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

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dc.contributor.authorThareja, Suresh
dc.contributor.authorVerma, Sant Kumar
dc.contributor.authorJain, Akhlesh Kumar
dc.contributor.authorKumar, Manoj
dc.contributor.authorBhardwaj, Tilak Raj
dc.date.accessioned2024-01-21T10:38:28Z
dc.date.accessioned2024-08-13T12:05:24Z
dc.date.available2024-01-21T10:38:28Z
dc.date.available2024-08-13T12:05:24Z
dc.date.issued2022-11-12T00:00:00
dc.description.abstractTo 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_US
dc.identifier.doi10.1016/j.molstruc.2022.134546
dc.identifier.issn222860
dc.identifier.urihttp://10.2.3.109/handle/32116/3580
dc.identifier.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0022286022021913
dc.language.isoen_USen_US
dc.publisherElsevier B.V.en_US
dc.subjectBiphenylen_US
dc.subjectDiabesityen_US
dc.subjectInsulin resistanceen_US
dc.subjectProtein tyrosine phosphatase 1Ben_US
dc.subjectThiazolidinedioneen_US
dc.subjectType 2 diabetes mellitusen_US
dc.titleRational design and synthesis of novel biphenyl thiazolidinedione conjugates as inhibitors of protein tyrosine phosphatase 1B for the management of type 2 diabetesen_US
dc.title.journalJournal of Molecular Structureen_US
dc.typeArticleen_US
dc.type.accesstypeClosed Accessen_US

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