No abstract

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19 F ligand-observed NMR experiments.

An interesting competitive C-C vs. C-O bond coupling reaction on N,3,5-trisubstituted pyridones is reported. These coupling reactions provided selective access to C- or O-ring-fused pyridones, both at the challenging C6-pyridone position. 1,6-C-Annulated pyridones were generally achieved in good yields with excellent chemoselectivity under Pd(0) conditions. On the other hand, full C6-regioselective Csp(2) aryloxylation was achieved under oxidative coupling promoted by silver salts to access 5,6-O-annulated pyridones. Based on various experiments and observations, mechanistic evidence of these competitive reactions was provided and it was proposed that C-O bond formation proceeded through radical cyclization. These processes were performed under mild reaction conditions and offer an efficient and attractive methodology to selectively access a large scope of C-arylated and O-arylated pyridones of biological interest.

A Versatile Domino Process for the Synthesis of Substituted 3-Aminomethylene--chromanones and 2-Pyridones Catalyzed by CsF. -Addition reaction of amines to substrate (I) is followed by pyran ring opening which leads in the next step to the desired pyridone structure and/or an unexpected 3-aminomethylene chromanone product. Optimized conditions are elaborated (CsF as the catalyst and CH2Cl2 as the solvent) which allow formation of the single products following the domino process [cf. example (Va)→(VI)]. -(PINTIALA, C.; LAWSON*, A. M.; COMESSE, S.; DAICH, A.; Tetrahedron Lett. 54 (2013) 22, 2853-2857, http://dx.