Twelve 2,4-diamino-5-[(1,2-dihydro-6-quinolyl)methyl]pyrimidines containing gem-dimethyl or fluoromethyl substituents at the 2-position of the dihydroquinoline ring were prepared by condensations of dihydroquinolines with 2,4-diamino-5-(hydroxymethyl)pyrimidine. The dihydroquinolines were produced from the reaction of anilines with mesityl oxide or fluoroacetone. In some cases, 1-aryl-2,4-dimethylpyrroles were obtained as byproducts. Most of these pyrimidines were highly inhibitory to Escherichia coli dihydrofolate reductase (DHFR) and also had high specificity for the bacterial enzyme. 2,4-Diamino-5-[[1,2-dihydro-2,4-dimethyl-3-fluoro-2-(fluoromethyl)-8- methoxy-6(1H)quinolyl]methyl]pyrimidine had an apparent Ki value for E. coli DHFR 13 times lower than that of the control, trimethoprim (1), and was 1 order of magnitude more selective for the bacterial enzyme. It had outstanding activity against Gram-positive organisms in vitro, as well as broad-spectrum antibacterial activity equivalent to that of 1. The results of in vivo testing will be reported elsewhere. The gem-dimethyl substituents of the dihydroquinoline derivatives are considered to be responsible for the high selectivity, as well as contributing to potent bacterial DHFR inhibition. Molecular models are presented which suggest the probable interactions with the bacterial enzyme.
A series of 18 2,4-diamino-5-[(1,2,3,4-tetrahydro-6-quinolyl)methyl]pyrimidines has been prepared by the condensation of 2,4-diamino-5-(hydroxymethyl)pyrimidine with 1,2,3,4-tetrahydroquinolines in acidic medium. Several derivatives were catalytically aromatized; others were synthesized from these by routine aromatic substitution or by condensations of (anilinomethyl)pyrimidines to give quinolinylmethyl analogues. Compounds with 4-methyl-8-methoxy substitution are closely related to trimethoprim (1a) in structure and are excellent inhibitors of bacterial dihydrofolate reductase, with activity at least equivalent to that of 1a. The highest degree of inhibition was achieved with the rigid aromatic series, but greater specificity was accomplished among the tetrahydroquinoline derivatives. This was directly related to N-1 substitution of 4-methyl-8-methoxy derivatives. The spatial relationships around N-1 and protonation at this site may both affect selectivity. Such compounds also had excellent broad-spectrum in vitro antibacterial activity.
The synthesis and thymidylate synthase (TS) inhibitory activity of a series of simple benzo[f]-quinazolin-1(2H)-ones are described. Fully aromatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolated enzyme, and represent the first examples of potent, folate-based TS inhibitors that completely lack any structural feature corresponding to the (p-aminobenzoyl)glutamate moiety of the cofactor. A number of the compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 microM.
Several folate-like thymidylate synthase inhibitors are described in which the pteridine nucleus of the folic acid molecule is replaced by a benzoquinazoline moiety, which in turn is attached to the benzoylglutamate side chain by a sulfonamide link. The most potent compounds had Ki values as low as 2.5 nM against the human enzyme, were good substrates for the cellular reduced folate transport system and for folylpolyglutamate synthetase, and had IC50 values for growth inhibition of tumor cell lines as low as 70 nM.
214ChemInform Abstract Cyclocondensation of the anilines (I) with mesityl oxide (II) in the presence of iodine gives low yields of the quinolines (III). In the same way, the aminoquinoline (IV) reacts with (II) to yield the phenanthroline(V). The quinolines (III) and (V) are coupled with the hydroxylmethylpyrimidine (VI) under acidic conditions, forming the substituted quinolines (VII) and (VIII) respectively. Fluoroacetone (IX) reacts with anisidine (Ib) to produce a mixture of the regioisomers (X) and (XI) which are combined with (VI) to yield the substituted quinolines (XII) and (XIII).
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