Orally active esters of cephalosporin antibiotics. 3. Synthesis and biological properties of aminoacyloxymethyl esters of 7-[D-(-)-mandelamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylic acid

Abstract

The synthesis of six amino acid acyloxymethyl esters of cefamandole (1), a semisynthetic broad-spectrum cephalosporin antibiotic, is described. These esters were examined as potentially useful orally active antibiotic prodrugs. When tested for oral efficacy against Streptococcus pyogenes C203 in mouse protection tests, the esters were not notably more active than lithium cefamandole. Further studies demonstrated that significant blood and urine levels of 1 were not obtained after dosing 2a, 2b, and 2f orally at 17 mg/kg in mice. A study of the stability to chemical hydrolysis and the possible relationship of hydrolysis to the lack of oral absorption of these esters is also presented.

Discovery of the Hemifumarate and (α-l-Alanyloxy)methyl Ether as Prodrugs of an Antirheumatic Oxindole: Prodrugs for the Enolic OH Group

“…The [(aminoacyl)oxy]methyl ether derivatives 17 − 21 were prepared in the hope that the ionizable amino functionality would further increase aqueous solubility . This appears to have been the case based on the >300-fold increase in solubility of the (α- l -alanyloxy)methyl ether tosylate 18 (150 μg/mL) over the lactate ether 12 .…”

Ncm, a Photolabile Group for Preparation of Caged Molecules: Synthesis and Biological Application

“…Rapid spontaneous hydrolysis of an α-amino ester, as observed for O -Ncm-Gly, is not unusual, and has been observed in many systems [ 35 – 42 ]. A plausible explanation is neighboring group participation: The α-amino/ammonio group can perform intramolecular general acid-base catalysis and can stabilize the tetrahedral intermediate resulting from nucleophilic attack on the carbonyl [ 36 , 43 ].…”

Improved Synthesis of Amino Acid and Dipeptide Chloromethyl Esters Using Bromochloromethane

“…[10,11] The overall yields of [4] and [5] herein described range from 50 to 74% (Table 1), representing a significant improvement over the previous method using chloroiodomethane as the chloromethylating agent. [7] The formation of the gem-diester [2] was almost completely suppressed, and thus it was easily separated from [4] or [5] by column chromatography.…”

“…[7] However, they obtained rather low global yields (9-25%) of [1], and had to face the difficulties of separating the desired ester from large amounts of the gem-diester [2], also formed as a by-product. [7] Recent work from Tsujihara's group describes an alternative synthetic route to N-blocked amino acid chloromethyl esters [1] using the reagent chloromethyl chlorosulfate, with good to excellent yields (79-100%). [8] Even though chloromethyl chlorosulfate is an excellent reagent for this reaction step, its synthesis occurs in modest yields (ca.…”

“…Synthetic route to chloromethyl esters by Wheeler and co-workers. [7] chloromethyl esters [5] (Table 1). To our best knowledge, this is the first report on the synthesis of N-blocked dipeptide chloromethyl esters.…”