Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents.
Pyrazinoic acid
Tuberculosis
pyrazinamide
Journal
Bioorganic & medicinal chemistry
ISSN: 1464-3391
Titre abrégé: Bioorg Med Chem
Pays: England
ID NLM: 9413298
Informations de publication
Date de publication:
15 11 2022
15 11 2022
Historique:
received:
31
05
2022
revised:
29
09
2022
accepted:
30
09
2022
pubmed:
14
10
2022
medline:
16
11
2022
entrez:
13
10
2022
Statut:
ppublish
Résumé
Tuberculosis (TB) remains a leading cause of infectious disease-related mortality and morbidity. Pyrazinamide (PZA) is a critical component of the first-line TB treatment regimen because of its sterilizing activity against non-replicating Mycobacterium tuberculosis (Mtb), but its mechanism of action has remained enigmatic. PZA is a prodrug converted by pyrazinamidase encoded by pncA within Mtb to the active moiety, pyrazinoic acid (POA) and PZA resistance is caused by loss-of-function mutations to pyrazinamidase. We have recently shown that POA induces targeted protein degradation of the enzyme PanD, a crucial component of the coenzyme A biosynthetic pathway essential in Mtb. Based on the newly identified mechanism of action of POA, along with the crystal structure of PanD bound to POA, we designed several POA analogs using structure for interpretation to improve potency and overcome PZA resistance. We prepared and tested ring and carboxylic acid bioisosteres as well as 3, 5, 6 substitutions on the ring to study the structure activity relationships of the POA scaffold. All the analogs were evaluated for their whole cell antimycobacterial activity, and a few representative molecules were evaluated for their binding affinity, towards PanD, through isothermal titration calorimetry. We report that analogs with ring and carboxylic acid bioisosteres did not significantly enhance the antimicrobial activity, whereas the alkylamino-group substitutions at the 3 and 5 position of POA were found to be up to 5 to 10-fold more potent than POA. Further development and mechanistic analysis of these analogs may lead to a next generation POA analog for treating TB.
Identifiants
pubmed: 36228522
pii: S0968-0896(22)00439-4
doi: 10.1016/j.bmc.2022.117046
pmc: PMC10551889
mid: NIHMS1932231
pii:
doi:
Substances chimiques
pyrazinoic acid
2WB23298SP
Pyrazinamide
2KNI5N06TI
Antitubercular Agents
0
Amidohydrolases
EC 3.5.-
Carboxylic Acids
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
117046Subventions
Organisme : NIAID NIH HHS
ID : R01 AI106398
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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