Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update

Kumar, Sanjay; Guha, Mithu; Choubey, Vinay; Maity, Pallab; Bandyopadhyay, Uday

doi:10.1016/j.lfs.2006.11.008

Cited by 166 publications

(171 citation statements)

References 108 publications

(151 reference statements)

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“…Four different parasites of the Plasmodium genus affect humans-P. falciparum, P. vivax, P. malariae, and P. ovale; the first two are the most common and P. falciparum causes the most deadly form of the disease [1,2]. Since the discovery and purification of quinine from the bark of the cinchona tree, several antimalarial drugs have become available, notably quinolines [chloroquine (CQ), amodiaquine, mefloquine, primaquine], inhibitors of enzymes required for folate metabolism (pyrimethamine/sulfadoxine, proguanil), and endoperoxides derived from the natural product artemisinin [3][4][5][6]. CQ ( Fig.…”

Section: Introductionmentioning

confidence: 99%

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

et al. 2008

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The mechanism of antimalarial action of the ruthenium-chloroquine complex [RuCl 2 (CQ)] 2 (1), previously shown by us to be active in vitro against CQ-resistant strains of Plasmodium falciparum and in vivo against P. berghei, has been investigated. The complex is rapidly hydrolyzed in aqueous solution to [RuCl(OH 2 ) 3 (CQ)] 2 [Cl] 2 , which is probably the active species. This compound binds to hematin in solution and inhibits aggregation to β-hematin at pH ∼ 5 to a slightly lower extent than chloroquine diphosphate; more importantly, the heme aggregation inhibition activity of complex 1 is significantly higher than that of CQ when measured at the interface of noctanol-aqueous acetate buffer mixtures under acidic conditions modeling the food vacuole of the parasite. Partition coefficient measurements confirmed that complex 1 is considerably more lipophilic than CQ in n-octanol-water mixtures at pH ∼ 5. This suggests that the principal target of complex 1 is the heme aggregation process, which has recently been reported to be fast and spontaneous at or near water-lipid interfaces. The enhanced antimalarial activity of complex 1 is thus probably due to a higher effective concentration of the drug at or near the interface compared with that of CQ, which accumulates strongly in the aqueous regions of the vacuole under those conditions. Furthermore, the activity of complex 1 against CQ-resistant strains of P. falciparum is probably related to its greater lipophilicity, in line with previous reports indicating a lowered ability of the mutated transmembrane transporter PfCRT to promote the efflux of highly lipophilic drugs. The metal complex also interacts with DNA by intercalation, to a comparable extent and in a similar manner to uncomplexed CQ and therefore DNA binding does not appear to be an important part of the mechanism of antimalarial action in this case.

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Section: Introductionmentioning

confidence: 99%

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

et al. 2008

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“…During that stage, the malaria parasite digests enormous quantities of hemoglobin inside the food vacuole and thereby releasing high quantities of toxin-free heme (13)(14)(15)(16). Free heme can change membrane permeability by intercalating into the cell membrane and also may induce oxidative stress (17,18), which may lead to parasite death.…”

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confidence: 99%

“…Free heme can change membrane permeability by intercalating into the cell membrane and also may induce oxidative stress (17,18), which may lead to parasite death. However, by converting heme into the less-toxic hemozoin, parasites cleverly evade the toxicity of free heme (13,14,19). Oxidative stress-mediated parasite death through the prevention of hemozoin formation is also an accepted therapeutic strategy against malaria (20).…”

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confidence: 99%

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

Sarkar

Siddiqui

Saha

et al. 2016

Antimicrob Agents Chemother

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bWe synthesized a new series of conjugated hydrazones that were found to be active against malaria parasite in vitro, as well as in vivo in a murine model. These hydrazones concentration-dependently chelated free iron and offered antimalarial activity. Upon screening of the synthesized hydrazones, compound 5f was found to be the most active iron chelator, as well as antiplasmodial. Compound 5f also interacted with free heme (K D [equilibrium dissociation constant] ‫؍‬ 1.17 ؎ 0.8 M), an iron-containing tetrapyrrole released after hemoglobin digestion by the parasite, and inhibited heme polymerization by parasite lysate. Structureactivity relationship studies indicated that a nitrogen-and sulfur-substituted five-membered aromatic ring present within the benzothiazole hydrazones might be responsible for their antimalarial activity. The dose-dependent antimalarial and heme polymerization inhibitory activities of the lead compound 5f were further validated by following [ 3 H]hypoxanthine incorporation and hemozoin formation in parasite, respectively. It is worth mentioning that compound 5f exhibited antiplasmodial activity in vitro against a chloroquine/pyrimethamine-resistant strain of Plasmodium falciparum (K1). We also evaluated in vivo antimalarial activity of compound 5f in a murine model where a lethal multiple-drug-resistant strain of Plasmodium yoelii was used to infect Swiss albino mice. Compound 5f significantly suppressed the growth of parasite, and the infected mice experienced longer life spans upon treatment with this compound. During in vitro and in vivo toxicity assays, compound 5f showed minimal alteration in biochemical and hematological parameters compared to control. In conclusion, we identified a new class of hydrazone with therapeutic potential against malaria.

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“…O parasita possui um mecanismo classicamente conhecido para lidar com a hemina, um produto tóxico da digestão da hemoglobina: a formação de hemozoína (Kumar et al, 2007). Em mamíferos a principal via de degradação da hemina é a degradação em biliverdina (BV), catalisada pela enzima heme oxigenase (HO) (Docherty et al, 1984).…”

Section: Papel Da Heme Oxigenase Em P Falciparumunclassified

“…Plasmodium (Asawamahasakda et al,1994), esta inibição está possivelmente associada a alcalinização dos compartimentos ácidos onde ocorre a formação da hemozoína (Gazarini et al, 2007) uma vez que a cloroquina é capaz de inibir os canais iônicos (Kumar et al, 2007) importantes no transportede prótons H + no lúmem do vacúolo ácido. Como esperado, após duas horas de incubação com 1 µM de cloroquina, observamos uma diminuição na área da hemozoína em P. falciparum ( 72 ±5%) ( figura 32 A).…”

Section: Foi Demonstrado Que a Cloroquina Inibe A Formação Do Cristalunclassified

Papel do IP3 na transdução de sinal e função da heme oxigenase em Plasmodium falciparum.

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Aos meus pais e a cada professor que deparei em meu percurso. AGRADECIMENTOSÀ minha querida orientadora, Professora Dra. Célia Regina da Silva Garcia por ter aberto as portas de seu laboratório nos meus passos iniciais na ciência, pelas oportunidades dadas e ajuda nas horas difíceis, pela orientação e discussões tanto no período de iniciação científica quanto no doutorado. À Dra. Paula Barttlet e Professor Dr. Andrew P. Thomas pela colaboração no início do meu doutorado, pela paciência e ajuda na microscopia, pelas dicas e apoio. A todos os membros do laboratório na UMDNJ que me fizeram sentir em casa durante meu estágio no exterior.Aos colegas de laboratório com os quais tive o privilégio de conviver durante meu percurso. Todos sempre solícitos e abertos a discussões: Dr. Alexandre Budu, Dra. Mirian Moraes, Ms. Desiree Schuck, Dra Fernanda Koyama, Lucas Borges, Dra. Laura Cruz, Dr. Plasmodium falciparum, agente etiológico da malária, possui um ciclo de vida que envolve dois hospedeiros (fêmea do mosquito Anopheles e humanos) onde apresenta refinadas estratégias que envolvem mudanças morfológicas e bioquímicas em diferentes ambientes para garantir a sua sobrevivência. O estudo da maquinaria de sinalização deste parasita tem revelado a geração de segundos mensageiros e proteínas efetoras da sinalização celular importantes na percepção de estímulos extracelulares no parasita. Esta tese tem como finalidade demonstrar que o P. falciparum dentro do eritrócito é capaz de usar a via de sinalização celular dependente do segundo mensageiro inositol trifosfato (IP 3 ). Para isto usamos um IP 3 permeável a membrana celular denominado (caged-IP 3 ) que é liberado para atuar como segundo mensageiro na presença de luz ultravioleta. Investigamos os estoques de Ca 2+ intracelular sensíveis ao IP 3 neste parasita e exploramos a sensibilidade ao IP 3 em diferentes estágios no ciclo intraeritrocítico. Demonstramos que o hormônio melatonina, importante na manuntenção da sincronicidade da fase intraeritrocítica de P. falciparum, é capaz de aumentar a concentração de IP 3 neste parasita. Com o uso de uma coluna de afinidade ao IP 3 tentamos encontrar proteínas candidatas ao receptor de IP 3 em P. falciparum. Este trabalho também estuda a enzima heme oxigenade de P. falciparum (PfHO). Testamos a capacidade desta enzima em converter biliverdina (BV) em bilirubina (BR), uma importante reação do catabolismo da hemina. Estudamos a modulação desta atividade na presença de diversas metaloprotoporfirinas e o potencial destes compostos como antimaláricos. Reportamos que a biliverdina é capaz de modular o ciclo intraeritrocítico de P. falciparum e apresentamos a proteína enolase de P. falciparum como candidato ao sensor de BV neste parasita. Plasmodium falciparum, the etiological agent of malaria, possesses a life cycle that involves two hosts (the female of Anopheles mosquito and human) on which has refined strategies involving morphological and biochemical changes in different environments to ensure its survival. The study of the signaling m...

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Antimalarial drugs inhibiting hemozoin (β-hematin) formation: A mechanistic update

Cited by 166 publications

References 108 publications

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

The mechanism of antimalarial action of the ruthenium(II)–chloroquine complex [RuCl2(CQ)]2

Antimalarial Activity of Small-Molecule Benzothiazole Hydrazones

Papel do IP3 na transdução de sinal e função da heme oxigenase em Plasmodium falciparum.

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