title: Effect of 9-hydroxy-α- and 7-hydroxy-β-pyran naphthoquinones on Trypanosoma cruzi and structure-activity relationship studies.
abstract: The available treatment for the prevention and cure of Chagas disease, caused by the protozoan Trypanosoma cruzi, is still unsatisfactory. Thus, there is an urgent need to develop new drugs. In the last few years, our research group has focused on finding a new chemical entity able to target the infectious bloodstream trypomastigotes. In this study, we assayed 16 β-lapachone analogous with modifications in the pyran and aromatic ring to find a new prototype with high trypanocidal activity. Interestingly, two ortho-naphthoquinones presented the best trypanocidal profile (8c and 8d with an IC50/24 h of 26.9 ± 1.3 and 23.5 ± 2.5 μM, respectively), which were 4 to 17 times more effective than β-lapachone (391.5 ± 16.5 μM) and the standard drug benznidazole (103.6 ± 0.6 μM). The introduction of a hydroxyl group on the compounds' aromatic ring modulated their biological profile by increasing their activity not only for cancer cells (MDAMB435), as previously described in literature, but also against T. cruzi. The Structure-Activity Relationship (SAR) study indicated that this introduction modulated HOMO and MEP parameters, improving the trypanocidal activity.
authors.forename: David R
authors.initials: DR
authors.lastname: da Rochaa
authors.forename: Alessandra M T
authors.initials: AM
authors.lastname: de Souza
authors.forename: Ana Carolina G
authors.initials: AC
authors.lastname: de Souza
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Rubem F S
authors.initials: RF
authors.lastname: Menna-Barreto
authors.forename: Solange L
authors.initials: SL
authors.lastname: de Castro
authors.affiliation: Departamento de Quimica Organica, Instituto de Quimica,UFF, 24020-150, Niteroi, RJ, Brazil. cegvito@vm.uff.br.
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000097:blood / Q000188:drug therapy; D004195:Disease Models, Animal; D020128:Inhibitory Concentration 50; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D011714:Pyrans / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000254:growth & development / Q000472:pathogenicity
chemical_list: D009285:Naphthoquinones; D011714:Pyrans; D014344:Trypanocidal Agents