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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

Docked poses of 1 and 4 on heme.Both aminoquinoline molecules were employed in the diprotonated form. Atom color code: white: H, brown: C, blue: N, red: O, and gold: Fe. Only polar hydrogens are shown for clarity.
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pone.0140878.g004: Docked poses of 1 and 4 on heme.Both aminoquinoline molecules were employed in the diprotonated form. Atom color code: white: H, brown: C, blue: N, red: O, and gold: Fe. Only polar hydrogens are shown for clarity.

Mentions: Aminoquinoline drugs exert their antimalarial action by disrupting aggregation of heme into hemozoin. It is therefore interesting to examine the interactions of new drug candidates with heme, to try to find correlations with antimalarial potency. The binding of 1–5, CQ, and AQ to heme was analyzed by use of Autodock 4.2.11 (Details in Materials and Methods Section). For all the compounds studied the energetically most favorable binding is guided by H-bonding as well as π-stacking interactions between the aminoquinoline and heme. Although the docking energies shown in Table 4 are comparable for compounds 1–5 and only marginally stronger than for CQ, a significant difference in the nature of the interactions among the molecules studied is that stacking of 4 over the porphyrin takes place through the biphenyl moiety, whereas for all other systems the stacking happens via the quinoline ring (Fig 4 and S1 Fig in Supporting Information). This different binding mode of 4 to heme is likely related to the localization of the HOMO over the biphenyl unit, unlike the other four molecules for which the HOMO is concentrated mostly over the quinoline moeity (Fig 5, and S2 Fig, Supporting Information). This structural difference could be in part responsible for the high activity observed for this compound.


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)

Docked poses of 1 and 4 on heme.Both aminoquinoline molecules were employed in the diprotonated form. Atom color code: white: H, brown: C, blue: N, red: O, and gold: Fe. Only polar hydrogens are shown for clarity.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140878.g004: Docked poses of 1 and 4 on heme.Both aminoquinoline molecules were employed in the diprotonated form. Atom color code: white: H, brown: C, blue: N, red: O, and gold: Fe. Only polar hydrogens are shown for clarity.
Mentions: Aminoquinoline drugs exert their antimalarial action by disrupting aggregation of heme into hemozoin. It is therefore interesting to examine the interactions of new drug candidates with heme, to try to find correlations with antimalarial potency. The binding of 1–5, CQ, and AQ to heme was analyzed by use of Autodock 4.2.11 (Details in Materials and Methods Section). For all the compounds studied the energetically most favorable binding is guided by H-bonding as well as π-stacking interactions between the aminoquinoline and heme. Although the docking energies shown in Table 4 are comparable for compounds 1–5 and only marginally stronger than for CQ, a significant difference in the nature of the interactions among the molecules studied is that stacking of 4 over the porphyrin takes place through the biphenyl moiety, whereas for all other systems the stacking happens via the quinoline ring (Fig 4 and S1 Fig in Supporting Information). This different binding mode of 4 to heme is likely related to the localization of the HOMO over the biphenyl unit, unlike the other four molecules for which the HOMO is concentrated mostly over the quinoline moeity (Fig 5, and S2 Fig, Supporting Information). This structural difference could be in part responsible for the high activity observed for this compound.

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