np300638f_si_001.pdf (239.42 kB)
8,8-Dialkyldihydroberberines with Potent Antiprotozoal Activity
journal contribution
posted on 2013-03-22, 00:00 authored by 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. WerbovetzSemisynthetic 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.