8-Mercaptoguanine-based inhibitors of Mycobacterium tuberculosis dihydroneopterin aldolase: synthesis, in vitro inhibition and docking studies. (1st January 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 36:Number 1(2021)
• Page Start: 847
• Page End: 855
• Publication Date: 2021-01-01
• Subjects: Tuberculosis -- dihydroneopterin aldolase -- 8-mercaptoguanine -- MtDHNA/MtFolB inhibition; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2021.1900157
• Languages: English
• ISSNs: 1475-6366

Abstract

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 ( Mt FolB) 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 Mt FolB. 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 Mt FolB inhibitors.