- 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
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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).
- Wakiyama, Yoshinari,Kumura, Ko,Umemura, Eijiro,Masaki, Satomi,Ueda, Kazutaka,Sato, Yasuo,Watanabe, Takashi,Hirai, Yoko,Ajito, Keiichi
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- LINCOSAMIDE DERIVATIVE, AND ANTIBACTERIAL AGENT COMPRISING THE SAME AS ACTIVE INGREDIENT
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An objective of the present invention is to provide compounds of formula (I) or their pharmacologically acceptable salts or solvates wherein A represents aryl while R1 represents a five- or six-membered monocyclic heterocyclic group, or A represents a four- to six-membered monocyclic heterocyclic group while R1 represents aryl or a five- or six-membered monocyclic heterocyclic group; R2 represents a hydrogen atom or C1-6 alkyl; R3 represents C1-6 alkyl or C3-6 cycloalkyl-C1-4 alkyl; R4, R5, and R6 represent a hydrogen atom; R7 represents C1-6 alkyl; and m is 1 to 3. The compounds are novel lincosamide derivatives that have a potent activity against resistant Streptococcus pneumoniae. Further, the compounds are usable as antimicrobial agents and are useful for preventing or treating bacterial infectious diseases.
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(2010/04/24)
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