Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and “Anagrams” Generated Potent Antituberculosis Agents
文摘
Zolpidem (Ambien, 1) is an imidazo[1,2-<i>ai>]pyridine-3-acetamide and an approved drug for the treatment of insomnia. As medicinal chemists enamored by how structure imparts biological function, we found it to have strikingly similar structure to the antitubercular imidazo[1,2-<i>ai>]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10–50 μM) when screened against replicating <i>Mycobacterium tuberculosisi> (<i>Mtbi>) H37Rv. Manipulation of the Zolpidem structure, notably, to structural isomers (“anagrams”), attains remarkably improved potency (5, MIC of 0.004 μM) and impressive potency against clinically relevant drug-sensitive, multi- and extensively drug-resistant <i>Mtbi> strains (MIC < 0.03 μM). Zolpidem anagrams and analogues were synthesized and evaluated for their antitubercular potency, toxicity, and spectrum of activity against nontubercular mycobacteria and Gram-positive and Gram-negative bacteria. These efforts toward the rational design of isomeric anagrams of a well-known sleep aid underscore the possibility that further optimization of the imidazo[1,2-<i>ai>]pyridine core may well “put TB to rest”.
