Monika Rakse*, Chandrabose Karthikeyan, Narayana Subbiah Hari Narayana Moorthy and Ram Kishore Agrawal Pages 46 - 56 ( 11 )
Background: Protein Tyrosine Phosphatase 1B (PTP1B) is an attractive target for antidiabetic drug discovery owing to its pivotal role as a negative regulator of insulin and leptin signaling.
Objective: The objective of this research is to design, synthesize, and evaluate some acetamidobenzoic acid derivatives as a novel class of protein tyrosine phosphatase 1B inhibitors with therapeutic potential for Type II diabetes.
Methods: 3-(2-(Benzo[d]thiazol-2-ylthio)acetamido)benzoic acid derivatives 4(a-j) were synthesized and characterized by employing spectral studies. All the synthesized compounds were screened for in vitro PTP1B inhibitory activity and the most potent compound in the series was also evaluated for in vivo anti-hyperglycemic activity using STZ induced diabetic Wistar rat model. Molecular docking studies were also performed with the most potent analog using FlexX docking algorithm to delineate its binding mode to the active site of the PTP1B.
Results: Among all the synthesized compounds, 3-(2-(benzo[d]thiazol-2-ylthio)acetamido)-4- methylbenzoic acid (4f) displayed good PTP1B inhibitory activity with an IC50 value of 11.17 μM. The compound also exhibited good anti hyperglycemic efficacy in streptozotocin induced diabetic Wistar rats. Docking studies with 4f revealed that the compound bound in the catalytic and second aryl binding site of the PTP1B.
Conclusion: Overall, compound 4f with good in vitro PTP1B inhibitory potency and in vivo antihyperglycemic efficacy would be a valuable lead molecule for the development of acetamidobenzoic acid based PTP1B inhibitors with antidiabetic potential.
Type II diabetes, protein tyrosine phosphatase 1B inhibitors, acetamidobenzoic acid derivatives, antidiabetic activity, molecular docking, insulin.
Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, MP, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, MP, Department of Pharmacy, Indira Gandhi National Tribal University, Lalpur, Amarkantak, MP, Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya Sagar, MP