In order to modify lincomycin at the C-6 and C-7 positions, we prepared target molecules, which have substituted pipecolinic acid at the 6-amino group and a para-substituted phenylthio group at the C-7 position, in application of palladium-catalyzed cross-coupling as a key reaction. As the result of structure-activity relationship (SAR) studies at the 6-position, analogs possessing 4'-cis-(cyclopropylmethyl)piperidine showed significantly strong antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with an erm gene. On the basis of SAR, we further synthesized novel analogs possessing 4'-cis-(cyclopropylmethyl)piperidine by transformation of a C-7 substituent. Consequently, novel derivatives possessing a para-heteroaromatic-phenylthio group at the C-7 position exhibited significantly strong activities against S. pneumoniae and S. pyogenes with an erm gene even when compared with those of telithromycin. Finally, in vivo efficacy of selected two derivatives was evaluated in a rat pulmonary infection model with resistant S. pneumoniae with erm + mef genes. One of them exhibited strong and constant in vivo efficacy in this model, and both compounds showed strong in vivo efficacy against resistant S. pneumoniae with a mef gene.
We synthesized 7(S)-7-deoxy-7-arylthiolincomycin derivatives possessing a heterocyclic ring at the C-7 position via sulfur atom by either Mitsunobu reaction of 2,3,4-tris-O-(trimethylsiliyl)lincomycin or SN2 reaction of 7-O-methanesulfonyl-2,3,4-tri-O-trimethylsiliyllincomycin. As a result, 7(S)-7-deoxy-7-arylthiolincomycin derivatives 16, 21 and 27 exhibited antibacterial activities against respiratory infection-related Gram-positive bacteria with erm gene, although clindamycin did not have any activities against those pathogens. Furthermore, 7(S)-configuration of lincomycin derivatives was found to be necessary for enhancing antibacterial activities from the comparison results of configurations of 16 (S-configuration) and 30 (R-configuration) at the 7-position.
The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.