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Isaac O. Donkor Rajesh Devraj Sherry F. Queener Louis R. Barrows Aleem Gangjee 《Journal of heterocyclic chemistry》1996,33(6):1653-1661
A series of diaminobenzo[f]- and diaminobenzo[h]pyrimido[4,5-b]quinolines 1–11 were designed as 5-deaza tetracyclic nonclassical, lipophilic antifolates. The compounds were designed as conformationally semi-rigid and rigid analogs of 2,4-diamino-6-phenyl- 12 and 2,4-diamino-7-phenylpyrido[2,3-d]pyrimidines 13 and 14 . The target compounds were synthesized by cyclocondensation of chlorovinyl aldehydes obtained from appropriately substituted 1- or 2-tetralone, with 2,4,6-friaminopyrimidine. Compounds 1–11 were evaluated as inhibitors of P. carinii and T. gondii dihydrofolate reductases. These pathogens cause fatal opportunistic infections in AIDS patients. In addition, the selectivity of these agents was evaluated using rat liver dihydrofolate reductase as the mammalian source. In general the benzo[f]pyrimido[4,5-b]quinolines 1–5 were more potent than the corresponding benzo[h]pyrimido[4,5-b]quinoline analogues 6–11 against P. carinii and rat liver dihydrofolate reductase and were equipotent against T. gondii dihydrofolate reductase. Compounds 6–11 were moderately selective towards T. gondii dihydrofolate reductase with IC50S in the 10−7 M range. In contrast analogues 1–5 lacked selectivity against P. carinii or T. gondii dihydrofolate reductase and were, in general, potent inhibitors of rat liver dihydrofolate reductase with IC50S in the 10−8 M range. Analogues 1 and 4 were evaluated against a series of tumor cell lines in vitro and were found to have moderate antitumor activity (IC50 10−6 M). The structure activity/selectivity relationships suggest that benzo[f]pyrimido analogues 1–5 with the phenyl ring substitution in the “upper” portion of the tetracyclic ring are better accommodated within the rat liver (mammalian) dihydrofolate reductase and P. carinii dihydrofolate reductase active sites compared to the benzo[h]pyrimido analogues 6–11 which have the phenyl ring substitution in the “lower” portion of the tetracyclic ring. In contrast T. gondii dihydrofolate reductase does not discriminate between the isomers and binds to both series of compounds with similar affinities. 相似文献
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Robert D. Barrows Mark J. Dresel Thomas J. Emge Paul R. Rablen Spencer Knapp 《Molecules (Basel, Switzerland)》2022,27(1)
The amidation reaction of a tetrahydroisoquinolin-1-one-4-carboxylic acid is a key step in the multi-kilogram-scale preparation of the antimalarial drug SJ733, now in phase 2 clinical trials. In the course of investigating THIQ carboxamidations, we found that propanephosphonic acid anhydride (T3P) is an effective reagent, although the yield and byproducts vary with the nature and quantity of the base. As a control, the T3P reaction of a 3-(2-thienyl) THIQ was performed in the absence of the amine, and the products were characterized: among them are three dimeric allenes and two dimeric lactones. A nucleophile-promoted ketene dimerization process subject to subtle steric and stereoelectronic effects accounts for their formation. Two novel monomeric products, a decarboxylated isoquinolone and a purple, fused aryl ketone, were also isolated, and mechanisms for their formation from the ketene intermediate are proposed. 相似文献
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This review consolidates biological activity data reported for pyridoacridine 1 molecules in the literature from 1983-2003 into several tables with brief discussions of assays used and results obtained. This review summarizes recent progress in structure activity relationships for analogues of amphimedine 2 and ascididemin 3 classes of pyridoacridines and correlates reported molecular mechanisms of action with biological activities. 相似文献
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Theresa Hague Andrea Petroczi Paul LR Andrews James Barker Declan P Naughton 《Chemistry Central journal》2010,4(1):2
This is a correction to the following paper: Hague T, Petroczi A, Andrews PR, Barker J, Naughton DP: Determination of metal
ion content of beverages and estimation of target hazard quotients: a comparative study. Chem Central J 2008, 2:13. 相似文献
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The relative differential cross sections have been measured for the 2H(d, p)3H and the 2H(d, n)3He reactions from 300 keV to 700 keV in 50 keV steps. Angular distributions of all charged particles from the reactions were taken from 20° to 160° in the laboratory system. Energy-dependent asymmetry coefficients from the expansion of the centre-of-mass angular distributions in terms of even powers of cos θ were obtained as were the branching ratios between the two reaction modes. The different energy dependences of the moments of the two cross sections were used to test the need for the existence of a recently reported T = 0 state in 4He. 相似文献
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Rachanida Praparatana Pattaravan Maliyam Louis R. Barrows Panupong Puttarak 《Molecules (Basel, Switzerland)》2022,27(8)
Bioactive compounds from medicinal plants are good alternative treatments for T2DM. They are also sources of lead molecules that could lead to new drug discoveries. In this study, Bauhinia strychnifolia Craib. stem, a traditional Thai medicinal plant for detoxification, was extracted into five fractions, including crude extract, BsH, BsD, BsE, and BsW, by ethanolic maceration and sequential partition with hexane, dichloromethane, ethyl acetate, and water, respectively. Among these fractions, BsE contained the highest amounts of phenolics (620.67 mg GAE/g extract) and flavonoids (131.35 mg QE/g extract). BsE exhibited the maximum inhibitory activity against α-glucosidase (IC50 1.51 ± 0.01 µg/mL) and DPP-IV (IC50 2.62 ± 0.03 µg/mL), as well as dominantly promoting glucose uptake on 3T3-L1 adipocytes. Furthermore, the four compounds isolated from the BsE fraction, namely resveratrol, epicatechin, quercetin, and gallic acid, were identified. Quercetin demonstrated the highest inhibitory capacity against α-glucosidase (IC50 6.26 ± 0.36 µM) and DPP-IV (IC50 8.25 µM). In addition, quercetin prominently enhanced the glucose uptake stimulation effect on 3T3-L1 adipocytes. Altogether, we concluded that quercetin was probably the principal bioactive compound of the B. strychnifolia stem for anti-diabetic, and the flavonoid-rich fraction may be sufficiently potent to be an alternative treatment for blood sugar control. 相似文献
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Theresa Hague Andrea Petroczi Paul LR Andrews James Barker Declan P Naughton 《Chemistry Central journal》2008,2(1):13
Background
Considerable research has been directed towards the roles of metal ions in nutrition with metal ion toxicity attracting particular attention. The aim of this study is to measure the levels of metal ions found in selected beverages (red wine, stout and apple juice) and to determine their potential detrimental effects via calculation of the Target Hazard Quotients (THQ) for 250 mL daily consumption. 相似文献10.