title: Identification of benzoylisoquinolines as potential anti-Chagas agents.
abstract: A set of three 3-benzoyl substituted isoquinolones was synthesized in good yields and assayed for in vitro trypanocidal activity against Trypanosoma cruzi, the protozoan parasite that causes Chagas' disease. Depending on the concentration evaluated, a greater or equivalent reduction in the number of bloodborne trypomastigotes compared to that observed with benznidazole, a drug currently used to attack the parasite, was observed for two of the samples. In order to assess the potential of the 3-benzoylisoquinolone nucleus as a possible scaffold in the design of novel anti-trypanosomal lead structures, a computational analysis was performed using structural and inhibition information from both functional and target assays archived in the online database, ChEMBL. Chemical space projection of the synthesized compounds along with 3067 structures with known activities against T. cruzi shows that the isoquinolones occupy a sparsely-populated region of chemical space, indicating their potential for development as a novel class of trypanocidals. In addition, 2D and 3D structural similarity analyses revealed micromolar and submicromolar inhibitors of T. cruzi in ChEMBL with high similarity to the synthesized structures.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
authors.forename: Kendall G
authors.initials: KG
authors.lastname: Byler
authors.forename: Marco
authors.initials: M
authors.lastname: Brito-Arias
authors.forename: Adrian
authors.initials: A
authors.lastname: Marquez-Navarro
authors.forename: Benjamin
authors.initials: B
authors.lastname: Nogueda-Torres
authors.forename: Luis G
authors.initials: LG
authors.lastname: Torres-Bustillos
authors.forename: Karina
authors.initials: K
authors.lastname: Martínez-Mayorga
mesh_terms: D014355:Chagas Disease / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D025341:Principal Component Analysis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D007546:Isoquinolines