Acyloxymethyl esters of ampicillin

Daehne, W. von; Frederiksen, E; Gundersen, E.; Lund, Frederick H.; Morch, P.; Petersen, H; Roholt, K.; Tybring, L.; Godtfredsen, W. O.

doi:10.1021/jm00298a005

Cited by 154 publications

(56 citation statements)

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“…Since anionic metalloporphyrins are negatively charged molecules which are generally poorly absorbed, we also evaluated a second series of compounds with the negative 86 charge transiently masked by esterification. Because simple alkyl or aryl esters are slowly hydrolysed, we also prepared acyloxymethylesters (acetoxymethyl-and pivaloyloxymethylesters) which are known to be rapidly hydrolysed after absorption (Daehne et al, 1970;Shimizu et al, 1993). …”

Section: Introductionmentioning

confidence: 99%

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Song

Witvrouw

Schols

et al. 1997

Antivir Chem Chemother

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SummaryVarious water-soluble polysulphonated and polycarboxylated porphyrins and some of their metallated derivatives have been prepared and their antiviral properties against human immunodeficiency virus (HIV-1, HIV-2), simian immunodeficiency virus and other viruses are reported. Besides these polyanionic compounds, two new series of porphyrins were included and studied from the perspective of bio-availability modulation: (i) acetylsulphonamido derivatives endowed with weak acidity properties (deprotonation gives the corresponding anionic derivatives in a pH range 4.5-8.5) and (ii) compounds with the anionic charge transiently masked by esterification (acetoxymethyl-and pivaloyloxymethylesters). Among the more active compounds in inhibiting HIV-induced cytopathic effects, the sulphonated and carboxylated porphyrin complexes were found to interact directly with the HIV protein gp 120 and not with the CD4 cellular receptor.

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Section: Introductionmentioning

confidence: 99%

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Song

Witvrouw

Schols

et al. 1997

Antivir Chem Chemother

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“…The separated organic solution was washed with brine, dried over Na2SO4 and evaporated in vacuo. The residue was crystallized from dichloromethane -ethyl acetate to yield 60 g of 5; mp 108°C (dec); IR (Nujol) 3400, 3350,1810, 1780, 1730 cm-1; NMR (DMSO-d6) 8 2.18 (s, 3H, dioxole-CH3), 2.6 (br, 2H, NH2), 2.67 (s, 3H, thiadiazole-CH3), 3 …”

Section: Methodsmentioning

confidence: 99%

KY-109, a new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties.

Kakeya

Nishizawa²,

Nishimura

et al. 1985

J. Antibiot.

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hydrochloride (KY-109) was synthesized as a bifunctional pro-drug designed to improve the oral absorption of the parent drug (KY-087), a cephalosporin similar in activity to cefamandole.The pro-drug was found to possess the desired factors for an orally active pro-drug, that is, appropriate solubility, lipophilicity and ease hydrolysis into the parent drug. As predicted from these factors, the pro-drug when administered orally to rats was well absorbed, and gave high blood levels of the parent drug.(KY-087)1) is a cephalosporin with a broad spectrum of antibacterial activity in vitro. It is, however, poorly absorbed from the gastro-intestinal tract after oral administration, probably due to its low lipo-philicity. An ester pro-drug approach is frequently utilized as a method for increasing the lipophilicity of a drug and thereby improving its absorption after oral administration. A j5-lactam antibiotic containing a relatively basic amino group can give an ester with high lipophilicity and sufficient aqueous solubility, which is significantly better absorbed orally than the parent drug1). Examples of such successful compounds are the pivaloyloxymethyl3), 1-ethoxycarbonyloxyethyl4), phtalidyl5) and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl6) esters of ampicillin. In contrast, esters of 3-lactam antibiotics lacking a basic amino group in the side chain, such as KY-087, generally seem to be weakly active when given orally, probably because they lack sufficient solubility in water for efficient absorption from the gastro-intestinal tract to occur2,7). To overcome the low aqueous solubility of such esters of KY-087, we have prepared (5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-3-cephem-4-carboxylate hydrochloride, having in addition to the ester group in the 4-position an L-alanine ester formed with the side chain a-hydroxyl group. Due to the amino group in the alanine residue, the bifunctional pro-drug might be expected to have increased aqueous solubility along with a lipophilic character.In this report we describe the physico-chemical and biological properties of the bifunctional prodrug KY-109 in comparison with those of the parent drug (KY-087) and the monofunctional pro-drug (KY-106) having only the ester group in the 4-position.

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“…Most work so far has been done on ion chelators (Grynkiewicz et al, 1985;Tsien, 1981), nucleotides (Friis and Bundgaard, 1996;Peyrottes et al, 2004;Schultz, 2003;Schultz et al, 1994Schultz et al, , 1993, inositol phosphates (Li et al, 1998;Rudolf et al, 2003;Vajanaphanich et al, 1994), phosphoinositides (Dinkel et al, 2001;Jiang et al, 1998), and other lipid derivatives . In addition, some small molecule sensor molecules (Wichmann et al, 2006;Zlokarnik et al, 1998) but also some commercial drugs rely on this technique (Krapcho et al, 1988;Starret et al, 1994;von Daehne et al, 1970).…”

Section: Membrane Permeabilitymentioning

confidence: 99%

Molecular tools for cell and systems biology

Schultz

2007

HFSP Journal

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Acyloxymethyl esters of ampicillin

Cited by 154 publications

References 0 publications

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

Anti-HIV Activities of Anionic Metalloporphyrins and Related Compounds

KY-109, a new bifunctional pro-drug of a cephalosporin. Chemistry, physico-chemical and biological properties.

Molecular tools for cell and systems biology

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