Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds

Abstract

Tuberculosis (TB) is a devastating disease resulting in a death every 20s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds-oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine-which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC's as low as <0.195 μM (9 and 11). Overall, the imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H(37)Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.

Figure 1

Various heterocyclic classes (1–14) explored for antitubercular activity.

Figure 2

Comparison of the MIC range against Mtb H₃₇Rv of the various heteroaromatic scaffolds prepared (MIC in μM).

Scheme 1

Synthesis of oxazoline (1) and oxazoles (2, 3) analogs. Reagents: (a) L-serine benzyl ester, DIPEA, CH₂Cl₂, 0°C to 50°C, 14 h; (b) DAST, K₂CO₃, −78°C, CH₂Cl₂, 1 h; (c) DBU, BrCCl₃, CH₂Cl₂, 0°C to RT, 2 h; (d) H₂, Pd-C, 14h; (e) Benzyl amine, EDC, DMAP, CH₃CN, room temp, 14 h.

Scheme 2

Syntheses of thiazoline (4) and thiazole (5) benzyl esters. Regents: (a) L-cysteine, NaHCO₃, MeOH/H₂O (pH = 7), reflux, 14 h; (b) Benzyl alcohol, EDC, DMAP, CH₃CN, room temp, 14 h; (c) DBU, BrCCl₃, CH₂Cl₂, 0°C to RT, 4 h.

Scheme 3

One step syntheses of benzyl 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxylate (10), benzyl 2-methylimidazo[1,2-a]pyrimidine-3-carboxylate (13) and benzyl 2,5,7-trimethylimidazo[1,2-c]pyrimidine-3-carboxylate (14). Reagents: (a) Benzyl 2-bromo-3-oxobutanoate, NaHCO₃, 1,2-dimethoxyethane, 110°C, 24–36 h.