Rational design and synthesis of novel biphenyl thiazolidinedione conjugates as inhibitors of protein tyrosine phosphatase 1B for the management of type 2 diabetes
Date
2022-11-12Author
Thareja, Suresh
Verma, Sant Kumar
Jain, Akhlesh Kumar
Kumar, Manoj
Bhardwaj, Tilak Raj
Metadata
Show full item recordAbstract
To achieve the unmet discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors, we have rationally designed novel biphenyl thiazolidinedione conjugates (8a-n). The designed molecules were found fit on in silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) screening criteria of drug-likeness. Ligand-target binding study revealed that N-methyl benzoic acid derivative (8j) was best target fit and displayed extended plausible binding interactions with phospho-tyrosine (pTyr) loop of PTP1B, a unique bidentate binding mode for PTP1B selectivity over other PTPs. The designed analogues (8a-n) were synthesized (Scheme 1) and accessed for their in vitro PTP1B inhibitory potency, in vivo anti-hyperglycemic efficacy as well as the effect of treatment on weight and pancreatic safety. Molecules 8a-n showed moderate to good PTP1B inhibitory activity (IC50 = 5.897�48.150 �M) compared to Suramin (IC50 = 11.104 �M) and exhibited time-dependent in vivo efficacy, ranging from inferior to better, as compared to Pioglitazone. Moreover, 8j was found best pre-clinical candidate exhibiting good in vitro potency (IC50 = 5.897 �M), better in vivo efficacy with the advantage of control in weight and pancreatic safety, compared to glitazone therapy. � 2022 Elsevier B.V.
Journal
Journal of Molecular Structure
Access Type
Closed Access