Rational design and synthesis of novel biphenyl thiazolidinedione conjugates as inhibitors of protein tyrosine phosphatase 1B for the management of type 2 diabetes

• Structure guided designing of Biphenyl TZD conjugates as PTP1B Inhibitors • In silico ADMET screening to identify orally active drug-like candidates • Docking study to access target binding affinity and allosteric binding features • Synthesis and characterization of designed PTP1B inhibitors • In vitro PTP1B inhibitory assay and in vivo anti-hyperglycaemic efficacy study 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 (IC 50 = 5.897-48.150 µM) compared to Suramin (IC 50 = 11.104 µM) 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 (IC 50 = 5.897 µM), better in vivo efficacy with the advantage of control in weight and pancreatic safety, compared to glitazone therapy.