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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.

Background: 3,5-Bis(arylidene)-4-piperidinones (BAP) belong to a wide class of cross conjugated dienones. The 1,5-diaryl-3-oxo-1,4-pentadienyl fragment of the BAP moiety is responsible for the molecule's anti-tumor, antioxidant, antimicrobial and anti-inflammatory manifestations. In the present study, we present combinations of phosphonate and 3,5-bis(arylidene)-4- piperidone pharmacophores. The anti-inflammatory, anti-oxidant potential, anti-proliferative, cytotoxic potential and antimicrobial of the title compounds were evaluated in in-vitro bioassay paradigms. Methods: A novel class of phosphonate linked 3,5-Bis(aryl methylene)-4-piperidone derivatives were synthesized from simple, versitalie and efficient synthetic methodology. All of the synthesized compounds were screened for their in vitro anti-inflammatory, in vitro anti-oxidant potential, in vitro anti-proliferative, in vitro cytotoxic potential and in vitro antimicrobial activity. Amongst all the synthesized compounds in series, phosphonate derivatives of 3,5-Bis(arylmethylene)-4- piperidone containing 4-hydroxy-3-methoxyphenyl curcumin like prototype were more active than phenyl substituted compounds. Results: The results of the screening revealed that compounds 5e, 5f, 5g, 5h were more active candidates as compared to 5a, 5b, 5c and 5d, however 5d can be readily endorsed as the most active compound of the series. Structure- activity relationship of the synthesized series suggested that structural resemblance of the synthesized compounds with that of curcumin was enormously accountable for the compounds anti-inflammatory, antioxidant and cytotoxic potential activity. Conclusion: The in-vitro biological spectrum indicated that the substitution of groups at third and fourth position and alkyl phosphonates substitution potentiates the activity as compared to curcumin.