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The Journal of Antibiotics (2017) 70, 655663& 2017 Japan Antibiotics Research Association All rights reserved 0021-8820/17 http://www.nature.com/ja
Web End =www.nature.com/ja
ORIGINAL ARTICLE
Synthesis and antibacterial activity of novel lincomycin derivatives. II. Exploring (7S)-7-(5-aryl-1,3,4-thiadiazol-2-yl-thio)-7-deoxylincomycin derivatives
Ko Kumura, Yoshinari Wakiyama, Kazutaka Ueda, Eijiro Umemura, Takashi Watanabe, Megumi Kumura, Takuji Yoshida and Keiichi Ajito
The synthesis and antibacterial activity of (7S)-7-(5-aryl-1,3,4-thiadiazol-2-yl-thio)-7-deoxylincomycin derivatives are described. These derivatives were mainly prepared by the Mitsunobu reaction of 2,3,4-tris-O-(trimethylsilyl)lincomycin and the corresponding thiols. Exploring structureactivity relationships of the substituent at the 5 position of a thiadiazole ring revealed that compounds with the ortho substituted phenyl group showed improved antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene compared with the reported compound (1) that had an unsubstituted benzene ring.
The Journal of Antibiotics (2017) 70, 655663; doi:http://dx.doi.org/10.1038/ja.2016.139
Web End =10.1038/ja.2016.139; published online 7 December 2016
INTRODUCTION
Lincomycin1 is a secondary metabolite of Streptomyces lincolnensis and active mainly against Gram positive bacteria. Clindamycin2 (CLDM) derived from lincomycin is a useful semisynthetic antibiotic that is most widely used in the lincosamide class (Figure 1). Lincosamide antibiotics are protein synthesis inhibitors3 that act on 50S ribosome in a similar way to macrolide antibiotics such as clarithromycin.4However, CLDM shows almost no antibacterial activity against resistant pathogens such as Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as shown in Table 1. Moreover, major macrolides, clarithromycin and azithromycin,5 are also not active against those pathogens with erm gene. Erm methyltransferases methylate A2058Ec of rRNA and diminish the afnity of clinically important macrolides, lincosamides and streptogramin B3, and this mode of resistance is referred to as MLS resistance.6 Increased emergence of resistant bacteria has been causing serious problems at clinical sites.7 CLDM is attractive because of its safety and effectiveness against resistant pathogens with efux pump. It is known that the antibacterial activities of macrolide antibiotics are inuenced by efux pumps of resistant S. pneumoniae and S. pyogenes with mef gene (Figure 1; Table 1). Furthermore, CLDM can be administered as oral and injectable agents. As a rare case, moreover, it has been reported that CLDM is effective for invasive group A streptococcal infections caused by S. pyogenes.8 According to these reasons, we selected lincosamide (not macrolide) as a starting material for medicinal chemistry. In...