2. Academic Validation
  3. 8-Mercaptoguanine-based inhibitors of Mycobacterium tuberculosis dihydroneopterin aldolase: synthesis, in vitro inhibition and docking studies

8-Mercaptoguanine-based inhibitors of Mycobacterium tuberculosis dihydroneopterin aldolase: synthesis, in vitro inhibition and docking studies

  • J Enzyme Inhib Med Chem. 2021 Dec;36(1):847-855. doi: 10.1080/14756366.2021.1900157.
Alexia de Matos Czeczot 1 2,  Candida Deves Roth 1,  Rodrigo Gay Ducati 1 3,  Kenia Pissinate 1,  Raoní Scheibler Rambo 1,  Luís Fernando Saraiva Macedo Timmers 3,  Bruno Lopes Abbadi 1,  Fernanda Souza Macchi 1 2,  Víctor Zajaczkowski Pestana 1,  Luiz Augusto Basso 1 2 4,  Pablo Machado 1 2,  Cristiano Valim Bizarro 1 2
Affiliations

Affiliations

  • 1 Instituto Nacional de Ciência e Tecnologia em Tuberculose, Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
  • 2 Programa de Pós-Graduação em Biologia Celular e Molecular, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
  • 3 Programa de Pós-Graduação em Biotecnologia, Universidade do Vale do Taquari, Lajeado, Brazil.
  • 4 Programa de Pós-Graduação em Medicina e Ciências da Saúde, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
PMID: 33752554 DOI: 10.1080/14756366.2021.1900157
Abstract

The dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of FolB protein is required for the conversion of 7,8-dihydroneopterin (DHNP) to 6-hydroxymethyl-7,8-dihydropterin (HP) and glycolaldehyde (GA) in the folate pathway. FolB protein from Mycobacterium tuberculosis (MtFolB) is essential for bacilli survival and represents an important molecular target for drug development. S8-functionalized 8-mercaptoguanine derivatives were synthesised and evaluated for inhibitory activity against MtFolB. The compounds showed IC50 values in the submicromolar range. The inhibition mode and inhibition constants were determined for compounds that exhibited the strongest inhibition. Additionally, molecular docking analyses were performed to suggest enzyme-inhibitor interactions and ligand conformations. To the best of our knowledge, this study describes the first class of MtFolB inhibitors.

Keywords

8-mercaptoguanine; MtDHNA/MtFolB inhibition; Tuberculosis; dihydroneopterin aldolase.

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