Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents

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 appro...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2013-06, Vol.64, p.200-214
Main Authors: Jorge, Salomão Dória, Palace-Berl, Fanny, Mesquita Pasqualoto, Kerly Fernanda, Ishii, Marina, Ferreira, Adilson Kleber, Berra, Carolina Maria, Bosch, Rosemary Viola, Maria, Durvanei Augusto, Tavares, Leoberto Costa
Format: Article
Language:English
Subjects:
Benzofuroxan derivatives
Benzoxazoles - chemical synthesis
Benzoxazoles - chemistry
Benzoxazoles - pharmacology
Cell Survival
Dose-Response Relationship, Drug
Drug Design
Exploratory data analysis
External prediction
Fibroblasts - cytology
Humans
Ligands
Models, Molecular
Molecular Structure
Parasitic Sensitivity Tests
QSAR approaches
Quantitative Structure-Activity Relationship
Trypanocidal Agents - chemical synthesis
Trypanocidal Agents - chemistry
Trypanocidal Agents - pharmacology
Trypanosoma cruzi
Trypanosoma cruzi - drug effects
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Summary: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; R2 = 0.90 and Q2 = 0.77 (SDEP = 0.15)], and according to the optimum 3D-QSAR model [R2 = 0.98, Q2 = 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 (Rpred2 = 0.91) and 3D-QSAR (Rpred2 = 0.77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3.04 μM). [Display omitted] •A set of benzofuroxan derivatives as anti-Trypanosoma cruzi agents is presented.•Exploratory data analysis, Hansch approach and VolSurf formalism were applied.•The predictability for the both QSAR models was experimentally validated.•Cytotoxicity assays were performed with human fibroblasts cells.•The most active compound of the entire set was identified.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2013.03.053