Insights into the Role of Heme in the Mechanism of Action of Antimalarials

Combrinck, Jill M.; Mabotha, Tebogo E; Ncokazi, Kanyile K.; Ambele, Melvin Anyasi; Taylor, Dale; Smith, Peter J.; Hoppe, Heinrich C.; Egan, Timothy J.

doi:10.1021/cb300454t

Cited by 199 publications

(238 citation statements)

References 24 publications

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“…show that whilst CQ can induce formation of the μ-oxo dimer of FePPIX in solution [16], the key effect of CQ is probably the inhibition of crystallization of FePPIX by adsorption of the drug onto the most rapidly growing crystal faces of haemozoin [7,17]. Nevertheless, no X-ray crystal structure of a CQ-FePPIX complex has been …”

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confidence: 99%

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Acharige

Durrant

2014

Transition Met Chem

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An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Acharige

Durrant

2014

Transition Met Chem

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“…Indeed, recently chloroquine has been shown to increase free Fe(III)PPIX and decrease hemozoin in the P. falciparum cell in a dose-dependent manner. 11 The detailed mechanism of inhibition has been a matter of debate, with one school of thought proposing that it involves complex formation in solution, [12][13][14] while another postulates inhibition of crystal growth via interaction with the crystal surface. 15 It is known that quinolines form complexes with Fe(III)PPIX in solution, 12,16 while it is also the case that the inhibitory effects of these compounds can be described by a surface interaction model.…”

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confidence: 99%

“…Thus, a role for solution association cannot necessarily be ruled out for all series of 4-aminoquinoline compounds. Finally, the correlation equations permit the prediction of both log K and log BHIA 50 for these series of [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] aminoquinolines. Interestingly, they do not suggest that the lipophilicity of the group X plays a major role in -hematin inhibition.…”

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Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

Nsumiwa

Kuter

Wittlin

et al. 2013

Bioorganic & Medicinal Chemistry

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In order to probe structure-activity relationships of association with ferriprotoporphyrin IX (log K) and inhibition of -hematin formation, a series of 4-aminoquinolines with varying substituents at the 7-position (X) have been synthesized. These have been further elaborated by introduction of two different R groups on the 4-amino nitrogen atom in the form of methyl (R = Me) and ethylamine (R = EtNH 2 ) side chains. Data for a previously investigated series containing an N,N-diethyl-ethylamine side chain were also compared with the findings of this study. Experimentally, log K values for the simple 4-aminoquinoline series (R = H) were found to correlate with the hydrophobicity constant () of the group X. The log K values for the series with R = Me and EtNH 2 were found to correlate with those of the series with R = H. The log of the 50% -hematin inhibitory activity (log BHIA 50 ) was found to correlate with log K and either meta ( m ) or para ( p ) Hammett constants for the series with R = Me and EtNH 2 , but not the simple series with R = H. To further improve predictability, correlations with ab initio electrostatic parameters, namely Mulliken and CHelpG charges were investigated. The best correlations were found with CHelpG charges which indicated that log K values can be predicted from the charges on atom H-8 and the group X in the quinolinium species computed in vacuum, while log BHIA 50 values can be predicted from the CHelpG charges on C-7, C-8 and N-1 for the neutral species in vacuum. These correlations indicate that association and inhibition of -hematin formation are separately determined. They also suggest that electron withdrawing groups at the 7-position, but not necessarily hydrophobic groups are required for hemozoin inhibition. The upshot is that the correlations imply that considerably more hydrophilic hemozoin inhibitors are feasible.Keywords: hemozoin; DFT; antimalarials; quinolines; structure-activity relationships; ferriprotoporphyrin IX 3 IntroductionQuinoline antimalarials such as quinine and chloroquine have had a long and successful history. 1 Subsequent emergence of chloroquine resistance has led to the use of other quinoline derivative antimalarials such as mefloquine and amodiaquine. Indeed, the development and clinical deployment of new quinoline antimalarials continues to this day.For example, piperaquine, a bis-4-aminoquinoline effective against chloroquine-resistant strains that consists of two 4-aminoquinoline moieties attached by a linker has only recently been introduced into clinical use. 2 Ferroquine, a 4-amino-7-chloroquinoline with a ferrocenyl side-chain is currently in phase IIB clinical trials. 3 In addition, research on new quinoline antimalarials retains considerable interest, such as that on so-called "reversed chloroquines"and related compounds that are both antimalarially active and inhibit the chloroquine resistance mechanism of the parasite. 4-10The class of 4-aminoquinoline antimalarials are believed to act by inhibiting the incorporation of ferrih...

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“…The drug is believed to interact with haem (or its precursors) or to inhibit one of the enzymes involved in the synthesis if haem, possibly haem polymerase [172][173][174][175]. [186].…”

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Metabolic enzymes of helminth parasites: potential as drug targets

Timson¹

2015

CPPS

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Metabolic pathways which extract energy from carbon compounds are essential for an organism's survival. Therefore, inhibition of enzymes in these pathways represents a potential therapeutic strategy to combat parasitic infections. However, the high degree of similarity between host and parasite enzymes makes this strategy potentially difficult. Nevertheless, several existing drugs to treat infections by parasitic helminths (worms) target metabolic enzymes. These include the trivalent antimonials which target phosphofructokinase and Clorsulon which targets phosphoglycerate mutase and phosphoglycerate kinase. Glycolytic enzymes from a variety of helminths have been characterised biochemically, and some inhibitors identified. To date none of these inhibitors have been developed into therapies. Many of these enzymes are externalised from the parasite and so are also of interest in the development of potential vaccines. Less work has been done on tricarboxylic acid cycle enzymes and oxidative phosphorylation complexes. Again, while some inhibitors have been identified none have been developed into drug-like molecules. Barriers to the development of novel drugs targeting metabolic enzymes include the lack of experimentally determined structures of helminth enzymes, lack of direct proof that the enzymes are vital in the parasites and lack of cell culture systems for many helminth species. Nevertheless, the success of Clorsulon (which discriminates between highly similar host and parasite enzymes) should inspire us to consider making serious efforts to discover novel anthelminthics which target metabolic enzymes.

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Insights into the Role of Heme in the Mechanism of Action of Antimalarials

Cited by 199 publications

References 24 publications

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

An atomic scale mechanism for the antimalarial action of chloroquine from density functional theory calculations

Structure–activity relationships for ferriprotoporphyrin IX association and β-hematin inhibition by 4-aminoquinolines using experimental and ab initio methods

Metabolic enzymes of helminth parasites: potential as drug targets

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