Structure-activity relationship-guided design of carbazole-thiazole hybrids as α-glucosidase inhibitors: DFT analysis, molecular modelling, ADMET prediction and in vivo validation.
| Title: | Structure-activity relationship-guided design of carbazole-thiazole hybrids as α-glucosidase inhibitors: DFT analysis, molecular modelling, ADMET prediction and in vivo validation. |
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| Authors: | Thi Mai Tho N; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: nguyenthimaitho@iuh.edu.vn.; Van Thoi N; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: Bentre_nguyenvanthoi@bentre.edu.vn.; Tran NNH; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: 23002961.tran@student.iuh.edu.vn.; Khanh ND; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: khanhnd2441@pgr.iuh.edu.vn.; Van Son N; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: nguyenvanson@iuh.edu.vn.; Thi Nhat Thang N; Faculty of Health Science, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: nguyenthinhatthang@iuh.edu.vn.; Thi Hong Anh N; Faculty of Chemical Engineering, Ho Chi Minh City University of Industry and Trade, 140 Le Trong Tan Street, Tay Thanh Ward, Ho Chi Minh 70000, Vietnam. Electronic address: anhnth@huit.edu.vn.; Thi Thu Ha N; Faculty of Health Science, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: 22706731.ha@student.iuh.edu.vn.; An TNM; Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, 12 Nguyen Van Bao, Hanh Thong Ward, Ho Chi Minh 70000, Vietnam. Electronic address: trannguyenminhan@iuh.edu.vn. |
| Source: | Computational biology and chemistry [Comput Biol Chem] 2026 Apr 16; Vol. 124 (Pt 1), pp. 109077. Date of Electronic Publication: 2026 Apr 16. |
| Publication Model: | Ahead of Print |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | 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 |
| Imprint Name(s): | Publication: Oxford : Elsevier; Original Publication: Oxford : Pergamon, c2003- |
| Abstract: | A series of novel carbazole-thiazole hybrids (5a-5q) was synthesised to explore structure-activity relationships (SAR) toward α-glucosidase inhibition. Enzymatic evaluation identified compound 5k as the most potent inhibitor (IC₅₀ = 5.23 µM), exhibiting approximately 20-fold greater activity than acarbose (IC₅₀ = 117.12 µM). Kinetic analysis indicated that 5k decreased both Vmax and Km, with near-parallel Lineweaver-Burk plots, suggesting a mixed-type inhibition with a predominant uncompetitive component. SAR analysis showed that electronic effects of substituents significantly influence inhibitory potency. Molecular docking revealed that 5k favourably binds within the α-glucosidase active site, forming interactions with Gly383, Phe385, and Lys439. Molecular dynamics simulations supported complex stability (RMSD < 2 Å). In silico ADMET analysis (ADMETlab 2.0) suggested low BBB permeability and limited oral bioavailability, indicating potential for intestinal-targeted activity. DFT calculations (ΔEgap=3.770 eV; dipole moment=2.225 D) provided theoretical insight into electronic properties, although their biological relevance remains tentative. In vivo evaluation using a zebrafish model of postprandial hyperglycaemia demonstrated that 5k significantly reduced glucose levels (Cmax ↓36.4%, AUC0-180 ↓27.7%) at 75 mg.kg-1, outperforming acarbose. These results support 5k as a promising lead for further optimisation.; (Copyright © 2026 Elsevier Ltd. All rights reserved.) |
| Competing Interests: | Declaration of Competing Interest There are no conflicts to declare. |
| Contributed Indexing: | Keywords: 1,3-thiazole; Anti-diabetic activities; DFT analysis; Docking; Enzyme kinetics; Molecular dynamics simulation |
| Entry Date(s): | Date Created: 20260423 Latest Revision: 20260423 |
| Update Code: | 20260424 |
| DOI: | 10.1016/j.compbiolchem.2026.109077 |
| PMID: | 42025267 |
| Database: | MEDLINE |
Journal Article