Isoxazole analogs of curcuminoids with highly potent multidrug-resistant antimycobacterial activity

Abstract

Curcumin ( 1), demethoxycurcumin ( 2) and bisdemethoxycurcumin ( 3), the curcuminoid constituents of the medicinal plant Curcuma longa L., have been structurally modified to 55 analogs and antimycobacterial activity against Mycobacterium tuberculosis has been evaluated. Among the highly active curcuminoids, the isoxazole analogs are the most active group, with mono- O-methylcurcumin isoxazole ( 53) being the most active compound (MIC 0.09 μg/mL). It was 1131-fold more active than curcumin ( 1), the parent compound, and was approximately 18 and 2-fold more active than the standard drugs kanamycin and isoniazid, respectively. Compound 53 also exhibited high activity against the multidrug-resistant M. tuberculosis clinical isolates, with the MICs of 0.195–3.125 μg/mL. The structural requirements for a curcuminoid analog to exhibit antimycobacterial activity are the presence of an isoxazole ring and two unsaturated bonds on the heptyl chain. The presence of a suitable para-alkoxyl group on the aromatic ring which is attached in close proximity to the nitrogen function of the isoxazole ring and a free para-hydroxyl group on another aromatic ring enhances the biological activity.