Discovery of novel isoxazolines as anti-tuberculosis agents

Abstract

Nitrofuranyl isoxazolines with increased proteolytic stability over nitrofuranyl amides were designed and synthesized leading to discovery of several compounds with potent in vitro anti-tuberculosis activity. However, their in vivo activity was limited by high protein binding and poor distribution. Consequently, a series of non-nitrofuran containing isoxazolines were prepared to determine if the core had residual anti-tuberculosis activity. This led to the discovery of novel isoxazoline 12 as anti-tuberculosis agent with a MIC(90) value of 1.56microg/mL.

Figure 1

Discovery of novel isoxazoline compound in the course of developing nitrofuran anti-tuberculosis agents.

Scheme 1. Synthesis of nitrofuranyl derivatives with an isoxazoline linker

^aReagents and conditions: a) N-Boc piperazine or piperidine, PdCl₂[P(o-tol)₃], NaO^tBu, Toluene, 100 °C, 3 h; b) N-chlorosuccinimide, pyridine, dry Et₃N, CHCl₃, 60 °C - rt, 2 h; c) CF₃COOH-H₂O, THF, rt; d) BnBr, K₂CO₃, DMF, rt, 6 h; e) EtOCOCl, Et₃N, THF, rt, 6 h; f) ⁱPrNCO, Et₃N, THF, rt, 6 h.

Scheme 2. Synthesis of Isoxazoline compounds by altering the nitrofuran motif

^aReagents and conditions: a) PdCl₂[P(o-tol)₃], NaO^tBu, Toluene, 100 °C, 3 h; b) Oxime, 5% NaOCl, cat. Et₃N, CH₂Cl₂, rt, c) Et₃N, CH₂Cl₂, rt.