期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 28, 期 23-24, 页码 3712-3720出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2018.10.024
关键词
Diabetes mellitus; Designed multiple ligands; 4-Thiazolidinone derivatives; Aldose reductase; Protein tyrosine phosphatase 1B
资金
- University of Messina
- University of Pisa
- Italian Ministry of University and Research (Miur-Finanziamento annuale individuale delle attivita base di ricerca 2018)
- University of Florence
Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1-17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.
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