Computational Investigation of Coumarin-Triazole- Chalcone Hybrids as Potential Antidiabetic Agents: Molecular Docking and ADMET Studies
Abstract
The current work focuses on the design and computational assessment of new coumarin-triazole-chalcone hybrids as possible carbohydrate hydrolyzing enzyme inhibitors for diabetic control. To study possible antidiabetic action, a series of derivatives (1a-1j) were designed and tested using molecular docking against α -amylase (PDB: 1B2Y) and α glucosidase (PDB: 3W37). The docking data showed that the majority of the proposed compounds had substantial binding affinities for both enzymes. Compounds 1a and 1b have the greatest binding affinity to α-amylase (-10.8 kcal/mol) forming stable interactions with critical catalytic residues in the active region. Docking against α-glucosidase showed that compound 1f (-11.4 kcal/mol) had binding energy equivalent to the reference inhibitor acarbose, while compounds 1b and 1j also had substantial interactions with the enzyme. In addition, the ADMET and pharmacokinetic parameters of chosen drugs were predicted using the pkCSM web server. The results showed good drug-likeness, high intestine absorption, acceptable permeability, moderate distribution and a minimal mutagenesis risk. The hybrids were also expected to have poor blood-brain barrier penetration, implying little central nervous system exposure. The computational findings indicate that the coumarin-triazole-chalcone hybrids have good inhibitory ability against α-amylase and α-glucosidase, making them suitable lead candidates for developing novel antidiabetic medicines.
References
[2] K.L. Ong, L.K. Stafford, S.A. McLaughlin, E.J. Boyko, S.E. Vollset, A.E. Smith, B.E. Dalton, J. Duprey, J.A. Cruz, H. Hagins, Global, regional, and national burden of diabetes from 1990 to 2021, with projections of prevalence to 2050: a systematic analysis for the Global Burden of Disease Study 2021, The Lancet, 402 (2023) 203-234.
[3] M.A. Nauck, J. Wefers, J.J. Meier, Treatment of type 2 diabetes: challenges, hopes, and anticipated successes, The lancet Diabetes & endocrinology, 9 (2021) 525-544.
[4] A. Kanwal, N. Kanwar, S. Bharati, P. Srivastava, S.P. Singh, S. Amar, Exploring new drug targets for type 2 diabetes: success, challenges and opportunities, Biomedicines, 10 (2022) 331.
[5] F. Khan, M.V. Khan, A. Kumar, S. Akhtar, Recent advances in the development of alpha-glucosidase and alpha-amylase inhibitors in type 2 diabetes management: insights from in silico to in vitro studies, Current Drug Targets, 25 (2024) 782-795.
[6] N. Kaur, V. Kumar, S.K. Nayak, P. Wadhwa, P. Kaur, S.K. Sahu, Alphaamylase as molecular target for treatment of diabetes mellitus: A comprehensive review, Chemical biology & drug design, 98 (2021) 539-560.
[7] A.M. Dirir, M. Daou, A.F. Yousef, L.F. Yousef, A review of alphaglucosidase inhibitors from plants as potential candidates for the treatment of type-2 diabetes, Phytochemistry Reviews, 21 (2022) 10491079.
[8] A. Mushtaq, U. Azam, S. Mehreen, M.M. Naseer, Synthetic αglucosidase inhibitors as promising anti-diabetic agents: Recent developments and future challenges, European journal of medicinal chemistry, 249 (2023) 115119.
[9] H. Kashtoh, K.-H. Baek, Recent updates on phytoconstituent alphaglucosidase inhibitors: an approach towards the treatment of type two diabetes, Plants, 11 (2022) 2722.
[10] A. Jaggal, K.S. Katagi, M. Akki, V. Babagond, V. Kamat, S. Joshi, A click-chemistry based strategy for synthesizing coumarin piperazine analogues: Assessment of anti-tubercular, anti-cancer, antiinflammatory and antioxidant potentials, Journal of Molecular Structure, 1320 (2025) 139388.
[11] M. Akki, D.S. Reddy, K.S. Katagi, A. Kumar, H.C. Devarajegowda, S. Kumari M, V. Babagond, S.D. Joshi, Coumarin Hydrazone Oxime Scaffolds as Potent Anti‐tubercular Agents: Synthesis, X‐ray crystal and Molecular Docking Studies, ChemistrySelect, 7 (2022) e202203260.
[12] S. Khatoon, R. Naaz, U. Khan, F. Qayyum, S. Ahmad, M. Saquib, M.K. Hussain, Natural coumarins as anti-diabetic agents: Mechanisms, therapeutic potential, and amelioration of diabetic complications, Phytomedicine, (2025) 157339.
[13] S. Ranđelović, R. Bipat, A review of coumarins and coumarin-related compounds for their potential antidiabetic effect, Clinical Medicine
Insights: Endocrinology and Diabetes, 14 (2021) 11795514211042023.
[14] H. Li, Y. Yao, L. Li, Coumarins as potential antidiabetic agents, Journal of Pharmacy and Pharmacology, 69 (2017) 1253-1264.
[15] B. Debnath, S. Manna, A. Maity, S. Panda, K. Bandyopadhyay, S. Bhattacharjee, S. Khan, S.M. Islam, D. Thekkekkara, S.A. Khan, Synthetic Strategies and Structure Activity Relationships (SAR) of Biologically Active Coumarin‐Based Hybrids, ChemistrySelect, 10 (2025) e202406069.
[16] Y. Pan, T. Liu, X. Wang, J. Sun, Research progress of coumarins and their derivatives in the treatment of diabetes, Journal of enzyme inhibition and medicinal chemistry, 37 (2022) 616-628.
[17] V. Babagond, K. Katagi, M. Akki, V. Kamat, D.A. Barretto, A. Jaggal, S. Kademani, A. Shirahatti, A Click chemistry approach for the synthesis of triazole linked vanillin scaffolds as potent pharmacophores: anti-diabetic, anti-inflammatory, antioxidant, molecular docking and admet investigations, Polycyclic Aromatic Compounds, 45 (2025) 1717-1740.
[18] A. Jaggal, K.S. Katagi, M. Akki, V. Babagond, V. Kamat, D.A. Barretto, S. Kademani, Design and synthesis of potent coumarin-1, 2, 3-triazole conjugates: An approach to docking studies for their therapeutic applications, Journal of Molecular Structure, (2025) 143519.
[19] A. Sharma, R. Dubey, R. Bhupal, P. Patel, S.K. Verma, S. Kaya, V. Asati, An insight on medicinal attributes of 1, 2, 3‐and 1, 2, 4‐triazole derivatives as alpha-amylase and alpha-glucosidase inhibitors, Molecular Diversity, (2023) 1-30.
[20] A. Singh, K. Singh, A. Sharma, U. Kaur, K. Kaur, P. Mohinder Singh Bedi, Recent developments in 1, 2, 3‐triazole based α‐glucosidase inhibitors: design strategies, structure‐activity relationship and mechanistic insights, Chemistry & Biodiversity, 21 (2024) e202401109.
[21] S. Rocha, D. Ribeiro, E. Fernandes, M. Freitas, A systematic review on anti-diabetic properties of chalcones, Current medicinal chemistry, 27 (2020) 2257-2321.
[22] S. Welday Kahssay, G.S. Hailu, K. Taye Desta, Design, synthesis, characterization and in vivo antidiabetic activity evaluation of some chalcone derivatives, Drug Design, Development and Therapy, (2021) 3119-3129.
[23] S. Rocha, A. Sousa, D. Ribeiro, C.M. Correia, V.L. Silva, C.M. Santos, A.M. Silva, A.N. Araújo, E. Fernandes, M. Freitas, A study towards drug discovery for the management of type 2 diabetes mellitus through inhibition of the carbohydrate-hydrolyzing enzymes α-amylase and αglucosidase by chalcone derivatives, Food & function, 10 (2019) 55105520.
[24] V. NAHOUM, G. ROUX, V. ANTON, P. ROUGÉ, A. PUIGSERVER, H. BISCHOFF, B. Henrissat, F. PAYAN, Crystal structures of human pancreatic α-amylase in complex with carbohydrate and proteinaceous inhibitors, Biochemical Journal, 346 (2000) 201-208.
[25] T. Tagami, K. Yamashita, M. Okuyama, H. Mori, M. Yao, A. Kimura, Molecular basis for the recognition of long-chain substrates by plant αglucosidases, Journal of Biological Chemistry, 288 (2013) 1929619303.
[26] H. Krishnapura Nagaraja Rao, V.B. Das, V. Kamat, M. Akki, B. Poojary, S. Gowdar, S. Asthana, M. Pareek, Design, Synthesis, and Fungicidal Activity of a New Class of Thiadiazolylpyrimidine Carboxamide Derivatives Against R. solani Kuhn, Chemistry & Biodiversity, 22 (2025) e01520.
[27] O. Trott, A.J. Olson, AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading, Journal of computational chemistry, 31 (2010) 455-461.
[28] C.A. Lipinski, F. Lombardo, B.W. Dominy, P.J. Feeney, Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings, Advanced drug delivery reviews, 23 (1997) 3-25.
[29] D.F. Veber, S.R. Johnson, H.-Y. Cheng, B.R. Smith, K.W. Ward, K.D. Kopple, Molecular properties that influence the oral bioavailability of drug candidates, Journal of medicinal chemistry, 45 (2002) 2615-2623.
[30] A. Daina, O. Michielin, V. Zoete, SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Scientific reports, 7 (2017) 42717.
To ensure uniformity of treatment among all contributors, other forms may not be substituted for this form, nor may any wording of the form be changed. This form is intended for original material submitted to AJCT and must accompany any such material in order to be published by AJCT. Please read the form carefully.
The undersigned hereby assigns to the Asian Journal of Convergence in Technology Issues ("AJCT") all rights under copyright that may exist in and to the above Work, any revised or expanded derivative works submitted to AJCT by the undersigned based on the Work, and any associated written, audio and/or visual presentations or other enhancements accompanying the Work. The undersigned hereby warrants that the Work is original and that he/she is the author of the Work; to the extent the Work incorporates text passages, figures, data or other material from the works of others, the undersigned has obtained any necessary permission. See Retained Rights, below.
AUTHOR RESPONSIBILITIES
AJCT distributes its technical publications throughout the world and wants to ensure that the material submitted to its publications is properly available to the readership of those publications. Authors must ensure that The Work is their own and is original. It is the responsibility of the authors, not AJCT, to determine whether disclosure of their material requires the prior consent of other parties and, if so, to obtain it.
RETAINED RIGHTS/TERMS AND CONDITIONS
1. Authors/employers retain all proprietary rights in any process, procedure, or article of manufacture described in the Work.
2. Authors/employers may reproduce or authorize others to reproduce The Work and for the author's personal use or for company or organizational use, provided that the source and any AJCT copyright notice are indicated, the copies are not used in any way that implies AJCT endorsement of a product or service of any employer, and the copies themselves are not offered for sale.
3. Authors/employers may make limited distribution of all or portions of the Work prior to publication if they inform AJCT in advance of the nature and extent of such limited distribution.
4. For all uses not covered by items 2 and 3, authors/employers must request permission from AJCT.
5. Although authors are permitted to re-use all or portions of the Work in other works, this does not include granting third-party requests for reprinting, republishing, or other types of re-use.
INFORMATION FOR AUTHORS
AJCT Copyright Ownership
It is the formal policy of AJCT to own the copyrights to all copyrightable material in its technical publications and to the individual contributions contained therein, in order to protect the interests of AJCT, its authors and their employers, and, at the same time, to facilitate the appropriate re-use of this material by others.
Author/Employer Rights
If you are employed and prepared the Work on a subject within the scope of your employment, the copyright in the Work belongs to your employer as a work-for-hire. In that case, AJCT assumes that when you sign this Form, you are authorized to do so by your employer and that your employer has consented to the transfer of copyright, to the representation and warranty of publication rights, and to all other terms and conditions of this Form. If such authorization and consent has not been given to you, an authorized representative of your employer should sign this Form as the Author.
Reprint/Republication Policy
AJCT requires that the consent of the first-named author and employer be sought as a condition to granting reprint or republication rights to others or for permitting use of a Work for promotion or marketing purposes.
GENERAL TERMS
1. The undersigned represents that he/she has the power and authority to make and execute this assignment.
2. The undersigned agrees to indemnify and hold harmless AJCT from any damage or expense that may arise in the event of a breach of any of the warranties set forth above.
3. In the event the above work is accepted and published by AJCT and consequently withdrawn by the author(s), the foregoing copyright transfer shall become null and void and all materials embodying the Work submitted to AJCT will be destroyed.
4. For jointly authored Works, all joint authors should sign, or one of the authors should sign as authorized agent
for the others.
Licenced by :
Creative Commons Attribution 4.0 International License.
