title: Design, synthesis and enzymatic evaluation of 3-O-substituted aryl β-D-galactopyranosides as inhibitors of Trypanosoma cruzi trans-sialidase.
abstract: The trans-sialidase of Trypanosoma cruzi (TcTS) is a surface enzyme that modifies the parasite glycocalyx covering it with sialic acid. This process is essential to adhesion and invasion mechanisms in life cycle of the protozoan in the human host, making TcTS a very attractive molecular target for drug design. Using the TcTS substrate 3'-sialyllactose as prototype, D-galactose-derived potential inhibitors of TcTS were designed using strategies of molecular modification. Ten new aryl galactosides modified at carbon-3 were synthesized employing classical carbohydrate chemistry and dibutyltin oxide method for regioselective 3-O-alkylations and evaluated against TcTS by spectrofluorimetry. The 4-methoxycarbonyl-2-nitrophenyl 3-O-carboxymethyl-β-D-galactopyranoside was the most active compound inhibiting 21% of TcTS enzymatic activity at 1 mM.
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, Belo Horizonte, MG 31.270-901, Brazil.
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Silva
authors.affiliation: Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais (UFMG), Brazil.
authors.forename: José D
authors.initials: JD
authors.lastname: S Filho
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida Café S/N, Ribeirão Preto, SP 14.040-903, Brazil.
authors.forename: Peterson
authors.initials: P
authors.lastname: Andrade
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (USP), Avenida Café S/N, Ribeirão Preto, SP 14.040-903, Brazil.
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
authors.affiliation: Departamento de Produtos Farmacêuticos, Faculdade de Farmácia, Universidade Federal de Minas Gerais (UFMG), Avenida Antônio Carlos 6627, Belo Horizonte, MG 31.270-901, Brazil. Electronic address: ricardodylan@farmacia.ufmg.br.
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Alves
mesh_terms: D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005690:Galactose / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014349:Trypanosoma cruzi / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D006023:Glycoproteins; C069715:trans-sialidase; D009439:Neuraminidase; D005690:Galactose
keywords: Aryl galactosides; Dibutyltin oxide method; Drug design; Sialic acid; Trypanosoma cruzi trans-sialidase