title: 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.
abstract: 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).
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Wakiyama
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Ko
authors.initials: K
authors.lastname: Kumura
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Eijiro
authors.initials: E
authors.lastname: Umemura
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Masaki
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirai
authors.affiliation: Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd., Yokohama, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ajito
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D008034:Lincomycin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008034:Lincomycin