5407-57-8Relevant articles and documents
Application of multi-component reactions to antimalarial drug discovery. Part 1: Parallel synthesis and antiplasmodial activity of new 4-aminoquinoline Ugi adducts
Musonda, Chitalu C.,Taylor, Dale,Lehman, Julie,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
, p. 3901 - 3905 (2004)
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
Synthesis and evaluation of chalcone-quinoline based molecular hybrids as potential anti-malarial agents
Vinindwa, Bonani,Dziwornu, Godwin Akpeko,Masamba, Wayiza
, (2021)
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.
Design, synthesis and antiplasmodial activity of novel imidazole derivatives based on 7-chloro-4-aminoquinoline
Kondaparla, Srinivasarao,Manhas, Ashan,Dola, Vasantha Rao,Srivastava, Kumkum,Puri, Sunil K.,Katti
, p. 204 - 211 (2018)
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.
N-Substituted aminoquinoline-pyrimidine hybrids: Synthesis, in vitro antimalarial activity evaluation and docking studies
Maurya, Shiv S.,Bahuguna, Aparna,Khan, Shabana I.,Kumar, Deepak,Kholiya, Rohit,Rawat, Diwan S.
, p. 277 - 289 (2019)
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.
Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain
Iwaniuk, Daniel P.,Whetmore, Eric D.,Rosa, Nicholas,Ekoue-Kovi, Kekeli,Alumasa, John,de Dios, Angel C.,Roepe, Paul D.,Wolf, Christian
, p. 6560 - 6566 (2009)
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.
Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies
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
, p. 68 - 81 (2018)
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.
Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold
Avilés, Edward,Prudhomme, Jacques,Le Roch, Karine G.,Franzblau, Scott G.,Chandrasena, Kevin,Mayer, Alejandro M.S.,Rodríguez, Abimael D.
, p. 5339 - 5343 (2015)
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
Highly active 4-aminoquinoline-pyrimidine based molecular hybrids as potential next generation antimalarial agents
Manohar, Sunny,Satya Pavan,Taylor, Dale,Kumar, Deepak,Ponnan, Prija,Wiesner, Lubbe,Rawat, Diwan S.
, p. 28171 - 28186 (2015)
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.
Synthesis and biological activity of novel 4-aminoquinoline/1,2,3-triazole hybrids against Leishmania amazonensis
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
, (2021)
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.
N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives, synthesized by thermal and ultrasonic means, are endowed with anti-Zika virus activity
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.
, p. 434 - 441 (2017)
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.
