Nerolidol exhibited antileishmanial activity against Leishmania amazonensis amastigotes and promastigotes. The IC₅₀ values were dependent on cell concentration. The mean cw₅₀ (aqueous phase concentration causing 50% inhibition) was 56 µM for amastigotes and 74 µM for promastigotes. The corresponding critical membrane concentration (cm₅₀) was between 2.6 and 3.0 M, indicating significant accumulation in the parasite membrane.
Nerolidol showed cytotoxicity against J774.A1 murine macrophages with a cw₅₀ of 125 µM.
Nerolidol significantly reduced the percentage of GFP-positive J774.A1 macrophages infected with L. amazonensis starting at a concentration of 100 µM after 24 hours of treatment.
Electron paramagnetic resonance (EPR) spectroscopy using the spin label 5-DSA demonstrated that nerolidol at 60 µM increased the fluidity of the plasma membrane of L. amazonensis amastigotes.

Antiproliferative assay against Leishmania and macrophages: Parasites (promastigotes or amastigotes) or J774.A1 macrophages at various cell concentrations were treated with increasing concentrations of nerolidol. The compound was initially diluted in ethanol and then in culture medium supplemented with 10% FCS. Samples were incubated for 24 hours in 96-well plates at 26°C (promastigotes), 32°C (amastigotes), or 37°C (macrophages). Cell viability was assessed using the MTT reduction assay. The percentage of viable cells relative to the control was calculated, and IC₅₀/CC₅₀ values were determined by fitting the concentration-response data to a sigmoid curve.
Infection assay in macrophages: J774.A1 macrophages were infected with GFP-transfected L. amazonensis promastigotes for 3 hours. After washing, cells were cultured for an additional 24 hours in the presence of nerolidol at different concentrations. Cells were then collected and analyzed by flow cytometry to determine the percentage of GFP-positive cells.
Hemolysis assay: Erythrocytes were washed and resuspended in PBS at various concentrations. Nerolidol was initially diluted in ethanol and then in PBS containing 5% ethanol. Erythrocyte suspensions were incubated with different concentrations of nerolidol for 2 hours at 36.5 ± 1°C. After incubation, samples were centrifuged, and hemoglobin release in the supernatant was measured at 540 nm to determine the percentage of hemolysis. The HC₅₀ was determined by fitting the concentration-response data to a sigmoid curve.
Hemolysis assay in whole blood: Plasma was separated from whole blood by centrifugation. Plasma samples containing different concentrations of nerolidol were prepared, and erythrocytes were added back to reconstitute whole blood. Samples were incubated for 24 hours at 7 ± 1°C with gentle stirring. Hemolysis percentage was determined as described above.

The membrane-water partition coefficient (K_M/W) of nerolidol was determined in different cell types: 35,300 in promastocytes, 53,500 in amastocytes, 23,200 in macrophages, and 1,300 in erythrocytes. The membrane-plasma partition coefficient (K_M/P) of nerolidol in blood was estimated to be 5.7. In whole blood, the concentration of nerolidol causing 50% hemolysis (HC₅₀) was 32 mM, approximately 16 times higher than that in PBS at 42% erythrocyte hematocrit, indicating its chelation by plasma albumin.

The hemolytic potential of nerolidol is concentration-dependent. In PBS buffer containing 5% ethanol, the HC₅₀ value is approximately 300 µM at low erythrocyte concentrations and approximately 2.3 mM at high erythrocyte concentrations. In whole blood, the HC₅₀ value is 32 mM. The cytotoxicity of nerolidol (CC₅₀ = 125 µM in macrophages) is lower than its anti-leishmaniasis activity (cw₅₀ = 56–74 µM in the parasite), but its selectivity window is narrower than that of mitifoxin. EPR spectroscopy showed that a 2 mM HC₅₀ concentration of nerolidol in PBS buffer increased erythrocyte membrane fluidity.

[1]. In vitro antileishmanial and cytotoxic activities of nerolidol are associated with changes in plasma membrane dynamics. Biochim Biophys Acta Biomembr. 2019 Jun 1;1861(6):1049-1056.

Nerolidol is a farnesane sesquiterpene compound belonging to the 12-carbon-1,6,10-triene class, with methyl groups at positions 3, 7, and 11 and a hydroxyl group at position 3. It is a natural product found in a variety of fragrant flowers and plants. Chemically, it exists as both trans and cis isomers. Nerolidol is widely used in cosmetics (e.g., shampoos and perfumes), non-cosmetic products (e.g., detergents and cleaning agents), and food flavorings. It also possesses various functions, including as a flavoring agent, cosmetic ingredient, pheromone, neuroprotective agent, antifungal agent, anti-inflammatory agent, antihypertensive agent, antioxidant, volatile oil component, insect attractant, and herbicide. It is a farnesane sesquiterpene compound belonging to the tertiary allyl alcohol class and is also a volatile organic compound. Nerolidol has been reported in Aristolochia triangularis, Rhododendron dauricum, and other organisms with relevant data.
Nerolidol is also found in bitter melon. It is a component of many essential oils. The (S)-enantiomer is more common, but it mainly exists as the (S)-(E)-isomer. Nerolidol is a flavoring agent.
Studies have shown that nerolidol has antifungal activity (A7933).
Nerolidol belongs to the sesquiterpenoid class of compounds. These are terpenoids containing three consecutive isoprene units.
See also: Nerolidol (note moved to).

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Nerolidol is an aliphatic sesquiterpene alcohol found in many plant essential oils and has been approved by the US FDA as a food flavoring agent. Its concern threshold is 1.8 mg/person/day.
The main mechanism of action of nerolidol against Leishmania protozoa is through interaction with the cell membrane, increasing membrane fluidity and leading to cell lysis. This membrane-targeting mechanism is consistent with its broad-spectrum activity against a variety of pathogens. Compared to mitifoxin, nerolipid has a lower affinity for erythrocyte membranes, requiring higher concentrations to disrupt them. However, because its cytotoxic and antiparasitic concentrations are closer, its therapeutic index is also lower.

C15H26O

222.3663

222.198

7212-44-4

cis-Nerolidol;3790-78-1

5284507

Colorless to light yellow liquid

0.9±0.1 g/cm3

276.0±0.0 °C at 760 mmHg

-75 °C

96.1±0.0 °C

0.0±1.2 mmHg at 25°C

1.480

5.32

1

1

7

16

269

0

O([H])C(C([H])=C([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])C([H])([H])/C(/[H])=C(\C([H])([H])[H])/C([H])([H])[H]

FQTLCLSUCSAZDY-GOFCXVBSSA-N

InChI=1S/C15H26O/c1-6-15(5,16)12-8-11-14(4)10-7-9-13(2)3/h6,9,11,16H,1,7-8,10,12H2,2-5H3/b14-11+/t15-/m0/s1

(R,E)-3,7,11-trimethyldodeca-1,6,10-trien-3-ol

Nerolidol; BRN 1724135; BRN1724135; BRN 1724135; FCI 119b; FCI119b; FCI-119b

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~100 mg/mL (~449.70 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (11.24 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (11.24 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (11.24 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)