Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug

María Celeste Vega, Miriam Rolón, Alina Montero-Torres, Cristina Fonseca-Berzal, José Antonio Escario, Alicia Gómez-Barrio, Jorge Gálvez, Yovani Marrero-Ponce, Vicente J. Arán

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48 Scopus citations

Abstract

Chagas disease chemotherapy, currently based on only two drugs, nifurtimox and benznidazole, is far from satisfactory and therefore the development of new antichagasic compounds remains an important goal. On the basis of antichagasic properties previously described for some 1,2-disubstituted 5-nitroindazolin-3- ones (21, 33) and in order to initiate the optimization of activity of this kind of compounds, we have prepared a series of related analogs (22-32, 34-38, 58 and 59) and tested in vitro these products against epimastigote forms of Trypanosoma cruzi. 2-Benzyl-1-propyl (22), 2-benzyl-1-isopropyl (23) and 2-benzyl-1-butyl (24) derivatives have shown high trypanocidal activity and low unspecific toxicity. Other indazole derivatives with different substitution patterns (1-substituted 3-alkoxy-1H-indazoles and 2-substituted 3-alkoxy-2H-indazoles), arising from the synthetic procedures used to prepare the mentioned indazolinones, have moderate to low effectiveness. The exploration of SAR information using the concept of an activity landscape has been carried out with SARANEA software. We have also searched for structural similarities between 225 known antiprotozoan drugs and compound 22. The results confirm that compounds 22-24 constitute promising leads and that 5-nitroindazolin-3-one system is a novel anti-T. cruzi scaffold which may represent an important therapeutic alternative for the treatment of Chagas disease.

Original languageEnglish
Pages (from-to)214-227
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume58
DOIs
StatePublished - Dec 2012
Externally publishedYes

Keywords

  • Antiprotozoan agents
  • Chagas disease
  • Cluster analysis
  • Cytotoxicity
  • Indazoles
  • Structure-activity relationships

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