Synthesis and in Vitro and in Vivo Antimalarial Activity of N-(7-Chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine Derivatives

Ryckebusch, Adina; Deprez-Poulain, Rébecca; Maes, Louis; Debreu-Fontaine, Marie-Ange; Mouray, Elisabeth; Grellier, Philippe; Sergheraert, Christian

doi:10.1021/jm020960r

Cited by 115 publications

(67 citation statements)

References 31 publications

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“…CQ and amodiaquine-derived compounds were synthesized as previously described (18)(19)(20)(21)(22). The level of purity of the compounds was higher than 98%.…”

Section: Methodsmentioning

confidence: 99%

“…We were therefore interested to test other derivatives of 4-aminoquinoline-based molecules for their anti-HCV activity. Here, we tested a series of molecules from three different families of antimalarial compounds (18)(19)(20), and we observed an anti-HCV activity for several of them. Based on its current development for another medical condition, we selected one of them (B5) for further characterization of its anti-HCV activity.…”

Section: H Epatitis C Virus (Hcv) Infection Remains a Global Epidemicmentioning

confidence: 99%

“…2A. Compounds A1, B2, B3, B5, C1, and C3 showed efficient antimalarial activities against CQ-resistant strains (18)(19)(20)(21)(22) and were selected according to their chemical diversity. The others were chosen as structural analogs to allow structure-activity relationship studies.…”

Section: B5 Inhibits Hcv Infectionmentioning

confidence: 99%

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Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Vausselin

Séron

Lavie

et al. 2016

J Virol

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Aminoquinolines and piperazines, linked or not, have been used successfully to treat malaria, and some molecules of this family also exhibit antiviral properties. Here we tested several derivatives of 4-aminoquinolines and piperazines for their activity against hepatitis C virus (HCV). We screened 11 molecules from three different families of compounds, and we identified anti-HCV activity in cell culture for six of them. Of these, we selected a compound (B5) that is currently ending clinical phase I evaluation for neurodegenerative diseases. In hepatoma cells, B5 inhibited HCV infection in a pangenotypic and dose-dependent manner, and its antiviral activity was confirmed in primary hepatocytes. B5 also inhibited infection by pseudoparticles expressing HCV envelope glycoproteins E1 and E2, and we demonstrated that it affects a postattachment stage of the entry step. Virus with resistance to B5 was selected by sequential passage in the presence of the drug, and reverse genetics experiments indicated that resistance was conferred mainly by a single mutation in the putative fusion peptide of E1 envelope glycoprotein (F291I). Furthermore, analyses of the effects of other closely related compounds on the B5-resistant mutant suggest that B5 shares a mode of action with other 4-aminoquinoline-based molecules. Finally, mice with humanized liver that were treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle. IMPORTANCEIn the last 4 years, HCV therapy has been profoundly improved with the approval of direct-acting antivirals in clinical practice. Nevertheless, the high costs of these drugs limit access to therapy in most countries. The present study reports the identification and characterization of a compound (B5) that inhibits HCV propagation in cell culture and is currently ending clinical phase I evaluation for neurodegenerative diseases. This molecule inhibits the HCV life cycle by blocking virus entry. Interestingly, after selection of drug-resistant virus, a resistance mutation in the putative fusion peptide of E1 envelope glycoprotein was identified, indicating that B5 could be used to further investigate the fusion mechanism. Furthermore, mice with humanized liver treated with B5 showed a delay in the kinetics of the viral infection. In conclusion, B5 is a novel interesting anti-HCV molecule that could be used to decipher the early steps of the HCV life cycle.

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“…CQ and amodiaquine-derived compounds were synthesized as previously described (18)(19)(20)(21)(22). The level of purity of the compounds was higher than 98%.…”

Section: Methodsmentioning

confidence: 99%

Section: H Epatitis C Virus (Hcv) Infection Remains a Global Epidemicmentioning

confidence: 99%

See 1 more Smart Citation

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Vausselin

Séron

Lavie

et al. 2016

J Virol

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“…In an attempt to overcome the drug efflux mechanism of the parasite, Vennerstrom et al have investigated a series of bisquinolines (Figure 1) against CQ-sensitive and CQ resistant strains [8]. In this scenario, Ryckebusch et al have prepared several N 1 -(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine derivatives ( Figure 1) by replacing one of the 7-chloro-4-aminoquinoline moieties of the bisquinolines with various amines and amides and evaluated them for antimalarial activity against the chloroquine-resistant P. falciparum FcB1 strain [9]. For these analogues, Ryckebusch et al have propounded CQ-like mechanism as well as the involvement of other mechanisms [9].…”

Section: Introductionmentioning

confidence: 99%

Topological descriptors in modelling antimalarial activity: N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

Deshpande

Solomon

Katti

et al. 2008

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…The compounds displayed moderate to good activity when quinoline and/or aryl moieties were attached to the abovementioned linker. In this series, compounds containing a piperazine moiety were found to be active against CQ-resistant strains of P. falciparum (10)(11)(12).…”

mentioning

confidence: 99%

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

Dola

Soni

Agarwal

et al. 2017

Antimicrob Agents Chemother

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A novel 4-aminoquinoline derivative [(S)-7-chloro-N-(4-methyl-1-(4-methylpiperazin-1-yl)pentan-2-yl)-quinolin-4-amine triphosphate] exhibiting curative activity against chloroquine-resistant malaria parasites has been identified for preclinical development as a blood schizonticidal agent. The lead molecule selected after detailed structure-activity relationship (SAR) studies has good solid-state properties and promising activity against in vitro and in vivo experimental malaria models. The in vitro absorption, distribution, metabolism, and excretion (ADME) parameters indicate a favorable drug-like profile.

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Synthesis and in Vitro and in Vivo Antimalarial Activity of N-(7-Chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine Derivatives

Cited by 115 publications

References 31 publications

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Topological descriptors in modelling antimalarial activity: N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

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Synthesis and in Vitro and in Vivo Antimalarial Activity of N-(7-Chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine Derivatives

Cited by 115 publications

References 31 publications

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Identification of a New Benzimidazole Derivative as an Antiviral against Hepatitis C Virus

Topological descriptors in modelling antimalarial activity: N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

Synthesis and Evaluation of Chirally Defined Side Chain Variants of 7-Chloro-4-Aminoquinoline To Overcome Drug Resistance in Malaria Chemotherapy

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Topological descriptors in modelling antimalarial activity: N¹-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype