The first chemical synthesis of the core structure of the benzoylhydrazine-NAD adduct, a competitive inhibitor of the Mycobacterium tuberculosis enoyl reductase.
[reaction: see text] An isoniazid-NAD adduct has been recently proposed as the ultimate metabolite responsible for the antituberculous activity of isoniazid (INH). Its structure results from binding of the isonicotinoyl radical at C4 position of the nicotinamide ring of NAD with further possible and debated cyclization to form a cyclic hemiamidal derivative. Replacing the pyridine cycle of INH in INH-NAD adduct by a phenyl cycle (BH-NAD adduct) was shown previously to still retain the activity. On these bases, the core structure (4-benzoyl-1,4-dihydronicotinamide ribonucleoside) of the BH-NAD adduct and a series of analogues have been synthesized by using 3,4-pyridinedicarboximide as starting material. Depending on the nature of the substituent (pyridine or aryl) and on the oxidized or the reduced state of the nicotinamide nucleus, they were found either in a cyclized hemiamidal or an opened form or were shown to exist in equilibrium under cyclized or opened forms. Although none of these compounds could significantly inhibit activity of the InhA or MabA reductases (two possible targets of isoniazid), they represent attractive targets to develop potential second-generation inhibitors, including the total chemical synthesis of the bioactive BH-NAD adduct.
Broussy
Sylvain
S
Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, 31077 Toulouse Cedex 4, France.
Bernardes-Génisson
Vania
V
Quémard
Annaïk
A
Meunier
Bernard
B
Bernadou
Jean
J
D000995:Antitubercular Agents / Q000138:chemical synthesis*; D001667:Binding, Competitive; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D009243:NAD / Q000138:chemical synthesis* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*
D000995:Antitubercular Agents; D004791:Enzyme Inhibitors; D006834:Hydrazines; D009243:NAD; D010088:Oxidoreductases; C006712:benzoylhydrazine