2. Academic Validation
  3. Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of α-glucosidase inhibitors with potent in vivo antihyperglycemic activities

Discovery of triazole tethered thymol/carvacrol-coumarin hybrids as new class of α-glucosidase inhibitors with potent in vivo antihyperglycemic activities

  • Eur J Med Chem. 2023 Nov 15:263:115948. doi: 10.1016/j.ejmech.2023.115948.
Atamjit Singh 1,  Karanvir Singh 2,  Kirandeep Kaur 2,  Aman Sharma 2,  Pallvi Mohana 3,  Jignesh Prajapati 4,  Uttam Kaur 5,  Dweipayan Goswami 4,  Saroj Arora 3,  Renu Chadha 6,  Preet Mohinder Singh Bedi 7
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India. Electronic address: atampanesar@gmail.com.
  • 2 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
  • 3 Department of Botanical and Environmental Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India.
  • 4 Department of Microbiology & Biotechnology, University School of Sciences, Gujrat University, Ahmedabad, Gujrat, 380009, India.
  • 5 University School of Business Management, Chandigarh University, Gharuan, 140413, India.
  • 6 University Institute of Pharmaceutical Sciences, Punjab University, Chandigarh, 160014, India.
  • 7 Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, Punjab, 143005, India; Drug and Pollution Testing Laboratory, Guru Nanak Dev University, Amritsar, Punjab, 143005, India. Electronic address: bedi_preet@yahoo.com.
PMID: 37984299 DOI: 10.1016/j.ejmech.2023.115948
Abstract

Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against α-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, synthesized and evaluated for α-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 ± 0.11 μM was selective α-glucosidase inhibitor over α-amylase (IC50 = 37.36 ± 0.84 μM). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 μM). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with α-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects [reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively] as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential α-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer α-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.

Keywords

Carvacrol; Coumarin; Diabetes mellitus; Thymol; Triazole; α-glucosidase.

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