2. Academic Validation
  3. Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling

Synthesis of new lophine-carbohydrate hybrids as cholinesterase inhibitors: cytotoxicity evaluation and molecular modeling

  • Medchemcomm. 2019 Nov 8;10(12):2089-2101. doi: 10.1039/c9md00358d.
João Paulo Bizarro Lopes 1,  Luana Silva 1,  Marco Antonio Ceschi 1,  Diogo Seibert Lüdtke 1,  Aline Rigon Zimmer 2,  Thais Carine Ruaro 2,  Rafael Ferreira Dantas 3,  Cristiane Martins Cardoso de Salles 4,  Floriano Paes Silva-Jr 3,  Mario Roberto Senger 3,  Gisele Barbosa 5,  Lídia Moreira Lima 5,  Isabella Alvim Guedes 6,  Laurent Emmanuel Dardenne 6
Affiliations

Affiliations

  • 1 Instituto de Química , Universidade Federal do Rio Grande do Sul , Av. Bento Gonçalves 9500, Campus do Vale , 91501-970 , Porto Alegre , RS , Brazil . Email: mceschi@iq.ufrgs.br.
  • 2 Faculdade de Farmácia, Programa de Pós-Graduação em Ciências Farmacêuticas , Universidade Federal do Rio Grande do Sul , Av. Ipiranga 2752, Bairro Petrópolis , 90610-000 , Porto Alegre , RS , Brazil.
  • 3 Laboratório de Bioquímica Experimental e Computacional de Fármacos , Instituto Oswaldo Cruz , Fundação Oswaldo Cruz , Av. Brasil, 4365 , 21040-360 , Rio de Janeiro , RJ , Brazil.
  • 4 Instituto de Ciências Exatas , Universidade Federal Rural do Rio de Janeiro , BR 465, Km 7, Campus Universitário , 23890-000 , Seropédica , RJ , Brazil.
  • 5 Laboratório de Avaliação e Síntese de Substâncias Bioativas , Centro de Ciências da Saúde , Universidade Federal do Rio de Janeiro , Cidade Universitária , 21941-902 , Rio de Janeiro , RJ , Brazil.
  • 6 Laboratório Nacional De Computação Científica-LNCC , Av. Getúlio Vargas, 333 , Petrópolis , 25651-075 , RJ , Brazil.
PMID: 32904099 DOI: 10.1039/c9md00358d
Abstract

In this study, we synthesized nine novel hybrids derived from d-xylose, d-ribose, and d-galactose sugars connected by a methylene chain with lophine. The compounds were synthesized by a four-component reaction to afford the substituted imidazole moiety, followed by the displacement reaction between sugar derivatives with an appropriate N-alkylamino-lophine. All the compounds were found to be the potent and selective inhibitors of BuChE activity in mouse serum, with compound 9a (a d-galactose derivative) being the most potent inhibitor (IC50 = 0.17 μM). According to the molecular modeling results, all the compounds indicated that the lophine moiety existed at the bottom of the BuChE cavity and formed a T-stacking interaction with Trp231, a residue accessible exclusively in the BuChE cavity. Noteworthily, only one compound exhibited activity against AChE (8b; IC50 = 2.75 μM). Moreover, the in silico ADME predictions indicated that all the hybrids formulated in this study were drug-likely, orally available, and able to reach the CNS. Further, in vitro studies demonstrated that the two most potent compounds against BuChE (8b and 9a) had no cytotoxic effects in the Vero (kidney), HepG2 (hepatic), and C6 (astroglial) cell lines.

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