11,12-Carbamate ketolides

In Vitro Evaluation of 11,12-Carbamate Ketolides with Heteroatom Aryl Chains... 

The Sonogashira reaction can also be applied in quinoline halogens, attaching alkynes the quinoline ring. This method has been employed as an easy way to connect the quinoline pharmacophore tmit in interesting biological molecules as in the derivatization of 2-fluoro-6-0-propargyl-11,12-carbamate ketolide of erythromycin. ... 

X. Xu, T. Henninger, D. Abbanat, K. Bush, B. Foleno, J. Hilliard, M. Macielag, Synthesis and antibacterial activity of C2-fluoro, C6-carbamate ketolides, and their C9-oximes, Bioorg. Med. Chem. Lett. 15 (2005) 883-887. 

HMR-3647 (telithromycin TLM) (91i), one of the 11,12-cyclic carbamate ketolides bearing various heterocyclic butyl substituents at 11-Ai of carbamate (91), was synthesized from 10,ll-anhydro-12-O-imidazolyl carbonyl ketolide (90) by the reaction with the corresponding amine (Scheme 8) [125]. The synthesis of the heterocyclicbutylamines (Scheme 8, a-i) was achieved by alkylation of the respective heterocyclic amine with 4-bromobutylphthalimide in the presence of NaH or K2CO3 in DMF, followed by hydrazinolysis of phthalimide intermediates. The overall yields of these steps were 24-64%. 

Phan LT, Clark RF, Rupp M, Or YS, Chu DTW, Ma Z. Synthesis of 2-fluoro-6-0-propargyl-ll, 12-carbamate ketolides. A novel class of antibiotics. Org. Lett. 2000 2 2951-2954. 

Modification of C6-OH of the aglycone is not only possible, it is preferable. Methylation I of this hydroxyl group yields an antibiotic (cla-I rithromycin) with superior pharmacokinetics I (82). Numerous 6-0-aryl derivatives yielded I agents with superior antibiotic activity for I erythromycin, ketolide, and 11,12-carbamate derivatives (106, 116). The authors of this I study speculated that the newly introduced... 

Macrolides such as erythromycin bind 50S by occupying one large pocket formed by nucleotides within the central loop of domain V and then branch out into other neighboring pockets by way of external sugar groups or, in the case of the ketolides, by extensions from either the 11,12-carbamate or the C6-OH. With the possible exception of the 11,12-carbamate and C6-OH extensions, interactions with these satellite pockets are essentially in-... 

Douthwaite, S., Mauvaris, P, and Haastrup Hansen, L. (2(XX)). TheC 11,12-carbamate side chain of the ketolide antimicrobial telithromycin (HMR 3647) enhances binding to both MLS-sensitive and -resistant ribosome. Presented at 5th ICMAS-KO (Jan. 26-28, Seville). Poster No. 02.01. 

ABT-773, 1 l-amino-3-O-descladinosyl-l l-deoxy-3-oxo-6-0-(3"-quinolyl-2 -propenyl) erythromycin A 11,12-cyclic carbamate, is a novel ketolide antimicrobial being developed for clinical use. ABT-773 has demonstrated in vitro activity against community-acquired respiratory pathogens including penicillin/ erythromycin sensitive and resistant strains of S. pneumoniae. Due to its in vitro activity against resistant pathogens, ABT-773 may represent another therapeutic option for community-acquired pneumonia and other respiratory infections [106]. To date, published pharmacokinetic information about clinical trials is not available. The following preclinical results could be used to assist in the prediction of potential in vivo human pharmacokinetic profiles with ABT-773. 

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