- Design, synthesis and biological evaluation of 4-aminoquinoline-guanylthiourea derivatives as antimalarial agents
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Guanylthiourea (GTU) has been identified as an important antifolate antimalarial pharmacophore unit, whereas, 4-amino quinolones are already known for antimalarial activity. In the present work molecules carrying 4-aminoquinoline and GTU moiety have been designed using molecular docking analysis with PfDHFR enzyme and heme unit. The docking results indicated that the necessary interactions (Asp54 and Ile14) and docking score (?9.63 to ?7.36 kcal/mmol) were comparable to WR99210 (?9.89 kcal/mol). From these results nine molecules were selected for synthesis. In vitro analysis of these synthesized compounds reveal that out of the nine molecules, eight show antimalarial activity in the range of 0.61–7.55 μM for PfD6 strain and 0.43–8.04 μM for PfW2 strain. Further, molecular dynamics simulations were performed on the most active molecule to establish comparative binding interactions of these compounds and reference ligand with Plasmodium falciparum dihydrofolate reductase (PfDHFR).
- Bhagat, Shweta,Arfeen, Minhajul,Das, Gourav,Ramkumar, Mridula,Khan, Shabana I.,Tekwani, Babu L.,Bharatam, Prasad V.
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- A convenient preparation of heteroaryl sulfonamides and sulfonyl fluorides from heteroaryl thiols
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Heteroaromatic thiols may be oxidized to the sulfonyl chloride at low temperature (-25 °C) by using 3.3 equiv of aqueous sodium hypochlorite. The reaction is rapid, avoids the use of chlorine gas, and succeeds with substrates that have previously been found to afford little or none of the sulfonamide product with other procedures. The method allows the preparation of the sulfonyl fluorides, which are stable enough to be purified and stored, making them potentially useful monomers in parallel chemistry efforts.
- Wright, Stephen W.,Hallstrom, Kelly N.
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p. 1080 - 1084
(2007/10/03)
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- Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities
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A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
- Madrid, Peter B.,Sherrill, John,Liou, Ally P.,Weisman, Jennifer L.,DeRisi, Joseph L.,Guy, R. Kiplin
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p. 1015 - 1018
(2007/10/03)
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- QUINOLINE COMPOUNDS AND THEIR USES
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The present invention provides quinoline compounds that inhibit the IgE receptor signaling cascade that leads to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE receptor signaling cascade.
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Page/Page column 38
(2008/06/13)
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- NOVEL QUINOLINE DERIVATIVES
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The invention relates to compounds represented by Formula (I): and to pharmaceutically acceptable salts or solvates of said compounds, wherein each of A, R3-8, X3, X5, m, and n are defined herein. The invention also relates to pharmaceutical compositions containing the compounds of Formula (I) and to methods of treating hyperproliferative disorders in a mammal by administering compounds of Formula (I).
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Page/Page column 46
(2008/06/13)
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- Process for the preparation of fluorinated heterocyclic compounds
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A method of fluorinating a heterocyclic organic compound comprises the step of reacting a heterocyclic compound with elemental fluorine in the presence of another halogen. The reaction may be conducted in the presence of a base.
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- Structure-activity relationships for antiplasmodial activity among 7- substituted 4-aminoquinolines
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Aminoquinolines (AQs) with diaminoalkane side chains (-HNRNEt2) shorter or longer than the isopentyl side chain [-HNCHMe(CH2)3NEt2] of chloroquine are active against both chloroquine-susceptible and -resistant Plasmodium falciparum. (De, D.; et al. Am. J. Trop. Med. Hyg. 1996, 55, 579-583). In the studies reported here, we examined structure-activity relationships (SARs) among AQs with different N,N-diethyldiaminoalkane side chains and different substituents at the 7-position occupied by Cl in chloroquine. 7-Iodo- and 7- bromo-AQs with diaminoalkane side chains [-HN(CH2)2NEt2, -HN(CH2)3NEt2, or -HNCHMeCH2NEt2] were as active as the corresponding 7-chloro-AQs against both chloroquine-susceptible and -resistant P. falciparum (IC50s of 3-12 nM). In contrast, with one exception, 7-fluoro-AQs and 7-trifluoromethyl-AQs were less active against chloroquine-susceptible P. falciparum (IC50s of 15-50 nM) and substantially less active against chloroquine-resistant P. falciparum (IC50s of 18-500 nM). Furthermore, most 7-OMe-AQs were inactive against both chloroquine-susceptible (IC50s of 17-150 nM) and -resistant P. falciparum (IC50s of 90-3000 nM).
- De, Dibyendu,Krogstad, Frances M.,Byers, Larry D.,Krogstad, Donald J.
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p. 4918 - 4926
(2007/10/03)
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- Addition of nitroalkanes toortho-halonitrobenzenes: A new synthesis of 4-chloro-7-(trifluoromethyl)quinoline
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Base-mediated reaction of ortho-nitroaryl chlorides and fluorides with nitroalkanes followed by an oxidative Nef reaction provides aryl ketones. With this simple procedure, methylketone 6 was prepared in 91% yield. 6 was then converted in three steps (60-65% yield) to 4-chloro-7-(trifluoromethyl)quinoline (2), an intermediate in the synthesis of the antihypertensive agent losulazine (U-54,669, 1).
- Gregory Reid,Reny Runge, Jean H.
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p. 1093 - 1096
(2007/10/02)
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