Anti-leishmanial activity of betulin derivatives

Abstract

Leishmanicidal activity of 24 derivatives of naturally occurring and abundant triterpenes belonging to the lupane series, betulin, betulinic acid and betulonic acid, is described in this study. The easily modified positions of the lupane skeleton, the hydroxy groups of C-3 and C-28, as well as the carbon-carbon double bond C-20-C-29 were used as a starting point to prepare a library of triterpenoid derivatives for bioactivity studies. The compounds were evaluated against Leishmania donovani axenic amastigotes on a microplate assay at 50 lM. GI 50 values of the most effective compounds were evaluated, as well as their cytotoxicity on the human macrophage cell line THP-1, and anti-leishmanial activity against L. donovani-infected THP-1 macrophages was determined. Betulonic acid was the most potent derivative, yielding a GI 50 value of 14.6 lM. Promising and distinct structure-activity relationships were observed, and these compounds can be regarded as significant lead molecules for further improvement and optimization.

New acetylenic derivatives of betulin and betulone, synthesis and cytotoxic activity

“…It has already been reported that betulone 2 possess interesting pharmacological activities such as anti-leishmanial, anti-inflammatory, and aniparasitic against Plasmodium falciparum and Trypanosoma brucei rhodesiense (Alakurtti et al, 2010; Gachet et al, 2011; Reyes et al, 2006). Triterpene 2 exhibited also antifouling activity against cyprid larvae of the barnacle Balanus albicostatus with the EC 50 value 8.73 µg/mL slightly higher than betulin 1 (Chen et al, 2011).…”

Disuccinyl Betulin Triggers Metacaspase-Dependent Endonuclease G-Mediated Cell Death in Unicellular Protozoan Parasite Leishmania donovani

“…Betulin induces cell death more rapidly than does betulinic acid, but to achieve a similar degree of cell death, a considerably higher concentration of betulin is needed (20). Although a few reports exist that show antiprotozoal activities of betulin derivatives, there is no extensive study on cell death induced by betulin derivatives (21,22,23). We have shown that 3-O,28-Odisuccinyl betulin (DiSB) is a potent antileishmanial agent that binds to topoisomerase I and inhibits the binding of the enzyme to DNA, which thus affects the relaxation activity of Leishmania topoisomerase (18).…”

Lup-20(29)-en-28-ol-3-one (betulone)

“…For the isolation of betulone from plants, see: Cole et al (1991); Reyes et al (2006); Diouf et al (2009) ;Liu et al (2010); Kim et al (2002); Garcez et al (2003); Fuchino et al (1996). For the biological activity of betulone, see: Alakurtti et al (2010); Hata et al (2002); Reyes et al (2006). For related structures, see: Mohamed et al (2006); Ding et al (2009) ;Drebushchak et al (2010); Boryczka et al (2011Boryczka et al ( , 2012a Refinement R[F 2 > 2(F 2 )] = 0.051 wR(F 2 ) = 0.141 S = 1.03 5036 reflections 609 parameters H atoms treated by a mixture of independent and constrained refinement Á max = 0.55 e Å À3 Á min = À0.50 e Å À3 Table 1 Hydrogen-bond geometry (Å , ).…”