Prediction of Terpenoid Toxicity Based on a Quantitative Structure–Activity Relationship Model

Abstract

Terpenoids, including monoterpenoids (C 10 ), norisoprenoids (C 13 ), and sesquiterpenoids (C 15 ), constitute a large group of plant-derived naturally occurring secondary metabolites with highly diverse chemical structures. A quantitative structure-activity relationship (QSAR) model to predict terpenoid toxicity and to evaluate the influence of their chemical structures was developed in this study by assessing in real time the toxicity of 27 terpenoid standards using the Gram-negative bioluminescent Vibrio fischeri. Under the test conditions, at a concentration of 1 µM, the terpenoids showed a toxicity level lower than 5%, with the exception of geraniol, citral, (S)-citronellal, geranic acid, (±)-α-terpinyl acetate, and geranyl acetone. Moreover, the standards tested displayed a toxicity level higher than 30% at concentrations of 50-100 µM, with the exception of (+)-valencene, eucalyptol, (+)-borneol, guaiazulene, β-caryophellene, and linalool oxide. Regarding the functional group, terpenoid toxicity was observed in the following order: alcohol > aldehyde~ketone > ester > hydrocarbons. The CODESSA software was employed to develop QSAR models based on the correlation of terpenoid toxicity and a pool of descriptors related to each chemical structure. The QSAR models, based on t-test values, showed that terpenoid toxicity was mainly attributed to geometric (e.g., asphericity) and electronic (e.g., maximum partial charge for a carbon (C) atom (Zefirov's partial charge (PC)) descriptors. Statistically, the most significant overall correlation was the four-parameter equation with a training coefficient and test coefficient correlation higher than 0.810 and 0.535, respectively, and a square coefficient of cross-validation (Q 2 ) higher than 0.689. According to the obtained data, the QSAR models are suitable and rapid tools to predict terpenoid toxicity in a diversity of food products.

Relationship between Chemical Composition and Nematicidal Activity of Different Essential Oils

“…As for the two terpenes described above, the higher nematicidal activity of E. citriodora EO can be ascribed to the functional groups present in citronellal (aldehydic function) and its derivatives compared to eucalyptol ( Figure 1 ). In specific studies aimed to evaluate the toxicity of a series of terpenes against bacterial and microbial systems [ 31 , 32 ], it was found that the presence of an oxygen-related function (as in citronellal and citronellol) and a double bond (as in citronellal) contributes to enhance the reactivity of the molecule towards biological processes involving the transfer of electrons by increasing its electronegativity.…”

Chemical Composition and Nematicidal Properties of Sixteen Essential Oils—A Review

“…Analysis of compositional profiles and nematicidal performances of the 16 EOs as well as of structure of their major constituents allowed some considerations on structure-activity relationships. As documented by specific studies, toxicity of natural terpenoids to nematode and bacterial and microbial systems is influenced by type and position of functional groups in their molecular structure [ 11 , 24 , 25 , 27 , 64 ]. In particular, it has been shown that biocidal activity of monoterpenoids is enhanced by the presence of an oxygen-related function (aldheyde, ketone, or alcohol group) in their molecule as well as by the presence of a double bond system which would favor biological processes involving transfer of electrons, thus increasing terpenes reactivity towards nematodes [ 27 , 64 ].…”

“…As documented by specific studies, toxicity of natural terpenoids to nematode and bacterial and microbial systems is influenced by type and position of functional groups in their molecular structure [ 11 , 24 , 25 , 27 , 64 ]. In particular, it has been shown that biocidal activity of monoterpenoids is enhanced by the presence of an oxygen-related function (aldheyde, ketone, or alcohol group) in their molecule as well as by the presence of a double bond system which would favor biological processes involving transfer of electrons, thus increasing terpenes reactivity towards nematodes [ 27 , 64 ]. Consistently, our in vitro assays [ 25 , 27 ] evidenced that EOs rich in citronellal, citronellol, linalool, geraniol, and E -cinnamaldehyde, such as those from C. verum , P. asperum, and E. citrodora, were highly active against M. incognita .…”

“…In agreement, the ketone monoterpenoid thujone was also strongly toxic to root-knot nematode J2 and eggs in the in vitro experiments reported in literature [ 16 , 49 ]. Moreover, it has been described that acyclic monoterpenoids are more active than cyclic terpenoids with the same above functional groups [ 64 ]. This could explain the relatively lower nematicidal effect of menthol and menthane-type monoterpenoids or 1,8-cineole-containing EOs, such as those of M. piperita or E. globulus [ 24 , 27 ].…”

In situ solid-liquid extraction enhances recovery of taxadiene from engineered Saccharomyces cerevisiae cell factories

“…Some terpenoids in particular are drug candidates for the treatment of human disease; examples include the sesquiterpenoid anti-malarial drug, artemisinin and diterpenoid chemotherapy drug, paclitaxel [7,8]. Most terpenoids are hydrophobic in nature and often become toxic to heterologous hosts at industrially feasible concentrations [9]. To minimize the detrimental effects of terpenoids on the host, in situ product recovery methods have become common practice at laboratory scale [10,11].…”