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Biomedical subjects

D R Brittelli

Publications and source records attributed to D R Brittelli.

6 recordsLinked to original sources
PubMed1995

An approach to the design of novel cognitive enhancers using molecular modeling and X-ray crystallography.

A novel series of cognition enhancers was designed based on molecular modeling and X-ray structure analysis of EXP-9121 (2). This new series features a spirocyclic ring system that constrains the side chain substituents into the orientation seen in the X-ray crystal structure of 2. MM2 calculations preformed on 2 accurately predicted the solid state conformation. Compounds could be rapidly assembled using a bis-Michael addition reaction. Unfortunately, in vitro testing showed moderate activity at best, suggesting the X-ray structure of 2 does not mimic the bioactive conformation.

Acetylcholine↗
PubMed1992

Antibacterials. synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 4. Multiply-substituted aryl derivatives.

The synthesis and structure-activity relationship (SAR) studies of the effect of different polysubstitution patterns in the aromatic ring of 5-(acetamidomethyl)oxazolidinone antibacterials (I) on antibacterial activity are presented. Compounds I were prepared by the six-step synthesis described previously (Gregory, W. A.; et al. J. Med. Chem. [formula: see text] 1989, 32, 1673), electrophilic aromatic substitution reactions of 3-substituted compounds, and functional-group interchange reactions of 3,4-disubstituted compounds. Antibacterial evaluation of compounds I against Staphylococcus aureus and Enterococcus faecalis gave the following results. The 2,4- and 2,5-disubstituted derivatives have weak or no antibacterial activity. Antibacterial activities of 3,4-disubstituted compounds are comparable to those of the 4-monosubstituted analogues for small 3-substituents (smaller than Br), but decline rapidly for larger 3-substituents. 3,4-Annulated derivatives are comparable in activity to their open-chain analogues. 3,5-Disubstituted and 3,4,5- and 2,4,6-trisubstituted derivatives are devoid of antibacterial activity.

Anti-Bacterial Agents↗
PubMed1990

Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 2. The "A" group.

The synthesis and structure-activity relationship (SAR) studies of the effect of varying the "A" group in a series of 5-(acetamidomethyl)oxazolidonone antibacterials (2) are described. Compounds 2 were principally prepared either by the six-step synthesis described previously (J. Med. Chem. 1989, 32, 1673) or by elaboration of the synthetic intermediate 2 (A = H) via electrophilic aromatic substitution or elaboration of the intermediate 2 (A = I) by transition metal catalyzed carbon-carbon bond-forming reactions. Antibacterial evaluation of compounds 2 with A = alkyl, ethenyl, ethynyl, hydroxyalkyl, aldo and keto, oximinoakyl, carboalkoxy, nitro, amino, halo and psi-halo, alkylthio, alkylsulfinyl, and alkysulfonyl against Staphylococcus aureus and Enterococcus faecalis led to the identification of several SAR trends. In several series of homologues (alkyl, ketyl, aximinoalkyl, amino, halo and psi-halo, and alkythio), antibacterial activity increased with increasing lipophilicity. But in series with where A is a substituent with a trior tetrasubstituted (substituent larger than H) quaternary atom attached directly to the aromatic ring (hydroxyalkyl, alkylsulfinyl, alkylsufonyl), the activity peaked at the member of the series with the "tert-butyl" connectivity pattern. Conjugated electron-withdrawing substituents also had increased activity relative to nonconjugated analogues of comparable lipophilicity.

Anti-Bacterial Agents↗
PubMed1990

An automated pulse labelling method for structure-activity relationship studies with antibacterial oxazolidinones.

The 3-aryl-2-oxooxazolidinones are a new class of synthetic antibacterial agents that potently inhibit protein synthesis. An automated pulse labelling method with [3H]-lysine was developed with Bacillus subtilis to obtain additional quantitative activity data for structure-activity relationship studies with the oxazolidinones. Inhibition constants were calculated after a Logit fit of the data into the formula: % of control = 100/(1 + e[-B(X - A)]), where B is the slope of the model, X is the natural log of the inhibitor concentration and A is the natural log of the inhibitor concentration required to inhibit protein synthesis by 50% (ln IC50). When substituents at the 5-methyl position of the heterocyclic ring (B-substituent) were NHCOCH3, OH or Cl, the correlation coefficient was 0.87 between the MIC and IC50 values (for all compounds with MICs less than or equal to 16 micrograms/ml). The D-isomers of DuP 721 (A-substituent = CH3CO) and DuP 105 (A-substituent = CH3SO) gave MICs of 128 micrograms/ml and IC50s of greater than or equal to 50 micrograms/ml for protein synthesis, showing that only the L-isomers were active. By MIC testing, oxazolidinones with the B-substituent of NHCOCH3 and the A-substituent of CH3CO, NO2, CH3S, CH3SO2 or (CH3)2CH had comparable antibacterial potency; however, pulse labelling analysis showed that compounds with an A-substituent of CH3CO or NO2 were more potent inhibitors of protein synthesis.

Anti-Infective Agents↗
PubMed1989

Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 1. The "B" group.

The synthesis and structure/activity studies of the effect of varying the "B" group in a series of oxazolidinone antibacterials (I) are described. Two synthetic routes were used: (1) alkylation of aniline with glycidol followed by dialkyl carbonate heterocyclization to afford I (A = H, B = OH), whose arene ring was further elaborated by using electrophilic aromatic substitution methodology; (2) cycloaddition of substituted aryl isocyanates with epoxides to give A and B with a variety of values. I with B = OH or Br were converted to other "B" functionalities by using SN2 methodology. Antibacterial evaluation of compounds I with A = acetyl, isopropyl, methylthio, methylsulfinyl, methylsulfonyl, and sulfonamido and a variety of different "B" groups against Staphylococcus aureus and Enterococcus faecalis concluded that the compounds with B = aminoacyl, and particularly acetamido, were the most active of those examined in each A series, possessing MICs in the range of 0.5-4 micrograms/mL for the most active compounds described.

Anti-Bacterial Agents↗