Enoyl reductases as targets for the development of anti-tubercular and anti-malarial agents

• Published in: Current drug targets Vol. 8; no. 3; p. 399
• Main Authors: Oliveira, J S, Vasconcelos, I B, Moreira, I S, Santos, D S, Basso, L A
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.03.2007
• Subjects: Animals; Antimalarials - administration & dosage; Antimalarials - chemical synthesis; Antitubercular Agents - administration & dosage; Antitubercular Agents - chemical synthesis; Drug Delivery Systems - methods; Drug Delivery Systems - trends; Drug Design; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - antagonists & inhibitors; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - chemistry; Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) - metabolism; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - chemical synthesis; Humans
• ISSN: 1873-5592
• DOI: 10.2174/138945007780058942

Tuberculosis (TB) and Malaria are neglected diseases, which continue to be major causes of morbidity and mortality worldwide, killing together around 5 million people each year. Mycolic acids, the hallmark of mycobacteria, are high-molecular-weight alpha-alkyl, beta-hydroxy fatty acids. Biochemical and genetic experimental data have shown that the product of the M. tuberculosis inhA structural gene (InhA) is the primary target of isoniazid mode of action, the most prescribed anti-tubercular agent. InhA was identified as an NADH-dependent enoyl-ACP(CoA) reductase specific for long-chain enoyl thioesters and is a member of the Type II fatty acid biosynthesis system, which elongates acyl fatty acid precursors of mycolic acids. M. tuberculosis and P. falciparum enoyl reductases are targets for the development of anti-tubercular and antimalarial agents. Here we present a brief description of the mechanism of action of, and resistance to, isoniazid. In addition, data on inhibition of mycobacterial and plasmodial enoyl reductases by triclosan are presented. We also describe recent efforts to develop inhibitors of M. tuberculosis and P. falciparum enoyl reductase enzyme activity.