- Design and Synthesis of Orally Bioavailable Piperazine Substituted 4(1H)-Quinolones with Potent Antimalarial Activity: Structure-Activity and Structure-Property Relationship Studies
-
Malaria deaths have been decreasing over the last 10-15 years, with global mortality rates having fallen by 47% since 2000. While the World Health Organization (WHO) recommends the use of artemisinin-based combination therapies (ACTs) to combat malaria, the emergence of artemisinin resistant strains underscores the need to develop new antimalarial drugs. Recent in vivo efficacy improvements of the historical antimalarial ICI 56,780 have been reported, however, with the poor solubility and rapid development of resistance, this compound requires further optimization. A series of piperazine-containing 4(1H)-quinolones with greatly enhanced solubility were developed utilizing structure-activity relationship (SAR) and structure-property relationship (SPR) studies. Furthermore, promising compounds were chosen for an in vivo scouting assay to narrow selection for testing in an in vivo Thompson test. Finally, two piperazine-containing 4(1H)-quinolones were curative in the conventional Thompson test and also displayed in vivo activity against the liver stages of the parasite.
- Neelarapu, Raghupathi,Maignan, Jordany R.,Lichorowic, Cynthia L.,Monastyrskyi, Andrii,Mutka, Tina S.,LaCrue, Alexis N.,Blake, Lynn D.,Casandra, Debora,Mashkouri, Sherwin,Burrows, Jeremy N.,Willis, Paul A.,Kyle, Dennis E.,Manetsch, Roman
-
p. 1450 - 1473
(2018/03/05)
-
- Quinolone-based compounds, formulations, and uses thereof
-
Provided herein are quinolone-based compounds that can be used for treatment and/or prevention of malaria and formulations thereof. Also provided herein are methods of treating and/or preventing malaria in a subject by administering a quinolone-based compound or formulation thereof provided herein.
- -
-
Page/Page column 90
(2018/07/02)
-
- FLUORESCENT PROBES FOR DETECTION OF COPPER
-
The invention provides fluorescent sensors for the selective detection of a metal such as copper. The sensors may be considered to be derivatives of cyanine, fluorescein, rhodamine, rhodol, Tokyo green, or BODIPY. The sensors find particular use in detecting copper in cells and living animals.
- -
-
Paragraph 0204; 0236; 0239-0240
(2014/03/24)
-
- A new disubstituted polyacetylene bearing DDTC moieties: Postfunctional synthetic strategy, selective and sensitive chemosensor towards mercury ions
-
A new DDTC-functionalized disubstituted polyacetylene (P2) with strong green fluorescence was successfully synthesized by utilizing the postfunctional method. The polymer was soluble in common organic solvents, and its strong green fluorescence could be q
- Ou, Daxin,Qin, Jingui,Li, Zhen
-
p. 5691 - 5698
(2013/01/15)
-
- Synthesis, crystal structure and biological activity of novel diester cyclophanes
-
A series of novel diester cyclophanes was synthesized by esterification of 1,2-benzenedicarbonyl chloride with eight different diols under high dilution conditions. The structures of the compounds were verified by elemental analysis, 1H nuclear magnetic resonance (NMR), IR spectroscopy and high resolution mass spectrometry (HRMS). The crystal structures of two compounds were characterized by single crystal X-ray diffractometry (XRD). All the new cyclophanes were evaluated for biological activities and the results showed that some of these compounds have low antibacterial or antifungal activities.
- Zhang, Pengfei,Yang, Bingqin,Fang, Xianwen,Cheng, Zhao,Yang, Meipan
-
p. 1771 - 1775
(2013/03/13)
-
- Synthesis and structure-analgesic activity relationships of a novel series of monospirocyclopiperazinium salts (MSPZ)
-
A series of monospirocyclopiperazinium salts were designed and synthesized to search for a peripherally-acting analgesic drug with low side effects. Extensive SAR studies revealed that a suitable NR2R3 was critical for the analgesic activity, which might be beneficial to expose the cationic nitrogen to bind to the receptor, and possibly interact with the receptor via π-π interaction. Introduction of substituting group on the N4-phenyl ring could improve the activity, and the best position was the 4-position. Compound 14n showed more potent analgesic activity (63%, 20 μM/kg, sc) and holds promise for development as a mechanically new analgesic drug.
- Lin, Song-Wen,Sun, Qi,Ge, Ze-Mei,Wang, Xin,Ye, Jia,Li, Run-Tao
-
supporting information; experimental part
p. 940 - 943
(2011/03/21)
-
- Synthesis and characterization of three novel nitrogen-containing macrolides
-
Three novel nitrogen-containing macrolides have been synthesized by esterification. All of them have been characterized by infrared (IR), elemental analysis, mass spectra (MS), and 1H NMR spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction. The preparation methods and the intermolecular associations based on C-H···O hydrogen bonds and π-π stacking interactions are discussed.
- Leng, Xin,Yang, Bingqin,Liu, Yuanyuan,Xie, Yi,Tong, Jie
-
experimental part
p. 930 - 934
(2011/10/11)
-
- The reaction of primary aromatic amines with alkylene carbonates for the selective synthesis of bis-N-(2-hydroxy)alkylanilines: The catalytic effect of phosphonium-based ionic liquids
-
At T ≥ 140 °C, different primary aromatic amines (pX-C 6H4NH2; X = H, OCH3, CH3, Cl) react with both ethylene- and propylene-carbonates to yield a chemoselective N-alkylation process: bis-N-(2-hydroxyalkyl)anilines [pX-C 6H4N(CH2CH(R)OH)2; R = H, CH 3] are the major products and the competitive formation of carbamates is substantially ruled out. At 140 °C, under solventless conditions, the model reaction of aniline with ethylene carbonate goes to completion by simply mixing stoichiometric amounts of the reagents. However, a class of phosphonium ionic liquids (PILs) such as tetraalkylphosphonium halides and tosylates turn out to be active organocatalysts for both aniline and other primary aromatic amines. A kinetic analysis monitored by 13C NMR spectroscopy, shows that bromide exchanged PILs are the most efficient systems, able to impart a more than 8-fold acceleration to the reaction. The reactions of propylene carbonate take place at a higher temperature than those of ethylene carbonate, and only in the presence of PIL catalysts. A mechanism based on the Lewis acidity of tetraalkylphosphonium cations and the nucleophilicity of halide anions has been proposed to account for both the reaction chemoselectivity and the function of the catalysts.
- Selva, Maurizio,Fabris, Massimo,Lucchini, Vittorio,Perosa, Alvise,Noe, Marco
-
experimental part
p. 5187 - 5198
(2010/12/25)
-
- A new one-pot, four-component synthesis of 1,2-amino alcohols: TiCl 3/t-BuOOH-mediated radical hydroxymethylation of imines
-
(Chemical Equation Presented) An amine, an aldehyde, and methanol can be readily assembled in one pot under very mild conditions through a free-radical multicomponent reaction by using an aqueous acidic TiCl3/t-BuOOH system to afford 1,2-amino alcohols in fair to excellent yields.
- Clerici, Angelo,Ghilardi, Alessandra,Pastori, Nadia,Punta, Carlo,Porta, Ombretta
-
supporting information; experimental part
p. 5063 - 5066
(2009/05/31)
-
- Synthesis of β-amino alcohols from aromatic amines and alkylene carbonates using Na-Y zeolite catalyst
-
A simple, efficient, and environmentally benign methodology for the synthesis of β-amino alcohols from aromatic amines and alkylene carbonates in the presence of the highly active and reusable solid base catalyst Na-Y zeolite is demonstrated. Georg Thieme Verlag Stuttgart.
- Shivarkar, Anandkumar B.,Gupte, Sunil P.,Chaudhari, Raghunath V.
-
p. 1374 - 1378
(2007/10/03)
-
- Hypoxia-Selective Antitumor Agents. 3. Relationships between Structure and Cytotoxicity against Cultured Tumor Cells for Substituted N,N-Bis(2-chloroethyl)anilines
-
A series of aniline mustards with a wide range of electron-donating and -withdrawing substituents in the 3- and 4-positions has been synthesized and evaluated for cytotoxicity in cell culture to examine the potential of using nitro group deactivated nitrogen mustards for the design of novel hypoxia-selective anticancer drugs (Denny, W.A.; Wilson, W.R.J.Med Chem. 1986, 29, 879).Hydrolytic half-lives in tissue culture media, determined by bioassay against a cell line (UV4) defective in the repair of DNA interstrand cross-links showed the expected dependence on the Hammett electronic parameter, ?, varying from 0.13 h for the 4-amino analogue to >100 h for analogues with strongly electron-withdrawing substituents.Cytotoxic potencies in aerobic UV4 cultures showed a similar dependence on ?.This dependence predicted that the 4-nitroaniline mustard would be 7200-fold less potent than its potential six-electron reduction product, the 4-amino compound, in growth inhibition assays using a 1-h drug exposure.The measured differential was much lower (225-fold) because of the instability of the latter compound, but a differential of 17500-fold was observed in the initial rate of killing by using a clonogenic assay.The potential for formation of reactive mustards by reduction to the amine or hydroxylamine was demonstrated by the 4-nitroso compound, which had an aerobic toxicity similar to that of the amine.Although these features confirmed the original rationale, the 3-nitro- and 4-nitroaniline mustards had only minimal hypoxic selectivity against UV cells.Toxicity to hypoxic cells appears to be limited by the low reduction potentials of these compounds and consequent lack of enzymatic nitroreduction.However, this study has demonstrated that nitro groups can be used to latentiate aromatic nitrogen mustards and indicates that examples with higher reduction potentials could provide useful hypoxia-selective therapeutic agents.
- Palmer, Brian D.,Wilson, William R.,Pullen, Susan M.,Denny, William A.
-
p. 112 - 121
(2007/10/02)
-