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

To achieve the unmet discovery of protein tyrosine phosphatase 1B (PTP1B) inhibitors, we have ratio-nally 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 mu M) compared to Suramin (IC50 = 11.104 mu M) and exhibited time-dependent in vivo efficacy, ranging from inferior to better, as com-pared to Pioglitazone. Moreover, 8j was found best pre-clinical candidate exhibiting good in vitro potency (IC50 = 5.897 mu M), better in vivo efficacy with the advantage of control in weight and pancreatic safety, compared to glitazone therapy.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

In order to discover protein tyrosine phosphatase 1B (PTP1B) inhibitors, we designed novel biphenyl thiazolidinedione conjugates (8a-n) that met the criteria of drug-likeness. One of the derivatives, N-methyl benzoic acid derivative (8j), showed strong binding interactions with PTP1B and exhibited selectivity over other PTPs. The synthesized analogues (8a-n) demonstrated moderate to good PTP1B inhibitory activity and showed time-dependent in vivo efficacy.