Development of isoniazid-NAD truncated adducts embedding a lipophilic fragment as potential bi-substrate InhA inhibitors and antimycobacterial agents.
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.
Delaine
Tamara
T
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse, Cedex 4, France.
Bernardes-Génisson
Vania
V
Quémard
Annaïk
A
Constant
Patricia
P
Meunier
Bernard
B
Bernadou
Jean
J
D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009243:NAD / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology
D000995:Antitubercular Agents; D001426:Bacterial Proteins; C525017:isonicotinyl-NAD; D009243:NAD; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium; D007538:Isoniazid