- Application of multi-component reactions to antimalarial drug discovery. Part 1: Parallel synthesis and antiplasmodial activity of new 4-aminoquinoline Ugi adducts
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The synthesis of a new class of Ugi adducts incorporating the 4-aminoquinoline moiety is described. The novel compounds are active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum with the best compound showing
- Musonda, Chitalu C.,Taylor, Dale,Lehman, Julie,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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- Synthesis and evaluation of chalcone-quinoline based molecular hybrids as potential anti-malarial agents
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Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by the fusion (usually via a covalent linker) of two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome of this chemical modification is to produce a new hybrid compound with improved affinity and efficacy compared to the parent drugs. Additionally, this strategy can result in compounds presenting modified selectivity profiles, different and/or dual modes of action, reduced undesired side effects and ultimately lead to new therapies. In this study, molecular hybridization was used to generate new molecular hybrids which were tested against the chloroquine sensitive (NF54) strain of P. falciparum. To prepare the new molecular hybrids, the quinoline nucleus, one of the privileged scaffolds, was coupled with various chalcone derivatives via an appropriate linker to produce a total of twenty-two molecular hybrids in 11%–96% yield. The synthesized compounds displayed good antiplasmodial activity with IC50 values ranging at 0.10–4.45 μM.
- Vinindwa, Bonani,Dziwornu, Godwin Akpeko,Masamba, Wayiza
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- Design, synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline
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A series of short chain 4-aminoquinoline-imidazole derivatives have been synthesized in one pot two step multicomponent reaction using van leusen standard protocol. The diethylamine function of chloroquine is replaced by substituted imidazole derivatives containing tertiary terminal nitrogen. All the synthesized compounds were screened against the chloroquine sensitive (3D7) and chloroquine resistant (K1) strains of Plasmodium falciparum. Some of the compounds (6, 8, 9 and 17) in the series exhibited comparable activity to CQ against K1 strain of P. falciparum. All the compounds displayed resistance factor between 0.09 and 4.57 as against 51 for CQ. Further, these analogues were found to form a strong complex with hematin and inhibit the β-hematin formation, therefore these compounds act via heme polymerization target.
- Kondaparla, Srinivasarao,Manhas, Ashan,Dola, Vasantha Rao,Srivastava, Kumkum,Puri, Sunil K.,Katti
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- N-Substituted aminoquinoline-pyrimidine hybrids: Synthesis, in vitro antimalarial activity evaluation and docking studies
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A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC50 values in the range 0.0189–0.945 μM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction.
- Maurya, Shiv S.,Bahuguna, Aparna,Khan, Shabana I.,Kumar, Deepak,Kholiya, Rohit,Rawat, Diwan S.
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- Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain
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We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11-15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.
- Iwaniuk, Daniel P.,Whetmore, Eric D.,Rosa, Nicholas,Ekoue-Kovi, Kekeli,Alumasa, John,de Dios, Angel C.,Roepe, Paul D.,Wolf, Christian
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- Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies
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Emergence of drug resistance and targeting all stages of the parasite life cycle are currently the major challenges in antimalarial chemotherapy. Molecular hybridization combining two scaffolds in a single molecule is an innovative strategy for achieving these goals. In this work, a series of novel quinoxaline 1,4-di-N-oxide hybrids containing either chloroquine or primaquine pharmacophores was designed, synthesized and tested against both chloroquine sensitive and multidrug resistant strains of Plasmodium falciparum. Only chloroquine-based compounds exhibited potent blood stage activity with compounds 4b and 4e being the most active and selective hybrids at this parasite stage. Based on their intraerythrocytic activity and selectivity or their chemical nature, seven hybrids were then evaluated against the liver stage of Plasmodium yoelii, Plasmodium berghei and Plasmodium falciparum infections. Compound 4b was the only chloroquine-quinoxaline 1,4-di-N-oxide hybrid with a moderate liver activity, whereas compound 6a and 6b were identified as the most active primaquine-based hybrids against exoerythrocytic stages, displaying enhanced liver activity against P. yoelii and P. berghei, respectively, and better SI values than primaquine. Although both primaquine-quinoxaline 1,4-di-N-oxide hybrids slightly reduced the infection of mosquitoes, they inhibited sporogony of P. berghei and compound 6a showed 92% blocking of transmission. In vivo liver efficacy assays revealed that compound 6a showed causal prophylactic activity affording parasitaemia reduction of up to 95% on day 4. Absence of genotoxicity and in vivo acute toxicity were also determined. These results suggest the approach of primaquine-quinoxaline 1,4-di-N-oxide hybrids as new potential dual-acting antimalarials for further investigation.
- Bonilla-Ramirez, Leonardo,Rios, Alexandra,Quiliano, Miguel,Ramirez-Calderon, Gustavo,Beltrán-Hortelano, Iván,Franetich, Jean Fran?ois,Corcuera, Luis,Bordessoulles, Mallaury,Vettorazzi, Ariane,López de Cerain, Adela,Aldana, Ignacio,Mazier, Dominique,Pabón, Adriana,Galiano, Silvia
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- Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold
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A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-compo
- Avilés, Edward,Prudhomme, Jacques,Le Roch, Karine G.,Franzblau, Scott G.,Chandrasena, Kevin,Mayer, Alejandro M.S.,Rodríguez, Abimael D.
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- Highly active 4-aminoquinoline-pyrimidine based molecular hybrids as potential next generation antimalarial agents
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In order to overcome the problem of emerging drug resistance in malarial chemotherapy, a series of highly active 4-aminoquinoline-pyrimidine hybrids were synthesized and evaluated for their antimalarial activity against CQ-sensitive (NF54) and CQ-resistant (Dd2) strains of P. falciparum in an in vitro assay. The most active hybrid 19f exhibited 74-fold better potency than chloroquine and 4-fold better potency than artesunate against the drug-resistant strain of P. falciparum. Compound 19e, when evaluated for in vivo activity in the P. berghei-mouse malaria model showed 93.9% parasite suppression at 30 mg kg-1 dose on Day 4 with a mean survival time of 11 days. To gain insights towards the mechanism of action of these hybrids, heme binding and molecular modelling studies were performed on the most active hybrids. It was observed that inhibition of formation of β-hematin and dihydrofolate reductase-thymidylate synthase Pf-DHFR-TS enzyme could be associated with the observed antimalarial activity of these compounds.
- Manohar, Sunny,Satya Pavan,Taylor, Dale,Kumar, Deepak,Ponnan, Prija,Wiesner, Lubbe,Rawat, Diwan S.
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- Synthesis and biological activity of novel 4-aminoquinoline/1,2,3-triazole hybrids against Leishmania amazonensis
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Quinoline and 1,2,3-triazoles are well-known nitrogen-based heterocycles presenting diverse pharmacological properties, although their antileishmanial activity is still poorly exploited. As an effort to contribute with studies involving these interesting chemical groups, in the present study, a series of compounds derived from 4-aminoquinoline and 1,2,3-triazole were synthetized and biological studies using L. amazonensis species were performed. The results pointed that the derivative 4, a hybrid of 4-aminoquinoline/1,2,3-triazole exhibited the best antileishmanial action, with inhibitory concentration (IC50) values of ~1 μM against intramacrophage amastigotes of L. amazonensis, and being 16-fold more active to parasites than to the host cell. The mechanism of action of derivative 4 suggest a multi-target action on Leishmania parasites, since the treatment of L. amazonensis promastigotes caused mitochondrial membrane depolarization, accumulation of ROS products, plasma membrane permeabilization, increase in neutral lipids, exposure of phosphatidylserine to the cell surface, changes in the cell cycle and DNA fragmentation. The results suggest that the antileishmanial effect of this compound is primarily altering critical biochemical processes for the correct functioning of organelles and macromolecules of parasites, with consequent cell death by processes related to apoptosis-like and necrosis. No up-regulation of reactive oxygen and nitrogen intermediates was promoted by derivative 4 on L. amazonensis -infected macrophages, suggesting a mechanism of action independent from the activation of the host cell. In conclusion, data suggest that derivative 4 presents selective antileishmanial effect, which is associated with multi-target action, and can be considered for future studies for the treatment against disease.
- Glanzmann, Nícolas,Antinarelli, Luciana Maria Ribeiro,da Costa Nunes, Isabelle Karine,Pereira, Henrique Marcelo Gualberto,Coelho, Eduardo Antonio Ferraz,Coimbra, Elaine Soares,da Silva, Adilson David
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- N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity
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Zika virus (ZIKV), an emerging Flavivirus, was recently associated with severe neurological complications and congenital diseases. Therefore, development of antiviral agents capable of inhibiting ZIKV replication is urgent. Chloroquine is a molecule with a confirmed safety history for use with pregnant women, and has been found to exhibit anti-ZIKV activity at concentrations around 10?μM. This suggests that modifications to the chloroquine structure could be promising for obtaining more effective anti-ZIKV agents. Here, we report the ability of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives to inhibit ZIKV replication in?vitro. We have found that the quinoline derivative, N-(2-((5-nitrofuran-2-yl)methylimino)ethyl)-7-chloroquinolin-4-amine, 40, was the most potent compound within this series, reducing ZIKV replication by 72% at 10?μM. Compound 40 exhibits an EC50value of 0.8?±?0.07?μM, compared to that of chloroquine of 12?±?3.2?μM. Good activities were also obtained for other compounds, including those with aryl groups?=?phenyl, 4-fluorophenyl, 4-nitrophenyl, 2,6-dimethoxyphenyl, 3-pyridinyl and 5-nitrothien-2-yl. Syntheses of these quinoline derivatives have been obtained both by thermal and ultrasonic means. The ultrasonic method produced comparable yields to the thermal (reflux) method in very much shorter times 30–180?s compared to 30–180?min reactions times. These results indicate that this group of compounds is a good follow-up point for the potential discovery of new drugs against the Zika disease.
- Barbosa-Lima, Giselle,da Silveira Pinto, Ligia S.,Kaiser, Carlos R.,Wardell, James L.,De Freitas, Caroline S.,Vieira, Yasmine R.,Marttorelli, Andressa,Cerbino Neto, José,Bozza, Patrícia T.,Wardell, Solange M.S.V.,de Souza, Marcus V.N.,Souza, Thiago M.L.
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- Property-Based Design and Synthesis of New Chloroquine Hybrids via Simple Incorporation of 2-Imino-thiazolidin-4-one or 1H-Pyrrol-2,5-dione Fragments on the 4-Amino-7-chloroquinoline Side Chain
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In the present work, the syntheses of new 4-amino-7-chloroquinoline N-derivatives were performed by selective modification of the side chain amino group of N-(7-chloroquinolin-4-yl)alkyldiamines, basis framework of chloroquine (CQ) drug through the incorporation of heterocyclic 2-imino-thiazolidin-4-one and 1H-pyrrol-2,5-dione systems. These potential activity modulators were selected thanks to their characteristic properties, and evaluated by virtual screening employing the OSIRIS and Molinspirations platforms. Designed and synthesized quinolinic derivatives could increase the antimalarial activity of CQ analogues without affecting the lipophilicity as described in literature, suggesting them as candidates for further biological assessments. ?2011 Sociedade Brasileira de Qui?mica.
- Rojas, Fernando A.,Kouznetsov, Vladimir V.
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- Design, synthesis, and in vitro activity of novel 2′- O -substituted 15-membered azalides
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Malaria remains one of the most widespread human infectious diseases, and its eradication will largely depend on antimalarial drug discovery. Here, we present a novel approach to the development of the azalide class of antimalarials by describing the design, synthesis, and characterization of novel 2′-O-substituted-9-deoxo-9a-methyl-9a-aza-9a-homoerythromycin A derivatives consisting of different quinoline moieties covalently liked to a 15-membered azalide scaffold at position 2′. By multistep straightforward synthesis, 19 new, stable, and soluble compounds were created and biologically profiled. Most active compounds from the 4-amino-7-chloroquinoline series showed high selectivity for P. falciparum parasites, and in vitro antimalarial activity improved 1000-fold over azithromycin. Antimalarial potency was equivalent to chloroquine against the sensitive strain (3D7A) and up to 48-fold enhanced over chloroquine against the chloroquine-resistant strain (W2). Concurrently, the antibacterial activity of the compounds was eliminated, thus facilitating the development of malaria-specific macrolide agents.
- Pe?i?, Dijana,Star?evi?, Kristina,Toplak, Ana,Herreros, Esperanza,Vidal, Jaume,Almela, Maria Jesus,Jeli?, Dubravko,Alihod?i?, Sulejman,Spaventi, Radan,Peri?, Mihaela
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- Synthesis, antimalarial activity, heme binding and docking studies of N-substituted 4-aminoquinoline-pyrimidine molecular hybrids
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A series of novel N-substituted 4-aminoquinoline-pyrimidine hybrids have been synthesized via simple and economic route and evaluated for their antimalarial activity. Most compounds showed potent antimalarial activity against both CQ-sensitive and CQ-resistant strains with high selectivity index. All the compounds were found to be non-toxic to the mammalian cell lines. The most active compound 7b was analysed for heme binding activity using UV-spectrophotometer. Compound was found to interact with heme and a complex formation between compound and heme in a 1:1 stoichiometry ratio was determined using job plots. The interaction of these hybrids was also investigated by the molecular docking studies in the binding site of wild type Pf-DHFR-TS and quadruple mutant Pf-DHFR-TS. The pharmacokinetic property analysis of best active compounds was also studied by ADMET prediction.
- Maurya, Shiv Shyam,Khan, Shabana I.,Bahuguna, Aparna,Kumar, Deepak,Rawat, Diwan S.
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- N-Piperonyl substitution on aminoquinoline-pyrimidine hybrids: Effect on the antiplasmodial potency
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A series of 4-aminoquinoline-piperonyl-pyrimidine hybrids were synthesized with the aim of identifying compounds with enhanced antimalarial activity. All the synthesized molecules were evaluated in?vitro against cultured Plasmodium falciparum W2 and D6 strains and exhibited potent antiplasmodial activities with IC50 values in the range of 0.02–5.16?μM. Out of the 22 synthesised hybrids, 12 were found to be better (up to eight-fold more active) than chloroquine (CQ), particularly against the CQ-resistant W2 strain of P.?falciparum with no significant cytotoxicity towards the mammalian cells. Mechanistic studies reveal that these compounds bind with heme and computational docking studies showed good docking interactions within the active site of Pf-DHFR.
- Kholiya, Rohit,Khan, Shabana I.,Bahuguna, Aparna,Tripathi, Mohit,Rawat, Diwan S.
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- Synthesis, Cytotoxicity, Molecular Docking, Molecular Simulation and ADME Properties of Cinnamoylated Chloroquine Hybrid Analogues as Corona Virus Protease Inhibitors
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In an attempt to challenge COVID-19, molecular docking of cinnamoylated chloroquine compounds 1–15 against main protease (Mpro) enzyme of SARS-CoV-2 was undertaken. To study the stability of the complex formed between the drug and the receptor, suitable docking possesses were selected and put into molecular dynamics studies. Further ADME properties were determined using SWISS ADME software. In the docking studies compounds 5, 9, 14 and 15 exhibited encouragable binding with the Mpro crystal structure with docking scores of -8.1, -7.9, -7.8 and -7.9 Kcal/mole respectively. It was observed that CYS145 and GLU166 played a significant role during the interaction of molecules with the active site of COVID-19 Mpro. Among compounds 5, 9, 14 and 15, compound 5 had stable interactions with the protein, which might be the reason for the optimum RMSD, RMSF, radius of gyration and protein–ligand contacts (hydrogen bonding) values. The compound 5 was synthesised and tested for its cytotoxic activity against fibroblast L929 cell line. The above study indicated that the compound 5 as a promising agent, and during the drug discovery process it could be taken as a starting point for lead optimization.
- Hemapriya, K.,Jayanthi, K. R.,Ravi, Subban
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p. 163 - 171
(2022/03/16)
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- A simple quinoline salt derivative is active in vitro against Plasmodiumf alciparum asexual blood stages and inhibits the development of cerebral malaria in murine model
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Chloroquine (CQ) was the most effective and widely used drug for the prophylaxis and treatment of severe and non-severe malaria. Although its prophylactic use has led to resistance to P. falciparum in all endemic countries, CQ still remains the drug of choice for the treatment of vivax malaria. Otherwise, the speed in which parasite resistance to available antimalarials rises and spreads in endemic regions points to the urgent need for the development of new antimalarials. Quinoline derivatives have been used as a tool in the search for new drugs and were investigated in the present study in an attempt to produce a HIT compound to avoid the cerebral malarial (CM). Seven compounds were synthesized, including three quinoline derivate salts. The cytotoxicity and antiplasmodial activity were assayed in vitro, highlighting compound 3 as a HIT, which also showed interaction with ferriprotoporphyrin IX similarly to CQ. Physicochemical and pharmacokinetic properties of absorption were found to be favorable when analyzed in silico. The in vivo assays, using the experimental cerebral malaria (ECM) model, showed important values of parasite growth inhibition on the 7th day-post infection (Q15 15 mg/kg: 76.9%, Q30 30 mg/kg: 90,1% and Q50 50 mg/kg: 92,9%). Compound 3 also showed significant protection against the development of CM, besides hepatic and renal parameters better than CQ. In conclusion, this quinoline derivative demonstrated promising activity for the treatment of malaria and was able to avoid the development of severe malaria in mice.
- Azevedo, Marina Rocha,Barreto, Livia Maria,Bezerra Bellei, Jessica Correa,Coimbra, Elaine Soares,David da Silva, Adilson,Gualberto Pereira, Henrique Marcelo,Karine da Costa Nunes, Isabelle,Marques, Carolina Brandi,Renhe, Daniela Chaves,Rocha, Vinicius Novaes,de Pilla Varotti, Fernando,Carpinter, Bárbara Albuquerque,Ferraz Coelho, Eduardo Ant?nio,Glanzmann, Nícolas,Gorza Scopel, Kézia Katiani
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- Anti-SARS-CoV-2 Inhibitory Profile of New Quinoline Compounds in Cell Culture-Based Infection Models
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The presently ongoing pandemic of human SARS-CoV-2 infections (COVID-19) presents an enormous challenge in surveillance, vaccine and antiviral drug development. Here we report the synthesis of new bioactive quinoline-morpholine hybrid compounds and their
- Herrmann, Lars,Hahn, Friedrich,Wangen, Christina,Marschall, Manfred,Tsogoeva, Svetlana B.
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supporting information
(2022/01/06)
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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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- SMALL MOLECULE INHIBITORS OF AUTOPHAGY AND HISTONE DEACTYLASES AND USES THEREOF
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This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinoline or thioxanthenone (or similar) structure which function as autophagy inhibitors and/or histone deactylase inhibitors, and their use as therapeutics for the treatment of conditions characterized with aberrant autophagy activity and/or aberrant HDAC activity (e.g., cancer, pulmonary hypertension, diabetes, neurodegenerative disorders, aging, heart disease, rheumatoid arthritis, infectious diseases, conditions and symptoms caused by a viral infection (e.g., COVID-19)).
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Page/Page column 44-45
(2021/05/07)
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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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- 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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- Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity
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A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50 values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.
- Athanassopoulos, Constantinos M.,Baltas, Michel,Grellier, Philippe,Menendez, Christophe,Mouray, Elisabeth,Papaioannou, Dionissios,Pepe, Dionissia A.,Toumpa, Dimitra,André-Barrès, Christiane
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supporting information
p. 921 - 927
(2020/07/21)
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- In-vitro evaluation studies of 7-chloro-4-aminoquinoline Schiff bases and their copper complexes as cholinesterase inhibitors
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Alzheimer's disease (AD) is one of the most common age-related neurodegenerative disorders. Aggregation of amyloid-β peptide into extracellular plaques with incorporation of metal ions, such as Cu2+, and reduction of the neurotransmitter acetylcholine levels are among the factors associated to the AD brain. Hence, a series of 7-chloro-4-aminoquinoline Schiff bases (HLa–e) were synthesized and their cytotoxicity and anti-cholinesterase activity, assessed for Alzheimer's disease. The intrinsic relationship between Cu2+ and the amyloidogenic plaques encouraged us to investigate the chelating ability of HLa–e. Dimeric tetracationic compounds, [Cu2(NHLa–e)4]Cl4, containing quinoline protonated ligands were isolated from the reactions with CuCl2·2H2O and fully characterized in the solid state, including an X ray diffraction study, whereas EPR data showed that the complexes exist as monomers in DMSO solution. The inhibitory activity of all compounds was evaluated by Ellman's spectrophotometric method in acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from equine serum. HLa–e and [Cu(NHLd)2]Cl2 were selective for AChE (IC50 = 4.61–9.31 μM) and were not neurotoxic in primary brain cultures. Docking and molecular dynamics studies of HLa–e inside AChE were performed and the results suggested that these compounds are able to bind inside AChE similarly to other AChE inhibitors, such as donepezil. Studies of the affinity of HLd for Cu2+ in DMSO/HEPES at pH 6.6 and pH 7.4 in μM concentrations showed formation of analogous 1:2 Cu2+/ligand complexes, which may suggest that in the AD-affected brain HLd may scavenge Cu2+ and the complex, also inhibit AChE.
- Zanon, Vanessa S.,Lima, Josélia A.,Cuya, Teobaldo,Lima, Flavia R.S.,da Fonseca, Anna C.C.,Gomez, Javier G.,Ribeiro, Ronny R.,Fran?a, Tanos C.C.,Vargas, Maria D.
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p. 183 - 193
(2018/12/13)
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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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p. 484 - 493
(2019/02/07)
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- Structural aspects of 4-aminoquinolines as reversible inhibitors of human acetylcholinesterase and butyrylcholinesterase
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Eight derivatives of 4-aminoquinolines differing in the substituents attached to the C(4)-amino group and C(7)were synthesised and tested as inhibitors of human acetylcholinesterase (AChE)and butyrylcholinesterase (BChE). Both enzymes were inhibited by all of the compounds with inhibition constants (Ki)ranging from 0.50 to 50 μM exhibiting slight selectivity toward AChE over BChE. The most potent inhibitors of AChE were compounds with an n-octylamino chain or adamantyl group. The shortening of the chain length resulted in a decrease in AChE inhibition by 5–20 times. Docking studies revealed that the quinoline group within the AChE active site was positioned in the choline binding site, while the C(4)-amino group substituents, depending on their lipophilicity, could establish hydrogen bonds or π-interactions with residues of the peripheral anionic site. The most potent inhibitors of BChE were compounds with the most voluminous substituent on C(4)-amino group (adamantyl)or those with a stronger electron withdrawing substituent on C(7)(trifluormethyl group). Based on AChE inhibition, compounds with an n-octylamino chain or adamantyl substituent were shown to possess the capacity for further development as potential drugs for treatment of neurodegenerative diseases.
- Bosak, Anita,Opsenica, Dejan M.,?inko, Goran,Zlatar, Matija,Kovarik, Zrinka
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p. 101 - 109
(2019/05/22)
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- Artemisinin–(Iso)quinoline Hybrids by C?H Activation and Click Chemistry: Combating Multidrug-Resistant Malaria
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A substantial challenge worldwide is emergent drug resistance in malaria parasites against approved drugs, such as chloroquine (CQ). To address these unsolved CQ resistance issues, only rare examples of artemisinin (ART)-based hybrids have been reported. Moreover, protein targets of such hybrids have not been identified yet, and the reason for the superior efficacy of these hybrids is still not known. Herein, we report the synthesis of novel ART–isoquinoline and ART–quinoline hybrids showing highly improved potencies against CQ-resistant and multidrug-resistant P. falciparum strains (EC50 (Dd2) down to 1.0 nm; EC50 (K1) down to 0.78 nm) compared to CQ (EC50 (Dd2)=165.3 nm; EC50 (K1)=302.8 nm) and strongly suppressing parasitemia in experimental malaria. These new compounds are easily accessible by step-economic C?H activation and copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) click reactions. Through chemical proteomics, putatively hybrid-binding protein targets of the ART-quinolines were successfully identified in addition to known targets of quinoline and artemisinin alone, suggesting that the hybrids act through multiple modes of action to overcome resistance.
- ?apc?, Aysun,Ackermann, Lutz,Borges Silva, Mariana C.,Chen, Jia Yun,Friedrich, Oliver,Kappes, Barbara,Lee, Yew Mun,Leidenberger, Maria,Lorion, Mélanie M.,Meng, Yuqing,Moreira, Diogo R. M.,Simon, Nina,Tsogoeva, Svetlana B.,Wang, Hui,Wang, Jigang,Zhu, Yongping
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supporting information
p. 13066 - 13079
(2019/08/21)
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- N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives: A new and potent class of anticancer agents
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Background: In this study, we reported the in vitro cytotoxicity activities of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives against four human cancer cell lines. Methods: Good activities were obtained for compounds having aryl groups = 2-hydroxyphenyl, pyridinyl, 5-nitrofuran-2-yl and 5-nitrothiophen-2-yl. Results and Conclusion: The results indicate that this group of compounds is a good starting point for the potential discovery of new prototypes against cancer.
- da Silveira Pinto, Ligia S.,de Souza, Marcus V. N.,Kaiser, Carlos R.,Wardell, James L.,Wardell, Solange M. S. V.
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p. 113 - 117
(2018/03/21)
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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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supporting information
p. 1287 - 1291
(2018/03/23)
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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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- 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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- Cinnamoylated chloroquine analogues: A new structural class of antimalarial agents
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A novel series of cinnamoylated chloroquine hybrid analogues were synthesized and evaluated as antimalarial agents. The trans cinnamic acid derivatives (3–8) were synthesized by utilizing substituted aldehydes and malanoic acid in DMF catalysed by DABCO. The final cinnamoylated chloroquine analogues (9–14) were synthesized by utilizing DCC coupling reagent. The amido chloroquine (17) was prepared from acid (16) and compound 2 in benzene using SOCl2 as chlorinating agent. The corresponding ester (15) was prepared from 2-hydroxy acetophenone and 2-bromoacetates in actonitrile in presence of K2CO3?as?base followed by basic hydrolysis. The preparation of amide based chloroquine-chalcone analogues (18–22), were obtained by the combination of amido chloroquine (17) and aldehydes in 10% aq. KOH in methanol at room temperature. Further we prepared epichlorohydrin based chloroquine-chalcone analogues (25–28), by reacting the epoxide (24a, 24b and 24c) with 2 and methelenedioxy aniline. In?vitro antimalarial activity against chloroquine sensitive strain 3D7, chloroquine resistant strain K1 of P.?falciparum and in?vitro cytotoxicity of compounds using VERO cell line was carried out. The synthesized molecules showed significant in?vitro antimalarial activity especially against CQ resistant strain (K1). Among tested compounds, 13, 9 and 10 were found to be the most potent compounds of the series with IC50 value of 44.06, 48.04 and 59.37?nM against chloroquine resistant K1 strain.
- Gayam, Venkatareddy,Ravi, Subban
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p. 382 - 391
(2017/05/04)
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- USE OF CYMANQUINE COMPOUNDS AS ANTIMALARIAL AGENTS
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Organometallic compounds comprising a chloroquinoline moiety for use in the prophylaxis and treatment of malaria. The compounds can be manganese or rhenium complexes of a ligand comprising a chloroquinoline moiety.
- -
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Paragraph 0063; 0064
(2017/02/09)
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- New derivatives of 7-chloroquinolin-4-amine with antiprotozoal activity
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Novel ω-aminoacyl and -alkyl derivatives of 7-chloroquinolin-4-amine were prepared and their structures confirmed by NMR spectroscopy. Their antiprotozoal activities were examined in vitro against the sensitive NF54 strain as well as against the multiresistant K1strain of Plasmodium falciparum and against Trypanosoma brucei rhodesiense (STIB 900). The results were compared with the activities of clinically used drugs. Their antitrypanosomal activities were only moderate whereas their antiplasmodial activities looked very promising. Some were equal or slightly more active than chloroquine against the sensitive strain. However, in comparison to chloroquine, the activity of the new compounds was decreased much less in the resistant strain. Several possessed activity against both strains in low nanomolar concentration.
- Faist, Johanna,Hinteregger, Clemens,Seebacher, Werner,Saf, Robert,M?ser, Pascal,Kaiser, Marcel,Weis, Robert
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p. 941 - 948
(2017/02/18)
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- Design, synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine-resistant strain
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A series of novel bisquinoline compounds comprising N1-(7-chloroquinolin-4-yl) ethane-1,2-diamine and 7-chloro-N-(2-(piperazin-1-yl)ethyl)quinolin-4-amine connected with 7-chloro-4-aminoquinoline containing various amino acids is described. We have bio-evaluated the compounds against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8- and 10.6-fold superior activity as compared to chloroquine (CQ; IC50?=?0.255?±?0.049?μm) against the K1 strain with IC50 values 0.137?±?0.014 and 0.026?±?0.007?μm, respectively. Furthermore, compound 7 also displayed promising activity against the 3D7 strain (IC50?=?0.024?±?0.003?μm) of P.?falciparum when compared to CQ. All the compounds in the series displayed resistance factor between 0.57 and 4.71 as against 51 for CQ. These results suggest that bisquinolines can be explored for further development as new antimalarial agents active against chloroquine-resistant P.?falciparum.
- Kondaparla, Srinivasarao,Agarwal, Pooja,Srivastava, Kumkum,Puri, Sunil K.,Katti, Seturam B.
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p. 901 - 906
(2017/05/19)
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- Senescence tracers
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The instant invention relates to novel compounds useful for visualizing cell senescence, their preparation and use. In particular, this invention relates to novel fucose and amino-quinoline derivatives useful as senescence traces and their preparation.
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Page/Page column 10; 11
(2018/01/05)
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- CYMANQUINE COMPOUNDS AND DERIVATIVES THEREOF AND USES THEREOF
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Organometallic compounds comprising a chloroquinoline moiety and uses the compounds. The compounds are, for example, manganese or rhenium complexes of a ligand comprising a chloroquinoline moiety. The compounds can be used in, for example, methods of inhibiting cell growth.
- -
-
Paragraph 0071
(2016/08/03)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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- N-(7-Chloroquinolinyl-4-aminoalkyl)arylsulfonamides as antimalarial agents: Rationale for the activity with reference to inhibition of hemozoin formation
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New N-(7-chloroquinolinyl-4-aminoalkyl)arylsulfonamides were synthesized and tested in vitro against P. falciparum 3D7 and K1 strains and hemozoin formation. Compounds 16 and 17 showed promising antimalarial activity (IC50 3D7: 0.05 and 0.01 μM; K1: 0.41 and 0.36 μM) and exceedingly well inhibited hemozoin formation (IC50, 3.23 and 2.40 μM). Considering hemozoin inhibition was due to the affinity of the compounds towards heme, its μ-oxo dimer and/or heme detoxification protein (HDP), they were used in docking experiments for probing intermolecular interactions with the compounds. The docked structures indicated that quinoline, 4-amino and sulfonamide moieties interacted with one or more key constituents of the targets. In heme and μ-oxo dimer, the key constituents for interactions were ferriprotoporphyrin and propionic acid side chains. In the case of HDP, the key constituents were His175 and Glu126, and rationalized the antimalarial activity and functional use of the sulfonamide moiety. Thus, these compounds opened an avenue for exploration of hemozoin inhibition in malaria chemotherapy.
- Verma, Saroj,Pandey, Shashi,Agarwal, Pooja,Verma, Pravesh,Deshpande, Shreekant,Saxena, Jitendra Kumar,Srivastava, Kumkum,Chauhan, Prem M. S.,Prabhakar, Yenamandra S.
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p. 25584 - 25593
(2016/03/22)
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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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supporting information
p. 1881 - 1884
(2016/04/05)
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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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- 4-Aminoquinoline derivatives: Synthesis, in?vitro and in?vivo antiplasmodial activity against chloroquine-resistant parasites
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Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in?vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in?vivo. These 4-aminoquinolines cured BALB/c mice infected with P.?berghei. The ED50values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18?mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500?mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.
- Singh, Shailja,Agarwal, Drishti,Sharma, Kumkum,Sharma, Manish,Nielsen, Morten A.,Alifrangis, Michael,Singh, Ashok K.,Gupta, Rinkoo D.,Awasthi, Satish K.
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p. 394 - 407
(2016/07/15)
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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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p. 5979 - 5984
(2015/11/11)
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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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- 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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p. 519 - 525
(2015/02/19)
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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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p. 3474 - 3483
(2015/05/20)
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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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- 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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- 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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p. 5516 - 5519
(2015/01/08)
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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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p. 566 - 573
(2015/03/14)
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