2,4-Diamino-5-benzylpyrimidines and analogs as antibacterial agents. 12. 1,2-Dihydroquinolylmethyl analogs with high activity and specificity for bacterial dihydrofolate reductase

Abstract

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.

Quinolines spiro annulated at heterocyclic fragment: Synthesis and properties

“…The chemistry and biological activity of this type of spiro heterocompounds remain largely unexplored. Nevertheless, diverse spiro dihydroquinolines that could be useful for many sectors of the chemical industry have attracted the attention of synthetic organic chemists due to antibacterial [28], anti-inflammatory [29] and herbicidal [30,31] properties. Related substances act upon the central nervous system [32].…”

A mild and efficient synthesis of chiral tetrahydroquinolino pyranose derivatives catalyzed by lanthanum(iii) nitrate hexahydrate

“…The chemistry of tetrahydroquinoline derivatives is interesting to organic chemists owing to the presence of these scaffolds within the framework of numerous biologically interesting natural products and synthetic pharmaceutical agents [1,2]. The tetrahydroquinoline skeleton is present in many alkaloids [3][4][5], such as flindersine, orcine, and veprisine, and derivatives of these alkaloids possess a wide range of biological activities such as psychotropic, antiallergic, antiinflammatory, and estrogenic activities [6][7][8]. Therefore, many synthetic methods have been developed for these classes of compounds.…”

Synthesis of novel nitrogen containing naphtho[2,1-b]furan derivatives and investigation of their anti microbial activities

“…[14][15][16][17][18] Since the discovery of penicillin, azetidinone based heterocycles have been an important class of drugs with wide therapeutic activities [19][20][21][22][23][24] and the heterocycles containing quionolines moieties also maintain wide range of biological activities. [25][26][27][28] Hence, with these observation we examine the feasibility …”