Haematin (haem) polymerization and its inhibition by quinoline antimalarials

Ridley, Robert G.; Dorn, Arnulf; Vippagunta, Sudha R.; Vennerstrom, Jonathan L.

doi:10.1080/00034983.1997.11813174

Cited by 53 publications

(52 citation statements)

References 42 publications

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“…It has become increasingly apparent over recent years that chloroquine most likely exerts its antimalarial activity through interaction with hematin in the lysosomal digestive vacuole of the malaria parasite (4,9,17,24). It is believed that this interaction affects the ability of the parasite to adequately sequester the toxic hematin that is released during the process of proteolytic degradation of hemoglobin into hemozoin, an inert pigment that develops within the parasite digestive vacuole during its growth within the erythrocyte.…”

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confidence: 99%

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Hematin Polymerization Assay as a High-Throughput Screen for Identification of New Antimalarial Pharmacophores

Kurosawa

Dorn

Kitsuji-Shirane

et al. 2000

Antimicrob Agents Chemother

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Hematin polymerization is a parasite-specific process that enables the detoxification of heme following its release in the lysosomal digestive vacuole during hemoglobin degradation, and represents both an essential and a unique pharmacological drug target. We have developed a high-throughput in vitro microassay of hematin polymerization based on the detection of 14 C-labeled hematin incorporated into polymeric hemozoin (malaria pigment). The assay uses 96-well filtration microplates and requires 12 h and a Wallac 1450 MicroBeta liquid scintillation counter. The robustness of the assay allowed the rapid screening and evaluation of more than 100,000 compounds. Random screening was complemented by the development of a pharmacophore hypothesis using the "Catalyst" program and a large amount of data available on the inhibitory activity of a large library of 4-aminoquinolines. Using these methods, we identified "hit" compounds belonging to several chemical structural classes that had potential antimalarial activity. Follow-up evaluation of the antimalarial activity of these compounds in culture and in the Plasmodium berghei murine model further identified compounds with actual antimalarial activity. Of particular interest was a triarylcarbinol (Ro 06-9075) and a related benzophenone (Ro 22-8014) that showed oral activity in the murine model. These compounds are chemically accessible and could form the basis of a new antimalarial medicinal chemistry program.

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“…A recent model of the structure of hemozoin (12) suggests that it is not a polymeric substance as originally hypothesized (21) but an association of dimers. However, none of these debates affect the core hypothesis that chloroquine, and possibly many other quinoline antimalarials (8), exerts its activity through binding to hematin (17).…”

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confidence: 99%

Hematin Polymerization Assay as a High-Throughput Screen for Identification of New Antimalarial Pharmacophores

Kurosawa

Dorn

Kitsuji-Shirane

et al. 2000

Antimicrob Agents Chemother

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“…25 There is no current consensus on the mode of action of artemisinin, whereas chloroquine is widely believed to act through inhibition of the enzyme that polymerizes and detoxifies ferriprotoporphyrin in the parasite food vacuole. 26 The discovery of antitrypanosomal and antimalarial activities in the 10 antibiotics from our compound libraries is the first report of such properties for these metabolites. More significantly, our data show that small structural changes in a parent compound can cause a major difference in antiprotozoal properties.…”

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confidence: 99%

Promising lead compounds for novel antiprotozoals

et al. 2010

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“…It is essential to continue the search for novel antimalarial drugs, especially for countries where malaria is endemic. An ideal target is the blocking of the heme detoxification pathway of the parasite (10)(11)(12)(13). Indeed, this mechanism is also one of the main targets of current antimalarial drugs like quinine and has been the major target of several antimalarial screening projects.…”

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confidence: 99%

High-Throughput Screening and Prediction Model Building for Novel Hemozoin Inhibitors Using Physicochemical Properties

Huy

Lan

Nagai

et al. 2017

Antimicrob Agents Chemother

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It is essential to continue the search for novel antimalarial drugs due to the current spread of resistance against artemisinin by Plasmodium falciparum parasites. In this study, we developed in silico models to predict hemozoin inhibitors as a potential first-step screening for novel antimalarials. An in vitro colorimetric highthroughput screening assay of hemozoin formation was used to identify hemozoin inhibitors from 9,600 structurally diverse compounds. The physicochemical properties of positive hits and randomly selected compounds were extracted from the ChemSpider database; they were used for developing prediction models to predict hemozoin inhibitors using two different approaches, i.e., traditional multivariate logistic regression and Bayesian model averaging. Our results showed that a total of 224 positive-hit compounds exhibited the ability to inhibit hemozoin formation, with 50% inhibitory concentrations (IC 50 s) ranging from 3.1 M to 199.5 M. The best model according to traditional multivariate logistic regression included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and number of atoms of hydrogen, while the best model according to Bayesian model averaging included the three variables octanol-water partition coefficient, number of hydrogen bond donors, and index of refraction. Both models had a good discriminatory power, with area under the curve values of 0.736 and 0.781 for the traditional multivariate model and Bayesian model averaging, respectively. In conclusion, the prediction models can be a new, useful, and cost-effective approach for the first screen of hemozoin inhibition-based antimalarial drug discovery.

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Haematin (haem) polymerization and its inhibition by quinoline antimalarials

Cited by 53 publications

References 42 publications

Hematin Polymerization Assay as a High-Throughput Screen for Identification of New Antimalarial Pharmacophores

Hematin Polymerization Assay as a High-Throughput Screen for Identification of New Antimalarial Pharmacophores

Promising lead compounds for novel antiprotozoals

High-Throughput Screening and Prediction Model Building for Novel Hemozoin Inhibitors Using Physicochemical Properties

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