- Pentacycloundecylamines and conjugates thereof as chemosensitizers and reversed chloroquine agents
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The control of malaria has been complicated by increased resistance of the malaria parasite to existing antimalarials such as chloroquine (CQ). Herein, we report the ability of NGP1-01, the prototype pentacycloundecylamine (PCU), to reverse CQ resistance (>50%) and act as a chemosensitizer. Based on this finding we set out to synthesize a small series of novel agents comprising of a PCU moiety as the reversal agent conjugated to a CQ-like aminoquinoline (AM) molecule and evaluate the potential of these PCU-AM derivatives as reversed CQ agents. PCU-AM derivatives 1-3 showed anti-plasmodial IC50 values in the ranges of 3.74-17.6 nM and 27.6-253.5 nM against CQ-sensitive (D10) and CQ-resistant strains (Dd2) of Plasmodium falciparum, respectively. Compound 1 presented with the best antiplasmodial activity at low nM concentrations against both strains and was found to be 5 fold more active against the resistant strain than CQ. Compound 1 can be considered as a lead compound to develop reversed CQ agents with improved pharmacodynamic and pharmacokinetic properties.
- Joubert, Jacques,Fortuin, Elton E.,Taylor, Dale,Smith, Peter J.,Malan, Sarel F.
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- Targeting Asexual and Sexual Blood Stages of the Human Malaria Parasite P. falciparum with 7-Chloroquinoline-Based 1,2,3-Triazoles
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Novel 4-amino-7-chloroquinoline-based 1,2,3-triazole hybrids were synthesised in good yields by CuI-catalysed Huisgen 1,3-dipolar cycloaddition reactions of 2-azido-N-(7-chloroquinolin-4-ylaminoalkyl)acetamides with various terminal alkynes. Th
- Wadi, Ishan,Prasad, Davinder,Batra, Neha,Srivastava, Kumkum,Anvikar, Anupkumar R.,Valecha, Neena,Nath, Mahendra
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- Incorporation of Fluorinated Pyridine in the Side Chain of 4-Aminoquinolines: Synthesis, Characterization and Antibacterial Activity
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A series of hybrid of 4-aminoquinoline and fluorinated pyridine derivatives were synthesized and their chemical structure were confirmed by 19 F-NMR, 1 H-NMR, 13 C-NMR and FT-IR. All compounds were tested against one Gram-positive and one Gram-negative bacteria to assess their in vitro antibacterial activity. Compounds 10a, 10b, 11a and 12b showed moderate antibacterial activity against Gram-positive bacterium, Staphylococcus aureus.
- Ranjbar-Karimi, Reza,Poorfreidoni, Alireza
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- Application of multicomponent reactions to antimalarial drug discovery. Part 2: New antiplasmodial and antitrypanosomal 4-aminoquinoline γ- and δ-lactams via a 'catch and release' protocol
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A parallel synthesis of a new series of 4-aminoquinoline γ- and δ-lactams synthesized via the Ugi 3-component 4-centre multicomponent reaction is described. The basicity of the quinoline nitrogen was exploited in the purification of compounds via a 'catch and release' protocol. Yields ranging from 60% to 77% and purities as high as 96% were obtained. Compound 29, the most active against a chloroquine-resistant W2 strain of Plasmodium falciparum with an IC50 of 0.096 μM, also inhibited recombinant falcipain-2 in vitro (IC50 = 17.6 μM). Compound 17 inhibited the growth of Trypanosoma brucei with an ED50 of 1.44 μM whilst exhibiting a favourable therapeutic index of 409 against a human KB cell line.
- Musonda, Chitalu C.,Gut, Jiri,Rosenthal, Philip J.,Yardley, Vanessa,Carvalho de Souza, Renata C.,Chibale, Kelly
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- 4-N-, 4-S-, and 4-O-chloroquine analogues: Influence of side chain length and quinolyl nitrogen pKa on activity vs chloroquine resistant malaria
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Using predictions from heme-quinoline antimalarial complex structures, previous modifications of chloroquine (CQ), and hypotheses for chloroquine resistance (CQR), we synthesize and assay CQ analogues that test structure-function principles. We vary side chain length for both monoethyl and diethyl 4-N CQ derivatives. We alter the pKa of the quinolyl N by introducing alkylthio or alkoxy substituents into the 4 position and vary side chain length for these analogues. We introduce an additional titratable amino group to the side chain of 4-O analogues with promising CQR strain selectivity and increase activity while retaining selectivity. We solve atomic resolution structures for complexes formed between representative 4-N, 4-S, and 4-O derivatives vs μ-oxo dimeric heme, measure binding constants for monomeric vs dimeric heme, and quantify hemozoin (Hz) formation inhibition in vitro. The data provide additional insight for the design of CQ analogues with improved activity vs CQR malaria.
- Natarajan, Jayakumar K.,Alumasa, John N.,Yearick, Kimberly,Ekoue-Kovi, Kekeli A.,Casabianca, Leah B.,De Dios, Angel C.,Wolf, Christian,Roepe, Paul D.
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- Antimalarial and anti-inflammatory activities of new chloroquine and primaquine hybrids: Targeting the blockade of malaria parasite transmission
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Malaria is a disease that requires new drugs not only to fight Plasmodium but also to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection. The compounds were assayed with nine different biological methods. The carbonylated CQ derivative 6 (n = 3; R1 = Cl) was more potent than CQ in vitro, and 8 (n = 4; R1 = H) reduced P. berghei parasitemia up to 37% on day 7. The carbonylated PQ derivative 17 (R = Br) was slightly less potent than PQ. The gem-difluoro PQ derivative 20 (R = Cl) exhibited high transmission blockade of the malaria sporogonic cycle in mosquitoes. Compounds 6 and 20 dose-dependently reduced nitric oxide (NO) production and inhibited TNFα production by LPS-stimulated J774A.1 macrophages. Our results indicate a viable and interesting approach in planning new chemical entities that act as transmission-blocking drugs for treating malaria caused by P. falciparum and P. vivax and the anti-inflammatory process related to this disease.
- Boechat, Nubia,Carvalho, Rita C.C.,Ferreira, Maria de Lourdes G.,Coutinho, Julia Penna,Sa, Paula M.,Seito, Leonardo N.,Rosas, Elaine C.,Krettli, Antoniana U.,Bastos, Monica M.,Pinheiro, Luiz C.S.
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- Coupling the antimalarial cell penetrating peptide TP10 to classical antimalarial drugs primaquine and chloroquine produces strongly hemolytic conjugates
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Recently, we disclosed primaquine cell penetrating peptide conjugates that were more potent than parent primaquine against liver stage Plasmodium parasites and non-toxic to hepatocytes. The same strategy was now applied to the blood-stage antimalarial chl
- Aguiar, Luísa,Biosca, Arnau,Lantero, Elena,Gut, Jiri,Vale, Nuno,Rosenthal, Philip J.,Nogueira, Fátima,Andreu, David,Fernàndez-Busquets, Xavier,Gomes, Paula
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- Design and synthesis of new antimalarial agents from 4-aminoquinoline
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This study describes the synthesis of new 4-aminoquinoline derivatives and evaluation of their activity against a chloroquine sensitive strain of P. falciparum in vitro and chloroquine resistant N-67 strain of P. yoelii in vivo. All the analogues were found to form strong complex with hematin and inhibit the β-hematin formation in vitro. These results suggest that these compounds act on heme polymerization target.
- Solomon, V. Raja,Puri, Sunil K.,Srivastava, Kumkum,Katti
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- Modulation of human mammary cell sensitivity to paclitaxel by new quinoline sulfonamides
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Sulfonamide derivatives of chloroquine and primaquine were synthesised and evaluated against both paclitaxel-sensitive and paclitaxel-resistant mammarian cancer cell lines. All derivatives exhibited at least 96% MDR reversal activity when co-administered with paclitaxel at 5 μM. The best compound, a chloroquine derivative, exhibited 99% MDR reversal activity when co-administered with paclitaxel at 1 μM. Molecular modelling studies reveal that these derivatives share a common pharmacophore with taxane MDR reversal agents.
- Chibale, Kelly,Ojima, Iwao,Haupt, Hayley,Geng, Xugong,Pera, Paula,Bernacki, Ralph J.
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- 4-Aminoquinoline-pyrimidine-aminoalkanols: Synthesis, in vitro antimalarial activity, docking studies and ADME predictions
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Twenty-four new 4-aminoquinoline-pyrimidine hybrids containing a terminal aliphatic amino-alcohol chain were synthesized and assessed for their antimalarial activity against chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum. All of the compounds displayed potent antiplasmodial activities (IC50 values in the range of 0.05-10.47 μM) with no appreciable cytotoxicity towards mammalian cells, up to the highest tested concentration of 12 μM. Molecular docking studies of the most active compounds (8b-8f, 8u and 8v) with both wild type and quadruple mutant Pf-DHFR-TS were performed, which exhibited interactions comparable to conventional folate inhibitors. ADME predictions also revealed favourable pharmacokinetic parameters for the synthesized hybrids, which warrants their suitability for development as potent antimalarials.
- Tripathi, Mohit,Khan, Shabana I.,Thakur, Anuj,Ponnan, Prija,Rawat, Diwan S.
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- Synthesis and in vitro antiplasmodial activity of ferrocenyl aminoquinoline derivatives
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The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-resistant). Some of the ferrocenyl compounds exhibited
- Mwande Maguene, Gabin,Lekana-Douki, Jean-Bernard,Mouray, Elisabeth,Bousquet, Till,Grellier, Philippe,Pellegrini, Sylvain,Toure Ndouo, Fousseyni Samba,Lebibi, Jacques,Pélinski, Lydie
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- β-amino-alcohol tethered 4-aminoquinoline-isatin conjugates: Synthesis and antimalarial evaluation
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A series of β-amino alcohol tethered 4-aminoquinoline-isatin conjugates were synthesized with the aim of probing their antimalarial structure activity relationship. Two of the most active conjugates (11 b and 11 f) exhibited antimalarial efficacy comparable to that of chloroquine, with IC50 values of 11.8 and 13.5 nM, respectively against chloroquine resistant W2 strain of Plasmodium falciparum and are devoid of any cytotoxicity.
- Nisha,Gut, Jiri,Rosenthal, Philip J.,Kumar, Vipan
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- Novel 4-aminoquinoline-pyrimidine based hybrids with improved in vitro and in vivo antimalarial activity
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A class of hybrid molecules consisting of 4-aminoquinoline and pyrimidine were synthesized and tested for antimalarial activity against both chloroquine (CQ)-sensitive (D6) and chloroquine (CQ)-resistant (W2) strains of Plasmodium falciparum through an in vitro assay. Eleven hybrids showed better antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum in comparison to standard drug CQ. Four molecules were more potent (7-8-fold) than CQ in D6 strain, and eight molecules were found to be 5-25-fold more active against resistant strain (W2). Several compounds did not show any cytotoxicity up to a high concentration (60 μM), others exhibited mild toxicities, but the selective index for the antimalarial activity was very high for most of these hybrids. Two compounds selected for in vivo evaluation have shown excellent activity (po) in a mouse model of Plasmodium berghei without any apparent toxicity. The X-ray crystal structure of one of the compounds was also determined.
- Manohar, Sunny,Rajesh, U. Chinna,Khan, Shabana I.,Tekwani, Babu L.,Rawat, Diwan S.
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- Incorporation of an intramolecular hydrogen-bonding motif in the side chain of 4-aminoquinolines enhances activity against drug-resistant P. falciparum
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Previous data showing that several chloroquine analogues containing an intramolecular hydrogen-bonding motif were potent against multidrug-resistant P. falciparum led to the exploration of the importance of this motif. A series of 116 compounds containing
- Madrid, Peter B.,Liou, Ally P.,DeRisi, Joseph L.,Guy, R. Kiplin
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- Anti-cancer effects of CQBTO, a chloroquine, and benzo(e)triazine oxide conjugate
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Aim: Autophagy is a self-protective process, and it confers cancer cells resistance against radio-chemotherapeutics. To induce cancer cell death, a series of compounds of 3-((4-((7-chloroquinolin-4-yl)amino)butyl)amino)-7-substituted benzo[e][1,2,4]triazine 1-oxide or CQBTO containing two critical chemical groups were designed and synthesized. One compound, benzo[e][1,2,4]triazine 1-oxide, yielded free radicals to trigger autophagy, and the other one, chloroquine (CQ), was an inhibitor of autophagy. We hypothesized that the compounds could kill cancer cells effectively by inducing incomplete autophagy. Methods: In vitro cultured non-small cell lung carcinoma cells and primary lung tumors in mice in vivo were used to test the lethal effects of CQBTO on cancer cells and toxicity to normal tissues. Cell viability was examined using the CCK8 assay. Genomic instability was determined with the cytochalasin B-blocked micronucleus assay. Cell cycle distribution was analyzed by propidium iodide staining and flow cytometry. Western blotting and immunofluorescence were used to detect the induction and localization of LC3, a biomarker for autophagy. Results: Compared with CQ, three CQBTO compounds were lethal to lung cancer cells, and CQBTO-3 was the most effective. The LD50 for CQBTO-3 was 21?μΜ in A549 cells and 21.5?μΜ in Calu-1 cells, which was lower than that of CQBTO-2 or CQBTO-1. Induction of LC3 foci and an increase in the LC3II/LC3I ratio demonstrated the induction of autophagy by CQBTO-3 in A549 cells, whereas no obvious micronuclei or cell cycle arrest was observed. No detectable toxicity to normal mice was observed. CQBTO-3 improved the quality of mouse life, reduced the number and size of existing tumors, and suppressed tumor formation. Conclusion: CQBTO-3 is a potential chemical compound for lung cancer treatment.
- Guo, Ziyang,Pei, Hailong,Nie, Jing,Hu, Wentao,Zhang, Jian,Ding, Jiahan,Pan, Shuxian,Li, Bingyan,Hei, Tom K.,Chen, Weiqiang,Zhou, Guangming
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- New amine and urea analogs of ferrochloroquine: Synthesis, antimalarial activity in vitro and electrochemical studies
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Amine and urea analogs of ferrochloroquine with varying methylene spacer lengths were synthesised, studied by cyclic voltammetry and evaluated in vitro against a sensitive (D10) and resistant (K1) strain of Plasmodium falciparum. Most analogs were found to be more active than chloroquine in both strains. In D10 ureas were more active than amines and antimalarial activity in this strain correlated well with the length of the methylene spacer and redox potentials. The length of the methylene spacer was a major determinant of antimalarial activity in K1. (C) 2000 Elsevier Science Ltd.
- Chibale,Moss,Blackie,Van Schalkwyk,Smith
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- Structural characteristics of chloroquine-bridged ferrocenophane analogues of ferroquine may obviate malaria drug-resistance mechanisms
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Five compounds displaying an unprecedented binding mode of chloroquine to ferrocene through the bridging of the cyclopentadienyl rings were studied alongside their monosubstituted ferrocene analogues and organic fragments. The antiplasmodial activity was evaluated against strains of the malaria parasite (Plasmodium falciparum). While the chloroquine-bridged ferrocenyl derivatives were less active than their five monosubstituted ferrocenyl analogues, they retained activity in the drug-resistant strains. The biological and physical properties were correlated to antiplasmodial activity. Intramolecular hydrogen bonding was associated with increased antiplasmodial action, but it is not the determining factor. Instead, balance between lipophilicity and hydrophilicity had a greater influence. It was found that calculated partition coefficient (log P) values of 4.5-5.0 and topological polar surfaces area (tPSA) values of ~26.0 ?2 give the best balance. The particular conformation, compact size, and lipophilicity/hydrophilicity balance observed in the bridged compounds provide them with the structural characteristics needed to escape the mechanisms responsible for resistance.
- Salas, Paloma F.,Herrmann, Christoph,Cawthray, Jacqueline F.,Nimphius, Corinna,Kenkel, Alexander,Chen, Jessie,De Kock, Carmen,Smith, Peter J.,Patrick, Brian O.,Adam, Michael J.,Orvig, Chris
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- Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth
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We report an improved, nonhazardous, high-throughput assay for in vitro quantification of antimalarial drug inhibition of β-hematin (hemozoin) crystallization performed under conditions that are more physiological relative to previous assays. The assay uses the differential detergent solubility of crystalline and noncrystalline forms of heme and is optimized via the use of lipid catalyst. Using this assay, we quantify the effect of pH on the crystal growth-inhibitory activities of current quinoline antimalarials, evaluate the catalytic efficiencies of different lipids, and test for a possible correlation between hemozoin inhibition by drugs versus their antiplasmodial activity. Consistent with several previous reports, we found a good correlation between hemozoin inhibition potency versus cytostatic antiplasmodial potency (50% inhibitory concentration) for a series of chloroquine (CQ) analogues. However, we found no correlation between hemozoin inhibition potency and cytocidal antiplasmodial potency (50% lethal dose) for the same drugs, suggesting that cellular targets for these two layers of 4-aminoquinoline drug activity differ. This important concept is also explored further for QN and its stereoisomers in the accompanying paper (A. P. Gorka, K. S. Sherlach, A. C. de Dios, and P. D. Roepe, Antimicrob. Agents Chemother. 57:365-374, 2013). Copyright
- Gorka, Alexander P.,Alumasa, John N.,Sherlach, Katy S.,Jacobs, Lauren M.,Nickley, Katherine B.,Brower, Jonathan P.,De Dios, Angel C.,Roepe, Paul D.
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- Synthesis and antimalarial activity of a new series of trioxaquines
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Trioxanes 8a-b, easily accessible in two steps from allylic alcohol 6a-b, on reductive amination with 4-aminoquinolines 4a-c furnish a new series of trioxaquines 9a-b, 10a-b, 11a-b in 32-77% yields. Dicitrate salts of these trioxaquines have been evaluate
- Singh, Chandan,Malik, Heetika,Puri, Sunil K.
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- New pentasubstituted pyrrole hybrid atorvastatin-quinoline derivatives with antiplasmodial activity
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Cerebral malaria is caused by Plasmodium falciparum. Atorvastatin (AVA) is a pentasubstituted pyrrole, which has been tested as an adjuvant in the treatment of cerebral malaria. Herein, a new class of hybrids of AVA and aminoquinolines (primaquine and chloroquine derivatives) has been synthesized. The quinolinic moiety was connected to the pentasubstituted pyrrole from AVA by a linker group (CH2)n = 2-4 units. The activity of the compounds increased with the size of the carbons chain. Compound with n = 4 and 7-chloroquinolinyl has displayed better activity (IC50 = 0.40 μM) than chloroquine. The primaquine derivative showed IC50 = 1.41 μM, being less toxic and more active than primaquine.
- Carvalho, Rita C.C.,Martins, Wagner A.,Silva, Tayara P.,Kaiser, Carlos R.,Bastos, Mo?nica M.,Pinheiro, Luiz C.S.,Krettli, Antoniana U.,Boechat, Núbia
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- Comparative study of the inhibition of metallo-β-lactamases (IMP-1 and VIM-2) by thiol compounds that contain a hydrophobic group
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For the purpose of screening of inhibitors that are effective for wide range of metallo-β-lactamases, the inhibitory effect of two series of compounds, 2-ω-phenylalkyl-3-mercaptopropionic acid (PhenylCnSH (n=1-4)) and N-[(7-chloro-quinolin-4-ylamino)-alkyl]-3-mercapto-propionamide (QuinolineCnSH (n=2-6)), where n denotes the alkyl chain length, on metallo-β-lactamases IMP-1 and VIM-2 was examined. These inhibitors contain a thiol group and a hydrophobic group linked by variable-length methylene chain. PhenylCnSH (n=1-4) was found to be a potent inhibitor of both IMP-1 and VIM-2. PhenylC4SH was the potent inhibitor of both IMP-1 (IC50=1.2 μM) and VIM-2 (IC50=1.1 μM) among this study. When the number of methylene units was varied, QuinolineC4SH showed the maximum inhibitory activity against IMP-1 and VIM-2 (IC50=2.5 μM and IC 50=2.4 μM). The relationship between the inhibitory effect of the alkyl chain length was different for both series of inhibitors, suggesting that IMP-1 has a tighter binding site than VIM-2. QuinolineCnSH did not serve as a fluorescence reagent for metallo-β-lactamases.
- Jin, Wanchun,Arakawa, Yoshichika,Yasuzawa, Hisami,Taki, Tomoko,Hashiguchi, Ryo,Mitsutani, Kana,Shoga, Asumi,Yamaguchi, Yoshihiro,Kurosaki, Hiromasa,Shibata, Naohiro,Ohta, Michio,Goto, Masafumi
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- Itaconic acid hybrids as potential anticancer agents
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Abstract: In this paper, we report the synthesis of novel hybrids 2–14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2–13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI50 values between 0.7 and 8.6?μM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations. Graphic abstract: [Figure not available: see fulltext.].
- Perkovi?, Ivana,Beus, Maja,Schols, Dominique,Persoons, Leentje,Zorc, Branka
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- Design, synthesis, molecular modeling and neuroprotective effects of a new framework of cholinesterase inhibitors for Alzheimer’s disease
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In search of a novel class of compounds against Alzheimer’s disease (AD), a new series of 7-chloro-aminoquinoline derivatives containing methylene spacers of different sizes between the 7-chloro-4-aminoquinoline nucleus and imino methyl substituted phenolic rings, and also their reduced analogues, were designed, synthesized and evaluated as neuroprotective agents for AD in?vitro. In spite of the multifaceted feature of AD, cholinesterases continue to be powerful and substantial targets, as their inhibition increases both the level and duration of the acetylcholine neurotransmitter action. The compounds presented inhibitory activity in the micromolar range against acetylcholinesterase (AChE) (imines and amines) and butyrylcholineterase (BChE) (amines). The SAR study revealed that elongation of the imine side chain improved AChE activity, whereas the reduction of these compounds to amines was crucial for higher activity and indispensable for BChE inhibition. The most promising selective inhibitors were not cytotoxic and did not stimulate pro-inflammatory activity in glial cells. Kinetic and molecular modeling studies indicated that they also show mixed-type inhibition for both enzymes, behaving as dual-site inhibitors, which can interact with both the peripheral anionic site and the catalytic anionic site of AChE. They could therefore restore cholinergic transmission and also may inhibit the aggregation of Aβ promoted by AChE. Additionally, one compound showed promising anti-inflammatory activity by reducing the microglial release of NO? at a concentration that is equivalent to the IC50 against BChE (30.32 ± 0.18 μM) and 15-fold greater than the IC50 against AChE (1.97 ± 0.20 μM). Communicated by Ramaswamy H. Sarma.
- Zanon, Vanessa S.,Lima, Josélia A.,Amaral, Rackele F.,Lima, Flavia R. S.,Kitagawa, Daniel A. S.,Fran?a, Tanos C. C.,Vargas, Maria D.
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- N-Cinnamoylation of Antimalarial Classics: Effects of Using Acyl Groups Other than Cinnamoyl toward Dual-Stage Antimalarials
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In a follow-up study to our reports of N-cinnamoylated chloroquine and quinacrine analogues as promising dual-stage antimalarial leads with high in vitro potency against both blood-stage Plasmodium falciparum and liver-stage Plasmodium berghei, we decided
- Gomes, Ana,Machado, Marta,Lobo, Lis,Nogueira, Fátima,Prudêncio, Miguel,Teixeira, Cátia,Gomes, Paula
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- Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum
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Previously we have shown that pentacycloundecylamine-chloroquinoline (PCU-CQ) conjugates possess significant chemosensitizing abilities and can circumvent the resistance associated with chloroquine (CQ) resistant plasmodia. In order to further explore structurally related polycyclic compounds as reversed CQ agents we synthesized a series of eight aza-adamantanol (1–4) and adamantane-imine (5–8) CQ conjugates. All conjugates showed limited cytotoxicity against CHO cells (IC50 > 37 μM). Compounds 1, 2 and 5 were highly active (K1 IC50 100 nM) exhibiting a 3–4-fold increase in antiplasmodial activity against CQ resistant strain K1 compared to CQ. Reduced cross-resistance (resistance index, RI: 2–4.3) relative to CQ (RI = 38) was also observed for these compounds. Compound 1 which showed an 18-fold enhancement at retaining its activity against the K1 strain compared to CQ is a promising candidate to substitute CQ in P. falciparum resistant malaria.
- Yvette, Opute M.,Malan, Sarel F.,Taylor, Dale,Kapp, Erika,Joubert, Jacques
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- Anti-Plasmodium falciparum activity of quinoline-sulfonamide hybrids
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Fifteen quinoline-sulfonamide hybrids, with a 7-chloroquinoline moiety connected by a linker group to arylsulfonamide moieties with different substituents in the 4-position were synthesized and assayed against Plasmodium falciparum. The compounds displayed high schizonticidal blood activity in vitro, with IC50 values ranging from 0.05 to 1.63 μM, in the anti-HPR2 assay against clone W2-chloroquine-resistant; ten of them showed an IC50 (ranging from 0.05 to 0.40 μM) lower than that of chloroquine and sulfadoxine. Among them, two compounds inhibited Plasmodium berghei parasitemia by 47% and 49% on day 5 after mice inoculation. The most active, in vivo, hybrid 13 is considered to be a new prototype for the development of an antimalarial drug against chloroquine-resistant parasites.
- Pinheiro, Luiz C.S.,Boechat, Núbia,Ferreira, Maria De Lourdes G.,Júnior, Carlos C.S.,Jesus, Ant?nio M.L.,Leite, Milene M.M.,Souza, Nicolli B.,Krettli, Antoniana U.
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- Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors
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Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this
- Kayamba, Francis,Malimabe, Teboho,Ademola, Idowu Kehinde,Pooe, Ofentse Jacob,Kushwaha, Narva Deshwar,Mahlalela, Mavela,van Zyl, Robyn L.,Gordon, Michelle,Mudau, Pertunia T.,Zininga, Tawanda,Shonhai, Addmore,Nyamori, Vincent O.,Karpoormath, Rajshekhar
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- Synthesis and Antimicrobial Activity of Some Novel 7-Chloro-4-aminoquinoline Derivatives
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Abstract: A number of novel 7-chloro-4-aminoquinoline derivatives have been efficiently synthesized by nucleophilic aromatic substitution reaction of 4,7-dichloroquinoline with α,ω-diaminoalkanes of variable carbon-chain length. Treatment of the intermedi
- Fatima, Gul Naz,Paliwal, Sarvesh K.,Saraf, Shailendra K.
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p. 285 - 293
(2021/03/20)
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- NUCLEOSIDE AND NUCLEOTIDE CONJUGATE COMPOUNDS AND USES THEREOF
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This disclosure provides nucleoside and nucleotide conjugate compounds, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases,
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- Amalgamating Isatin/Indole/Nitroimidazole with 7-chloroquinolines via azide-alkyne cycloaddition: Synthesis, anti-plasmodial, and cytotoxic evaluation
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The present paper describes the synthesis, anti-plasmodial, and cytotoxic evaluation of 7-chloroquinoline-based conjugates with isatins/indoles/ nitroimidazoles, obtained via Cu-promoted 1,3-dipolar cycloadditions. On contemplating SAR of the synthesized series, the inclusion of indole and nitroimidazole-core improved the anti-plasmodial activities while the isatin seemed to have a lesser effect. The conjugate with a nitroimidazole-core and hexyl chain length as a spacer between the two pharmacophores was found to be most potent among the synthesized series and displayed an IC50 of 0.12?μM and a selectivity index of 1748.
- Kumar, Sumit,Saini, Anu,Legac, Jenny,Rosenthal, Philip J.,Raj, Raghu,Kumar, Vipan
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p. 1355 - 1361
(2020/07/04)
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- PHARMACEUTICAL FORMULATIONS AND METHODS FOR DELIVERING A THERAPEUTIC, DIAGNOSTIC, OR IMAGING AGENT TO CD206
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The present disclosure provides pharmaceutical formulations and methods for delivering a therapeutic, diagnostic, or imaging agent to CD206. In an aspect, the present disclosure encompasses a pharmaceutical formulation for administration. The pharmaceutical formulation comprises a recombinantly produced intrinsic factor (IF), wherein the IF has a glycosylation pattern that enables binding to CD206.
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Paragraph 0037; 0277
(2020/12/07)
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- Primaquine and chloroquine fumardiamides as promising antiplasmodial agents
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This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents.
- Beus, Maja,Fontinha, Diana,Held, Jana,Raji?, Zrinka,Uzelac, Lidija,Kralj, Marijeta,Prudêncio, Miguel,Zorc, Branka
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- Microwave-promoted facile access to 4-aminoquinoline-phthalimides: Synthesis and anti-plasmodial evaluation
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Microwave promoted high yielding synthesis of 4-aminoquinoline-phthalimides was developed with an aim to evaluate their anti-plasmodial potential. The scaffolds with longer spacer length (n = 6, 8) between two pharmacophores and a halogen substituent on the phthalimide ring displayed good antiplasmodial activity. Compound 5w, with an optimum combination of hexyl chain as spacer along with a tetra-bromophthalimide ring proved to be most potent and non-cytotoxic among the series exhibiting an IC50 value of 0.10 μM.
- Rani, Anu,Singh, Amandeep,Gut, Jiri,Rosenthal, Philip J.,Kumar, Vipan
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p. 150 - 156
(2017/11/27)
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- Benzo[e][1,2,4]triazine-1-oxygen derivative as well as composition and application thereof
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The invention relates to a 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2,4]triazine-1-oxygen derivative shown as a formula (1), and pharmaceutically acceptable salt, ester and solvate thereof. The formula (1) is shown in the description: R1 is selected from hydrogen, hydroxyl, C1-C6 alkyl, fluorine, chlorine and bromine; R2 is selected from hydrogen and C1-C12 alkyl or hydroxyl; and R3 is selected from hydrogen and C1-C12 alkyl or hydroxyl. The invention further provides a composition which comprises the 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2,4]triazine-1-oxygen derivative shown as the formula (1), pharmaceutically acceptable salt, ester and solvate thereof and pharmaceutically acceptable auxiliary materials thereof; the formula (1) is shown in the description: R1 is selected from hydrogen, hydroxyl, C1-C6 alkyl, fluorine, chlorine and bromine; R2 is selected from hydrogen and C1-C12 alkyl or hydroxyl; and R3 is selected from hydrogen and C1-C12 alkyl or hydroxyl. The invention further provides application of the 3-[(7-chloroquinoline-4-amino)butylamino]-7-substituted-benzo[e][1,2,4]triazine-1-oxygen derivative and the pharmaceutically acceptable salt, ester and solvate thereof to preparation of a medicine for treating tumors.
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Paragraph 0046; 0052; 0057
(2017/07/22)
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- Overcoming chloroquine resistance in malaria: Design, synthesis, and structure-activity relationships of novel hybrid compounds
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Resistance to antimalarial therapies, including artemisinin, has emerged as a significant challenge. Reversal of acquired resistance can be achieved using agents that resensitize resistant parasites to a previously efficacious therapy. Building on our initial work describing novel chemoreversal agents (CRAs) that resensitize resistant parasites to chloroquine (CQ), we herein report new hybrid single agents as an innovative strategy in the battle against resistant malaria. Synthetically linking a CRA scaffold to chloroquine produces hybrid compounds with restored potency toward a range of resistant malaria parasites. A preferred compound, compound 35, showed broad activity and good potency against seven strains resistant to chloroquine and artemisinin. Assessment of aqueous solubility, membrane permeability, and in vitro toxicity in a hepatocyte line and a cardiomyocyte line indicates that compound 35 has a good therapeutic window and favorable drug-like properties. This study provides initial support for CQ-CRA hybrid compounds as a potential treatment for resistant malaria.
- Boudhar, Aicha,Ng, Xiao Wei,Loh, Chiew Yee,Chia, Wan Ni,Tan, Zhi Ming,Nosten, Francois,Dymock, Brian W.,Tan, Kevin S. W.
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p. 3076 - 3089
(2016/05/11)
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- Design, Synthesis, and Evaluation of Novel Ferroquine and Phenylequine Analogues as Potential Antiplasmodial Agents
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7-Chloroquinoline-based antimalarial drugs are effective in the inhibition of hemozoin formation in the food vacuole of the Plasmodium parasite, the causative agent of malaria. We synthesized five series of ferroquine (FQ) and phenylequine (PQ) derivatives, which display good in vitro efficacy toward both the chloroquine-sensitive (CQS) NF54 (IC50: 4.2 nm) and chloroquine-resistant (CQR) Dd2 (IC50: 33.7 nm) strains of P. falciparum. Several compounds were found to have good inhibitory activity against β-hematin formation in an NP-40 detergent assay, with IC50 values ranging between 10.4 and 19.2 μm.
- Jacobs, Leon,De Kock, Carmen,De Villiers, Katherine A.,Smith, Peter J.,Smith, Vincent J.,Van Otterlo, Willem A. L.,Blackie, Margaret A. L.
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p. 2099 - 2110
(2015/12/23)
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- 4-Aminoquinoline-Pyrimidine hybrids: Synthesis, antimalarial activity, heme binding and docking studies
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A series of novel 4-aminoquinoline-pyrimidine hybrids has been synthesized and evaluated for their antimalarial activity. Several compounds showed promising in vitro antimalarial activity against both CQ-sensitive and CQ-resistant strains with high select
- Kumar, Deepak,Khan, Shabana I.,Tekwani, Babu L.,Ponnan, Prija,Rawat, Diwan S.
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p. 490 - 502
(2014/12/11)
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- AMINOQUINOLINE DERIVATIVES AND USES THEREOF
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Described herein are aminoquinoline and aminoacridine based hybrids, pharmaceutical compositions and medicaments that include such aminoquinoline and aminoacridine based hybrids, and methods of using such compounds for diagnosing and/or treating infections, neurodegerative diseases or disorders, inflammation, inflammation associated diseases and disorders, and/or diseases or disorders that are treatable with dopamine agonists such as the restless leg syndrome.
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Paragraph 0417
(2015/02/18)
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- Quinoline-pyrimidine hybrids: Synthesis, antiplasmodial activity, SAR, and mode of action studies
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For the treatment of malaria which affects nearly 200 million people each year and the continued exacerbation by the emergence of drug resistance to most of the available antimalarials, the "covalent bitherapy" suggests hybrid molecules to be the next-generation antimalarial drugs. In this investigation, new hybrids of 4-aminoquinoline and pyrimidine moieties that show antiplasmodial activity in the nM range against chloroquine-resistant as well as chloroquine-sensitive strains of Plasmodium falciparum have been prepared. Cytotoxicity evaluation and mode of action of most potent hybrid molecule have been conducted.
- Singh, Kamaljit,Kaur, Hardeep,Smith, Peter,De Kock, Carmen,Chibale, Kelly,Balzarini, Jan
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p. 435 - 448
(2014/02/14)
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- Kojic acid derived hydroxypyridinone-chloroquine hybrids: Synthesis, crystal structure, antiplasmodial activity and β-haematin inhibition
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Aminochloroquinoline-kojic acid hybrids were synthesized and evaluated for β-haematin inhibition and antiplasmodial activity against drug resistant (K1) and sensitive (3D7) strains of Plasmodium falciparum. Compound 7j was the most potent compound in both strains (IC503D7 = 0.004 μM; IC50K1 = 0.03 μM) and had the best β-haematin inhibition activity (0.07 IC50 equiv vs 1.91 IC 50 equiv for chloroquine). One compound 8c was found to be equipotent in both strains (IC50 = 0.04 μM).
- Andayi, Warren Andrew,Egan, Timothy J.,Chibale, Kelly
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supporting information
p. 3263 - 3267
(2014/07/22)
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- Synthesis, in vitro antimalarial activity and cytotoxicity of novel 4-aminoquinolinyl-chalcone amides
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A series of 4-aminoquinolinyl-chalcone amides 11-19 were synthesized through condensation of carboxylic acid-functionalized chalcone with aminoquinolines, using 1,1′-carbonyldiimidazole as coupling agent These compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (W2) strains of Plasmodium falciparum Their cytotoxicity towards the WI-38 cell line of normal human fetal lung fibroblast was determined All compounds were found active, with IC50 values ranging between 0.04-0.5 μM and 0.07-1.8 μM against 3D7 and W2, respectively They demonstrated moderate to high selective activity towards the parasitic cells in the presence of mammalian cells However, amide 15, featuring the 1,6-diaminohexane linker, despite possessing predicted unfavourable aqueous solubility and absorption properties, was the most active of all the amides tested It was found to be as potent as CQ against 3D7, while it displayed a two-fold higher activity than CQ against the W2 strain, with good selective antimalarial activity (SI = 435) towards the parasitic cells During this study, amide 15 was thus identified as the best drug-candidate to for further investigation as a potential drug in search for new, safe and effective antimalarial drugs
- Smit, Frans J.,N'Da, David D.
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p. 1128 - 1138
(2014/02/14)
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- Synthesis, in vitro antiplasmodial and antiproliferative activities of a series of quinoline-ferrocene hybrids
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Series of quinoline-ferrocene hybrids containing various linkers were synthesized and evaluated for antimalarial and anticancer activities as well as cytotoxicity. The hybrids with rigid linkers were found to be inactive, while those with flexible spacers
- N'Da, David D.,Smith, Peter J.
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p. 1214 - 1224
(2014/03/21)
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- In vitro phenotypic screening of 7-chloro-4-amino(oxy)quinoline derivatives as putative anti-Trypanosoma cruzi agents
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In this study, a series of 22 pre-synthesized 7-chloro-4-amino(oxy) quinoline derivatives was assayed in vitro as potential antichagasic agents. A primary screening against Trypanosoma cruzi epimastigotes and a non-specific cytotoxicity assay on murine fibroblasts were simultaneously performed, resulting quinolines 3, 7 and 12 with great selectivity (SI) on the extracellular parasite (SI7, SI3, SI12 and SIBZ >9.44). Therefore, the activity of these derivatives was evaluated on intracellular amastigotes, achieving derivative 7 the best SI (SI = 12.73). These results, supported by the in silico prediction of a good oral bioavailability and a suitable risk profile, propose the 4-amino-7- chloroquinoline scaffold as a potential template for designing trypanocidal prototypes.
- Fonseca-Berzal, Cristina,Rojas Ruiz, Fernando A.,Escario, José A.,Kouznetsov, Vladimir V.,Gómez-Barrio, Alicia
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p. 1209 - 1213
(2014/03/21)
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- Synthesis, antimalarial activity, heme binding and docking studies of 4-aminoquinoline-pyrimidine based molecular hybrids
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A series of novel 4-aminoquinoline-pyrimidine hybrids was synthesized and evaluated for their antimalarial activity. Several compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains of P. falciparum with no cytotoxi
- Kumar, Deepak,Khan, Shabana I.,Tekwani, Babu L.,Ponnan, Prija,Rawat, Diwan S.
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p. 63655 - 63669
(2015/02/19)
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- Incorporation of a 3-(2,2,2-Trifluoroethyl)-γ-hydroxy-γ-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities
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In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated γ-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 μM. The most promising compounds (82 and 84) showed significant IC50 values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study.
- Cornut, Damien,Lemoine, Hugues,Kanishchev, Oleksandr,Okada, Etsuji,Albrieux, Florian,Beavogui, Abdoul Habib,Bienvenu, Anne-Lise,Picot, Stéphane,Bouillon, Jean-Philippe,Médebielle, Maurice
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- Synthesis, characterization and antimalarial activity of quinoline-pyrimidine hybrids
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The aim of this study was to synthesize a series of quinoline-pyrimidine hybrids and to evaluate their in vitro antimalarial activity as well as cytotoxicity. The hybrids were brought about in a two-step nucleophilic substitution process involving quinoli
- Pretorius, Stefan I.,Breytenbach, Wilma J.,De Kock, Carmen,Smith, Peter J.,N'Da, David D.
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supporting information
p. 269 - 277
(2013/02/22)
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- Conjugation to 4-aminoquinoline improves the anti-trypanosomal activity of Deferiprone-type iron chelators
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Iron is an essential growth component in all living organisms and plays a central role in numerous biochemical processes due to its redox potential and high affinity for oxygen. The use of iron chelators has been suggested as a novel therapeutic approach
- Gehrke, Sebastian S.,Pinto, Erika G.,Steverding, Dietmar,Pleban, Karin,Tempone, Andre G.,Hider, Robert C.,Wagner, Gerd K.
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p. 805 - 813
(2013/02/25)
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- N-Cinnamoylated chloroquine analogues as dual-stage antimalarial leads
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The control of malaria is challenged by drug resistance, and new antimalarial drugs are needed. New drug discovery efforts include consideration of hybrid compounds as potential multitarget antimalarials. Previous work from our group has demonstrated that hybrid structures resulting from cinnamic acid conjugation with heterocyclic moieties from well-known antimalarials present improved antimalarial activity. Now, we report the synthesis and SAR analysis of an expanded series of cinnamic acid derivatives displaying remarkably high activities against both blood-and liver-stage malaria parasites. Two compounds judged most promising, based on their in vitro activity and druglikeness according to the Lipinski rules and Veber filter, were active in vivo against blood-stage rodent malaria parasites. Therefore, the compounds reported represent a new entry as promising dual-stage antimalarial leads.
- Pérez, Bianca C.,Teixeira, Cátia,Albuquerque, Ine?s S.,Gut, Jiri,Rosenthal, Philip J.,Gomes, José R. B.,Prude?ncio, Miguel,Gomes, Paula
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p. 556 - 567
(2013/04/23)
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- Synthesis and biological evaluation of a new class of 4-aminoquinoline- rhodanine hybrid as potent anti-infective agents
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Synthesis of novel 4-aminoquinoline-rhodanine hybrid using inexpensive starting materials via easy to operate methodology, and their biological activity is reported. All the compounds were screened for their in vitro antimalarial activity against chloroqu
- Chauhan, Kuldeep,Sharma, Moni,Saxena, Juhi,Singh, Shiv Vardan,Trivedi, Priyanka,Srivastava, Kumkum,Puri, Sunil K.,Saxena,Chaturvedi, Vinita,Chauhan, Prem. M.S.
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p. 693 - 704
(2013/05/09)
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- 4-aminoquinoline-triazine-based hybrids with improved in vitro antimalarial activity against CQ-sensitive and CQ-resistant strains of plasmodium falciparum
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A systematic chemical modification in the triazine moiety covalently attached via suitable linkers to 4-amino-7-chloroquinolines yielded a series of new 7-chloro-4-aminoquinoline-triazine hybrids exhibiting high in vitro activity against W2 (chloroquine-resistant) and D6 (chloroquine-sensitive) strains of Plasmodium falciparum without any toxicity against mammalian cell lines (Vero, LLC-PK11, HepG2). Many of the compounds (6, 8, 10, 11, 13, 14, 16, 27, 29 and 33) showed excellent potency against chloroquine sensitive and resistant strains. In particular, compounds 6, 8, 14, 16 and 29 were found to be significantly more active than chloroquine against the chloroquine-resistant strains (W2 clone) of P. falciparum.
- Manohar, Sunny,Khan, Shabana I.,Rawat, Diwan S.
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p. 625 - 630
(2013/06/27)
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- Synthesis, antiplasmodial activity, and β-hematin inhibition of hydroxypyridone-chloroquine hybrids
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A series of noncytotoxic 4-aminoquinoline-3-hydroxypyridin-4-one hybrids were synthesized on the basis of a synergistic in vitro combination of a precursor N-alkyl-3-hydroxypyridin-4-one with chloroquine (CQ) and tested in vitro against CQ resistant (K1 and W2) and sensitive (3D7) strains of Plasmodium falciparum. In vitro antiplasmodial activity of the precursors was negated by blocking the chelator moiety via complexation with gallium(III) or benzyl protection. None of the precursors inhibited β-hematin formation. Most hybrids were more potent inhibitors of β-hematin formation than CQ, and a correlation between antiplasmodial activity and inhibition of β-hematin formation was observed. Potent hybrids against K1, 3D7, and W2, respectively, were 8c (0.13, 0.004, and 0.1 μM); 8d (0.08, 0.01, and 0.02 μM); and 7g (0.07, 0.03, and 0.08 μM).
- Andayi, Warren A.,Egan, Timothy J.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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supporting information
p. 642 - 646
(2013/07/26)
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- Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues
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Cinnamic acids and quinolines are known as useful scaffolds in the discovery of antitumor agents. Therefore, N-cinnamoylated analogues of chloroquine, recently reported as potent dual-action antimalarials, were evaluated against three different cancer cel
- Perez, Bianca C.,Fernandes, Iva,Mateus, Nuno,Teixeira, Catia,Gomes, Paula
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supporting information
p. 6769 - 6772
(2014/01/06)
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- In Vitro antimycobacterial activity of new 7-chloroquinoline derivatives
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The antimycobacterial activity of new 18 7-chloroquinoline derivatives, obtained from 4,7-dichloroquinoline, was evaluated against 15 Mycobacterium spp among standardized and clinical isolates using the MTT susceptibility test to obtain minimum inhibitory concentration values (MIC, μg/mL). The results suggested that 7-chloroquinoline compounds are useful leads for new anti-TB drug development. The most active compounds exhibited moderate activity with 16 μg/mL MIC values for all tested microorganisms.
- Bueno, Juan,Rojas Ruiz, Fernando A.,Villabona Estupinan, Santiago,Kouznetsov, Vladimir V.
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scheme or table
p. 126 - 134
(2012/07/28)
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- AMINOQUINOLINIUM SALTS, METHODS OF THEIR PRODUCTION AND THEIR USE AS ACTIVE AGENTS FOR BIOTECHNOLOGICAL AND MEDICAL APPLICATIONS AGAINST BINARY TOXINS
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The present invention relates to aminoquinoline salts, their uses and to methods of synthesizing such aminoquinoline salts. Moreover, the present invention relates to compositions comprising aminoquinoline salts in accordance with the present invention. The present invention relates to bioactive compounds from the class of aminoquinoline compounds, and in particular their inhibitory effects on the binary toxins of an AB-type of a number of bacteria, such as Clostridium perfringens, Clostridium botulinum, and Bacillus anthracis. The invention also relates to the use of these aminoquinoline compounds as drugs, more particularly as drugs for the treatment of bacterial infections, even more particularly bacterial infections caused by bacteria which produce pore forming toxins of a binary type. The present invention also relates to methods of producing the compounds in accordance with the present invention.
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Page/Page column 25-26
(2012/04/17)
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- Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy
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Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia
- Aminake, Makoah N.,Mahajan, Aman,Kumar, Vipan,Hans, Renate,Wiesner, Lubbe,Taylor, Dale,De Kock, Carmen,Grobler, Anne,Smith, Peter J.,Kirschner, Marc,Rethwilm, Axel,Pradel, Gabriele,Chibale, Kelly
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p. 5277 - 5289
(2012/11/07)
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- COMPOSITIONS AND METHODS FOR ENHANCING CELLULAR UPTAKE AND INTRACELLULAR DELIVERY OF LIPID PARTICLES
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Compositions, methods and compounds useful for enhancing the uptake of a lipid particle b\ a cell are described In particular embodiments, the methods of the invention include contacting a cell with a lipid particle and a compound that binds a Na+/K+ ATPase to enhance uptake of the lipid particle b\ the cell Related compositions useful in practicing methods include lipid particles comprising a conjugated compound that enhances uptake of the lipid particles b\ the cell The methods and compositions are useful in delivering a therapeutic agent to a cell, e g for the treatment of a disease or disorder in a subject
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Page/Page column 34
(2012/10/23)
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- Antiplasmodial and antitumor activity of dihydroartemisinin analogs derived via the aza-Michael addition reaction
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A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial acti
- Feng, Tzu-Shean,Guantai, Eric M.,Nell, Margo J.,Van Rensburg, Constance E.J.,Hoppe, Heinrich C.,Chibale, Kelly
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supporting information; experimental part
p. 2882 - 2886
(2011/06/26)
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