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.

Antiparasitic Activity of Diterpenoids Against Trypanosoma cruzi

“…The antiplasmodial activity of Plectranthus species has been attributed to the presence of abietane diterpenes [7]. Abietane diterpenes have been described as possessing cytotoxic, antibacterial and antiprotozoal effects [7][8][9][10][11][12][13], as inhibitors of T-and B-lymphocyte proliferation [14], and also as inhibitors of the growth of various human tumor cell lines [15,16]. Diterpenes from the Plectranthus genus have demonstrated antimicrobial activity against Mycobacterium tuberculosis, Staphylococcus aureus, and Enterococcus species [17,18].…”

Can the Cure for Chagas’ Disease be Found in Nature?

“…These compounds could participate in a conjugated addition of nucleophilic amino acid residues present in target enzymes on Leishmania. This reaction occurs usually via Michael type mechanism that was also reported for other α,β-unsaturated compounds such as lactones and chromones [13].…”

“…This infection is characterized by two distinct clinical stages: the acute phase, with high parasitemia, commonly progresses to a subsequent state of latency, and the chronic phase, with clinical manifestations in various organs. The most common symptoms characteristic of the chronic phase are enlargement of heart ventricles and enlarged esophagus or colon [13], and these manifestations are occasionally life threatening [14].…”

The Influence of Brazilian Biodiversity on Searching for Human Use Pharmaceuticals

“…In addition to the more "genomic" types of publications, the potential for secondary metabolites to provide new treatments for parasitic diseases have also been discussed. An example would be the 2011 paper 96 discussing the potential of marine-sourced antileishmanial compounds, and work reported from Finland where novel agents against both leishmania and Chagas disease have been derived from simple diterpenes that are known from plant and marine sources, the abietane amides with "compound 10" (33) in the paper by Pittimaa et al, 97 giving the best bioactivities against these two parasites.…”