Department Of Pharmaceutical Sciences and Natural Products

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Subject: search.filters.subject.Insulin resistance

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    Rational design and synthesis of novel biphenyl thiazolidinedione conjugates as inhibitors of protein tyrosine phosphatase 1B for the management of type 2 diabetes
    (Elsevier B.V., 2022-11-12T00:00:00) Thareja, Suresh; Verma, Sant Kumar; Jain, Akhlesh Kumar; Kumar, Manoj; Bhardwaj, Tilak Raj
    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.
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    A Review on Molecular Mechanism of Flavonoids as Antidiabetic Agents
    (Bentham Science, 2019) Jasmin; Jaitak, Vikas
    The development of drugs possessing anti-diabetic activities is a long pursued goal in drug discovery. It has been shown that deregulated insulin mediated signaling, oxidative stress, obesity, and β-cell dysfunction are the main factors responsible for the disease. With the advent of new and more powerful screening assays and prediction tools, the idea of a drug that can effectively treat diabetes by targeting different pathways has re-bloomed. Current anti-diabetic therapy is based on synthetic drugs that very often have side effects. For this reason, there is an instantaneous need to develop or search new alternatives. Recently, more attention is being paid to the study of natural products. Their huge advantage is that they can be ingested in everyday diet. Here, we discuss various causes, putative targets, and treatment strategies, mechanistic aspects as well as structural features with a particular focus on naturally occurring flavonoids as promising starting points for anti-diabetic led development.