Antileishmanial Activity of the Terpene Nerolidol

Abstract

The activity of nerolidol, a sesquiterpene used as a food-flavoring agent and currently under testing as a skin penetration enhancer for the transdermal delivery of therapeutic drugs, was evaluated against Leishmania species. Nerolidol inhibited the growth of Leishmania amazonensis, L. braziliensis, and L. chagasi promastigotes and L. amazonensis amastigotes with in vitro 50% inhibitory concentrations of 85, 74, 75, and 67 M, respectively. The treatment of L. amazonensis-infected macrophages with 100 M nerolidol resulted in 95% reduction in infection rates. Inhibition of isoprenoid biosynthesis, as shown by reduced incorporation of [2-14 C]mevalonic acid (MVA) or [1-14 C]acetic acid precursors into dolichol, ergosterol, and ubiquinone, was observed in nerolidol-treated promastigotes. This drug effect can be attributed to the blockage of an early step in the mevalonate pathway, since incorporation of the precursor [1(n)-3 H]farnesyl pyrophosphate in polyisoprenoids is not inhibited by nerolidol. L. amazonensis-infected BALB/c mice were treated with intraperitoneal doses of 100 mg/kg/day for 12 days or topically with 5 or 10% ointments for 4 weeks. Significant reduction of lesion sizes in nerolidol treated mice was observed for both treatment routes. However, long-term follow up indicated that the disease was not cured in this highly susceptible animal model. Nonetheless, the in vitro activity of nerolidol against these parasites may prove a useful tool for the development of new drugs for the treatment of leishmaniasis. In addition, biosynthesis of dolichols with 11 and 12 isoprene units was identified in Leishmania, as described for other trypanosomatids and Apicomplexa.

Chemical constituents of the volatile oil from leaves of Annona coriacea and in vitro antiprotozoal activity

“…Likewise, researches have attributed to the oxygenated sesquiterpenes the activity against different species of Leishmania (Arruda et al, 2005). In A. coriacea, these constituents represent 39.1% of the sesquiterpene compounds found in its oil.…”

A squalene synthase protein degradation method for improved sesquiterpene production in Saccharomyces cerevisiae

“…Trans-nerolidol is an important fragrance and flavour (Berger, 2007). Nerolidol also exhibits antiulcer (Klopell et al, 2007), antileishmanial (Arruda et al, 2005) and insect repelling (Di Campli et al, 2012) activities. It is the main component of the essential oil and the biologically active component from fragrant rosewood (Dalbergia odorifera; Jiang Xiang in Chinese) heart wood; D. odorifera essential oil is used in Traditional Chinese Medicine for dispersing blood stasis in organs/tissues, and applied for treating coronary heart disease and angina pectoris (Li et al, 2014).…”

Antimicrobial and antileishmanial activity of essential oil from the leaves of Annona foetida (Annonaceae)

“…28,29 but there is no scientific report on antileishmanial activity for unfunctionalized sesquiterpenes, and the mechanisms of action remain unclear. Recent studies on cultures of L. amazonensis promastigotes revealed that 30 This encourages an intensive investigation of the mechanisms of action of terpene essential oils. It has been also suggested that the low density of the essential oils and their ready diffusion across cell membranes contribute to enhance targeting intracellular protozoal malaria parasites.…”