Optimization of N-benzyl-5-nitrofuran-2-carboxamide as an antitubercular agent

Abstract

The optimization campaign for a nitrofuran antitubercular hit (N-benzyl-5-nitrofuran-2-carboxamide; JSF-3449) led to the design, synthesis, and biological profiling of a family of analogs. These compounds exhibited potent in vitro antitubercular activity (MIC = 0.019-0.20 μM) against the Mycobacterium tuberculosis H37Rv strain and low in vitro cytotoxicity (CC₅₀ = 40->120 μM) towards Vero cells. Significant improvements in mouse liver microsomal stability and mouse pharmacokinetic profile were realized by introduction of an α, α-dimethylbenzyl moiety. Among these compounds, JSF-4088 is highlighted due to its in vitro antitubercular potency (MIC = 0.019 μM) and Vero cell cytotoxicity (CC₅₀ > 120 μM). The findings suggest a rationale for the continued evolution of this promising series of antitubercular small molecules.

Keywords: Benzamide; Mycobacterium tuberculosis; Nitrofuran; α, α-Dimethyl.

Figure 1.

The chemical structures of delamanid, pretomanid, and metronidazole.

Figure 2.

A) Nitrofuranylbenzylamides as antitubercular agents and B) highlight of our introduction of α,α-dimethyl substitution of the benzylic carbon to afford JSF-4088.

Scheme 1.

Reagents and conditions: a) Et₃N, DCM; b) NaH, THF, 0 °C to rt.

Scheme 2.

Reagents and conditions: a) CeCl₃, CH₃Li, THF, −78 °C to rt; b) Et₃N, DCM.

Scheme 3.

Reagents and conditions: a) CS₂CO₃, CuI, N,N-Dimethylglycine hydrochloride, dioxane, reflux, 24 h; b) Red-Al, THF, 0 °C to rt; c) CeCl₃, CH₃Li, THF, −78 °C to rt; d) Et₃N, DCM.

Scheme 4.

Reagents and conditions: a) K₂CO₃, acetone, reflux, 48 h; b) Red-Al, THF, 0 °C to rt; c) CeCl₃, CH₃Li, THF, −78 °C to rt; d) Et₃N, DCM.