title: Abietane-Type Diterpenoid Amides with Highly Potent and Selective Activity against Leishmania donovani and Trypanosoma cruzi.
abstract: Dehydroabietylamine (1) was used as a starting material to synthesize a small library of dehydroabietyl amides by simple and facile methods, and their activities against two disease-causing trypanosomatids, namely, Leishmania donovani and Trypanosoma cruzi, were assayed. The most potent compound, 10, an amide of dehydroabietylamine and acrylic acid, was found to be highly potent against these parasites, displaying an IC50 value of 0.37 μM against L. donovani axenic amastigotes and an outstanding selectivity index of 63. Moreover, compound 10 fully inhibited the growth of intracellular amastigotes in Leishmania donovani-infected human macrophages with a low IC50 value of 0.06 μM. This compound was also highly effective against T. cruzi amastigotes residing in L6 cells with an IC50 value of 0.6 μM and high selectivity index of 58, being 3.5 times more potent than the reference compound benznidazole. The potent activity of this compound and its relatively low cytotoxicity make it attractive for further development in pursuit of better drugs for patients suffering from leishmaniasis and Chagas disease.
authors: VTT Technical Research Centre of Finland Ltd, VTT , P.O. Box 1000, FI-02044 VTT Espoo, Finland.
authors: Minni
authors: M
authors: Pirttimaa
authors: Department of Microbiology and Molecular Genetics, IMRIC, P.O. Box 12272, Hebrew University-Hadassah Medical School , 9112102 Jerusalem, Israel.
authors: Abedelmajeed
authors: A
authors: Nasereddin
authors: Department of Microbiology and Molecular Genetics, IMRIC, P.O. Box 12272, Hebrew University-Hadassah Medical School , 9112102 Jerusalem, Israel.
authors: Dmitry
authors: D
authors: Kopelyanskiy
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute , Socinstrasse 57, 4051 Basel, Switzerland.
authors: Marcel
authors: M
authors: Kaiser
authors: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , Viikinkaari 5 E (P.O. Box 56), FI-00014, Helsinki, Finland.
authors: Jari
authors: J
authors: Yli-Kauhaluoma
authors: VTT Technical Research Centre of Finland Ltd, VTT , P.O. Box 1000, FI-02044 VTT Espoo, Finland.
authors: Kirsi-Marja
authors: KM
authors: Oksman-Caldentey
authors: Department of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute , Socinstrasse 57, 4051 Basel, Switzerland.
authors: Reto
authors: R
authors: Brun
authors: Department of Microbiology and Molecular Genetics, IMRIC, P.O. Box 12272, Hebrew University-Hadassah Medical School , 9112102 Jerusalem, Israel.
authors: Charles L
authors: CL
authors: Jaffe
authors: Faculty of Pharmacy, Division of Pharmaceutical Chemistry and Technology, University of Helsinki , Viikinkaari 5 E (P.O. Box 56), FI-00014, Helsinki, Finland.
authors: Vânia M
authors: VM
authors: Moreira
authors: VTT Technical Research Centre of Finland Ltd, VTT , P.O. Box 1000, FI-02044 VTT Espoo, Finland.
authors: Sami
authors: S
authors: Alakurtti
mesh_terms: D045784:Abietanes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D014355:Chagas Disease / Q000188:drug therapy; D006801:Humans; D020128:Inhibitory Concentration 50; D007893:Leishmania donovani / Q000187:drug effects*; D007896:Leishmaniasis / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects; D015394:Molecular Structure; D009593:Nitroimidazoles / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D014344:Trypanocidal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects*
chemical_list: D045784:Abietanes; D000577:Amides; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C000600819:dehydroabietylamine; C009999:benzonidazole