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

• Published in: Journal of enzyme inhibition and medicinal chemistry 2021-01, Vol.36 (1), p.847-855
• Main Authors: Czeczot, Alexia de Matos, Roth, Candida Deves, Ducati, Rodrigo Gay, Pissinate, Kenia, Rambo, Raoní Scheibler, Timmers, Luís Fernando Saraiva Macedo, Abbadi, Bruno Lopes, Macchi, Fernanda Souza, Pestana, Víctor Zajaczkowski, Basso, Luiz Augusto, Machado, Pablo, Bizarro, Cristiano Valim
• Format: Article
• Language: English
• Subjects: 8-mercaptoguanine; dihydroneopterin aldolase; MtDHNA/MtFolB inhibition; Research Paper; Tuberculosis
• ISSN: 1475-6366; 1475-6374
• DOI: 10.1080/14756366.2021.1900157

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 IC 50 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.