2. Academic Validation
  3. Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: Discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors

Designed multiple ligands for the treatment of type 2 diabetes mellitus and its complications: Discovery of (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids active as novel dual-targeted PTP1B/AKR1B1 inhibitors

  • Eur J Med Chem. 2023 Apr 5;252:115270. doi: 10.1016/j.ejmech.2023.115270.
Rosanna Maccari 1,  Gerhard Wolber 2,  Massimo Genovese 3,  Gemma Sardelli 4,  Valerij Talagayev 2,  Francesco Balestri 4,  Simone Luti 3,  Alice Santi 3,  Roberta Moschini 4,  Antonella Del Corso 4,  Paolo Paoli 5,  Rosaria Ottanà 6
Affiliations

Affiliations

  • 1 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy. Electronic address: [email protected].
  • 2 Molecular Design Lab, Institute of Pharmacy, Freie Universität Berlin, Königin-Luisestr. 2 + 4, 14195, Berlin, Germany.
  • 3 Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134, Firenze, Italy.
  • 4 Department of Biology, Biochemistry Unit, University of Pisa, via S. Zeno, 51, 56123, Pisa, Italy.
  • 5 Department of Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, University of Firenze, Viale Morgagni 50, 50134, Firenze, Italy. Electronic address: [email protected].
  • 6 Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166, Messina, Italy.
PMID: 36934484 DOI: 10.1016/j.ejmech.2023.115270
Abstract

Type 2 diabetes mellitus (T2DM) is a serious chronic disease with an alarmingly growing worldwide prevalence. Current treatment of T2DM mainly relies on drug combinations in order to control blood glucose levels and consequently prevent the onset of hyperglycaemia-related complications. The development of multiple-targeted drugs recently emerged as an attractive alternative to drug combinations for the treatment of complex diseases with multifactorial pathogenesis, such as T2DM. Protein tyrosine Phosphatase 1B (PTP1B) and Aldose Reductase (AKR1B1) are two enzymes crucially involved in the development of T2DM and its chronic complications and, therefore, dual inhibitors targeted to both these enzymes could provide novel agents for the treatment of this complex pathological condition. In continuing our search for dual-targeted PTP1B/AKR1B1 inhibitors, we designed new (5-arylidene-4-oxo-2-thioxothiazolidin-3-yl)alkanoic acids. Among them, 3-(4-phenylbutoxy)benzylidene derivatives 6f and 7f, endowed with interesting inhibitory activity against both targets, proved to control specific cellular pathways implicated in the development of T2DM and related complications.

Keywords

4-thiazolidinone derivatives; Aldose reductase; Diabetes mellitus; Multiple ligands; Protein tyrosine phosphatase 1B.

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