Hetacillin (R)- and (S)-sulfoxides. Synthesis and structure-activity relationships

Gottstein, W. J.; Kim, C U; Shih, K. M.; Mcgregor, D. N.

doi:10.1021/jm00200a022

Cited by 14 publications

(13 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…83 Sulfoxides of the semi-synthetic antibiotic, hetacillin, were obtained in a 70:30 ratio on oxidation with m-chloroperbenzoic acid. 84 They had antibacterial activities that were less than those of hetacillin itself. The (R) isomer 35 was from four-to eightfold more active than the (S) diastereoisomer.…”

Section: Penicillin and Cephalosporin Sulfoxidesmentioning

confidence: 99%

Role of sulfur chirality in the chemical processes of biology

2005

View full text Add to dashboard Cite

Chiral structures profoundly influence chemical and biological processes. While chiral carbon biomolecules have received much attention, chirality is also possible in certain sulfur compounds; just as with carbon, there can be differences in the physiological behavior of chiral sulfur compounds. For instance, one drug enantiomer, Nexium (esomeprazole, a chiral sulfoxide), is used for its superior clinical properties as a proton pump inhibitor over the racemic mixture, Prilosec (Losec, omeprazole). This critical review introduces sulfur stereochemistry and nomenclature, and provides a comprehensive approach to chiral sulfur compounds and their enzymatic reactions in general and secondary metabolism. The major structural types of biological interest are sulfonium salts, sulfoxides, and sulfoximines. (103 references).

show abstract

Section: Penicillin and Cephalosporin Sulfoxidesmentioning

confidence: 99%

Role of sulfur chirality in the chemical processes of biology

2005

View full text Add to dashboard Cite

show abstract

“…Imidazolidin-4-one is an important structural moiety existed in many natural products [(-)-Dysibetaine PP], [1] pharmaceuticals [Hetacillin], [2] and privileged scaffolds of anticonvulsant compounds [3] and antimalarial agents [4] (Figure 1). Similar imidazolones were also found in both natural products and pharmaceut-icals such as Kottamide, [5] SCH900822, GSK2137305, [6] and Glucagon Receptor Antagonists.…”

mentioning

confidence: 99%

A Decarboxylative C(sp³)−N Bond Forming Reaction to Construct 4‐Imidazolidinones via Post‐Ugi Cascade Sequence in One Pot

Song

Lei

et al. 2020

Adv Synth Catal

View full text Add to dashboard Cite

A post-Ugi one-pot cascade was developed to access 4-imidazolidinones through an intramolecular decarboxylative C(sp 3)À N bond forming reaction. The reaction has a broad tolerance for a variety of substituted aldehydes, anilines, isocyanides and glyoxylic acids. The cascade reaction scope was expanded to synthesize spiroimidazolidinone by the replacement of aldehyde with aliphatic ketone in the Ugi reaction. Subsequently, the methodology was applied to synthesize the core structures of pharmaceuticals GSK2137305 and SCH 900822 under the mild and facile conditions with one purification. This cascade reaction generates opportunities for the tailored synthesis of a range of biologically active 4-imidazolidinones through tuneable Ugi inputs.

show abstract

“…CP-(R)-sulfoxide was found to be ∼83% as active as CP against B. subtilis ATCC 6051, whereas the CP-(S)-sulfoxide/CP-P24/CP-P28 mixture and CP-P33 were found to be inactive. These values are consistent with reports that β-lactam-(R)-sulfoxides universally exhibit much greater antibacterial activity than the corresponding (S)-sulfoxides, where (R)-sulfoxides have been found to possess from 1 / 10 to more than 10-times their corresponding parent β-lactam's antibacterial activity, while the (S)-sulfoxides generally exhibit no more than ∼3% of their parent β-lactam's activity, depending on the particular combination of β-lactam and reference organism tested (17)(18)(19).…”

Section: Resultsmentioning

confidence: 99%

“…Reaction of O 3 with the thioether group of many penicillin structures is known to lead to high yields (>95%) of stereoisomeric R - and S -sulfoxides (in R : S ratios ranging from 1:4 to 24:1) . Although ( S )-sulfoxide analogues of β-lactams are reported to exhibit negligible antibacterial activities, their ( R )-sulfoxide analogues can be quite potent – , suggesting that these latter products may be at least partially responsible for the residual antibacterial activities observed during treatment of PG and CP with O 3 . However, the C-2/C-3 double bond or primary amine characteristic of cephalosporins such as CP each present potential alternative targets for attack by O 3 , the chemical and biological consequences of which are unknown.…”

Section: Introductionmentioning

confidence: 99%

Transformation of β-Lactam Antibacterial Agents during Aqueous Ozonation: Reaction Pathways and Quantitative Bioassay of Biologically-Active Oxidation Products

Dodd

Rentsch

Singer

et al. 2010

Environ. Sci. Technol.

View full text Add to dashboard Cite

Reactions of ozone (O3) with the beta-lactam antibiotics penicillin G (PG) and cephalexin (CP) have previously been found to yield products retaining antibacterial activities. These products are unequivocally identified here as the stereoisomeric (R)-sulfoxides of each parent molecule and characterized by a combination of chemical analysis and an antibacterial activity assay. PG-(R)-sulfoxide, which is approximately 15% as potent as PG itself, is formed in approximately 55% yield, whereas CP-(R)-sulfoxide, which is 83% as active as CP, is formed with a maximum 34% yield. PG-(R)-sulfoxide is recalcitrant toward further oxidation by O3, but readily transformed by hydroxyl radical (HO*) (kHO*,app"=7.4x10(9) M(-1) s(-1), pH 7), resulting in quantitative elimination of its antibacterial activity. In contrast, CP-(R)-sulfoxide is degraded by both O3 and HO* (kO3,app"=2.6x10(4) M(-1) s(-1) and kHO*,app"= 7.6x10(9) M(-1) s(-1), pH 7), leading to quantitative elimination of its antibacterial activity. During ozonation of a secondary municipal wastewater effluent sample (pH 8.1, CDOC=4.0 mg/L, [alkalinity]=3.6 mM as HCO3-) spiked with [PG]0=1 microM, PG-(R)-sulfoxide yields did not exceed 0.15 microM for O3 doses up to 100 microM (4.8 mg/L), but reached 0.47 microM with 10-mM t-BuOH added as a HO* scavenger. In contrast, CP-(R)-sulfoxide yields did not exceed 0.1 microM for the same wastewater spiked with [CP]0=1 microM in either the presence or absence of t-BuOH, indicating that CP-(R)-sulfoxide transformation is governed primarily by direct reaction with O3. These findings suggest that, for a given degree of parent compound transformation, PG-(R)-sulfoxide yields would likely be greatest during ozonation of wastewaters characterized by low O3 demands and high HO* scavenging rates, whereas CP-(R)-sulfoxide yields would be less matrix-dependent. In general, complete deactivation of penicillins during wastewater treatment will likely require higher O3 exposures than necessary for deactivation of cephalosporins.

show abstract

Hetacillin (R)- and (S)-sulfoxides. Synthesis and structure-activity relationships

Cited by 14 publications

References 0 publications

Role of sulfur chirality in the chemical processes of biology

Role of sulfur chirality in the chemical processes of biology

A Decarboxylative C(sp³)−N Bond Forming Reaction to Construct 4‐Imidazolidinones via Post‐Ugi Cascade Sequence in One Pot

Transformation of β-Lactam Antibacterial Agents during Aqueous Ozonation: Reaction Pathways and Quantitative Bioassay of Biologically-Active Oxidation Products

Contact Info

Product

Resources

About

Hetacillin (R)- and (S)-sulfoxides. Synthesis and structure-activity relationships

Cited by 14 publications

References 0 publications

Role of sulfur chirality in the chemical processes of biology

Role of sulfur chirality in the chemical processes of biology

A Decarboxylative C(sp3)−N Bond Forming Reaction to Construct 4‐Imidazolidinones via Post‐Ugi Cascade Sequence in One Pot

Transformation of β-Lactam Antibacterial Agents during Aqueous Ozonation: Reaction Pathways and Quantitative Bioassay of Biologically-Active Oxidation Products

Contact Info

Product

Resources

About

A Decarboxylative C(sp³)−N Bond Forming Reaction to Construct 4‐Imidazolidinones via Post‐Ugi Cascade Sequence in One Pot