Thareja, SureshVerma, Sant KumarJain, Akhlesh KumarKumar, ManojBhardwaj, Tilak Raj2024-01-212024-08-132024-01-212024-08-132022-11-1222286010.1016/j.molstruc.2022.134546http://10.2.3.109/handle/32116/3580To 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.en-USBiphenylDiabesityInsulin resistanceProtein tyrosine phosphatase 1BThiazolidinedioneType 2 diabetes mellitusArticlehttps://linkinghub.elsevier.com/retrieve/pii/S0022286022021913