title: Compound profiling and 3D-QSAR studies of hydrazone derivatives with activity against intracellular Trypanosoma cruzi.
abstract: Chagas disease is a tropical disease caused by the parasite Trypanosoma cruzi, which is endemic in Central and South America. Few treatments are available with effectiveness limited to the early (acute) stage of disease, significant toxicity and widespread drug resistance. In this work we report the outcome of a HTS-ready assay chemical library screen to identify novel, nontoxic, small-molecule inhibitors of T. cruzi. We have selected 50 compounds that possess hydrazone as a common group. The compounds were screened using recombinant T. cruzi (Tulahuen strain) expressing beta-galactosidase. A 3D quantitative structure-activity relationship (QSAR) analysis was performed using descriptors calculated from comparative molecular field analysis (CoMFA). Our findings show that of the fifty selected hydrazones, compounds LpQM-19, 28 and 31 displayed the highest activity against T. cruzi, leading to a selectivity index (SI) of 20-fold. The 3D-QSAR analysis indicates that a particular electrostatic arrangement, where electron-deficient atoms are aligned along the molecule main axis positively correlates with compound biological activity. These results provide new candidate molecules for the development of treatments against Chagas disease.
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Lívia Bandeira
authors.initials: LB
authors.lastname: Costa
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Marcos Veríssimo de Oliveira
authors.initials: MV
authors.lastname: Cardoso
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Gevanio Bezerra
authors.initials: GB
authors.lastname: de Oliveira Filho
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Paulo André Teixeira
authors.initials: PA
authors.lastname: de Moraes Gomes
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: José Wanderlan Pontes
authors.initials: JW
authors.lastname: Espíndola
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil.
authors.forename: Thays Gabrielle
authors.initials: TG
authors.lastname: de Jesus Silva
authors.affiliation: Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, FIOCRUZ, 21040-900 Rio de Janeiro, RJ, Brazil.
authors.forename: Pedro Henrique Monteiro
authors.initials: PH
authors.lastname: Torres
authors.affiliation: Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, FIOCRUZ, 21040-900 Rio de Janeiro, RJ, Brazil.
authors.forename: Floriano Paes
authors.initials: FP
authors.lastname: Silva Junior
authors.affiliation: Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Martin
authors.affiliation: Departamento de Microbiologia, Centro de Pesquisas Aggeu Magalhães, 50670-420 Recife, PE, Brazil.
authors.forename: Regina Célia Bressan Queiroz
authors.initials: RC
authors.lastname: de Figueiredo
authors.affiliation: Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-520 Recife, PE, Brazil. Electronic address: acllb2003@yahoo.com.br.
authors.forename: Ana Cristina Lima
authors.initials: AC
authors.lastname: Leite
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; 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*
chemical_list: D006835:Hydrazones; D014344:Trypanocidal Agents
keywords: 3D-QSAR; Chagas disease; Drug design; Hydrazones; Thiazoles; Thiosemicarbazones