosidases*/metabolism , Glycoside Hydrolase Inhibitors*/chemistry , Glycoside Hydrolase Inhibitors*/pharmacology , Glycoside Hydrolase Inhibitors*/chemical synthesis , Nitrogen*/chemistry , Enzyme Inhibitors*/chemistry , Enzyme Inhibitors*/pharmacology , Enzyme Inhibitors*/chemical synthesis , Sulfur*/chemistry , Molecular Docking Simulation*, Indoles/chemistry ; Sulfonamides/chemistry ; Sulfonamides/pharmacology ; Thiadiazoles/chemistry ; Structure-Activity Relationship |
| Abstract: | This study reports the design, synthesis, and biological evaluation of a new series of indole-thiadiazole-sulfonamide hybrids as potential dual inhibitors of α-glucosidase and urease enzymes. Eighteen derivatives were synthesized and structurally characterized using standard spectroscopic techniques. Several compounds exhibited significant inhibitory activity, with IC₅₀ values ranging from 5.68 ± 1.28 to 45.42 ± 2.51 μM against α-glucosidase and from 12.99 ± 3.80 to 54.63 ± 3.26 μM against urease, compared to the reference inhibitors acarbose (18.73 ± 3.53 μM) and thiourea (21.70 ± 3.80 μM). Structure-activity relationship (SAR) analysis highlighted the influence of nitro, fluoro, trifluoromethyl, and chloro substituents on enzyme inhibition, with several derivatives surpassing the standards in potency. Molecular docking studies revealed key interactions with active-site residues, while ADME profiling indicated favorable drug-likeness. Overall, these findings identify indole-thiadiazole-sulfonamide hybrids as promising scaffolds for the development of multifunctional enzyme inhibitors. (Copyright © 2025 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest It is declared that there is no conflict of interest between the authors of the current manuscript. |
| Contributed Indexing: | Keywords: Docking Study & ADME; Indole; Sulfonamide; Thiadiazole; Urease; α-Glucosidase |
| Substance Nomenclature: | EC 3.5.1.5 (Urease) EC 3.2.1.20 (alpha-Glucosidases) 0 (Glycoside Hydrolase Inhibitors) N762921K75 (Nitrogen) 0 (Enzyme Inhibitors) 70FD1KFU70 (Sulfur) 0 (Indoles) 0 (Sulfonamides) 0 (Thiadiazoles) |
| Entry Date(s): | Date Created: 20251021 Date Completed: 20251123 Latest Revision: 20251124 |
| Update Code: | 20260130 |
| DOI: | 10.1016/j.ijbiomac.2025.148369 |
| PMID: | 41120081 |
| Database: | MEDLINE |
| ISSN: | 1879-0003 |
|---|---|
| DOI: | 10.1016/j.ijbiomac.2025.148369 |