Development of isoniazid-NAD truncated adducts embedding a lipophilic fragment as potential bi-substrate InhA inhibitors and antimycobacterial agents.
Eur J Med Chem
; 45(10): 4554-61, 2010 Oct.
Article
in En
| MEDLINE
| ID: mdl-20696503
Isoniazid-NAD truncated adducts embedding a lipophilic fragment were designed, synthesized and evaluated as inhibitors of the enoyl-acyl carrier protein (ACP) reductase (InhA) of Mycobacterium tuberculosis and as antimycobacterial agents. These compounds, planned as bi-substrate inhibitors and inspired from the active metabolite of isoniazid, combine both the nicotinamide moiety of the cofactor NAD and a lipophilic hydrocarbon chain mimic of the InhA substrate. The lipophilic fragment was introduced using either Suzuki-Miyaura cross-coupling or a classical nucleophilic substitution reaction. Several compounds developed in this work were indeed able to inhibit the InhA activity and showed promising antimycobacterial activities. However a direct correlation between the expressed activity and the bi-substrate mode of action could not yet be unambiguously demonstrated.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Oxidoreductases
/
Bacterial Proteins
/
Isoniazid
/
Mycobacterium tuberculosis
/
NAD
/
Antitubercular Agents
Limits:
Humans
Language:
En
Journal:
Eur J Med Chem
Year:
2010
Document type:
Article
Affiliation country:
France
Country of publication:
France