An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B, in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:28

Article

Maccari, Rosanna¹  Del Corso, Antonella²  Paoli, Paolo³  Adornato, Ilenia¹  Lori, Giulia³  Balestri, Francesco²  Cappiello, Mario²  Nass, Alexandra⁴  Wolber, Gerhard⁴  Ottana, Rosaria¹ 

[1] Univ Messina, Dept Chem Biol Pharmaceut & Environm Sci, Polo Univ Annunziata, Viale SS Annunziata, I-98168 Messina, Italy

[2] Univ Pisa, Dept Biol, Biochem Unit, Via S Zeno 51, I-56123 Pisa, Italy

[3] Univ Firenze, Dept Sci Biomed Sperimentali & Clin, Sez Sci Biochim, Viale Morgagni 50, I-50134 Florence, Italy

[4] Free Univ Berlin, Inst Pharm, Comp Aided Mol Design, Koenigin Luisestr 2 4, D-14195 Berlin, Germany

关键词: Diabetes mellitus;    Designed multiple ligands;    4-Thiazolidinone derivatives;    Aldose reductase;    Protein tyrosine phosphatase 1B;   

DOI  :  10.1016/j.bmcl.2018.10.024

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

Free