Sulfones systemic antibacterials

More recently, screening efforts at Novartis have identified a hydroxamic acid containing a benzothiazinone ring system (32) [108]. This inhibitor is very potent versus S. aureus Ni -PDF (<5nM) and displays good selectivity versus matrix metalloprotease-2 (MMP-2) and MMP-13. Unfortunately (32), and all other analogues prepared, such as carbon isosteres (33), sulfones (34), N-substituted analogues (35) and N-formyl-N-hydroxylamines (36), lacked appreciable antibacterial activity in spite of their potent enzyme inhibitory activity. Further studies performed by Novartis suggest that these molecules are unable to penetrate the outer cell membrane of E. coli, and may bind to the cell membrane of S. aureus [108]. 

The antibacterial agent flumequine 280 was synthetized in optically active form by starting with resolution of the two enantiomers of a suitably substituted racemic tetrahydroquinoline through formation of the (lf )-3-bromocamphor-8-sulfonates. After N-alkylation of the (2K)-tetrahydroisoquinoline enantiomer 277 with diethyl ethoxymethylene-malonate to give 278, the quinolizidine system 279 was formed by acylation onto the peri-position. This compound was finally hydrolyzed to afford 280 (Scheme 60) <1999TA1079>. 

A typical use of PCA is illustrated by an example from antibacterial research. The antibacterial effects of sulfones and sulfonamides in whole-cell and cell-free systems has been analyzed. In this example, some missing activity data (19%) have been estimated by an iterative process using PCA. However, estimation of missing values should be done with care and preferably avoided. 

Coats, E. A., Cordes, H.-R, Kulkarni, V. M., Richter, M., Schaper, K.-J., Wiese, M., Seydel, J. K. Multiple regression and principal component analysis of antibacterial activities of sulfones and sulfonamides in whole cell and cell-free systems of various DDS... 

---