title: Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents.
abstract: A set of substituted-[N'-(benzofuroxan-5-yl)methylene]benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases. Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents. The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0.11; F = 42.19; R(2) = 0.90 and Q(2) = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R(2) = 0.98, Q(2) = 0.93 (SDEP = 0.08)], three latent variables explained 62% of the total variance from original data. Steric and hydrophobic properties were pointed out as the key for biological activity. Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction. Then, the predictability for the both models, 2D-QSAR (Rpred(2) = 0.91) and 3D-QSAR (Rpred(2) = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 μM).
authors: Laboratório de Planejamento e Desenvolvimento de Fármacos, Departamento de Tecnologia Bioquímico Farmacêutica, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, Av. Prof Lineu Prestes, 580, São Paulo, SP 05508-900, Brazil. sdjorge@usp.br
authors: Salomão Dória
authors: SD
authors: Jorge
authors: Fanny
authors: F
authors: Palace-Berl
authors: Kerly Fernanda
authors: KF
authors: Mesquita Pasqualoto
authors: Marina
authors: M
authors: Ishii
authors: Adilson Kleber
authors: AK
authors: Ferreira
authors: Carolina Maria
authors: CM
authors: Berra
authors: Rosemary Viola
authors: RV
authors: Bosch
authors: Durvanei Augusto
authors: DA
authors: Maria
authors: Leoberto Costa
authors: LC
authors: Tavares
mesh_terms: D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D021281:Quantitative Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects*; D010069:Oxadiazoles
chemical_list: D001583:Benzoxazoles; D008024:Ligands; D014344:Trypanocidal Agents; C014354:benzofuroxan; D010069:Oxadiazoles