2. Academic Validation
  3. Systematic study of 1,2,3-triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases

Systematic study of 1,2,3-triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases

  • Eur J Med Chem. 2023 Jun 5:254:115378. doi: 10.1016/j.ejmech.2023.115378.
Exequiel O J Porta 1,  María Sol Ballari 1,  Renzo Carlucci 1,  Shane Wilkinson 2,  Guoyi Ma 3,  Babu L Tekwani 3,  Guillermo R Labadie 4
Affiliations

Affiliations

  • 1 Instituto de Química Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina.
  • 2 Queen Mary University of London, Mile End Road, London, E1 4NS, UK.
  • 3 Department of Infectious Diseases, Division of Scientific Platforms, Southern Research, Birmingham, AL, 35205, USA.
  • 4 Instituto de Química Rosario (IQUIR-CONICET), Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina; Departamento de Química Orgánica, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Suipacha 531, S2002LRK, Rosario, Argentina. Electronic address: labadie@iquir-conicet.gov.ar.
PMID: 37084599 DOI: 10.1016/j.ejmech.2023.115378
Abstract

A series of thirty 1,2,3-triazolylsterols, inspired by azasterols with proven antiparasitic activity, were prepared by a stereocontrolled synthesis. Ten of these compounds constitute chimeras/hybrids of 22,26-azasterol (AZA) and 1,2,3-triazolyl azasterols. The entire library was assayed against the kinetoplastid parasites Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, the causatives agents for visceral leishmaniasis, Chagas disease, and sleeping sickness, respectively. Most of the compounds were active at submicromolar/nanomolar concentrations with high selectivity index, when compared to their cytotoxicity against mammalian cells. Analysis of in silico physicochemical properties were conducted to rationalize the activities against the neglected tropical disease pathogens. The analogs with selective activity against L. donovani (E4, IC50 0.78 μM), T brucei (E1, IC50 0.12 μM) and T. cruzi (B1- IC50 0.33 μM), and the analogs with broad-spectrum antiparasitic activities against the three kinetoplastid parasites (B1 and B3), may be promising leads for further development as selective or broad-spectrum antiparasitic drugs.

Keywords

Antiparasitic; Azasterols; Click chemistry; Kinetoplastid diseases; NTDs.

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