Synthesis, anti-diabetic profiling and molecular docking studies of 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones 

Abstract

Aim: To synthesize novel more potent anti-diabetic agents. Methodology: A simple cost effective Hantzsch's synthetic strategy was used to synthesize 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones. Results: Fifteen new 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones were established to check their anti-diabetic potential. From alpha(α)-amylase inhibition, anti-glycation and anti-oxidant activities it is revealed that most of the compounds possess good anti-diabetic potential. All tested compounds were found to be more potent anti-diabetic agents via anti-glycation mode. The results of α-amylase and anti-oxidant inhibition revealed that compounds are less active against α-amylase and anti-oxidant assays. Conclusion: This study concludes that introduction of various electron withdrawing groups at the aryl ring and substitution of different functionalities around thiazolone nucleus could help to find out better anti-diabetic drug.

Plain language summary

Diabetes is a most spreading chronicle disease effecting millions of peoples across the globe every year and this number increases day by day. To cure the human population from this dilemma, we had synthesized, characterized and evaluated the anti-diabetic behavior of our synthesized compounds. α-Amylase, in vitro anti-glycation and anti-oxidant assays were performed to find out good lead for Diabetes Mellitus. All tested compounds were found to be excellent anti-glycating agents with IC₅₀ values far better than standard amino-guanidine (IC₅₀ = 3.582 ± 0.002 μM). Compound 4m was most efficient glycation inhibitor (IC₅₀ = 1.095 ± 0.002 μM). Cytotoxicity of all compounds was determined with in vitro hemolytic assay and found all compounds safe and bio-compatible to humans at all tested concentrations. The inhibition potential was also examined with theoretical docking studies to support our experimental results against human pancreatic alpha-amylase (HPA) and human serum albumin (HSA) proteins. All compounds showed excellent binding affinity with HSA active pockets however, only compound 4h and 4k binding affinity was good with HPA.

Summary points

• Thiazol-4-ones are the most effective heterocyclic compounds among other azoles due to large number of biological applications. A large number of commercially available pharmaceutical drugs contain this nucleus.

• In current study, a simple two-step synthetic protocol was adopted to synthesize 2-(2-arylidenehydrazinyl)thiazol-4(5H)-ones. The proposed structures were analyzed and confirmed with routine spectroscopic techniques.

• Functional groups were justified with FTIR spectroscopic data. Total number of proton and carbons present within the proposed structures were justified with NMR spectroscopic data and confirmation of proposed analogs was ascertain with HRMS.

• The synthesized analogs were tested for their anti-diabetic potential. Following biological assays were used to determine the anti-diabetic potential of synthesized compounds; α-amylase, anti-glycation and anti-oxidant.

• From α-amylase assay we concluded that none of the tested compounds is a better α-amylase inhibitor.

• All tested compounds showed excellent anti-glycation potential.

• Free radical scavenging assay revealed only compound 4h to be an excellent anti-oxidant agent.

• In vitro hemolytic assay determined almost all compounds are safe to use and found them bio-compatible.

• Molecular docking study was used to find out the ligand and receptor interactions with AutoDock vina software.

• From study, it is hypothesized that attachment of electron withdrawing groups and further substitution at the arylidene and thiazole-4-one rings could help to find out the best anti-diabetic scaffold.

Keywords: :

• anti-diabetic
• cyto-toxicity
• HRMS
• molecular docking
• NMR
• SAR
• thiazol-4(5H)-ones

Supplemental material

Supplemental data for this article can be accessed at https://doi.org/10.1080/17568919.2024.2342700

Acknowledgments

The authors thank the Researchers Supporting Project number (RSP2024R29) King Saud University, Riyadh, Saudi Arabia.

Author contributions

I, M Haroon, confirm that all authors played their role in this work and briefed as under; H Mehmood: performed the synthetic work and characterized the compounds, M Haroon: compiled the manuscript and corresponding author. T Akhtar: As supervisor of the first author, refined the paper and sharing the correspondence besides being project designer. S Woodward: supported in characterization and interpretation of data. S Haq and SM Alshehri: performed docking and its writeup.

Financial disclosure

The authors have no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Competing interests disclosure

The authors have no competing interests with any organization or entity with the materials discussed in the manuscript.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.