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At least 145 records · Page 8Linked to original sources
PubMed2006

Exploration of the diketoacid integrase inhibitor chemotype leading to the discovery of the anilide-ketoacids chemotype.

Integrase is one of three enzymes expressed by HIV and represents a validated target for therapy. A previous study of the diketoacid-based chemotype suggested that there are two aryl-binding domains on integrase. In this study, modifications to the indole-based diketoacid chemotype are explored. It is demonstrated that the indole group can be replaced with secondary but not tertiary (e.g., N-methyl) aniline-based amides without sacrificing in vitro inhibitory activity. The difference in activity between the secondary and tertiary amides is most likely due to the opposite conformational preferences of the amide bonds, s-trans for the secondary-amide and s-cis for the tertiary-amide. However, it was found that the conformational preference of the tertiary amide can be reversed by incorporating the amide nitrogen atom into an indoline heterocycle, resulting in very potent integrase inhibitors.

Amides↗
PubMed1997

Lipophilic benzamide and anilide derivatives as high-performance liquid chromatography internal standards: application to sirolimus (rapamycin) determination.

Finding a suitable internal standard in reversed-phase high-performance liquid chromatography is often difficult. A general approach for selecting and synthesizing the proper internal standard is presented and applied to a validated method for quantitation of sirolimus in several biological matrices. A series of fifteen N-alkylbenzamides, N-alkyltoluamides and N-alkanoylanilines with a log P range of 3.51 to 6.68 were synthesized as internal standards; N-undecyl-o-toluamide was evaluated most extensively. Sirolimus quantitation involves a simple sample clean-up procedure followed by isocratic chromatography on a heated C18 analytical column with an 70% methanol-water mobile phase and ultraviolet detection at 278 nm. This method was linear from 2.5 to 200 ng with a limit of quantitation of 2.5 ng using a 1-ml blood sample. Sirolimus recovery was above 72.1%. The intra-day and inter-day coefficients of variation were less than 11.7%. Several drugs and sirolimus metabolites do not interfere with the analysis. This method was used to measure sirolimus in blood from rats, rabbits and humans.

Administration, Oral↗
PubMed2003

Discovery of 2-amino-heteroaryl-benzothiazole-6-anilides as potent p56(lck) inhibitors.

A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.

Anilides↗
PubMed1976

Cryoenzymology of chymotrypsin: the detection of intermediates in the catalysis of a specific anilide substrate.

The reaction between chymotrypsin and N-acetyl-L-phenylalanine p-nitroanilide has been studied at subzero temperatures in fluid aqueous dimethyl sulfoxide solvent. Following initiation of the reaction at temperatures as low as -90 degrees C, a series of four reactions prior to the normal rate-limiting step (acylation) was detected spectrophotometrically. Various experimental observations have led to the following interpretation of these reactions. Reaction 1 corresponds to the binding of substrate yielding the initial Michaelis complex. Reactions 2 and 3 are two pH-independent reactions, ascribed to substrate-induced changes in the positions of active-site groups. Reaction 4 is a pH-dependent reaction (pK = 5.9) which involves the imidazole of His-57 but which is not the formation of a tetrahedral intermediate, oxazolinone, or acyl enzyme. The slowest detected step corresponded to the acylation reaction. No evidence for the accumulation of a tetrahedral intermediate was obtained. Spectral, kinetic, and thermodynamic data for these reactions are presented, as is justification for the relevance of these findings to the reaction under physiological conditions. These results demonstrate the utility of subzero temperatures in enzyme mechanism studies, especially with regard to allowing the accumulation of intermediates which may be quite stable at appropriate values of pH and low temperature.

Anilides↗