Synthesis and characterization of pyruvate–isoniazid analogs and their copper complexes as potential ICL inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2012-05, Vol.22 (9), p.3172-3176
• Main Authors: Shingnapurkar, Dipti, Dandawate, Prasad, Anson, Christopher E., Powell, Annie K., Afrasiabi, Zahra, Sinn, Ekkehard, Pandit, Shital, Venkateswara Swamy, K., Franzblau, Scott, Padhye, Subhash
• Format: Article
• Language: English
• Subjects: anaerobiosis; Anti-Bacterial Agents; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antitubercular Agents - chemical synthesis; Biological and medical sciences; Copper - chemistry; Copper complex; drugs; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; General pharmacology; Humans; Isocitrate lyase; Isocitrate Lyase - antagonists & inhibitors; Isoniazid - analogs & derivatives; Isoniazid - chemical synthesis; macrophages; Medical sciences; Miscellaneous; Mycobacterium tuberculosis; Mycobacterium tuberculosis - drug effects; Mycobacterium tuberculosis - enzymology; Persistent mycobacteria; Pharmacology. Drug treatments; Pyruvates - chemical synthesis; Pyruvic acid
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.03.047

Conjugates of pyruvate and hydrazides including INH and their corresponding copper complexes have been synthesized, characterized and screened against Mycobacterium tuberculosis strain H37Rv. Copper complexes were found to be more potent than respective ligands. The compounds have also been docked into active site of isocitrate lyase protein cavity by computer modeling studies. Currently used anti-tubercular drugs target actively growing Mycobacterium tuberculosis (Mtb) but there are no current therapies targeting persistent mycobacteria. Isocitrate lyase (ICL) is an important enzyme of the glyoxylate shunt pathway used by Mtb for sustaining intracellular infection in inflammatory macrophages under conditions of stress such as nutrient depletion and anaerobic metabolism. Since the humans do not possess this enzyme it constitutes an attractive target for selective drug design. Present work describes synthesis and structural characterization of pyruvate–isoniazid conjugates and their copper complexes with potent anti-tubercular activities against M. tuberculosis H37Rv.