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Discovery of dual function acridones as a new antimalarial chemotype.

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Title: Discovery of dual function acridones as a new antimalarial chemotype.
Authors: Kelly, Jane X., Smilkstein, Martin J., Brun, Reto, Wittlin, Sergio, Cooper, Roland A., Lane, Kristin D., Janowsky, Aaron, Johnson, Robert A., Dodean, Rozalia A., Winter, Rolf, Hinrichs, David J., Riscoe, Michael K.
Source: Nature. 5/14/2009, Vol. 459 Issue 7244, p270-273. 4p. 1 Black and White Photograph, 1 Diagram, 3 Charts, 1 Graph.
Subjects: Acridine, Antimalarials, Drug resistance, Drug development, Malaria treatment, Hemoglobins, Biodegradation, Quinoline, Drug interactions
Abstract: Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug–haem interaction as in the case of quinolines and many other drugs. Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum, efficacy and safety in vivo after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)-acridone), demonstrates unique synergistic properties. In addition to ‘verapamil-like’ chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations. [ABSTRACT FROM AUTHOR]
Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Psychology and Behavioral Sciences Collection
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  Data: <searchLink fieldCode="AR" term="%22Kelly%2C+Jane+X%2E%22">Kelly, Jane X.</searchLink><br /><searchLink fieldCode="AR" term="%22Smilkstein%2C+Martin+J%2E%22">Smilkstein, Martin J.</searchLink><br /><searchLink fieldCode="AR" term="%22Brun%2C+Reto%22">Brun, Reto</searchLink><br /><searchLink fieldCode="AR" term="%22Wittlin%2C+Sergio%22">Wittlin, Sergio</searchLink><br /><searchLink fieldCode="AR" term="%22Cooper%2C+Roland+A%2E%22">Cooper, Roland A.</searchLink><br /><searchLink fieldCode="AR" term="%22Lane%2C+Kristin+D%2E%22">Lane, Kristin D.</searchLink><br /><searchLink fieldCode="AR" term="%22Janowsky%2C+Aaron%22">Janowsky, Aaron</searchLink><br /><searchLink fieldCode="AR" term="%22Johnson%2C+Robert+A%2E%22">Johnson, Robert A.</searchLink><br /><searchLink fieldCode="AR" term="%22Dodean%2C+Rozalia+A%2E%22">Dodean, Rozalia A.</searchLink><br /><searchLink fieldCode="AR" term="%22Winter%2C+Rolf%22">Winter, Rolf</searchLink><br /><searchLink fieldCode="AR" term="%22Hinrichs%2C+David+J%2E%22">Hinrichs, David J.</searchLink><br /><searchLink fieldCode="AR" term="%22Riscoe%2C+Michael+K%2E%22">Riscoe, Michael K.</searchLink>
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  Data: Preventing and delaying the emergence of drug resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug-resistant malaria. Haem remains an immutable and vulnerable target, because it is not parasite-encoded and its detoxification during haemoglobin degradation, critical to parasite survival, can be subverted by drug–haem interaction as in the case of quinolines and many other drugs. Here we describe a new antimalarial chemotype that combines the haem-targeting character of acridones, together with a chemosensitizing component that counteracts resistance to quinoline antimalarial drugs. Beyond the essential intrinsic characteristics common to deserving candidate antimalarials (high potency in vitro against pan-sensitive and multi-drug-resistant Plasmodium falciparum, efficacy and safety in vivo after oral administration, inexpensive synthesis and favourable physicochemical properties), our initial lead, T3.5 (3-chloro-6-(2-diethylamino-ethoxy)-10-(2-diethylamino-ethyl)-acridone), demonstrates unique synergistic properties. In addition to ‘verapamil-like’ chemosensitization to chloroquine and amodiaquine against quinoline-resistant parasites, T3.5 also results in an apparently mechanistically distinct synergism with quinine and with piperaquine. This synergy, evident in both quinoline-sensitive and quinoline-resistant parasites, has been demonstrated both in vitro and in vivo. In summary, this innovative acridone design merges intrinsic potency and resistance-counteracting functions in one molecule, and represents a new strategy to expand, enhance and sustain effective antimalarial drug combinations. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Nature is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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