title: Synthesis, biological evaluation and chemometric analysis of indazole derivatives. 1,2-Disubstituted 5-nitroindazolinones, new prototypes of antichagasic drug.
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.
authors.affiliation: Departamento de Parasitología, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: María Celeste
authors.initials: MC
authors.lastname: Vega
authors.forename: Miriam
authors.initials: M
authors.lastname: Rolón
authors.forename: Alina
authors.initials: A
authors.lastname: Montero-Torres
authors.forename: Cristina
authors.initials: C
authors.lastname: Fonseca-Berzal
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Escario
authors.forename: Alicia
authors.initials: A
authors.lastname: Gómez-Barrio
authors.forename: Jorge
authors.initials: J
authors.lastname: Gálvez
authors.forename: Yovani
authors.initials: Y
authors.lastname: Marrero-Ponce
authors.forename: Vicente J
authors.initials: VJ
authors.lastname: Arán
mesh_terms: D004305:Dose-Response Relationship, Drug; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D007191:Indazoles; D014344:Trypanocidal Agents