title: 8,8-dialkyldihydroberberines with potent antiprotozoal activity.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University , Columbus, Ohio 43210, USA.
authors.forename: Molla
authors.initials: M
authors.lastname: Endeshaw
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhu
authors.forename: Shanshan
authors.initials: S
authors.lastname: He
authors.forename: Trupti
authors.initials: T
authors.lastname: Pandharkar
authors.forename: Emily
authors.initials: E
authors.lastname: Cason
authors.forename: Kiran V
authors.initials: KV
authors.lastname: Mahasenan
authors.forename: Hitesh
authors.initials: H
authors.lastname: Agarwal
authors.forename: Chenglong
authors.initials: C
authors.lastname: Li
authors.forename: Manoj
authors.initials: M
authors.lastname: Munde
authors.forename: W David
authors.initials: WD
authors.lastname: Wilson
authors.forename: Mark
authors.initials: M
authors.lastname: Bahar
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Doskotch
authors.forename: A Douglas
authors.initials: AD
authors.lastname: Kinghorn
authors.forename: Marcel
authors.initials: M
authors.lastname: Kaiser
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Mark E
authors.initials: ME
authors.lastname: Drew
authors.forename: Karl A
authors.initials: KA
authors.lastname: Werbovetz
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000494:pharmacology*; D001600:Berberine Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D005260:Female; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects; D014345:Trypanosoma / Q000187:drug effects
chemical_list: C580907:8,8-diethyldihydroberberine chloride; D000962:Antimalarials; D000981:Antiprotozoal Agents; D001600:Berberine Alkaloids