InhA inhibitors

The prodrug isoniazid (34) targets M. tuberculosis InhA [3] after activation by a mycobacterial catalase-peroxidase by reacting irreversibly with the cofactor nicotinamide adenine dinucleotide (NAD). This covalent adduct 

Direct InhA inhibitors have also been sought to avoid isoniazid resistance mediated by catalase-peroxidase mutation. Lipophilic analogs of triclosan such as 36 show a nanomolar K on the enzyme with an MIC of 1-2 pg/mL on isoniazid-resistant strains [56]. Structure-based optimization of two separate HTS leads afforded 37 and 38, both submicromolar inhibitors of InhA but devoid of any significant antibacterial activity [57,58], 

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Stratton CF, Li H-J, Kaur T, Amin A, Johnson F, Slayden RA, 48. Kisker C, Tonge PJ. High affinity InhA inhibitors with activity against drag-resistant strains of Mycobacterium tubercrrlosis. ACS Chem. Biol. 2006 1 43-53. 49. 

Wei, C.J., Lei, B., Musser, J.M., and Tu, S.C. (2003) Isoniazid activation defects in recombinant Mycobacterium tuberculosis catalase-peroxidase (KatG) mutants evident in InhA inhibitor production. Antimicrob. Agents. Chemother. 47, 670-675. 

A series of uncompetitive inhibitors of InhA were developed using structure-based design from the crystal structure of tri-closan (4) bound to both coli enoyl reductase (called ecFabl)... 

One striking example is the Mycobacterium tuberculosis enoyl-acyl carrier protein (AGP) reductase (InhA), which catalyzes the last reaction in fatty acid elongation. This enzyme is the target of isoniazid, one of the major drugs used for treatment of tuberculosis. Isoniazid is activated by KatG, a mycobacterial catalase—peroxidase, to a species that reacts with the NAD coenzyme of InhA. The resulting adduct is a potent inhibitor of InhA. Efforts are under way to make more potent inhibitors that do not require KatG activation. 

INH-NAD bound to InhA reveals that F149 has flipped up from its position in the binary enzyme complex so that the aromatic ring forms a stacking interaction with the acyl-pyridine group of the inhibitor. 

Ruiz, E Mendoza-Losana, A., Ballell Pages, L Castro-Pichel, J., and Evindar, G. (2014) Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA. Journal of Medicinal Chemistry, 57 (4),... 

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