Original Article

Synthesis and antibacterial activity of novel lincomycin derivatives. IV. Optimization of an N-6 substituent

  • The Journal of Antibiotics volume 70, pages 11121121 (2017)
  • doi:10.1038/ja.2017.143
  • Download Citation


The design and synthesis of lincomycin derivatives modified at the C-6 and C-7 positions are described. A substituent at the C-7 position is a 5-aryl-1,3,4-thiadiazol-2-yl-thio group that generates antibacterial activities against macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes carrying an erm gene. An additional modification at the C-6 position was explored in application of information regarding pirlimycin and other related compounds. These dual modifications were accomplished by using methyl α-thiolincosaminide as a starting material. As a result of these dual modifications, the antibacterial activities were improved compared with those of compounds with a single modification at the C-7 position. The antibacterial activities of selected compounds in this report against macrolide-resistant S. pneumoniae and S. pyogenes with an erm gene were superior to those of telithromycin.

  • Subscribe to The Journal of Antibiotics for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    , , & Chemical modification of erythromycins. I. Synthesis and antibacterial activity of 6-O-methylerythromycins A. J. Antibiot. 37, 187–189 (1984).

  2. 2.

    et al. Erythromycin series. Part 13. Synthesis and structure elucidation of 10-dihydro-10-deoxo-11-methyl-11-azaerythromycin A. J. Chem. Res. Synop. 1988, 152–153 (1988).

  3. 3.

    , , & Sixteen-membered macrolides: chemical modifications and future applications. Heterocycles 89, 281–352 (2014).

  4. 4.

    et al. In vitro antibacterial activity of modithromycin, a novel 6,11-bridged bicyclolide, against respiratory pathogens, including macrolide-resistant Gram-positive cocci. Antimicrob. Agents Chemother. 55, 1588–1593 (2011).

  5. 5.

    et al. Synthesis and antibacterial activity of HMR 3647 a new ketolide highly potent against erythromycin-resistant and susceptible pathogens. Bioorg. Med. Chem. Lett. 9, 3075–3080 (1999).

  6. 6.

    et al. Severe hepatotoxicity of telithromycin: three case reports and literature review. Ann. Intern. Med. 144, 415–420 (2006).

  7. 7.

    et al. Novel azalides derived from sixteen-membered macrolides. I. Isolation of the mobile dialdehyde and its one-pot macrocyclization with an amine. J. Antibiot. 60, 407–435 (2007).

  8. 8.

    et al. Novel azalides derived from 16-membered macrolides. III. Azalides modified at the C-15 and 4” positions: improved antibacterial activities. Bioorg. Med. Chem. 18, 2735–2747 (2010).

  9. 9.

    , & Lincomycin, a new antibiotic I. Discovery and biological properties. Antimicrob. Agents Chemother. 1962, 554–559 (1962).

  10. 10.

    & Lincomycin. XI. Synthesis and structure of clindamycin. A potent antibacterial agent. J. Med. Chem. 13, 616–619 (1970).

  11. 11.

    Erythromycin resistance by ribosome modification. Antimicrob. Agents Chemother. 39, 577–585 (1995).

  12. 12.

    et al. Motilides, macrolides with gastrointestinal motor stimulating activity. I. O-substituted and tertiary N-substituted derivatives of 8,9-anhydroerythromycin A 6,9-hemiacetal. Chem. Pharm. Bull. 37, 2687–2700 (1989).

  13. 13.

    , & Role of intravenous immune globulin in streptococcal toxic shock syndrome and Clostridium difficile infection. Am. J. Health Syst. Pharm. 72, 1013–1019 (2015).

  14. 14.

    et al. Semisynthetic modification of antibiotic lincomycin. J. Antibiot. 49, 941–943 (1996).

  15. 15.

    Structure activity relationships in lincosamide and streptogramin antibiotics. J. Antimicrob. Chemother. 16(Suppl A), 13–21 (1985).

  16. 16.

    et al. Synthesis of novel lincomycin derivatives and their in vitro antibacterial activities. J. Antibiot. 66, 195–198 (2013).

  17. 17.

    et al. Synthesis and structure–activity relationships of novel lincomycin derivatives. Part 1. Newly generated antibacterial activities against Gram-positive bacteria with erm gene by C-7 modification. J. Antibiot. 69, 368–380 (2016).

  18. 18.

    et al. Synthesis and structure-activity relationships of novel lincomycin derivatives. Part 2. Synthesis of 7(S)-7-deoxy-7-(4-morpholinocarbonylphenylthio)lincomycin and its 3-dimensional analysis with rRNA. J. Antibiot. 69, 428–439 (2016).

  19. 19.

    et al. 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. J. Antibiot. 70, 52–64 (2017).

  20. 20.

    et al. Synthesis and antibacterial activity of novel lincomycin derivatives. I. Enhancement of antibacterial activities by introduction of substituted azetidines. J. Antibiot. 69, 440–445 (2016).

  21. 21.

    et al. Synthesis and antibacterial activity of novel lincomycin derivatives. II. Synthesis and antibacterial activity of novel lincomycin derivatives. II. Exploring (7S -7-(5-aryl-1,3,4-thiadiazol-2-yl-thio)-7-deoxylincomycin derivatives. J. Antibiot. 70, 655–663 (2017).

  22. 22.

    et al. Synthesis and antibacterial activity of novel lincomycin derivatives. III. Optimization of a phenyl thiadiazole moiety. J. Antibiot. doi:10.1038/ja.2017.59 (2017).

  23. 23.

    , , , & Synthesis and antimicrobial activity of clindamycin analogues: pirlimycin, a potent antibacterial agent. J. Med. Chem. 27, 216–223 (1984).

  24. 24.

    et al The lincomycin derivatives possessing antibacterial activity. WO/2004/016632 A2, 26 February (2004).

  25. 25.

    et al Novel Antimicrobial 7-Methyl Lincosamides: Pipecolamide Analogs. 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy. Poster F-1389 (2004).

  26. 26.

    et al Characterization of the Spectrum of In Vitro Activity of VIC-105555, a New Lincosamide. 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Poster F-2038 (2004).

  27. 27.

    et al. Novel antibacterial azetidine lincosamides. Bioorg. Med. Chem. Lett 18, 2645–2648 (2008).

  28. 28.

    , , & An improved synthesis of homoproline and derivatives. J. Org. Chem. 55, 738–741 (1990).

  29. 29.

    , & Lincomycin. III. The structure and stereochemistry of the carbohydrate moiety. J. Am. Chem. Soc. 89, 2448–2453 (1967).

  30. 30.

    et al. Overview of antimicrobial options for Mycoplasma pneumoniae pneumonia: focus on macrolide resistance. Clin. Respir. J. 11, 419–429 (2017).

Download references


We thank Dr E Shitara, Mr. A Tamura and Dr T Okutomi for valuable scientific discussion. We are grateful to Professor Emeritus Dr M Konno for supervision through our in-house drug discovery program in lincomycin field. We are also grateful to Ms. T Miyara, Ms. S Miki, Ms. K Kaneda, Dr T Murata and Mr. S Sato for contribution toward analytical chemistry; Mr. Y Takayama for biological studies; and Ms. M Takagi for manuscript. We also thank Ms. M Ishii for direction in intellectual properties.

Author information


  1. Pharmaceutical Research Center, Meiji Seika Pharma Co., Ltd, Yokohama, Japan

    • Ko Kumura
    • , Yoshinari Wakiyama
    • , Kazutaka Ueda
    • , Eijiro Umemura
    • , Yoko Hirai
    • , Keiko Yamada
    •  & Keiichi Ajito


  1. Search for Ko Kumura in:

  2. Search for Yoshinari Wakiyama in:

  3. Search for Kazutaka Ueda in:

  4. Search for Eijiro Umemura in:

  5. Search for Yoko Hirai in:

  6. Search for Keiko Yamada in:

  7. Search for Keiichi Ajito in:

Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to Keiichi Ajito.