Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity
The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of d...
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| Main Authors: | , , , , , , , , , , , |
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Taylor & Francis Group,
2024-12-01T00:00:00Z.
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| 042 | |a dc | ||
| 100 | 1 | 0 | |a Alexia de Matos Czeczot |e author |
| 700 | 1 | 0 | |a Mauro Neves Muniz |e author |
| 700 | 1 | 0 | |a Marcia Alberton Perelló |e author |
| 700 | 1 | 0 | |a Éverton Edésio Dinis Silva |e author |
| 700 | 1 | 0 | |a Luís Fernando Saraiva Macedo Timmers |e author |
| 700 | 1 | 0 | |a Andresa Berger |e author |
| 700 | 1 | 0 | |a Laura Calle Gonzalez |e author |
| 700 | 1 | 0 | |a Guilherme Arraché Gonçalves |e author |
| 700 | 1 | 0 | |a Sidnei Moura |e author |
| 700 | 1 | 0 | |a Pablo Machado |e author |
| 700 | 1 | 0 | |a Cristiano Valim Bizarro |e author |
| 700 | 1 | 0 | |a Luiz Augusto Basso |e author |
| 245 | 0 | 0 | |a Crystal structure of dihydroneopterin aldolase from Mycobacterium tuberculosis associated with 8-mercaptoguanine, and development of novel S8-functionalized analogues as inhibitors: Synthesis, enzyme inhibition, in vitro toxicity and antitubercular activity |
| 260 | |b Taylor & Francis Group, |c 2024-12-01T00:00:00Z. | ||
| 500 | |a 10.1080/14756366.2024.2388207 | ||
| 500 | |a 1475-6374 | ||
| 500 | |a 1475-6366 | ||
| 520 | |a The crystallographic structure of the FolB enzyme from Mycobacterium tuberculosis (MtFolB), complexed with its inhibitor 8-mercaptoguanine (8-MG), was elucidated at a resolution of 1.95 Å. A novel series of S8-functionalized 8-MG derivatives were synthesised and evaluated as in vitro inhibitors of dihydroneopterin aldolase (DHNA, EC 4.1.2.25) activity of MtFolB. These compounds exhibited IC50 values in the submicromolar range. Evaluation of the activity for five compounds indicated their inhibition mode and inhibition constants. Molecular docking analyses were performed to determine the enzyme-inhibitor intermolecular interactions and ligand conformations upon complex formation. The inhibitory activities of all compounds against the M. tuberculosis H37Rv strain were evaluated. Compound 3e exhibited a minimum inhibitory concentration in the micromolar range. Finally, Compound 3e showed no apparent toxicity in both HepG2 and Vero cells. The findings presented herein will advance the quest for novel, specific inhibitors targeting MtFolB, an attractive molecular target for TB drug development. | ||
| 546 | |a EN | ||
| 690 | |a Dihydroneopterin aldolase inhibitors | ||
| 690 | |a 8-mercaptoguanine | ||
| 690 | |a SAR | ||
| 690 | |a Mycobacterium tuberculosis | ||
| 690 | |a Therapeutics. Pharmacology | ||
| 690 | |a RM1-950 | ||
| 655 | 7 | |a article |2 local | |
| 786 | 0 | |n Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 39, Iss 1 (2024) | |
| 787 | 0 | |n https://www.tandfonline.com/doi/10.1080/14756366.2024.2388207 | |
| 787 | 0 | |n https://doaj.org/toc/1475-6366 | |
| 787 | 0 | |n https://doaj.org/toc/1475-6374 | |
| 856 | 4 | 1 | |u https://doaj.org/article/c2c86a72e6544669bcd7eb8afcc9a3b3 |z Connect to this object online. |