Putting Tuberculosis (TB) To Rest: Transformation of the Sleep Aid, Ambien, and "Anagrams" Generated Potent Antituberculosis Agents

Abstract

Zolpidem (Ambien, 1) is an imidazo[1,2-a]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-a]pyridine-3-carboxyamides. Zolpidem was found to have antituberculosis activity (MIC of 10-50 μM) when screened against replicating Mycobacterium tuberculosis (Mtb) 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 Mtb 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-a]pyridine core may well "put TB to rest".

Keywords: Ambien; anti-TB; imidazopyridine analogues; tuberculosis; zolpidem.

Figure 1

(a) Probes of the SAR around the zolpidem scaffold in comparison to previously published antitubercular imidazo[1,2-a]pyridines (2–4). (b) Zolpidem “anagram” (isomeric) scaffold analogues explored for their antitubercular activity through specific site modifications. The conserved zolpidem structure remains in black, whereas anagram structure alterations are shown in red.

Scheme 1. Synthesis of Zolpidem “Anagrams” (5–8), Imidazo[1,2-a]pyridine-3-carboxamides (11, 12), Imidazo[1,2-a]pyridine-3-oxoacetamides (17, 21–24), and Imidazo[1,2-a]pyridine-3-acetamides (25, 29, 30)

Reagents: (a) NaHCO₃, DME, reflux, 32 h; (b) 1, LiOH, EtOH, 56 h; 2, HCl; (c) EDC, DMAP, R₁, CH₃CN, 16 h; (d) NaHCO₃, DME, reflux, 32 h; (e) 1, oxalyl chloride, 4 h; 2, R₂, Et₃N, DCE, 35 °C, 16 h; (f) 1, oxalyl chloride, DCE, 1 h; 2, Et₃N, 3 h; (g) 1, NaOH aq solution, 0 °C, 2 h; 2, HCl, 16 h; (h) EDC, DMAP, R₂, CH₃CN, 16 h; (i) zinc powder, pyridine, acetic anhydride, acetic acid, 55 °C, 16 h; (j) NBS, CH₂Cl₂, Et₃N, 12 h; (k) DME, reflux, 16 h; (l) 1. LiOH, EtOH, 56 h; 2, HCl; (m) EDC, DMAP, R₁, CH₃CN, 16 h.