8,8-Dialkyldihydroberberines with Potent Antiprotozoal Activity
详细信息 查看全文
- 作者：Molla Endeshaw ; Xiaohua Zhu ; Shanshan He ; Trupti Pandharkar ; Emily Cason ; Kiran V. Mahasenan ; Hitesh Agarwal ; Chenglong Li ; Manoj Munde ; W. David Wilson ; Mark Bahar ; Raymond W. Doskotch ; A. Douglas Kinghorn ; Marcel Kaiser ; Reto Brun ; Mark E. Drew ; Karl A. Werbovetz
- 刊名：Journal of Natural Products
- 出版年：2013
- 出版时间：March 22, 2013
- 年：2013
- 卷：76
- 期：3
- 页码：311-315
- 全文大小：238K
- 年卷期：v.76,no.3(March 22, 2013)
- ISSN：1520-6025
文摘
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路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.