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Chalcone-Based Aryloxypropanolamine as a Potential Antidiabetic and Antidyslipidaemic Agent


Affiliations
1 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
2 Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
3 Division of Pharmaceutics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
4 Division of Pharmacokinetics and Pharmaco-Dynamics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
5 Division of Biometry and Statistics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
6 Division of Toxicology, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
7 Division of Pharmacology, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
8 Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031
 

The hybrid congener 3 derived from hydroxychalcone and pharmacophore oxypropanolamine for adrenergic receptor, along with its enantiomers 9a and 9b were selected from a series of compounds for detailed studies of their antidiabetic profile in sucrose-challenged, low-dosed, streptozotocin-induced diabetic rats and in db/db mice, and antidyslipidaemic profile in high fat diet-induced dyslipidaemic hamsters. The test compounds exhibited significant and consistent antidiabetic and antidyslipidaemic activities in the above models. The pharmacodynamic studies of two metabolites, 10 and 11, were undertaken. Metabolite 10 having greater bioavailability in plasma was synthesized and found to exhibit significant antidiabetic activity. The parent compound together with its active metabolites exhibited significant oral bioavailability, thus establishing compound 3 as a potential lead molecule for further studies.

Keywords

Antidiabetic and Antidyslipidaemic Activity, Chalcone, Diabetes Mellitus, Metabolites, Rodents.
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  • Chalcone-Based Aryloxypropanolamine as a Potential Antidiabetic and Antidyslipidaemic Agent

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Authors

Poonam Shukla
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Mavurapu Satyanarayana
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Prem C. Verma
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Jaya Tiwari
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Atma P. Dwivedi
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Rohit Srivastava
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Neha Rehuja
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Swayam P. Srivastava
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Sudeep Gautam
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Akhilesh K. Tamrakar
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Anil K. Dwivedi
Division of Pharmaceutics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Hari N. Kushwaha
Division of Pharmacokinetics and Pharmaco-Dynamics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Nagsen Gautam
Division of Pharmacokinetics and Pharmaco-Dynamics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Shio K. Singh
Division of Pharmacokinetics and Pharmaco-Dynamics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Mukesh Srivastava
Division of Biometry and Statistics, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Chandishwar Nath
Division of Toxicology, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Ram Raghubir
Division of Pharmacology, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Arvind K. Srivastava
Division of Biochemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031, India
Ram Pratap
Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Sector-10 Jankipuram Extension, Sitapur Road, Lucknow 226 031

Abstract


The hybrid congener 3 derived from hydroxychalcone and pharmacophore oxypropanolamine for adrenergic receptor, along with its enantiomers 9a and 9b were selected from a series of compounds for detailed studies of their antidiabetic profile in sucrose-challenged, low-dosed, streptozotocin-induced diabetic rats and in db/db mice, and antidyslipidaemic profile in high fat diet-induced dyslipidaemic hamsters. The test compounds exhibited significant and consistent antidiabetic and antidyslipidaemic activities in the above models. The pharmacodynamic studies of two metabolites, 10 and 11, were undertaken. Metabolite 10 having greater bioavailability in plasma was synthesized and found to exhibit significant antidiabetic activity. The parent compound together with its active metabolites exhibited significant oral bioavailability, thus establishing compound 3 as a potential lead molecule for further studies.

Keywords


Antidiabetic and Antidyslipidaemic Activity, Chalcone, Diabetes Mellitus, Metabolites, Rodents.

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DOI: https://doi.org/10.18520/cs%2Fv112%2Fi08%2F1675-1689