Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species

Changtam, C., de Koning, H.P. , Ibrahim, H., Sajid, M.S., Gould, M.K. and Suksamrarn, A. (2010) Curcuminoid analogs with potent activity against Trypanosoma and Leishmania species. European Journal of Medicinal Chemistry, 45(3), pp. 941-956. (doi: 10.1016/j.ejmech.2009.11.035)

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The natural curcuminoids curcumin (1), demethoxycurcumin (2) and bisdemethoxycurcumin (3) have been chemically modified to give 46 analogs and 8 pairs of 1:1 mixture of curcuminoid analogs and these parent curcuminoids and their analogs were assessed against protozoa of the Trypanosoma and Leishmania species. The parent curcuminoids exhibited low antitrypanosomal activity (EC50 for our drug-sensitive Trypanosoma brucei brucei line (WT) of compounds 1, 2 and 3 are 2.5, 4.6 and 7.7á[mu]M, respectively). Among 43 curcuminoid analogs and 8 pairs of 1:1 mixture of curcuminoid analogs tested, 8 pure analogs and 5 isomeric mixtures of analogs exhibited high antitrypanosomal activity in submicromolar order of magnitude. Among these highly active analogs, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (40) was the most active compound, with an EC50 value of 0.053á¦á0.007á[mu]M; it was about 2-fold more active than the standard veterinary drug diminazene aceturate (EC50 0.12á¦á0.01á[mu]M). Using a previously characterized diminazene-resistant T. b. brucei (TbAT1-KO) and a derived multi-drug resistant line (B48), no cross-resistance of curcuminoids was observed to the diamidine and melaminophenyl arsenical drugs that are the current treatments. Indeed, curcuminoids carrying a conjugated keto (enone) motif, including 40, were significantly more active against T. b. brucei B48. This enone motif was found to contribute to particularly high trypanocidal activity against all Trypanosoma species and strains tested. The parent curcuminoids showed low antileishmanial activity (EC50 values of compounds 1 and 2 for Leishmania mexicana amastigotes are 16á¦á3 and 37á¦á6á[mu]M, respectively) while the control drug, pentamidine, displayed an EC50 of 16á¦á2á[mu]M. Among the active curcuminoid analogs, four compounds exhibited EC50 values of less than 5á[mu]M against Leishmania major promastigotes and four against L. mexicana amastigotes. No significant difference in sensitivity to curcuminoids between L. major promastigotes and L. mexicana amastigotes was observed. The parent curcuminoids and most of their analogs were also tested for their toxicity against human embryonic kidney (HEK) cells. All the curcuminoids exhibited lower toxicity to HEK cells than to T. b. brucei bloodstream forms and only one of the tested compounds showed significantly higher activity against HEK cells than curcumin (1). The selectivity index for T. b. brucei ranged from 3-fold to 1500-fold. The selectivity index for the most active analog, the enone 40, was 453-fold.

Item Type:Articles
Glasgow Author(s) Enlighten ID:De Koning, Professor Harry
Authors: Changtam, C., de Koning, H.P., Ibrahim, H., Sajid, M.S., Gould, M.K., and Suksamrarn, A.
Subjects:Q Science > QH Natural history > QH345 Biochemistry
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:European Journal of Medicinal Chemistry
ISSN (Online):1768-3254
Published Online:24 November 2009

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