Novel Pyrimidines as Antitubercular Agents

Abstract

Mycobacterium tuberculosis infection is responsible for a global pandemic. New drugs are needed that do not show cross-resistance with the existing front-line therapeutics. A triazine antitubercular hit led to the design of a related pyrimidine family. The synthesis of a focused series of these analogs facilitated exploration of their in vitro activity, in vitro cytotoxicity, and physiochemical and absorption-distribution-metabolism-excretion properties. Select pyrimidines were then evaluated for their pharmacokinetic profiles in mice. The findings suggest a rationale for the further evolution of this promising series of antitubercular small molecules, which appear to share some similarities with the clinical compound PA-824 in terms of activation, while highlighting more general guidelines for the optimization of small-molecule antitubercular agents.

Keywords: Mycobacterium tuberculosis; antitubercular; pharmacokinetics; pyrimidine.

FIG 1

Structures of JSF-2019 and its two pyrimidine analogs.

FIG 2

Synthetic route to JSF-2245. (a) PhNH₂, 2,6-lutidine, DMSO, room temperature; (b) PhNH₂, 2,6-lutidine, DMSO, room temperature; (c) NH₂NH₂, DMSO, 70°C; (d) 5-nitro-2-furaldehyde, methanol, room temperature.

FIG 3

Synthetic route to JSF-2332. (a) aniline (PhNH₂), lithium hexamethyldisilazide (LiHMDS), THF, −78°C; (b) PhNH₂, 2,6-lutidine, DMSO, 60°C; (c) NH₂NH₂, DMSO, 70°C; (d) 5-nitro-2-furaldehyde, methanol, room temperature.

FIG 4

Concentrations of compound in plasma (C_plasma) plotted as a function of time for mouse 1 (◇) and mouse 2 (□) treated with JSF-2019 (A), JSF-2245 (B), JSF-2247 (C), JSF-2332 (D), JSF-2371 (E), or JSF-2372 (F). The dashed lines indicate the approximate MIC of each compound.