92-81-9Relevant articles and documents
Structure-based design of selective inhibitors of dihydrofolate reductase: Synthesis and antiparasitic activity of 2,4-diaminopteridine analogues with a bridged diarylamine side chain
Rosowsky, Andre,Cody, Vivian,Galitsky, Nikolai,Fu, Hongning,Papoulis, Andrew T.,Queener, Sherry F.
, p. 4853 - 4860 (1999)
As part of a larger search for potent as well as selective inhibitors of dihydrofolate reductase (DHFR) enzymes from opportunistic pathogens found in patients with AIDS and other immune disorders, N-[(2,4-diaminopteridin-6- yl)methyl]dibenz[b,f]azepine (4a) and the corresponding dihydrodibenz[b,f]azepine, dihydroacridine, phenoxazine, phenothiazine, carbazole, and diphenylamine analogues were synthesized from 2,4-diamino-6- (bromomethyl)pteridine in 50-75% yield by reaction with the sodium salts of the amines in dry tetrahydrofuran at room temperature. The products were tested for the ability to inhibit DHFR from Pneumocystis carinii (pcDHFR), Toxoplasma gondii (tgDHFR), Mycobacterium avium (maDHFR), and rat liver (rlDHFR). The member of the series with the best combination of potency and species selectivity was 4a, with IC50 values against the four enzymes of 0.21, 0.043, 0.012, and 4.4μM, respectively. The dihydroacridine, phenothiazine, and carbazole analogues were also potent, but nonselective. Of the compounds tested, 4a was the only one to successfully combine the potency of trimetrexate with the selectivity of trimethoprim. Molecular docking simulations using published 3D structural coordinates for the crystalline ternary complexes of pcDHFR and hDHFR suggested a possible structural interpretation for the binding selectivity of 4a and the lack of selectivity of the other compounds. According to this model, 4a is selective because of a unique propensity of the seven-membered ring in the dibenz[b,f]azepine moiety to adopt a puckered orientation that allows it to fit more comfortably into the active site of the P. carinii enzyme than into the active site of the human enzyme. Compound 4a was also evaluated for the ability to be taken up into, and retard the growth of, P. carinii and T. gondii in culture. The IC50 of 4a against P. carinii trophozoites after 7 days of continuous drug treatment was 1.9μM as compared with previously observed IC50 values of >340μM for trimethoprim and 0.27 μM for trimetrexate. In an assay involving [3H]uracil incorporation into the nuclear DNA of T. gondii tachyzoites as the surrogate endpoint for growth, the IC50 of 4a after 5 h of drug exposure was 0.077 μM. The favorable combination of potency and enzyme selectivity shown by 4a suggests that this novel structure may be an interesting lead for structure-activity optimization.
-
Sargent,Small
, p. 447,451 (1948)
-
-
Cliff,Jones
, p. 1705 (1970)
-
Birch Reduction of Arenes Using Sodium Dispersion and DMI under Mild Conditions
Asako, Sobi,Ilies, Laurean,Kurogi, Takashi,Murakami, Yoshiaki,Takahashi, Ikko,Takai, Kazuhiko
supporting information, p. 38 - 40 (2022/01/12)
An easy-to-handle sodium dispersion in paraffin oil (SD), in combination with inexpensive and environmentally benign 1,3- dimethyl-2-imidazolidinone (DMI) as an additive enables the Birch-type reduction of a variety of arenes with high yields, selectivity, and tolerance of functionality such as ether, alcohol, amine, amide, and carboxylic acid.
Pd/c catalyzed decarboxylation-transfer hydrogenation of quinoline carboxylic acids
Chen, Xia,Zhou, Xiao-Yu
, p. 625 - 633 (2021/09/30)
Pd/C catalyzed decarboxylation-transfer hydrogenation of quinoline carboxylic acids and transfer hydrogenation of quinolines had been developed for the synthesis of 1,2,3,4-tetrahydroquinolines. These two processes were implemented smoothly using Pd/C (0.9 mol%) as a catalyst with ammonium formate as a hydrogen source in ethanol at 80oC. The reaction system can also be applied to transfer hydrogenation of benzo[h]quinoline and 2,9-dimethyl-1,10-phenanthroline with good to excellent yields. And the gram scale and recycling of catalyst had been tested with good results. Furthermore, the mechanism of Pd/C catalyzed reduction of quino-line carboxylic acids and quinolines had been proposed.
Cu-Catalyzed Chemoselective Reduction of N-Heteroaromatics with NH3·BH3 in Aqueous Solution
Gao, Chao,Xuan, Qingqing,Song, Qiuling
supporting information, p. 2504 - 2508 (2021/07/31)
An efficient catalytic system was successfully developed on reduction of N-heteroaromatics with H3N?BH3 as hydrogen source in CuSO4 solution, featuring excellent chemoselectivity as well as very broad functional group tolerance. Various challenging substrates, such as OH-, NH2-, Cl-, Br-, etc., contained quinolines, quinoxalines, 1,5-naphthyridines and quinazolines were all reduced smoothly. Mechanistic studies suggested that [Cu-H] intermediate might be generated from NH3?BH3, which was believed to form with H3N?BH3 in CuSO4 solution.
