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

Overview

Journal J Antibiot (Tokyo)

Specialties Infectious Diseases
Pharmacology

Date 2016 Oct 6

PMID 27703159

Citations 3

Authors

Yoshinari Wakiyama

Ko Kumura

Eijiro Umemura

Satomi Masaki

Kazutaka Ueda

Yasuo Sato

Takashi Watanabe

Yoko Hirai

Keiichi Ajito

Affiliations

Soon will be listed here.

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).

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Synthesis and structure-activity relationships of novel lincomycin derivatives. Part 4: synthesis of novel lincomycin analogs modified at the 6- and 7-positions and their potent antibacterial activities.

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