Arabinosyltransferase inhibitors

Several currently used TB drugs target the biosynthesis of the unique mycobacterial cell wall structures (O Fig. 23). Ethambutol is an arabinosyltransferase inhibitor [305], and mycolic acid synthesis is targeted by several commonly used antituberculosis drugs, including isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. In addition, pyrazinamide was shown to inhibit the s)mthesis of mycolic acid precursors [306]. 

In contrast to RCM, cross metathesis is more challenging to implement because undesired homodimerization of olefins can occur. However, Lowary and co-workers took advantage of this side-reaction to access to potential arabinosyltransferase inhibitors. They reported the synthesis of a C-analog of o -D-Ara/-(l— 5)-a-D-Ara/, a motif present in the mycobacteria cell wall [132] (O Scheme 65). 

Following this strategy, a straightforward approach was developed to d-arabinose-derived methylenebisphosphonate 76 in which one phosphorus atom belongs to the 1,2-phospholane moiety (Scheme 43) [95], This compound was designed as a possible transition state inhibitor of mycobacterial arabinosyltransferases, known to play a crucial role in the biosynthesis of arabinan part of the mycobacterial cell wall. 

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