Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A selective and sensitive high-performance liquid chromatographic method was developed for the determination of aditoprim, a new dihydrofolate reductase inhibitor, in the plasma of cows and pigs. The compound and its internal standard were extracted with chloroform from plasma buffered at pH 9 and chromatographed on a muBondapak reversed-phase column with a mixture of acetonitrile and 0.5% ammonium carbonate aqueous solution and detected by UV absorption. Aditoprim can be quantitatively extracted from plasma. The limit for quantitative determination was ca. 0.050 micrograms/ml with a standard deviation of +/- 0.006 micrograms/ml and an accuracy of +/- 3%. The assay was linear over the concentration range 0.1-5.0 micrograms/ml (precision 0.007-0.09 micrograms/ml), and the day-to-day accuracy was better than +/- 3.5%. No interference was observed from either metabolite(s) or coadministered sulphonamides. The new procedure was compared with a microbiological assay by analysing plasma samples from pigs treated with aditoprim. The two methods gave similar results in the range 0.5-5.0 micrograms/ml.
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PMID:Determination of aditoprim, a new dihydrofolate reductase inhibitor, in the plasma of cows and pigs. 381 29

The synthesis of 12 new 5,8-dideazafolates with isopropyl, cyclopropylmethyl, 2-fluoroethyl, carbamoylmethyl, phenacyl, 3-fluorobenzyl, 5-uracilylmethyl, carboxymethyl, 2-carboxyethyl, 3-cyanopropyl, 3-hydroxypropyl, and cyanomethyl substituents at N10 is described. In general, the synthetic route involved monoalkylation of diethyl N-(4-amino-benzoyl)-L-glutamate, coupling of the resulting secondary amine with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide in N,N-dimethylacetamide with calcium carbonate as the base, and deprotection using mild alkali. The cyanomethyl derivatives was found to be unexpectedly base labile and was therefore prepared by mild acid deprotection of a di-tert-butyl ester. The compounds were tested as inhibitors of purified L1210 thymidylate synthase (TS). Four members of the series were more potent that the N10-hydrogen compound, but none was superior to the previously described N10-propargyl-5,8-dideazafolic acid. Selected compounds were examined as inhibitors of purified L1210 dihydrofolate reductase (DHFR). As desired, N10 substitution in general reduced DHFR inhibitory activity; these results are discussed. As a measure of cytotoxicity, the compounds were examined for their inhibition of the growth of L1210 cells in culture. None of the new substituents conferred enhanced potency relative to N10-propargyl-5,8-dideazafolic acid (ID50 = 5 microM), which, as the best TS inhibitor and a relatively poor DHFR inhibitor, continues to lead this series.
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PMID:Quinazoline antifolates inhibiting thymidylate synthase: variation of the N10 substituent. 404 22

Triazenyl-substituted pyrimethamine derivatives 10a-s have been prepared by coupling diazotized 2,4-diamino-5-(3-amino-4-chlorophenyl)-6-ethyl pyrimidine (1c) with a series of secondary amines in aqueous sodium carbonate solution. The triazenes which are stable and poorly soluble as free bases form more soluble, but unstable, salts with alkanesulfonic acids. The lead dimethyltriazene 2,4-diamino-5[4-chloro-3-(3,3-dimethyltriazen-1-yl)phenyl]-6-et hylpyrimidine (4a) forms a crystalline ethanesulfonic acid salt (solvated with 2-propanol), which is protonated at the pyrimidine N-1 position, as determined by X-ray crystallography. The ability of these new triazenes to inhibit Pneumocystis carinii dihydrofolate reductase in vitro has been compared to that of triazene 4a. The most potent and selective compound, 2,4-diamino-5-[3-[3-[2-(acetyloxy)ethyl]-3-benzyltriazen-1-y l]-4- chlorophenyl]-6-ethylpyrimidine (14a), has an IC50 value of 0.17 microM against the microbial enzyme and potentially useful selectivity (rat liver IC50/P. carinii IC50 = 114).
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PMID:Structural studies on bioactive compounds. 28. Selective activity of triazenyl-substituted pyrimethamine derivatives against Pneumocystis carinii dihydrofolate reductase. 919 66