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

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 bac...

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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
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cited_by cdi_FETCH-LOGICAL-c534t-b21d8929d6c623cd3e664e2cb9afce92b3b4fa07d6fd9dccf45bf8beeef1666a3
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creator 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
description 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.
doi_str_mv 10.1080/14756366.2021.1900157
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subjects 8-mercaptoguanine
dihydroneopterin aldolase
MtDHNA/MtFolB inhibition
Research Paper
Tuberculosis
title 8-Mercaptoguanine-based inhibitors of Mycobacterium tuberculosis dihydroneopterin aldolase: synthesis, in vitro inhibition and docking studies
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