Synthesis and antibacterial activities of C-21 functionalized derivatives of (9R)-9-amino-9-deoxoerythromycins A and B.
Selective protection of (9R)-9-amino-9-deoxoerythromycin A allowed for elimination of the 12-hydroxyl group to afford a versatile 12,21-olefin intermediate. Further modifications of the intermediate led to the syntheses of (9R)-9-deoxo-9-(N,N-dimethylamino)-12,21-epoxyerythromycin B, (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin A, and (9R)-9-deoxo-9-(N,N-dimethylamino)-21-hydroxyerythromycin B. All three compounds retained antibacterial activity against several organisms normally susceptible to (9R)-9-deoxo-9-(N,N-dimethylamino)erythromycin A. However, the 21-hydroxylated erythromycin A analogue was weaker in potency than the corresponding erythromycin B congener and much weaker than the epoxy derivative. This suggests that while substitution of a polar functionality at C-21 does not abolish antibacterial activity, introduction of vicinal polar groups at both C-12 and C-21 may lead to reduction in potency. Nevertheless, these 21-functionalized derivatives of (9R)-erythromycylamine provide an entry into novel analogues of the important macrolide antibiotic erythromycin.
Lartey
P A
PA
Anti-Infective Drug Discovery and PPD Analytical Research, Abbott Laboratories, Abbott Park, Illinois 60064.
DeNinno
S L
SL
Faghih
R
R
Hardy
D J
DJ
Clement
J J
JJ
Plattner
J J
JJ
Stephens
R L
RL
D001419:Bacteria / Q000187:drug effects*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship
D004917:Erythromycin