Carborane clusters increase the potency of bis-substituted cyclam derivatives against Mycobacterium tuberculosis

Abstract

Bis-substituted cyclam derivatives have recently emerged as a promising new class of antibacterial agents, displaying excellent activity against drug-resistant Mycobacterium tuberculosis (Mtb) and in vivo efficacy in a zebrafish assay. Herein we report the synthesis and biological activity of new carborane derivatives within this class of antitubercular compounds. The resulting carborane-cyclam conjugates incorporating either hydrophobic closo-1,2-carborane or anionic, hydrophilic nido-7,8-carborane clusters display promising activity in an antibacterial assay employing the virulent Mtb strain H37Rv. The most active of these carborane derivatives exhibit MIC₅₀ values of <1 μM, making them the most active compounds in this unique class of antibacterial cyclams reported to date.

Fig. 1. Previously reported bis-substituted cyclam derivatives and their activity against Mtb strain H37Rv.

Scheme 1. Synthesis of closo-1,2- (8, 9) and nido-7,8- (Cs₂·10) carboranyl–cyclam derivatives.

Scheme 2. Synthesis of ‘click’ coupled carborane–cyclam conjugates 14 and Cs₂·15.

Scheme 3. Synthesis of (E)-alkenyl-linked closo-1,2- (19) and nido-7,8- (Cs₂·20) carborane–cyclam conjugates.