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Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.

Rajapakse CS, Lisai M, Deregnaucourt C, Sinou V, Latour C, Roy D, Schrével J, Sánchez-Delgado RA - PLoS ONE (2015)

Bottom Line: The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance.The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine.Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.

ABSTRACT
The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

No MeSH data available.


Related in: MedlinePlus

Synthetic strategy for compound 1 and other new aminoquinolines.
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pone.0140878.g003: Synthetic strategy for compound 1 and other new aminoquinolines.

Mentions: The new N-benzyl-4-aminoquinolines 1–4, and the reduced N-cyclohexadienylmethyl derivative 5 (Fig 2) were prepared by condensation of the appropriate amines 6–10 (Fig 2) with 4,7-dichloroquinoline (11) in N-methyl-2-pyrrolidone (NMP) in the presence of K2CO3 and triethylamine, as exemplified in Fig 3 for compound 1. The precursor amine 6 was obtained from the reaction of o-cyanobenzylbromide (12) with diethylamine in ethanol to yield o-(diethylaminomethyl)benzonitrile (13), followed by LiAlH4 reduction of the nitrile group in diethylether. The other (diethylaminomethyl)benzylamines used in this study (7–9) were prepared by analogous procedures, starting from the corresponding cyanobenzylbromides. Cyclohexadiene 10 was obtained by Birch reduction of 6. All new compounds were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry (complete data in Materials and Methods Section); the purity of all samples used in biological tests (> 95%) was established by elemental analysis and HPLC. It is worth noting that our high yield synthetic method for 1–5 relies on inexpensive commercially available starting materials.


Synthesis of New 4-Aminoquinolines and Evaluation of Their In Vitro Activity against Chloroquine-Sensitive and Chloroquine-Resistant Plasmodium falciparum.

Rajapakse CS, Lisai M, Deregnaucourt C, Sinou V, Latour C, Roy D, Schrével J, Sánchez-Delgado RA - PLoS ONE (2015)

Synthetic strategy for compound 1 and other new aminoquinolines.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4608832&req=5

pone.0140878.g003: Synthetic strategy for compound 1 and other new aminoquinolines.
Mentions: The new N-benzyl-4-aminoquinolines 1–4, and the reduced N-cyclohexadienylmethyl derivative 5 (Fig 2) were prepared by condensation of the appropriate amines 6–10 (Fig 2) with 4,7-dichloroquinoline (11) in N-methyl-2-pyrrolidone (NMP) in the presence of K2CO3 and triethylamine, as exemplified in Fig 3 for compound 1. The precursor amine 6 was obtained from the reaction of o-cyanobenzylbromide (12) with diethylamine in ethanol to yield o-(diethylaminomethyl)benzonitrile (13), followed by LiAlH4 reduction of the nitrile group in diethylether. The other (diethylaminomethyl)benzylamines used in this study (7–9) were prepared by analogous procedures, starting from the corresponding cyanobenzylbromides. Cyclohexadiene 10 was obtained by Birch reduction of 6. All new compounds were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry (complete data in Materials and Methods Section); the purity of all samples used in biological tests (> 95%) was established by elemental analysis and HPLC. It is worth noting that our high yield synthetic method for 1–5 relies on inexpensive commercially available starting materials.

Bottom Line: The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance.The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine.Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

View Article: PubMed Central - PubMed

Affiliation: Chemistry Department of Brooklyn College and Ph.D. Program in Chemistry, The Graduate Center of The City University of New York, New York, New York, United States of America.

ABSTRACT
The efficacy of chloroquine, once the drug of choice in the fight against Plasmodium falciparum, is now severely limited due to widespread resistance. Amodiaquine is one of the most potent antimalarial 4-aminoquinolines known and remains effective against chloroquine-resistant parasites, but toxicity issues linked to a quinone-imine metabolite limit its clinical use. In search of new compounds able to retain the antimalarial activity of amodiaquine while circumventing quinone-imine metabolite toxicity, we have synthesized five 4-aminoquinolines that feature rings lacking hydroxyl groups in the side chain of the molecules and are thus incapable of generating toxic quinone-imines. The new compounds displayed high in vitro potency (low nanomolar IC50), markedly superior to chloroquine and comparable to amodiaquine, against chloroquine-sensitive and chloroquine-resistant strains of P. falciparum, accompanied by low toxicity to L6 rat fibroblasts and MRC5 human lung cells, and metabolic stability comparable or higher than that of amodiaquine. Computational studies indicate a unique mode of binding of compound 4 to heme through the HOMO located on a biphenyl moeity, which may partly explain the high antiplasmodial activity observed for this compound.

No MeSH data available.


Related in: MedlinePlus