8,8-dialkyldihydroberberines with potent antiprotozoal activity

Endeshaw, Molla and Zhu, Xiaohua and He, Shanshan and Pandharkar, Trupti and Cason, Emily and Mahasenan, Kiran V. and Agarwal, Hitesh and Li, Chenglong and Munde, Manoj and Wilson, W. David and Bahar, Mark and Doskotch, Raymond W. and Kinghorn, A. Douglas and Kaiser, Marcel and Brun, Reto and Drew, Mark E. and Werbovetz, Karl A.. (2013) 8,8-dialkyldihydroberberines with potent antiprotozoal activity. Journal of natural products, Vol. 76, H. 3. pp. 311-315.

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Official URL: http://edoc.unibas.ch/dok/A6124540

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Semisynthetic 8,8-dialkyldihydroberberines (8,8-DDBs) were found to possess mid- to low-nanomolar potency against Plasmodium falciparum blood-stage parasites, Leishmania donovani intracellular amastigotes, and Trypanosoma brucei brucei bloodstream forms. For example, 8,8-diethyldihydroberberine chloride (5b) exhibited in vitro IC50 values of 77, 100, and 5.3 nM against these three parasites, respectively. In turn, two 8,8-dialkylcanadines, obtained by reduction of the corresponding 8,8-DDBs, were much less potent against these parasites in vitro. While the natural product berberine is a weak DNA binder, the 8,8-DDBs displayed no affinity for DNA, as assessed by changes in the melting temperature of poly(dA·dT) DNA. Selected 8,8-DDBs showed efficacy in mouse models of visceral leishmaniasis and African trypanosomiasis, with 8,8-dimethyldihydroberberine chloride (5a) reducing liver parasitemia by 46% in L. donovani-infected BALB/c mice when given at an intraperitoneal dose of 10 mg/kg/day for five days. The 8,8-DDBs may thus serve as leads for discovering new antimalarial, antileishmanial, and antitrypanosomal drug candidates.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Kaiser, Marcel and Brun, Reto
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society of Pharmacognosy
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:16 Aug 2013 07:34
Deposited On:16 Aug 2013 07:31

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