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Novel hybrid indazole-based 2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives: design, synthesis, spectroscopic characterization, SAR, molecular docking, pharmacokinetics and toxicological activities

  • Sabeen Arshad , Aneela Maalik EMAIL logo , Wajid Rehman ORCID logo EMAIL logo , Yousaf Khan , Liaqat Rasheed , Ashwag S. Alanazi , Mohamed Hefnawy , Ajaz Hussain , Safia Begum , Muhammad Yar and Khurshid Ayub
Published/Copyright: May 23, 2025
Pure and Applied Chemistry
From the journal Pure and Applied Chemistry

Abstract

There is an increasing prevalence of diabetes mellitus throughout the world, and new compounds are necessary to combat this. The currently available antidiabetic therapies are long-term complicated and side effect-prone, and this has led to a demand for more affordable and more effective methods of tackling diabetes. Research is focused on finding alternative medicinal remedies with significant antidiabetic efficacy as well as low adverse effects. In this research work, we have focused our efforts to synthesize a series of indazole-based 2,4-dihydro-3H-1,2,4-triazole-3-thone derivatives (1-17) and evaluated their antidiabetic properties. In addition, the precise structures of the synthesized derivatives were confirmed with the help of various spectroscopic techniques including 1H NMR, 13C NMR, and HRMS. To find the antidiabetic potentials of the synthesized compounds, in vitro α-glucosidase and α-amylase inhibitory activities were characterized using acarbose as the reference standard. From structure–activity (SAR) analysis, it was confirmed that any variation found in inhibitory activities of both α-amylase and α-glucosidase enzymes was due to the different substitution patterns of the substituent(s) at variable positions on the phenyl ring. The results of the antidiabetic assay were very encouraging and showed moderate to good inhibitory potentials with IC50 values of for α-glucosidase (3.42 ± 1.43 μM to 29.34 ± 0.79 μM) and α-amylase (3.44 ± 0.18 μM to 31.77 ± 0.90 μM), respectively. The obtained results were compared to those of the standard acarbose drug (IC50 = 10.30 ± 0.20 μM for α-amylase and IC50 = 9.80 ± 0.20 μM for α-glucosidase). Specifically, among the synthesized analogs, seven compounds (1, 5, 6, 8, 11,15, and 16) demonstrated superior inhibitory activity, surpassing acarbose with IC50 values ranging from for α-glucosidase and for α-amylase respectively. The outcome was further corroborated using in silico techniques, leading to the elucidation of plausible inhibition and metabolism mechanisms. These findings reveal that triazole-containing bis-hydrazones act as α-glucosidase and α-amylase inhibitors, which help develop novel therapeutics for treating type-II diabetes mellitus and can act as lead molecules in drug discovery as potential antidiabetic agents.

Keywords: α-amylase; α-glucosidase; indazole; molecular modelling; SAR; triazole
Corresponding authors: Aneela Maalik, Department of Chemistry, COMSATS University Islamabad, Islamabad, 22060, Pakistan, e-mail: ; and Wajid Rehman, Department of Chemistry, Hazara University Mansehra, Mansehra, 21120, Pakistan, e-mail:

Funding source: King Saud University

Award Identifier / Grant number: RSPD2025R754

Acknowledgments

The authors extend their appreciation to Princess Nourah bint Abdulrahman University researcher supporting project number (PNURSP2025R342), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia for supporting this work. The authors also extend their appreciation to the Researchers Supporting Project number (RSPD2025R754), King Saud University, Riyadh 11451, Saudi Arabia for supporting this work.

  1. Research ethics: Agreed and fulfil the research ethics.

  2. Informed consent: No consent required.

  3. Author contributions: SA: Methodology, AM: Conceptualization, Supervision; WR: supervision, MS Writing, Conceptualization: Y.K; methodology, LR: Data Curation; ASA: Validation, MS editing; MH; Formal Analysis, Visualization; AH: Software; SB: data curation; MY: Resources; KA: Softaware, data analysis.

  4. Use of Large Language Models, AI and Machine Learning Tools: No tool used.

  5. Conflict of interest: No conflict of interest.

  6. Research funding: This work is supported by Princess Nourah bint Abdulrahman University researcher supporting project number (PNURSP2025R342), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. This work is also supported by the Researchers Supporting Project number (RSPD2025R754), King Saud University, Riyadh 11451, Saudi Arabia.

  7. Data availability: The data could be made available, if requested.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/pac-2025-0459).

Received: 2025-03-13
Accepted: 2025-04-28
Published Online: 2025-05-23

© 2025 IUPAC & De Gruyter

https://doi.org/10.1515/pac-2025-0459
Keywords for this article
α-amylase; α-glucosidase; indazole; molecular modelling; SAR; triazole
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