Targeting InhA, the FASII Enoyl-ACP Reductase: SAR Studies on Novel Inhibitor Scaffolds

The bacterial type II fatty acid biosynthesis (FASII) pathway is an essential but unexploited target for drug discovery. In this review we summarize SAR studies on inhibitors of InhA, the enoyl-ACP reductase from the FASII pathway in M. tuberculosis. Inhibitor scaffolds that are described include the diaryl ethers, pyrrolidine carboxamides, piperazine indoleformamides, pyrazoles, arylamides, fatty acids and imidazopiperidines, all of which form ternary complexes with InhA and the NAD cofactor, as well as isoniazid and the diazaborines which covalently modify the cofactor. Analysis of the structural data has enabled the development of a common binding mode for the ternary complex inhibitors, which includes a hydrogen bond network, a large hydrophobic pocket and a third ‘ size-limited’ binding area comprised of both polar and non-polar groups. A critical factor in InhA inhibition involves ordering of the substrate binding loop, located close to the active site, and a direct link is proposed between loop ordering and slow onset enzyme inhibition. Slow onset inhibitors have long residence times on the enzyme target, a property that is of critical importance for in vivo activity.