Macrolide antibiotics are active against Gram-positive bacteria, especially Streptococcus pneumoniae, and their safety as an oral agent has already been proved. Therefore, macrolide antibiotics are regarded as very important chemotherapeutic agents against bacterial respiratory infections as in the case of β-lactam antibiotics or new quinolones. Although clarithromycin and azithromycin, which are representatives of widely used macrolides, exhibit enhanced antibacterial activities and characteristic pharmacokinetics compared with those of erythromycin, they are not active enough against resistant bacteria of S. pneumoniae with erm gene. Recently these resistant bacteria have widely spread, especially in European and Asian countries, and caused severe social problems. Chemical modifications of erythromycin provided the clinical site with two novel ketolides, telithromycin and cethromycin, which are effective against resistant bacteria of S. pneumoniae with erm gene. No oral antibiotic, however, has been launched so far, which is effective against the resistant bacteria of S. pneumoniae and does not have any problems in safety or taste.

Regarding chemical modification of LCM, Argoudelis et al.1 investigated fundamental SAR analysis focused on the C-6 (N-1′ and C-4′) and C-7 positions in 1960s and Magerlein et al.2, 3 generated U-24,279 A, (Figure 1) which exhibited much stronger in vitro and in vivo activities compared with LCM. On the other hand, Lewis et al.4, 5 disclosed VIC-105555 (Figure 1) and proved that its in vitro activity against Enterococcus faecalis was much stronger than that of CLDM and its half-life in plasma was greatly improved compared with that of CLDM in a variety of animal species. As a pioneer work, Sztaricskai and Ōmura et al.6 reported introduction of a heterocycle via sulfur atom onto the LCM carbon framework (1 and 2 shown in Figure 1) with (7R)-configuration, by means of SN2 reaction analogous to the synthesis of CLDM. All these derivatives introduced as shown in the above exhibited substantially same antibacterial spectra as those of LCM or CLDM, and there was no description about their antibacterial activities against resistant bacteria of S. pneumoniae with erm gene. Because 3D structural interaction of CLDM-rRNA complex by X-ray single crystallographic analysis7 indicated that there were several interactions, mainly a hydrogen bonding, between the peptidyl transferase cavity (A2058Ec, G2520Ec and A2059Ec) and hydroxyl groups at the sugar moiety of CLDM, chemical modification at the sugar part was supposed to be rather difficult for improving activity. As a matter of fact, 2-deoxy-LCM8 shows only 1% activity of LCM, and this result can be explained by lack of the hydrogen bonding between A2058Ec and 2-OH of LCM. We consequently pursued modification at C-7 and then C-6 (N-1′ and C-4′), focusing on hydrophilic interaction in extra 3D spaces in the above analysis.

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