Limits...
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

New aminoquinolines (1–5) and precursor amines (6–10) synthesized.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4608832&req=5

pone.0140878.g002: New aminoquinolines (1–5) and precursor amines (6–10) synthesized.

Mentions: Malaria continues to be a major global health problem. According to the WHO, an estimated 3.2 billion people are at risk of being infected with Plasmodium and developing disease, and 1.2 billion are at high risk. It is estimated that 198 million cases of malaria occurred globally in 2013, leading to 584,000 deaths, mainly in the African Region (90% of all malaria deaths), and mostly in children under 5 years of age (78% of deaths) [1]. For decades one of the most successful and widely used drugs for treating malaria, especially Plasmodium falciparum infection, was chloroquine (CQ, Fig 1); however, widespread resistance has rendered it essentially useless in most parts of the world [2]. The 4-aminoquinoline pharmacophore has been the focus of intense efforts to develop new drugs not susceptible to resistance; for instance, amodiaquine (AQ, Fig 1), which is structurally related to CQ but contains a p-hydroxyanilino ring in the side chain of the molecule, is considerably more potent than CQ and remains effective against most CQ-resistant strains. However, toxicity issues limit its clinical use, in particular the occurrence during prolonged treatment or prophylaxis of agranulocytosis and potentially fatal idiosyncratic hepatotoxicity, linked to the formation of a reactive quinone-imine metabolite [3–7]. Related compounds like tebuquine (Fig 1) and its analogs also display high activity against CQ-resistant P. falciparum but are equally susceptible to P450-induced oxidation to toxic quinone-imine metabolites [8]. In order to circumvent this particular type of toxicity, other AQ analogs unlikely to form quinone-imine intermediates have been considered. They include isoquine [5,9] and the related GSK369796 [6,9]; amopyroquines [10–12] (Fig 1) and fluoroamodiaquines [13]; N-tert-butylamino Mannich base derivatives [14,15], and benzoxazines [4], all of which display high antiplasmodial activity. Other important developments concerning quinoline antimalarials are the discovery of ferroquine, a highly active and selective organometallic agent against CQ-resistant P. falciparum [16], and of phenylequine, a compound closely related to the ones described in this paper, which displays activity comparable to that of ferroquine against CQ-resistant parasites (Fig 1) [17]. Other aminoquinolines [18–24] and organometallic CQ derivatives [25–27] with interesting antimalarial properties have been reported in recent times. In this paper we describe the synthesis and antiplasmodial evaluation of a group of new 4-aminoquinolines 1–5 (Fig 2) structurally related to AQ, but lacking the 4-hydroxyl group in the side ring. These compounds are highly active in vitro against CQ-sensitive and CQ-resistant P. falciparum and are incapable of generating toxic quinone-imine metabolites.


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)

New aminoquinolines (1–5) and precursor amines (6–10) synthesized.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0140878.g002: New aminoquinolines (1–5) and precursor amines (6–10) synthesized.
Mentions: Malaria continues to be a major global health problem. According to the WHO, an estimated 3.2 billion people are at risk of being infected with Plasmodium and developing disease, and 1.2 billion are at high risk. It is estimated that 198 million cases of malaria occurred globally in 2013, leading to 584,000 deaths, mainly in the African Region (90% of all malaria deaths), and mostly in children under 5 years of age (78% of deaths) [1]. For decades one of the most successful and widely used drugs for treating malaria, especially Plasmodium falciparum infection, was chloroquine (CQ, Fig 1); however, widespread resistance has rendered it essentially useless in most parts of the world [2]. The 4-aminoquinoline pharmacophore has been the focus of intense efforts to develop new drugs not susceptible to resistance; for instance, amodiaquine (AQ, Fig 1), which is structurally related to CQ but contains a p-hydroxyanilino ring in the side chain of the molecule, is considerably more potent than CQ and remains effective against most CQ-resistant strains. However, toxicity issues limit its clinical use, in particular the occurrence during prolonged treatment or prophylaxis of agranulocytosis and potentially fatal idiosyncratic hepatotoxicity, linked to the formation of a reactive quinone-imine metabolite [3–7]. Related compounds like tebuquine (Fig 1) and its analogs also display high activity against CQ-resistant P. falciparum but are equally susceptible to P450-induced oxidation to toxic quinone-imine metabolites [8]. In order to circumvent this particular type of toxicity, other AQ analogs unlikely to form quinone-imine intermediates have been considered. They include isoquine [5,9] and the related GSK369796 [6,9]; amopyroquines [10–12] (Fig 1) and fluoroamodiaquines [13]; N-tert-butylamino Mannich base derivatives [14,15], and benzoxazines [4], all of which display high antiplasmodial activity. Other important developments concerning quinoline antimalarials are the discovery of ferroquine, a highly active and selective organometallic agent against CQ-resistant P. falciparum [16], and of phenylequine, a compound closely related to the ones described in this paper, which displays activity comparable to that of ferroquine against CQ-resistant parasites (Fig 1) [17]. Other aminoquinolines [18–24] and organometallic CQ derivatives [25–27] with interesting antimalarial properties have been reported in recent times. In this paper we describe the synthesis and antiplasmodial evaluation of a group of new 4-aminoquinolines 1–5 (Fig 2) structurally related to AQ, but lacking the 4-hydroxyl group in the side ring. These compounds are highly active in vitro against CQ-sensitive and CQ-resistant P. falciparum and are incapable of generating toxic quinone-imine metabolites.

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