Synthesis and structure–activity relationships of novel lincomycin derivatives part 3: discovery of the 4-(pyrimidin-5-yl)phenyl group in synthesis of 7(S)-thiolincomycin analogs

Novel lincomycin derivatives possessing an aryl phenyl group or a heteroaryl phenyl group at the C-7 position via sulfur atom were synthesized by Pd-catalyzed cross-coupling reactions of 7( S )-7-deoxy-7-thiolincomycin ( 5 ) with various aryl halides. This reaction is the most useful method to synthesize a variety of 7( S )-7-deoxy-7-thiolincomycin derivatives. On the basis of analysis of structure–activity relationships of these novel lincomycin derivatives, we found that (a) the location of basicity in the C-7 side chain was an important factor to enhance antibacterial activities, and (b) compounds 22 , 36 , 42 , 43 and 44 had potent antibacterial activities against a variety of Streptococcus pneumoniae with erm gene, which cause severe respiratory infections, even compared with our C-7-modified lincomycin analogs ( 1 – 4 ) reported previously. Furthermore, 7( S )-configuration was found to be necessary for enhancing antibacterial activities from comparison of configurations at the 7-position of 36 ( S -configuration) and 41 ( R -configuration).