Next Article in Journal
Behavioral and Neuropathological Phenotyping of the Tau58/2 and Tau58/4 Transgenic Mouse Models for FTDP-17
Next Article in Special Issue
Poria cocos Lanostane Triterpenoids Extract Promotes Collagen and Hyaluronic Acid Production in D-Galactose-Induced Aging Rats
Previous Article in Journal
High Risk of Heart Tumors after COVID-19
Previous Article in Special Issue
In Silico Exploration and Experimental Validation of Camellia sinensis Extract against Rhipicephalus microplus and Sarcoptes scabiei: An Integrated Approach
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Life
Volume 13
Issue 10
10.3390/life13102086
life-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Therapeutic Potential of Myrtenal and Its Derivatives—A Review

by
Stela Dragomanova
1,
Velichka Andonova
2,
Konstantin Volcho
3,
Nariman Salakhutdinov
3,
Reni Kalfin
4,5,* and
Lyubka Tancheva
4
1
Department of Pharmacology, Toxicology and Pharmacotherapy, Faculty of Pharmacy, Medical University of Varna, 84 A Tsar Osvoboditel Blvd., 9002 Varna, Bulgaria
2
Department of Pharmaceutical Technologies, Faculty of Pharmacy, Medical University of Varna, 84 A Tsar Osvoboditel Blvd., 9002 Varna, Bulgaria
3
Department of Medicinal Chemistry, Novosibirsk Institute of Organic Chemistry of the Russian Academy of Sciences, 9 Lavrentiev Av., 630090 Novosibirsk, Russia
4
Institute of Neurobiology, Bulgarian Academy of Sciences, Acad. G. Bonchev St., Block 23, 1113 Sofia, Bulgaria
5
Department of Healthcare, South-West University, 66 Ivan Mihailov St., 2700 Blagoevgrad, Bulgaria
*
Author to whom correspondence should be addressed.
Life 2023, 13(10), 2086; https://doi.org/10.3390/life13102086
Submission received: 28 August 2023 / Revised: 10 October 2023 / Accepted: 17 October 2023 / Published: 20 October 2023
(This article belongs to the Special Issue Current and Recent Advances in Natural Products-Based Drug Discovery, Design and Development)
Browse Figures
Versions Notes

Abstract

:
The investigation of monoterpenes as natural products has gained significant attention in the search for new pharmacological agents due to their ability to exhibit a wide range in biological activities, including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, and vasodilating properties. In vitro and in vivo studies reveal their antidepressant, anxiolytic, and memory-enhancing effects in experimental dementia and Parkinson’s disease. Chemical modification of natural substances by conjugation with various synthetic components is a modern method of obtaining new biologically active compounds. The discovery of new potential drugs among monoterpene derivatives is a progressive avenue within experimental pharmacology, offering a promising approach for the therapy of diverse pathological conditions. Biologically active substances such as monoterpenes, for example, borneol, camphor, geraniol, pinene, and thymol, are used to synthesize compounds with analgesic, anti-inflammatory, anticonvulsive, antidepressant, anti-Alzheimer’s, antiparkinsonian, antiviral and antibacterial (antituberculosis) properties. Myrtenal is a perspective monoterpenoid with therapeutic potential in various fields of medicine. Its chemical modifications often lead to new or more pronounced biological effects. As an example, the conjugation of myrtenal with the established pharmacophore adamantane enables the augmentation of several of its pivotal properties. Myrtenal–adamantane derivatives exhibited a variety of beneficial characteristics, such as antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective properties, which are worth examining in more detail and at length.

1. Introduction

Essential oils have been used in traditional medicine to treat various diseases. Before research into their health benefits had begun, they were also used for perfumes and fragrances for many years. Some of their components possess rich biological activity [1,2,3,4,5,6,7] and are used as pharmacological agents such as the taxanes for their antitumor activity and artemisinin for its antimalarial properties [8,9]. Natural products and their derivatives dominate among drugs used to treat CNS diseases [10,11,12,13].
Terpenes constitute the largest cluster of secondary plant metabolites, encompassing a plethora of over 50,000 distinct substances, each characterized by a diverse array of biological attributes [14]. The most widespread terpenes are monoterpenes consisting of two isoprene fragments [15]. Monoterpenes that incorporate heteroatoms, such as oxygen, are categorized as monoterpenoids. As natural products, monoterpenes and monoterpenoids are the subject of increased attention from the world scientific community in the search for new pharmacological agents in various branches of medicine and pharmacy [16,17,18,19,20,21,22,23,24,25,26]. They have many biological properties, including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, vasodilating effects, etc. The review by Yang et al. (2020) on the biological properties of terpenoids addresses the topic of their therapeutic potential and confirms the interest of researchers in developing terpenoid derivatives with different pharmacological properties [27]. A recent study from 2022 (Kumar et al.) summarizes the current data about the therapeutic potential of terpenes and terpenoids, confirming that these natural substances are widely distributed in various plant and marine sources and possess a wide range in biological properties [28].
In vitro and in vivo studies reveal their potential therapeutic effects on diabetes, insulin resistance, and obesity, as described by Habtemariam (2017) [29] and Al Kury et al. (2021) [30]. Genipin and geniposide (Figure 1), along with iridoids and their glycosides, exhibit in vitro antidiabetic properties. Geniposide stimulates insulin secretion by activating the glucagon-like-1 (GLP-1) receptor [31]. Limonene showed a promising in vivo antidiabetic effect, established by Ramakrishnan and Ramalingam in 2012 [32]. Borneol, citronellol, and myrtenal increased liver glycogen levels. Carvacrol, carvone, citronellol, genposide, myrtenal, and paeoniflorin modulated key liver enzymes of glucose metabolism, reducing the activity of glucokinase and glucose-6-phosphate dehydrogenase.
In a clinical study from 2013, Luft et al. proved the role of chronic inflammation in the pathogenesis of diabetes and obesity [33]. Many of the monoterpenes exhibit positive effects on inflammatory conditions [34], also associated with diabetes. The in vitro study by Kong et al. (2013) reported that monoterpenes directly improve the lipid profile by affecting key enzymes for fatty acid synthesis (acetyl-CoA carboxylase and synthase) [35]. De Sousa (2011) summarized the available data about the analgesic potential of many plant essential oils that are rich in monoterpenes [36]. Numerous research works have been carried out in this important field in the last decade. High analgesic activity was demonstrated for (−)-linalool [37] and its acetate [38], citronellal [39], p-cymene [40,41], camphor [42], α-terpineol [43,44,45,46], menthol [47], myrcene [48], limonene [49,50], pulegone [51], citronellol [52], cuminic alcohol [53], and 1,8-cineole [54]. The anti-inflammatory activity of monoterpenes was reviewed by Araruna et al. (2020) [55].
In certain instances, positive outcomes have been observed as an adjunct to radiation therapy in the context of cancer treatment. They have the potential to be “radiosensitizers”, increasing the in vitro sensitivity of cancer cells (head and neck tumors) to radiation therapy with subsequent induction of apoptosis [56]. In addition to the studies on their cytotoxic properties as potential antitumor agents, research on their toxicity and potential risk of use is also of interest. Wojtunik-Kulesza (2022) revealed the toxic potential of α-terpinene, camphor, citral, limonene, pulegone, thujone (Figure 1), and the essential oils that contain them [57]. Genotoxicity, embryotoxicity, neurotoxicity, and allergenicity were indicated.
Memory-enhancing properties have also been reported for some of the studied monoterpenes [58]. For example, thymol’s positive effect on cognitive deficits, associated with a high-fat diet in mice, was found by Fang et al. (2017) [59]. According to Deng, Lu, and Teng (2013), carvacrol counteracted memory impairments in rats associated with experimental diabetes by affecting different mechanisms [60]. Some of the bicyclic monoterpenoids inhibit acetylcholinesterase activity, which is elevated in Alzheimer’s disease patients. In the Miyazawa and Yamafuji’s (2005) study of 17 representatives from this group of substances, (+)- and (−)-α-pinene and (+)-3-carene (Figure 1) appeared as moderate inhibitors of the enzyme, while bicyclic ketones and alcohols are weak anticholinesterase agents [61]. Their oxygenated derivatives and paramenthane monoterpenoids were found to be even less active.
Several monoterpenoid alcohols, including geraniol [62,63], diol 1 derived from verbenol [64], and a conjugate 2 obtained by reaction of (+)-2-carene with vanillin [65], demonstrated promising antiparkinsonian activity in vivo in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. Derivatives of diol 1, compounds 3 and 4, showed neuroprotective effects in vitro and in several experimental mice models (MPTP-, rotenone-, and haloperidol-induced) of Parkinson’s disease [66,67] (Figure 2). Neuroprotective potential was demonstrated also for carvacrol [68,69,70], limonene [71,72,73], geraniol [74,75], citronellol [76], carveol [77], 1,8-cineole [78], paeoniflorin [79], α-pinene [80], and linalool [81].
Guzmán-Gutiérrez et al. (2012) reported an antidepressant effect of β-pinene and linalool [82], and Deng et al. (2015) found that thymol demonstrated this property in a model of chronic mild stress in mice [83]. Several monoterpenoids have demonstrated anxiolytic effects in rodents [84]. In 2015, de Sousa et al. published a systematic review of the anxiolytic-like effect of essential oils and their components, mainly monoterpenoids [85].
The advancement of novel prospective medications within the domain of monoterpene derivatives represents a promising approach to the treatment of various diseases, signifying a progressive trajectory in the field of experimental pharmacology.

2. Therapeutic Potential of Monoterpenoid Derivatives

A scarcity of substantiated data exists regarding the positive effects of monoterpene derivatives. Shi et al. (2016) reported on the antiallergic properties of some peony monoterpenes derivatives [86]. The review by Salakhutdinov, Volcho, and Yarovaya (2017) summarized the currently available data on the presence of various types of biological activity exhibited by monoterpenes and their derivatives. Their analgesic, anti-inflammatory, anticonvulsant, antidepressant, anti-Alzheimer’s, antiparkinsonian, antiviral, and antibacterial (antituberculosis) properties were described [87]. In addition to these data, a compound synthesized by the interaction of (−)-myrtenal and 2-aminoadamatane was found to have anxiolytic activity in Elevated plus maze test in mice [88]. In 2020, Zielińska-Błajet and Feder-Kubis provided a comprehensive summary of recent advancements in using derivatives of borneol, camphor, geraniol, myrtenal, pinene, and thymol as biologically active substances [89]. In 2021, Silva et al. reviewed the potential of 16 monoterpenes and their derivatives to affect various models of cardiovascular disease [90]. According to Bergman, Franks, and Philips (2023), certain acyclic monoterpenes and their derivatives have demonstrated notable anti-inflammatory potential [91]. Several monoterpene–coumarin conjugates showed good antiviral activity [92,93], while others demonstrated the capacity to inhibit the enzyme TDP1, which serves as a pivotal target in the realm of anticancer therapy [94,95]. The same inhibitory activity was demonstrated for some monoterpenes conjugated with various heterocyclic fragments [96,97]. Cardoso et al. (2021) explored some monoterpene derivatives as P-glycoprotein inhibitory activity agents in cancer cell resistance [98]. Tree monoterpene alkaloid hydrazone derivatives studied by Paterna et al. (2015) showed apoptosis-inducing properties in human colon and liver carcinoma cells [99].
Therefore, chemical modification of natural substances by conjugation with various synthetic components is a modern method for obtaining new biologically active compounds. It had been established that in many cases the medicinal properties of the obtained derivatives are more pronounced than those of the parent substances, and may even exceed the effects of the standards used in various therapeutic areas. It is necessary to carry out more in-depth and extended studies of such compounds. In view of their sufficient safety profiles, these compounds could subsequently be included in a range of clinical studies.

3. Therapeutic Potential of Myrtenal

(−)-Myrtenal, (1R)-2-pinen-10-al, (1R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-carboxaldehyde (Figure 3), is a bicyclic monoterpenoid of natural origin.
Myrtenal is considered practically insoluble in water and relatively neutral. Data on its mammalian metabolism are limited. In plants, myrtenal is metabolically related to α-pinene [100] because α-pinene is metabolized to myrtenol with subsequent transformation to myrtenal [101]. The major metabolite of the monoterpenoid in rabbits is myrtenic acid [102]. Furthermore, according to Scheline (1991), the structural similarity between alpha-pinene and myrtenal and the formation of common metabolites is the reason to assume that M is a transition compound in pinene metabolism [103].
The toxicological characterization of myrtenal is incomplete and provides information only on the lack of genotoxicity (EFSA FAF Panel, 2019) [104].
The substance is a component in the essential oils of many plant species [105] (Dragomanova et al., 2018). It is naturally present in mandarin peel oil, raspberry, blackberry, strawberry, ginger, hop oil, black tea, peppermint oil, pepper, myrtle leaf or berry, and summer savory, along with other spices or foodstuffs including hyssops, rosemary, spearmint, and many more. Table 1 presents the sources with the highest myrtenal content in their essential oils.
Medicinal plants containing myrtenal in their essential oils possess a wide range of biological properties. In the 20th century, bronchodilator, anti-inflammatory, antiaggregative, antihemolytic (in vitro), and antibacterial (against G (+) pathogens) effects of myrtenal were discovered in experimental animals [122]. This explains the use of plant essential oils containing myrtenal in aromatherapy for infections of the upper respiratory tract. They have the potential to favorably affect various systems and organs, including CNS functions, which is discussed in the review by Dragomanova et al. (2018) [105].
According to Saito et al. (1996) [123] and Santos et al. (2011) [124], the compound induced vasodilation, decreased heart rate, and improved hypotension in doses 1 and 5 mg/kg b.wt. after i.v. application in laboratory rats. Many other biological properties of myrtenal have been established.

3.1. Antidiabetic Potential

Myrtenal exhibited an antihyperglycemic effect in rats with an experimental streptozotocin-induced diabetes mellitus model. The compound lowered plasma glucose levels, improved plasma insulin levels, upregulated various glucose transporters, and subsequently improved glucose uptake in the liver and skeletal muscle. In the study by Rathinam and Pari (2016) [125], oral administration of myrtenal (80 mg/kg b.wt.) for 28 days produced a number of effects in rats with induced diabetes. It reduced plasma glucose and glycated hemoglobin A1c (HbA1c); increased levels of insulin and hemoglobin; regained body weight; and normalized activity of hexokinase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase and liver enzymes AST, ALT, and ALP. Myrtenal also increased glycogen content in the liver and muscles; recovered the hepatocytes; and improved pancreatic insulin levels and lipid profile values (total cholesterol, triglycerides, phospholipids, low-density lipoprotein, very-low-density lipoprotein, atherogenic index) (Figure 4).

3.2. Antitumor Potential

Myrtenal has been shown to have antioxidant and antitumor activity in peroral administration at a dose of 230 mg/kg b.wt. in corn oil for 28 days. These effects were achieved through a variety of mechanisms of action, including stabilizing endogenous antioxidant protection, influencing apoptotic and proapoptotic signaling pathways, inhibiting the expression of TNF- and reducing tumor growth, and regulating the activity of several lysosomal and mitochondrial enzymes [126,127,128,129]. The monoterpenoid was administered for 28 days in the experimental protocols of Babu et al., and Venkatachalam’s research group applied it for 15 weeks. Myrtenal was found to inhibit V-type ATPase on the surface of tumor cells in an in vitro study in melanoma cell lines, leading to their death and also to the suppression of melanoma metastasis in experimental mice at a dose of 15 mg/kg b.wt. (i.p. application for 21 days) [130]. The monoterpenoid demonstrated the ability to inactivate free radicals, resulting in inhibition of colon carcinogenesis and suppression of tumor progression after 30 weeks of intragastric administration at a dose of 230 mg/kg b.wt. [131,132]. Trytek et al. (2018) investigated the antitumor potential of (−)-myrtenol, (−)-myrtanol, and (−)-myrtenal (Figure 1) on human colon carcinoma cells in vitro and found that myrtenal had the highest activity [133]. The proposed mechanism of antitumor characteristics was that these substances affect the mitochondrial enzymes’ activity and membrane stability (Figure 5).
Our results confirmed the antioxidant mechanisms in the CNS effect of myrtenal (40 mg/kg b.wt. applied intraperitoneally for 11 days) in intact rats, in the brain of which myrtenal caused SOD (superoxide dismutase) activity and malondialdehyde (MDA) levels to decrease, and total glutathione (tGSH) content to increase, compared to controls [134].

3.3. Analgesic Potential

Pinene, whose derivative is M, showed analgesic potential in various models of induced pain [135]. On the other hand, the hydroxyl derivative myrtenol suppressed nociceptive and inflammatory responses in experimental conditions by inhibiting cell migration and neuromediation in pain pathways [136]. Intraperitoneal administration of this alcohol in experimental mice reduced the number of spasms in the acetic acid writhing test. For the first time, a recent investigation demonstrated myrtenal’s analgesic potential in laboratory mice. After a single, 7-day, and 14-day i.p. administration (30 mg/kg), the analgesic effect of M was established in two pain models: the acetic acid writhing test (antipyretic type analgesia) and the hot plate test (narcotic-type analgesia) [134].

3.4. Anti-Inflammatory Potential

The anti-inflammatory activity of Myrtus communis, L. extracts was established in two chronic inflammation mice models: a xylene-induced ear edema and a cotton pellet test [137]. In rats with induced rheumatoid arthritis, myrtenal isolated from Liquidambra formosana L. exhibited anti-inflammatory properties [138]. They were manifested by lowering the plasma levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α), and also by suppressing the activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome, which was confirmed in vitro.

3.5. CNS-Affecting Potential

Subsequent research into the myrtenal effects on the CNS in our experiments on laboratory rodents showed potentiation of the classical sedative–hypnotic action of the drugs. In our opinion, these results are due to the interaction of myrtenal (20 and 30 mg/kg i.p. in a single dose) with the GABA receptor, since the introduction of the benzodiazepine antagonist Flumazenil (0.5 mg/kg) is followed by a sharp recovery in the condition of the experimental animals [134]. The central mechanism for action of myrtenal and its influence on GABA-ergic neurotransmission is related to the established anxiolytic properties of the substance. Hailu et al. (2011) reported substantial anxiolytic effects of myrtle essential oil, which were found to be comparable to those of diazepam [139]. Our studies in mice also confirmed the anxiolytic property of myrtenal according to the marble-burying test after single and repeated 7- and 14-day i.p. administration at 30 mg/kg dose, comparable to that of diazepam (1 mg/kg) as a reference [134].

3.6. Neuroprotective Potential

The neuroprotective potential of myrtenal was investigated in an injury model in which experimental mice were exposed to radiofrequency electromagnetic radiation during the gestational and neonatal periods. Akefe et al. (2023) administered myrtenal orally at doses of 100 and 200 mg/kg for 28 days, observing improvement in memory processes and in some biochemical parameters [140]. The substance improved short-term memory and spatial orientation. Additionally, it restored the activity of antioxidant enzymes, thereby rectifying the oxidative–inflammatory status within the brains of the experimental mice. The restoration of cholinergic neurotransmission and the levels of dopamine, noradrenaline, and serotonin manifested myrtenal’s neuromodulatory properties.
The ability of natural myrtenal to affect neurodegenerative diseases was demonstrated for the first time by our team. In two experimental models of neurodegeneration—6-OHDA-induced parkinsonism [141] and chemically induced dementia [142] in rats—we established the antioxidant potential of the compound (30 mg/kg i.p. for 5 days), as an element of its neuroprotective activity. There are limited data in the literature on myrtenal’s effects on the levels of major brain neurotransmitters. In the report by Kaufmann, Dogra, and Wink (2011) [143], in vitro anticholinesterase effects were not confirmed by the presence of direct inhibition of enzyme activity in our in vivo experiments in mice (20 mg/kg, i.p. for 11 days) [134] and rats (40 mg/kg, i.p. for 9 days) with experimental neurodegeneration [143]. We established a significant protective effect of myrtenal on neurodegenerative processes in experimental rodent models [140]. Under the conditions of our studies in a scopolamine injury model of dementia, the monoterpenoid exhibited neuromodulatory properties through a slight nonsignificant decrease in brain AChE activity, a significant decrease in hippocampal noradrenaline content, and increased hippocampal and cortical serotonin levels in experimental rats. Examining the myrtenal (50 mg/kg i.p. for 5 days) neuroprotective effects on an experimental 6-OHDA model of Parkinson’s disease further revealed the multitarget mechanism of its action. It demonstrated positive effects on the memory and learning abilities and on the coordination and exploratory behavior of experimental rats, via reducing the main parameters of brain oxidative stress, and increasing the dopamine content in the damaged cerebral hemisphere [141]. According to these first studies, we demonstrated at least two mechanisms of action that are involved in the protective effects of myrtenal on neurodegenerative processes: neuromodulatory and antioxidant (Figure 6).
Although many biological properties of myrtenal have been established, no therapeutic agents have yet been developed. Currently, only one pharmaceutical product based on natural myrtenal is available, Myrtecaine, and it has a local anesthetic effect. Its combination with diethyl amine and salicylic acid is used for muscle and joint pain topical treatment. On the other hand, there is increasing interest in its derivatives and their therapeutic potential in various fields of the medical practice.

4. Therapeutic Potential of Myrtenal Derivatives

Monoterpenes and their derivatives serve as pivotal starting components in the design and synthesis of novel biologically active compounds.

4.1. Antitumor Potential

Concepción et al. (2020) described several basic structures of myrtenal conjugates such as compound 5 (Figure 7) with high cytotoxicity against cancer cells with EC50 in the nanomolar range [144]. These novel myrtenal-conjugated pseudo-peptides have been synthesized and investigated as prospective antitumor agents. They represent potential candidates for anticancer therapy due to their selective cytotoxic activity. Some of these compounds exhibited notable in vitro cytotoxicity against human gastric, breast, and colon adenocarcinoma cell lines, while demonstrating no such effect against human dermal fibroblast cell lines. One derivative exhibited acceptable EC50 and Emax values in cancer cell lines and in inducing cytotoxicity in actively proliferating CD4+—T cells without affecting nonproliferating T cells.
Zielińska-Błajet and Feder-Kubis (2020) provided an overview of diverse therapeutic effects on selected aliphatic, monocyclic, and bicyclic monoterpenes such as geraniol, thymol, myrtenal, pinene, camphor, borneol, and their modified structures [89]. A recent study with fourteen newly synthesized perillaldehyde and myrtenal-based benzohydrazides revealed the antiproliferative potential for two of them [145]. Increasingly more literature data are available regarding new modifications of these natural compounds, including their biological effects and medical applications. However, information regarding the biological and pharmacological properties of monoterpene derivatives remains limited to several review articles, published in the last ten years [91,122,146,147,148,149,150,151,152].
In 2011, Wang and Sintim developed compound 6 (Figure 7), a myrtenal analog of natural antibiotics (platensimycin, platencina, and (−)-myrtamycin) with promising antibacterial activity at MIC 4 µg/mL [153].
In 2015, Suslov et al. published that amino adamantane derivatives of myrtenal 7 and 8 possess potent cytotoxic effects against the tumor lines used (CTD50 = 12÷21 μM), along with low toxicity with respect to MDCK cells [154]. Compound 7, which was synthesized from 1-amino adamantane and (–)-myrtenal, showed cytotoxic activity against CEM-13, MT-4, and U-937 human cancer cells. Adamantylamine derivative demonstrated high activity against all tumor lines used, along with low cellular toxicity, while the 1-amino adamantane and (+)-myrtenal-derived compound 9 exhibited antitumor potential by inhibiting tyrosyl-DNA phosphodiesterase 1 (TDP1) activity (IC50 6 μM), an important target for antitumor therapy, according to research by Ponomarev et al. (2018) [155]. These myrtenal derivatives do not exert genotoxic properties. An even more active TDP1 inhibitor with IC50 45 nM was developed by combining myrtenal and usnic acid fragments [156].
Gonda and Szakonyi (2018) reported the synthesis of 1,2,4- and 1,3,4-oxadiazole derivatives of (–)-myrtenal [157]. All compounds were tested in vitro for antiproliferative activity against four human malignant cell lines using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay [158]. One of them inhibited tumor growth, with IC50 values comparable to those of the reference cisplatin, but showed lower antiproliferative activity against the triple-negative breast cancer cell line (MDA-MB-231) compared to other cell lines used in gynecology. The remaining compounds exhibited a relatively diminished level of activity against ovarian cancer (cell line A2780).

4.2. Anxiolytic Potential

Kapitsa et al. (2012) described new nitrogen-containing compounds with an adamantane–myrtenal structure and then investigated the anxiolytic activity of the resulting products in male Balb/C mice by using the elevated plus maze test [88]. The results showed that compound 8 exhibited anxiolytic potential upon single administration.

4.3. Antiviral Potential

Teplov et al. (2013) tested in vitro the same conjugate of 2-amino adamantane and (–)-myrtenal for antiviral activity against influenza virus A/California/07/09 (H1N1)pdm09 and found that the introduction of a myrtenal fragment led to an increase in the antiviral activity of the adamantylamine derivatives against the adamantylamine-resistant virus [159]. The selectivity for most of the synthesized amines surpassed that for Rimantadine and Amantadine.

4.4. Antifungal Potential

Compound 10, which is a myrtenol-containing analogue of azole antifungals, demonstrated promising antifungal activity against both fluconazole-susceptible and fluconazole-resistant strains, including fluconazole-resistant clinical isolates of Candida parapsilosis and Candida glabrata, with excellent minimum inhibitory concentration in submicrogram and nanogram range. The compound was up to 100 times more active than fluconazole [160].

4.5. Analgesic Potential

A high analgesic effect with an active dose of 20 mg/kg was shown for myrtenal-derived diazaadamantanone 11 [161]. The compound has a low acute oral toxicity with LD50 of more than 1000 mg/kg and does not cause damage to the gastric mucosa. Similar analgesic activity was demonstrated for diazaadamantane–myrtenal conjugate 12 [162]. Having in mind evidences for analgesic potential of myrtenal established in our previous studies, it can be concluded that this analgesic potential can be improved and extended via synthesis of some diazaadamantanone analogues of myrtenal.

4.6. Memory-Improving Potential

The conjugates of amino adamantane with myrtenal 7 and 8, in the form of hydrochlorides, studied by Kapitsa (2012) [88] and Teplov (2013) [159], showed the potential to influence memory processes in intact rats after 11 days of repeated intraperitoneal administration at a dose of 1 mg/kg [163]. The two compounds of amino adamantane with myrtenal investigated in this study exhibited antiacetylcholinesterase activity. Additionally, they demonstrated the capability to influence the levels of norepinephrine and serotonin in the cerebral cortex and hippocampus of the experimental animals. Notably, one of these substances also displayed antidepressant potential, which can be attributed to the induced increase in brain monoamines concentrations, the reduced levels of which are associated with depressive conditions.
Our pilot study of these two amino adamantane compounds with myrtenal was extended by examining their effects on scopolamine-induced neurodegeneration in rats [164]. The derivatives again caused AChE activity inhibition in the cerebral cortex of dement rats, accompanied by some antioxidant capacity expressed by increased glutathione content. They also affected the levels of norepinephrine and serotonin in the cortex and hippocampus of laboratory rodents in an induced model of dementia, as was observed in intact rats in the previous study. These studies, for the first time, reveal the capacity of two amino adamantine conjugates with myrtenal to influence neurodegenerative processes through different mechanisms of action: antiacetylcholinesterase and neuromodulatory.

5. Future Perspectives

Myrtenal derivatives showed a broad spectrum of activities, which reveal myrtenal’s potential as a basis for the design of new pharmacological agents (Figure 8).
Some of the compounds showed new activities different from those of myrtenal, while others showed an enhancement of the effects of the natural substance. Different combinations of myrtenal and adamantane moieties have gained interest in various fields, including medical chemistry and drug discovery. Some research focuses on the design, synthesis, and evaluation of myrtenal–adamantane conjugates as potential pharmacological agents. Moreover, other analogs of these conjugates with modification of monoterpene, adamantine, and linker structures could be considered in the future. This group of compounds showcased a spectrum of beneficial properties that warrant comprehensive and in-depth examination. They have the potential to be introduced in the future into various areas of the pharmacotherapeutic practice. Several possible areas of applications of these derivatives include antimicrobial (antifungal and antiviral), anticancer, anxiolytic, and neuroprotective activity.

6. Conclusions

As a natural compound with a wide range in biological activities, myrtenal can have future implementation in medical practice. The chemical modification of this monoterpenoid with some pharmacophores will allow the enhancement of its essential properties, thereby augmenting its therapeutic potential.

Author Contributions

Conceptualization, S.D., K.V. and L.T.; investigation, S.D. and K.V.; writing—original draft preparation, S.D. and K.V.; writing—review and editing, R.K., L.T., N.S., K.V. and V.A.; visualization, K.V. and S.D.; supervision, L.T., R.K., N.S., K.V. and V.A. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Shaaban, H.A.E.; El-Ghorab, A.H.; Shibamoto, T. Bioactivity of essential oils and their volatile aroma components: Review. J. Essent. Oil Res. 2012, 24, 203–212. [Google Scholar] [CrossRef]
  2. Amorati, R.; Foti, M.C.; Valgimigli, L. Antioxidant Activity of Essential Oils. J. Agric. Food Chem. 2013, 61, 10835–10847. [Google Scholar] [CrossRef]
  3. Oliveira, F.D.A.; Andrade, L.N.; De Sousa, B.V.; De Sousa, D.P. Anti-Ulcer Activity of Essential Oil Constituents. Molecules 2014, 19, 5717–5747. [Google Scholar] [CrossRef]
  4. Dhifi, W.; Bellili, S.; Jazi, S.; Bahloul, N.; Mnif, W. Essential Oils’ Chemical Characterization and Investigation of Some Biological Activities: A Critical Review. Medicines 2016, 3, 25. [Google Scholar] [CrossRef]
  5. Ali-Shtayeh, M.S.; Jamous, R.M.; Abu-Zaitoun, S.Y.; Khasati, A.I.; Kalbouneh, S.R. Biological Properties and Bioactive Components of Mentha spicata L. Essential Oil: Focus on Potential Benefits in the Treatment of Obesity, Alzheimer’s Disease, Dermatophytosis, and Drug-Resistant Infections. Evid.-Based Complement. Altern. Med. 2019, 2019, 3834265. [Google Scholar] [CrossRef]
  6. Mancini, F.; Ebani, V.V. Biological Activity of Essential Oils. Molecules 2020, 25, 678. [Google Scholar] [CrossRef]
  7. Radice, M.; Durofil, A.; Buzzi, R.; Baldini, E.; Martínez, A.P.; Scalvenzi, L.; Manfredini, S. Alpha-Phellandrene and Alpha-Phellandrene-Rich Essential Oils: A Systematic Review of Biological Activities, Pharmaceutical and Food Applications. Life 2022, 12, 1602. [Google Scholar] [CrossRef]
  8. Cheuka, P.M.; Mayoka, G.; Mutai, P.; Chibale, K. The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases. Molecules 2017, 22, 58. [Google Scholar] [CrossRef]
  9. Naeem, A.; Hu, P.; Yang, M.; Zhang, J.; Liu, Y.; Zhu, W.; Zheng, Q. Natural Products as Anticancer Agents: Current Status and Future Perspectives. Molecules 2022, 27, 8367. [Google Scholar] [CrossRef]
  10. Zanforlin, E.; Zagotto, G.; Ribaudo, G. The Medicinal Chemistry of Natural and Semisynthetic Compounds against Parkinson’s and Huntington’s Diseases. ACS Chem. Neurosci. 2017, 8, 2356–2368. [Google Scholar] [CrossRef]
  11. Bharate, S.S.; Mignani, S.; Vishwakarma, R.A. Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis. J. Med. Chem. 2018, 61, 10345–10374. [Google Scholar] [CrossRef]
  12. Pluskal, T.; Weng, J.-K. Natural product modulators of human sensations and mood: Molecular mechanisms and therapeutic potential. Chem. Soc. Rev. 2018, 47, 1592. [Google Scholar] [CrossRef]
  13. Silva, A.R.; Grosso, C.; Delerue-Matos, C.; Rocha, J.M. Comprehensive review on the interaction between natural compounds and brain receptors: Benefits and toxicity. Eur. J. Med. Chem. 2019, 174, 87–115. [Google Scholar] [CrossRef]
  14. Ghosh, S.; Roy, K.; Pal, C. Terpenoids against Infectious Diseases; Roy, D., Ed.; Taylor & Francis Group, LLC: Boca Raton, FL, USA, 2019; 270p, ISBN 3 978-0-8153-7066-6. [Google Scholar] [CrossRef]
  15. De Alvarenga, J.F.R.; Genaro, B.; Costa, B.L.; Purgatto, E.; Manach, C.; Fiamoncini, J. Monoterpenes: Current knowledge on food source, metabolism, and health effects. Crit. Rev. Food Sci. Nutr. 2021, 63, 1352–1389. [Google Scholar] [CrossRef]
  16. Shen, Y.; Sun, Z.; Guo, X. Citral inhibits lipopolysaccharide-induced acute lung injury by activating PPAR-γ. Eur. J. Pharmacol. 2015, 747, 45–51. [Google Scholar] [CrossRef]
  17. Salgado, P.R.R.; Da Fonsêca, D.V.; Braga, R.M.; De Melo, C.G.F.; Andrade, L.N.; De Almeida, R.N.; De Sousa, D.P. Comparative Anticonvulsant Study of Epoxycarvone Stereoisomers. Molecules 2015, 20, 19660–19673. [Google Scholar] [CrossRef]
  18. Ribeiro-Filho, H.V.; de Silva, C.M.; de Siqueira, R.J.B.; Lahlou, S.; dos Santos, A.A.; Magalhães, P.J.C. Biphasic cardiovascular and respiratory effects induced by β-citronellol. Eur. J. Pharmacol. 2016, 775, 96–105. [Google Scholar] [CrossRef]
  19. Camargo, S.B.; Simões, L.O.; de Medeiros, A.C.F.; de Jesus, M.A.; Fregoneze, J.B.; Evangelista, A.; Villarreal, C.F.; de Araújo, S.A.A.; Quintans, L.J.; Silva, D.F. Antihypertensive potential of linalool and linalool complexed with β-cyclodextrin: Effects of subchronic treatment on blood pressure and vascular reactivity. Biochem. Pharmacol. 2018, 151, 38–46. [Google Scholar] [CrossRef]
  20. Nuutinen, T. Medicinal properties of terpenes found in Cannabis sativa and Humulus lupulus. Eur. J. Med. Chem. 2018, 157, 198–228. [Google Scholar] [CrossRef]
  21. Guimarães, A.C.; Meireles, L.M.; Lemos, M.F.; Guimarães, M.C.C.; Endringer, D.C.; Fronza, M.; Scherer, R. Antibacterial Activity of Terpenes and Terpenoids Present in Essential Oils. Molecules 2019, 24, 2471. [Google Scholar] [CrossRef]
  22. Iftikhar, F.; Khan, M.B.N.; Musharraf, S.G. Monoterpenes as therapeutic candidates to induce fetal hemoglobin synthesis and up-regulation of gamma-globin gene: An in vitro and in vivo investigation. Eur. J. Pharmacol. 2021, 891, 173700. [Google Scholar] [CrossRef] [PubMed]
  23. Wojtunik-Kulesza, K.; Rudkowska, M.; Kasprzak-Drozd, K.; Oniszczuk, A.; Borowicz-Reutt, K. Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review. Int. J. Mol. Sci. 2021, 22, 7366. [Google Scholar] [CrossRef]
  24. Paulino, B.N.; da Silva, G.N.S.; Araújo, F.F.; Néri-Numa, I.A.; Pastore, G.M.; Bicas, J.L.; Molina, G. Beyond natural aromas: The bioactive and technological potential of monoterpenes. Trends Food Sci. Technol. 2022, 128, 188–201. [Google Scholar] [CrossRef]
  25. Piccialli, I.; Tedeschi, V.; Caputo, L.; D’errico, S.; Ciccone, R.; De Feo, V.; Secondo, A.; Pannaccione, A. Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes. Front. Pharmacol. 2022, 13, 876614. [Google Scholar] [CrossRef] [PubMed]
  26. Yang, J.; Zhong, C.; Yu, J. Natural Monoterpenes as Potential Therapeutic Agents against Atherosclerosis. Int. J. Mol. Sci. 2023, 24, 2429. [Google Scholar] [CrossRef] [PubMed]
  27. Yang, W.; Chen, X.; Li, Y.; Guo, S.; Wang, Z.; Yu, X. Advances in Pharmacological Activities of Terpenoids. Nat. Prod. Commun. 2020, 15, 1934578X2090355. [Google Scholar] [CrossRef]
  28. Kumar Dash, D.; Kishore Tyagi, C.; Kumar Sahu, A.; Tripathi, V. Revisiting the Medicinal Value of Terpenes and Terpenoids [Internet]. In Revisiting Plant Biostimulants; IntechOpen: London, UK, 2022. [Google Scholar]
  29. Habtemariam, S. Antidiabetic Potential of Monoterpenes: A Case of Small Molecules Punching above Their Weight. Int. J. Mol. Sci. 2017, 19, 4. [Google Scholar] [CrossRef]
  30. Al Kury, L.T.; Abdoh, A.; Ikbariah, K.; Sadek, B.; Mahgoub, M. In Vitro and In Vivo Antidiabetic Potential of Monoterpenoids: An Update. Molecules 2021, 27, 182. [Google Scholar] [CrossRef]
  31. Zhang, Y.; Ding, Y.; Zhong, X.; Guo, Q.; Wang, H.; Gao, J.; Bai, T.; Ren, L.; Guo, Y.; Jiao, X.; et al. Geniposide acutely stimulates insulin secretion in pancreatic β-cells by regulating GLP-1 receptor/cAMP signaling and ion channels. Mol. Cell. Endocrinol. 2016, 430, 89–96. [Google Scholar] [CrossRef]
  32. Ramakrishnan, M.; Ramalingam, S. Antidiabetic effect of d-limonene, a monoterpene in streptozotocin-induced diabetic rats. Biomed. Prev. Nutr. 2012, 2, 269–275. [Google Scholar] [CrossRef]
  33. Luft, V.C.; Schmidt, M.I.; Pankow, J.S.; Couper, D.; Ballantyne, C.M.; Young, J.H.; Duncan, B.B. Chronic inflammation role in the obesity-diabetes association: A case-cohort study. Diabetol. Metab. Syndr. 2013, 5, 31. [Google Scholar] [CrossRef]
  34. De Cássia da Silveira e Sá, R.; Andrade, L.N.; de Sousa, D.P. A Review on Anti-Inflammatory Activity of Monoterpenes. Molecules 2013, 18, 1227–1254. [Google Scholar] [CrossRef] [PubMed]
  35. Kong, P.; Chi, R.; Zhang, L.; Wang, N.; Lu, Y. Effects of paeoniflorin on tumor necrosis factor-α-induced insulin resistance and changes of adipokines in 3T3-L1 adipocytes. Fitoterapia 2013, 91, 44–50. [Google Scholar] [CrossRef]
  36. De Sousa, D.P. Analgesic-like Activity of Essential Oils Constituents. Molecules 2011, 16, 2233–2252. [Google Scholar] [CrossRef]
  37. De Araujo, A.T.; Dos Passos, M.P.; de Carvalho, Y.M.B.G.; Dos Santos, L.B.; de Souza, E.P.B.S.S.; de Souza, A.A.A.; Melo, M.A.O.; Quintans, L.J., Jr.; de Souza, S.Q.J.; Guterres, S.S.; et al. (−)-linalool-Loaded Polymeric Nanocapsules Are a Potential Candidate to Fibromyalgia Treatment. AAPS PharmSciTech 2020, 21, 184. [Google Scholar] [CrossRef] [PubMed]
  38. Alqahtani, A.; Abdelhameed, M.F.; Abdou, R.; Ibrahim, A.M.; Dawoud, M.; Alasmari, S.M.; El Raey, M.A.; Attia, H.G. Mechanistic action of linalyl acetate: Acyclic monoterpene isolated from bitter orange leaf as anti-inflammatory, analgesic, antipyretic agent: Role of TNF-α, IL1β, PGE2, and COX-2. Ind. Crop. Prod. 2023, 203, 117131. [Google Scholar] [CrossRef]
  39. Costa, A.O.C.; Rego, R.I.A.; Andrade, H.H.N.; Costa, T.K.V.L.; Salvadori, M.G.S.S.; Almeida, R.N.; Castro, R.D. Evaluation of the antinociceptive effect generated by citronellal monoterpene isomers. Braz. J. Biol. 2023, 83, e271781. [Google Scholar] [CrossRef]
  40. Santos, W.B.R.; Melo, M.A.O.; Alves, R.S.; de Brito, R.G.; Rabelo, T.K.; Prado, L.d.S.; Silva, V.K.d.S.; Bezerra, D.P.; de Menezes-Filho, J.E.R.; Souza, D.S.; et al. p-Cymene attenuates cancer pain via inhibitory pathways and modulation of calcium currents. Phytomedicine 2019, 61, 152836. [Google Scholar] [CrossRef]
  41. Santos, W.B.R.; Pina, L.T.S.; de Oliveira, M.A.; Santos, L.A.B.O.; Batista, M.V.A.; Trindade, G.G.G.; Duarte, M.C.; Almeida, J.R.G.S.; Quintans-Júnior, L.J.; Quintans, J.S.S.; et al. Antinociceptive Effect of a p-Cymene/β-Cyclodextrin Inclusion Complex in a Murine Cancer Pain Model: Characterization Aided through a Docking Study. Molecules 2023, 28, 4465. [Google Scholar] [CrossRef]
  42. Li, Z.; Gan, Y.; Kang, T.; Zhao, Y.; Huang, T.; Chen, Y.; Liu, J.; Ke, B. Camphor Attenuates Hyperalgesia in Neuropathic Pain Models in Mice. J. Pain Res. 2023, 16, 785–795. [Google Scholar] [CrossRef]
  43. Gouveia, D.N.; Costa, J.S.; Oliveira, M.A.; Rabelo, T.K.; Silva, A.M.O.E.; Carvalho, A.A.; Miguel-Dos-Santos, R.; Lau-ton-Santos, S.; Scotti, L.; Scotti, M.T.; et al. α-Terpineol reduces cancer pain via modulation of oxidative stress and inhibition of iNOS. Biomed. Pharmacother. 2018, 105, 652–661. [Google Scholar] [CrossRef] [PubMed]
  44. Soleimani, M.; Sheikholeslami, M.A.; Ghafghazi, S.; Pouriran, R.; Parvardeh, S. Analgesic effect of alpha-terpineol on neuropathic pain induced by chronic constriction injury in rat sciatic nerve: Involvement of spinal microglial cells and inflammatory cytokines. Iran. J. Basic Med. Sci. 2019, 22, 1445–1451. [Google Scholar] [CrossRef]
  45. Bilbrey, J.A.; Ortiz, Y.T.; Felix, J.S.; McMahon, L.R.; Wilkerson, J.L. Evaluation of the terpenes β-caryophyllene, α-terpineol, and γ-terpinene in the mouse chronic constriction injury model of neuropathic pain: Possible cannabinoid receptor involvement. Psychopharmacology 2022, 239, 1475–1486. [Google Scholar] [CrossRef] [PubMed]
  46. Gouveia, D.; Guimarães, A.; Oliveira, M.; Rabelo, T.K.; Lts, P.; Rocha, W.; Almeida, I.; Andrade, T.; Serafini, M.; Lima, B.; et al. Nanoencapsulated α-terpineol attenuates neuropathic pain induced by chemotherapy through calcium channel modulation. Polym. Bull. 2022, 79, 2515–2532. [Google Scholar] [CrossRef]
  47. Petitjean, H.; Héberlé, E.; Hilfiger, L.; Łapieś, O.; Rodrigue, G.; Charlet, A. TRP channels and monoterpenes: Past and current leads on analgesic properties. Front. Mol. Neurosci. 2022, 15, 945450. [Google Scholar] [CrossRef]
  48. McDougall, J.J.; McKenna, M.K. Anti-Inflammatory and Analgesic Properties of the Cannabis Terpene Myrcene in Rat Adjuvant Monoarthritis. Int. J. Mol. Sci. 2022, 23, 7891. [Google Scholar] [CrossRef]
  49. Pereira, E.W.M.; Heimfarth, L.; Santos, T.K.B.; Passos, F.R.S.; Siqueira-Lima, P.; Scotti, L.; Scotti, M.T.; da Silva Almeida, J.R.G.; Campos, A.R.; Coutinho, H.D.M.; et al. Limonene, a citrus monoterpene, non-complexed and complexed with hydroxypropyl-β-cyclodextrin attenuates acute and chronic orofacial nociception in rodents: Evidence for involvement of the PKA and PKC pathway. Phytomedicine 2021, 96, 153893. [Google Scholar] [CrossRef]
  50. Estrella, G.-R.A.; Eva, G.-T.M.; Alberto, H.-L.; Guadalupe, V.-D.M.; Azucena, C.-V.; Sandra, O.-S.; Noé, A.-V.; Javier, L.-M.F. Limonene from Agastache mexicana essential oil produces antinociceptive effects, gastrointestinal protection and improves experimental ulcerative colitis. J. Ethnopharmacol. 2021, 280, 114462. [Google Scholar] [CrossRef]
  51. Hilfiger, L.; Triaux, Z.; Marcic, C.; Héberlé, E.; Emhemmed, F.; Darbon, P.; Marchioni, E.; Petitjean, H.; Charlet, A. Anti-Hyperalgesic Properties of Menthol and Pulegone. Front. Pharmacol. 2021, 12, 753873. [Google Scholar] [CrossRef]
  52. Santos, P.L.; Rabelo, T.K.; Matos, J.P.S.C.F.; Anjos, K.S.; Melo, M.A.O.; Carvalho, Y.M.B.G.; Lima, B.S.; Menezes, P.P.; Araújo, A.A.S.; Picot, L.; et al. Involvement of nuclear factor κB and descending pain pathways in the anti-hyperalgesic effect of β-citronellol, a food ingredient, complexed in β-cyclodextrin in a model of complex regional pain syndrome—Type 1. Food Chem. Toxicol. 2021, 153, 112260. [Google Scholar] [CrossRef]
  53. Sheikholeslami, M.A.; Ghafghazi, S.; Parvardeh, S.; Koohsari, S.; Aghajani, S.H.; Pouriran, R.; Vaezi, L.A. Analgesic effects of cuminic alcohol (4-isopropylbenzyl alcohol), a monocyclic terpenoid, in animal models of nociceptive and neuropathic pain: Role of opioid receptors, L-arginine/NO/cGMP pathway, and inflammatory cytokines. Eur. J. Pharmacol. 2021, 900, 174075. [Google Scholar] [CrossRef] [PubMed]
  54. Zhang, Y.-L.; Liu, Y.-G.; Li, Q.; Wang, X.-D.; Zheng, X.-B.; Yang, B.-L.; Wan, B.; Ma, J.-M.; Liu, Z.-X. 1,8-cineole decreases neuropathic pain probably via a mechanism mediating P2X3 receptor in the dorsal root ganglion. Neurochem. Int. 2018, 121, 69–74. [Google Scholar] [CrossRef] [PubMed]
  55. Araruna, M.E.; Serafim, C.; Alves Júnior, E.; Hiruma-Lima, C.; Diniz, M.; Batista, L. Intestinal Anti-Inflammatory Activity of Terpenes in Experimental Models (2010–2020): A Review. Molecules 2020, 25, 5430. [Google Scholar] [CrossRef] [PubMed]
  56. Samaila, D.; Toy, B.J.; Wang, R.C.; Elegbede, J.A. Monoterpenes enchanced the sensitivity of head and neck cancer cells to radiation treatment in vitro. Anticancer Res. 2004, 24, 3089–3095. [Google Scholar] [PubMed]
  57. Wojtunik-Kulesza, K.A. Toxicity of Selected Monoterpenes and Essential Oils Rich in These Compounds. Molecules 2022, 27, 1716. [Google Scholar] [CrossRef] [PubMed]
  58. Silva-Correa, C.R.; Campos-Reyna, J.L.; Villarreal-La Torre, V.E.; Calderón-Peña, A.A.; Sagastegui-Guarniz, W.A.; Guerrero-Espino, L.M.; Gonzalez-Siccha, A.D.; Aspajo-Villalaz, C.L.; González-Blas, M.V.; Cruzado-Razco, J.L.; et al. Potential Neuroprotective Activity of Essential Oils in Memory and Learning Impairment. Pharmacogn. J. 2021, 13, 1312–1322. [Google Scholar] [CrossRef]
  59. Fang, F.; Li, H.; Qin, T.; Li, M.; Ma, S. Thymol improves high-fat diet-induced cognitive deficits in mice via ameliorating brain insulin resistance and upregulating NRF2/HO-1 pathway. Metab. Brain Dis. 2017, 32, 385–393. [Google Scholar] [CrossRef]
  60. Deng, W.; Lu, H.; Teng, J. Carvacrol Attenuates Diabetes-Associated Cognitive Deficits in Rats. J. Mol. Neurosci. 2013, 51, 813–819. [Google Scholar] [CrossRef]
  61. Miyazawa, M.; Yamafuji, C. Inhibition of Acetylcholinesterase Activity by Bicyclic Monoterpenoids. J. Agric. Food Chem. 2005, 53, 1765–1768. [Google Scholar] [CrossRef]
  62. Rekha, K.R.; Selvakumar, G.P.; Santha, K.; Sivakamasundari, R.I. Geraniol attenuates α-synuclein expression and neuromuscular impairment through increase dopamine content in MPTP intoxicated mice by dose dependent manner. Biochem. Biophys. Res. Commun. 2013, 440, 664–670. [Google Scholar] [CrossRef]
  63. Rekha, K.R.; Selvakumar, G.P. Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson’s disease. Chem. Biol. Interact. 2014, 217, 57–66. [Google Scholar] [CrossRef] [PubMed]
  64. Ardashov, O.V.; Pavlova, A.V.; Il’ina, I.V.; Morozova, E.A.; Korchagina, D.V.; Karpova, E.V.; Volcho, K.P.; Tolstikova, T.G.; Salakhutdinov, N.F. Highly Potent Activity of (1R,2R,6S)-3-Methyl-6-(prop-1-en-2-yl)cyclohex-3-ene-1,2-diol in Animal Models of Parkinson’s Disease. J. Med. Chem. 2011, 54, 3866–3874. [Google Scholar] [CrossRef] [PubMed]
  65. Pavlova, A.; Il’ina, I.; Morozova, E.; Korchagina, D.; Kurbakova, S.; Sorokina, I.; Tolstikova, T.; Volcho, K.; Salakhutdinov, N. Potent Neuroprotective Activity of Monoterpene Derived 4-[(3aR,7aS)-1,3,3a,4,5,7a-Hexahydro-3,3,6-trimethylisobenzofuran-1-yl]-2-methoxyphenol in MPTP Mice Model. Lett. Drug Des. Discov. 2014, 11, 611–617. [Google Scholar] [CrossRef]
  66. Kotliarova, A.; Podturkina, A.V.; Pavlova, A.V.; Gorina, D.S.; Lastovka, A.V.; Ardashov, O.V.; Rogachev, A.D.; Izyurov, A.E.; Arefieva, A.B.; Kulikov, A.V.; et al. A Newly Identified Monoterpenoid-Based Small Molecule Able to Support the Survival of Primary Cultured Dopamine Neurons and Alleviate MPTP-Induced Toxicity In Vivo. Molecules 2022, 27, 8286. [Google Scholar] [CrossRef] [PubMed]
  67. Aleksandrova, Y.; Chaprov, K.; Podturkina, A.; Ardashov, O.; Yandulova, E.; Volcho, K.; Salakhutdinov, N.; Neganova, M. Monoterpenoid Epoxidiol Ameliorates the Pathological Phenotypes of the Rotenone-Induced Parkinson’s Disease Model by Alleviating Mitochondrial Dysfunction. Int. J. Mol. Sci. 2023, 24, 5842. [Google Scholar] [CrossRef]
  68. Lee, M.; Lee, S.H.; Choi, S.; Choi, B.Y.; Suh, S.W. Carvacrol Inhibits Expression of Transient Receptor Potential Melastatin 7 Channels and Alleviates Zinc Neurotoxicity Induced by Traumatic Brain Injury. Int. J. Mol. Sci. 2022, 23, 13840. [Google Scholar] [CrossRef]
  69. Rajaei, Z.; Amooheydari, Z.; Alaei, H.; Esmaeil, N. Supplementation of carvacrol attenuates hippocampal tumor necrosis factor-alpha level, oxidative stress, and learning and memory dysfunction in lipopolysaccharide-exposed rats. Adv. Biomed. Res. 2022, 11, 33. [Google Scholar] [CrossRef]
  70. Javed, H.; Fizur, N.M.M.; Jha, N.K.; Ashraf, G.M.; Ojha, S. Neuroprotective Potential and Underlying Pharmacological Mechanism of Carvacrol for Alzheimer’s and Parkinson’s Diseases. Curr. Neuropharmacol. 2023, 21, 1421–1432. [Google Scholar] [CrossRef]
  71. Eddin, L.B.; Jha, N.K.; Meeran, M.F.N.; Kesari, K.K.; Beiram, R.; Ojha, S. Neuroprotective Potential of Limonene and Limonene Containing Natural Products. Molecules 2021, 26, 4535. [Google Scholar] [CrossRef]
  72. Piccialli, I.; Tedeschi, V.; Caputo, L.; Amato, G.; De Martino, L.; De Feo, V.; Secondo, A.; Pannaccione, A. The Antioxidant Activity of Limonene Counteracts Neurotoxicity Triggered byAβ1–42 Oligomers in Primary Cortical Neurons. Antioxidants 2021, 10, 937. [Google Scholar] [CrossRef]
  73. Eddin, L.B.; Azimullah, S.; Jha, N.K.; Nagoor Meeran, M.F.; Beiram, R.; Ojha, S. Limonene, a Monoterpene, Mitigates Rotenone-Induced Dopaminergic Neurodegeneration by Modulating Neuroinflammation, Hippo Signaling and Apoptosis in Rats. Int. J. Mol. Sci. 2023, 24, 5222. [Google Scholar] [CrossRef] [PubMed]
  74. Bagheri, S.; Rashno, M.; Salehi, I.; Karimi, S.A.; Raoufi, S.; Komaki, A. Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer’s disease. Eur. J. Pharmacol. 2023, 951, 175714. [Google Scholar] [CrossRef] [PubMed]
  75. Buch, P.; Sharma, T.; Airao, V.; Vaishnav, D.; Mani, S.; Rachamalla, M.; Gupta, A.K.; Upadhye, V.; Jha, S.K.; Jha, N.K.; et al. Geraniol protects hippocampal CA1 neurons and improves functional outcomes in global model of stroke in rats. Chem. Biol. Drug Des. 2023, 102, 523–535. [Google Scholar] [CrossRef] [PubMed]
  76. Jayaraj, R.L.; Azimullah, S.; Parekh, K.A.; Ojha, S.K.; Beiram, R. Effect of citronellol on oxidative stress, neuroinflammation and autophagy pathways in an in vivo model of Parkinson’s disease. Heliyon 2022, 8, e11434. [Google Scholar] [CrossRef]
  77. Faheem, M.; Khan, A.-U.; Saleem, M.W.; Shah, F.A.; Ali, F.; Khan, A.W.; Li, S. Neuroprotective Effect of Natural Compounds in Paclitaxel-Induced Chronic Inflammatory Pain. Molecules 2022, 27, 4926. [Google Scholar] [CrossRef]
  78. An, F.; Bai, Y.; Xuan, X.; Bian, M.; Zhang, G.; Wei, C. 1,8-Cineole Ameliorates Advanced Glycation End Products-Induced Alzheimer’s Disease-like Pathology In Vitro and In Vivo. Molecules 2022, 27, 3913. [Google Scholar] [CrossRef]
  79. Wang, L.; An, H.; Yu, F.; Yang, J.; Ding, H.; Bao, Y.; Xie, H.; Huang, D. The neuroprotective effects of paeoniflorin against MPP+-induced damage to dopaminergic neurons via the Akt/Nrf2/GPX4 pathway. J. Chem. Neuroanat. 2022, 122, 102103. [Google Scholar] [CrossRef]
  80. Khan-Mohammadi-Khorrami, M.-K.; Asle-Rousta, M.; Rahnema, M.; Amini, R.J. Neuroprotective effect of alpha-pinene is mediated by suppression of the TNF-α/NF-κB pathway in Alzheimer’s disease rat model. J. Biochem. Mol. Toxicol. 2022, 36, e23006. [Google Scholar] [CrossRef]
  81. de Lucena, J.D.; Gadelha-Filho, C.V.J.; da Costa, R.O.; de Araújo, D.P.; Lima, F.A.V.; Neves, K.R.T.; de Barros Viana, G.S. L-linalool exerts a neuroprotective action on hemiparkinsonian rats. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2020, 393, 1077–1088. [Google Scholar] [CrossRef]
  82. Guzmán-Gutiérrez, S.L.; Gómez-Cansino, R.; García-Zebadúa, J.C.; Jiménez-Pérez, N.C.; Reyes-Chilpa, R. Antidepressant activity of Litsea glaucescens essential oil: Identification of β-pinene and linalool as active principles. J. Ethnopharmacol. 2012, 143, 673–679. [Google Scholar] [CrossRef]
  83. Deng, X.-Y.; Li, H.-Y.; Chen, J.-J.; Li, R.-P.; Qu, R.; Fu, Q.; Ma, S.-P. Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice. Behav. Brain Res. 2015, 291, 12–19. [Google Scholar] [CrossRef] [PubMed]
  84. Leu, R. Exploring the Role of Cannabidiol-Monoterpene Formulations in Modulating Anxiety Symptoms. Ph.D. Thesis, The University of Western Ontario, London, ON, Canada, 2020. [Google Scholar]
  85. De Sousa, D.P.; Soares Hocayen, P.D.A.; Andrade, L.N.; Andreatini, R. A Systematic Review of the Anxiolytic-Like Effects of Essential Oils in Animal Models. Molecules 2015, 20, 18620–18660. [Google Scholar] [CrossRef] [PubMed]
  86. Shi, Y.-H.; Zhu, S.; Ge, Y.-W.; He, Y.-M.; Kazuma, K.; Wang, Z.; Yoshimatsu, K.; Komatsu, K. Monoterpene derivatives with anti-allergic activity from red peony root, the root of Paeonia lactiflora. Fitoterapia 2016, 108, 55–61. [Google Scholar] [CrossRef] [PubMed]
  87. Salakhutdinov, N.F.; Volcho, K.P.; Yarovaya, O.I. Monoterpenes as a renewable source of biologically active compounds. Pure Appl. Chem. 2017, 89, 1105–1117. [Google Scholar] [CrossRef]
  88. Kapitsa, I.G.; Suslov, E.V.; Teplov, G.V.; Korchagina, D.V.; Komarova, N.I.; Volcho, K.P.; Voronina, T.A.; Shevela, A.I.; Salakhutdinov, N.F. Synthesis and anxiolytic activity of 2-aminoadamantane derivatives containing monoterpene fragments. Pharm. Chem. J. 2012, 46, 263–265. [Google Scholar] [CrossRef]
  89. Zielińska-Błajet, M.; Feder-Kubis, J. Monoterpenes and Their Derivatives—Recent Development in Biological and Medical Applications. Int. J. Mol. Sci. 2020, 21, 7078. [Google Scholar] [CrossRef]
  90. Silva, E.A.P.; Santos, D.M.; de Carvalho, F.O.; Menezes, I.A.C.; Barreto, A.S.; Souza, D.S.; Quintans-Júnior, L.J.; Santos, M.R.V. Monoterpenes and their derivatives as agents for cardiovascular disease management: A systematic review and meta-analysis. Phytomedicine 2021, 88, 153451. [Google Scholar] [CrossRef]
  91. Bergman, M.E.; Franks, A.E.; Phillips, M.A. Biosynthesis, natural distribution, and biological activities of acyclic monoterpenes and their derivatives. Phytochem. Rev. 2023, 22, 361–384. [Google Scholar] [CrossRef]
  92. Khomenko, T.M.; Zarubaev, V.V.; Orshanskaya, I.R.; Kadyrova, R.A.; Sannikova, V.A.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F. Anti-influenza activity of monoterpene-containing substituted coumarins. Bioorg. Med. Chem. Lett. 2017, 27, 2920–2925. [Google Scholar] [CrossRef]
  93. Khomenko, T.M.; Shtro, A.A.; Galochkina, A.V.; Nikolaeva, Y.V.; Garshinina, A.V.; Borisevich, S.S.; Korchagina, D.V.; Volcho, K.P.; Salakhutdinov, N.F. New Inhibitors of Respiratory Syncytial Virus (RSV) Replication Based on Monoterpene-Substituted Arylcoumarins. Molecules 2023, 28, 2673. [Google Scholar] [CrossRef]
  94. Khomenko, T.M.; Zakharenko, A.L.; Chepanova, A.A.; Ilina, E.S.; Zakharova, O.D.; Kaledin, V.I.; Nikolin, V.P.; Popova, N.A.; Korchagina, D.V.; Reynisson, J.; et al. Promising New Inhibitors of Tyrosyl-DNA Phosphodiesterase I (Tdp 1) Combining 4-Arylcoumarin and Monoterpenoid Moieties as Components of Complex Antitumor Therapy. Int. J. Mol. Sci. 2020, 21, 126. [Google Scholar] [CrossRef] [PubMed]
  95. Khomenko, T.M.; Zakharenko, A.L.; Kornienko, T.E.; Chepanova, A.A.; Dyrkheeva, N.S.; Artemova, A.O.; Korchagina, D.V.; Achara, C.; Curtis, A.; Reynisson, J.; et al. New 5-Hydroxycoumarin-Based Tyrosyl-DNA Phosphodiesterase I Inhibitors Sensitize Tumor Cell Line to Topotecan. Int. J. Mol. Sci. 2023, 24, 9155. [Google Scholar] [CrossRef] [PubMed]
  96. Munkuev, A.A.; Dyrkheeva, N.S.; Kornienko, T.E.; Ilina, E.S.; Ivankin, D.I.; Suslov, E.V.; Korchagina, D.V.; Gatilov, Y.V.; Zakharenko, A.L.; Malakhova, A.A.; et al. Adamantane-Monoterpenoid Conjugates Linked via Heterocyclic Linkers Enhance the Cytotoxic Effect of Topotecan. Molecules 2022, 27, 3374. [Google Scholar] [CrossRef]
  97. Ivankin, D.I.; Kornienko, T.E.; Mikhailova, M.A.; Dyrkheeva, N.S.; Zakharenko, A.L.; Achara, C.; Reynisson, J.; Golyshev, V.M.; Luzina, O.A.; Volcho, K.P.; et al. Novel TDP1 Inhibitors: Disubstituted Thiazolidine-2,4-Diones Containing Monoterpene Moieties. Int. J. Mol. Sci. 2023, 24, 3834. [Google Scholar] [CrossRef]
  98. Cardoso, D.S.P.; Kincses, A.; Nové, M.; Spengler, G.; Mulhovo, S.; Aires-De-Sousa, J.; dos Santos, D.J.V.A.; Ferreira, M.-U. Alkylated monoterpene indole alkaloid derivatives as potent P-glycoprotein inhibitors in resistant cancer cells. Eur. J. Med. Chem. 2021, 210, 112985. [Google Scholar] [CrossRef] [PubMed]
  99. Paterna, A.; Borralho, P.M.; Gomes, S.E.; Mulhovo, S.; Rodrigues, C.M.; Ferreira, M.-J.U. Monoterpene indole alkaloid hydrazone derivatives with apoptosis inducing activity in human HCT116 colon and HepG2 liver carcinoma cells. Bioorg. Med. Chem. Lett. 2015, 25, 3556–3559. [Google Scholar] [CrossRef] [PubMed]
  100. Hardie, J.; Isaacs, R.; Pickett, J.A.; Wadhams, L.J.; Woodcock, C.M. Methyl salicylate and (−)-(1R,5S)-myrtenal are plant-derived repellents for black bean aphid, Aphis fabae Scop. (Homoptera: Aphididae). J. Chem. Ecol. 1994, 20, 2847–2855. [Google Scholar] [CrossRef]
  101. Negoi, A.; Parvulescu, V.I.; Tudorache, M. Peroxidase-based biocatalysis in a two-phase system for allylic oxidation of α-pinene. Catal. Today 2017, 306, 199–206. [Google Scholar] [CrossRef]
  102. Ishida, T.; Toyota, M.; Asakawa, Y. Terpenoid biotransformation in mammals. V. Metabolism of (+)-citronellal, (±)-7-hydroxycitronellal, citral, (−)-perillaldehyde, (−)-myrtenal, cuminaldehyde, thujone, and (±)-carvone in rabbits. Xenobiotica 1989, 19, 843–855. [Google Scholar] [CrossRef]
  103. Scheline, R. Handbook of Mammalian Metabolism of Plant Compounds; CRC Press: Boca Raton, FL, USA, 1991; 522p, Available online: https://books.google.bg/books?id=LwZDDwAAQBAJ&printsec=frontcover&hl=bg#v=onepage&q&f=false (accessed on 4 June 2019).
  104. EFSA FAF Panel (EFSA Panel on Food Additives and Flavourings); Younes, M.; Aquilina, G.; Castle, L.; Engel, K.-H.; Fowler, P.; Frutos Fernandez, M.J.; Fürst, P.; Gürtler, R.; Gundert-Remy, U.; et al. Scientific Opinion on Flavouring Group Evaluation 208 Revision 3 (FGE.208Rev3): Consideration of genotoxicity data on alicyclic aldehydes with α,β-unsaturation in ring/side-chain and precursors from chemical subgroup 2.2 of FGE.19. EFSA J. 2019, 17, 5569. [Google Scholar] [CrossRef]
  105. Dragomanova, S.; Tancheva, L.; Georgieva, M. A review: Biological activity of myrtenal and some myrtenal-containing medicinal plant essential oils. Scr. Sci. Pharm. 2018, 31, 22–33. [Google Scholar] [CrossRef]
  106. Radulović, N.S.; Randjelović, P.J.; Stojanović, N.M.; Blagojević, P.D.; Stojanović-Radić, Z.Z.; Ilić, I.R.; Djordjević, V.B. Toxic essential oils. Part II: Chemical, toxicological, pharmacological and microbiological profiles of Artemisia annua L. volatiles. Food Chem. Toxicol. 2013, 58, 37–49. [Google Scholar] [CrossRef] [PubMed]
  107. Pino, J.A.; Rosado, A.; Fuentes, V. Chemical Composition of the Seed Oil ofCoriandrum sativum L. from Cuba. J. Essent. Oil Res. 1996, 8, 97–98. [Google Scholar] [CrossRef]
  108. Hajlaoui, H.; Mighri, H.; Noumi, E.; Snoussi, M.; Trabelsi, N.; Ksouri, R.; Bakhrouf, A. Chemical composition and biological activities of Tunisian Cuminum cyminum L. essential oil: A high effectiveness against Vibrio spp. strains. Food Chem. Toxicol. 2010, 48, 2186–2192. [Google Scholar] [CrossRef] [PubMed]
  109. Moraghebi, F. Introduction of myrtenal as an indicator component in essential oil of Cuminum cyminum Isfahan variety. JBES 2013, 3, 112–117. Available online: https://api.semanticscholar.org/CorpusID:55592393 (accessed on 10 April 2018).
  110. Wong, K.; Chong, T.; Chee, S. Essential oil of Curcuma manga Val. and van Zijp rhizomes. J. Essent. Oil Res. 1999, 11, 349–351. [Google Scholar] [CrossRef]
  111. Blake, S. Medicinal Plant Constituents. LifeLong Press www.NaturalHealthWizards.com, 2004. Copyright 2004 Steve Blake. Available online: https://drsteveblake.com/MedicinalPlantsConstituentSample.pdf (accessed on 10 April 2018).
  112. Etievant, P.X.; Azar, M.; Pham-Delegue, M.H.; Masson, C.J. Isolation and identification of volatile constituents of sunflowers (Helianthus annuus L.). J. Agric. Food Chem. 1984, 32, 503–509. [Google Scholar] [CrossRef]
  113. Kizil, S.; Haşimi, N.; Tolan, V.; Kilinç, E.; Karataş, H. Chemical composition, antimicrobial and antioxidant activities of Hyssop (Hyssopus officinalis, L.) essential oil. Not. Bot. Hort. Agrobot. 2010, 38, 99–103. [Google Scholar] [CrossRef]
  114. Rather, M.A.; Dar, B.A.; Dar, M.Y.; Wani, B.A.; Shah, W.A.; Bhat, B.A.; Ganai, B.A.; Bhat, K.A.; Anand, R.; Qurishi, M.A. Chemical composition, antioxidant and antibacterial activities of the leaf essential oil of Juglans regia L. and its constituents. Phytomedicine 2012, 19, 1185–1190. [Google Scholar] [CrossRef]
  115. Smigielski, K.; Raj, A.; Krosowiak, K.; Gruska, R. Chemical Composition of the Essential Oil of Lavandula angustifolia Cultivated in Poland. J. Essent. Oil Bear. Plants 2009, 12, 338–347. [Google Scholar] [CrossRef]
  116. Tattje, D.H.E.; Bos, R. Composition of Essential Oil of Ledum palustre. Planta Medica 1981, 41, 303–307. [Google Scholar] [CrossRef] [PubMed]
  117. Gardeli, C.; Vassiliki, P.; Athanasios, M.; Kibouris, T.; Komaitis, M. Essential oil composition of Pistacia lentiscus L. and Myrtus communis L.: Evaluation of antioxidant capacity of methanolic extracts. Food Chem. 2008, 107, 1120–1130. [Google Scholar] [CrossRef]
  118. De Falco, E.; Mancini, E.; Roscigno, G.; Mignola, E.; Taglialatela-Scafati, O.; Senatore, F. Chemical Composition and Biological Activity of Essential Oils of Origanum vulgare L. subsp. vulgare L. under Different Growth Conditions. Molecules 2013, 18, 14948–14960. [Google Scholar] [CrossRef] [PubMed]
  119. Esin, H.K.E.; Demirci, B.; Uzel, A.; Demirci, F. Volatile composition of Anatolian propolis by headspace-solid-phase microextraction (HS-SPME), antimicrobial activity against food contaminants and antioxidant activity. J. Med. Plants Res. 2013, 7, 2140–2149. [Google Scholar] [CrossRef]
  120. El Ghadraoui, L.; Essakhi, D.; Benjelloun, M.; Errabhi, N.; El Harchli, E.H.; Alaoui, M.M.; Petit, D. Chemical Composition of Essential Oils from Rosmarinus officinalis L. and Acridicide Activity on Dociostaurus maroccanus Thunberg, 1815 in Morocco. IJSER 2015, 6, 166–171. [Google Scholar]
  121. Salgueiro, L.R.; Vila, R.; Tomàs, X.; Cañigueral, S.; Paiva, J.; da Cunha, A.P.; Adzet, T. Essential oil composition and variability of Thymus lotocephalus and Thymus × mourae. Biochem. Syst. Ecol. 2000, 28, 457–470. [Google Scholar] [CrossRef]
  122. Vegezzi, D. United States Patent 1980. Available online: http://www.google.fr/patents/US4190675?hl=fr&dq=myrt%C3%A9nal#v=onepage&q&f=false (accessed on 11 November 2017).
  123. Saito, K.; Okabe, T.; Inamori, Y.; Tsujibo, H.; Miyake, Y.; Hiraoka, K.; Ishida, N. The biological properties of monoterpenes: Hypotensive effects on rats and antifungal activities on plant pathogenic fungi of monoterpenes. Mokuzai Gakkaishi 1996, 42, 677–680. [Google Scholar]
  124. Santos, M.R.V.; Moreira, F.V.; Fraga, B.P.; de Souza, D.P.; Bonjardim, L.R.; Quintans-Junior, L.J. Cardiovascular effects of monoterpenes: A review. Rev. Bras. Farm. 2011, 21, 764–771. [Google Scholar] [CrossRef]
  125. Rathinam, A.; Pari, L. Myrtenal ameliorates hyperglycemia by enhancing GLUT2 through Akt in the skeletal muscle and liver of diabetic rats. Chem. Biol. Interact. 2016, 256, 161–166. [Google Scholar] [CrossRef]
  126. Babu, H.L.; Perumal, S.; Balasubramanian, M.P. Myrtenal, a natural monoterpene, down-regulates TNF-α expression and suppresses carcinogen-induced hepatocellular carcinoma in rats. Mol. Cell. Biochem. 2012, 369, 183–193. [Google Scholar] [CrossRef]
  127. Babu, L.H.; Perumal, S.; Balasubramanian, M.P. Myrtenal attenuates diethylnitrosamine-induced hepatocellular carcinoma in rats by stabilizing intrinsic antioxidants and modulating apoptotic and anti-apoptotic cascades. Cell. Oncol. 2012, 35, 269–283. [Google Scholar] [CrossRef] [PubMed]
  128. Babu, L.H.; Natarajan, N.; Thamaraiselvan, R.; Srinivasan, P.; Periyasamy, B.M. Myrtenal ameliorates diethylnitrosamine-induced hepatocarcinogenesis through the activation of tumor suppressor protein p53 and regulation of lysosomal and mitochondrial enzymes. Fundam. Clin. Pharmacol. 2013, 27, 443–454. [Google Scholar] [CrossRef]
  129. Venkatachalam, S.; Boobathi, L.; Balasubramanian, M.P. Salubrious therapeutic efficacy of myrtenal on colon carcinoma induced by 1,2-dimethyl-hydrazine studied in experimental albino rats. Res. J. Pharmacol. Pharmacodyn. 2014, 6, 146–152. Available online: https://rjppd.org/AbstractView.aspx?PID=2014-6-3-17 (accessed on 30 October 2018).
  130. Martins, B.X.; Arruda, R.F.; Costa, G.A.; Jerdy, H.; de Souza, S.B.; Santos, J.M.; de Freitas, W.R.; Kanashiro, M.M.; de Carvalho, E.C.Q.; Sant’Anna, N.F.; et al. Myrtenal-induced V-ATPase inhibition—A toxicity mechanism behind tumor cell death and suppressed migration and invasion in melanoma. BBA-Gen. Subj. 2019, 1863, 1–12. [Google Scholar] [CrossRef] [PubMed]
  131. Lokeshkumar, B.; Sathishkumar, V.; Nandakumar, N.; Rengarajan, T.; Madankumar, A.; Balasubramanian, M.P. Anti-Oxidative Effect of Myrtenal in Prevention and Treatment of Colon Cancer Induced by 1, 2-Dimethyl Hydrazine (DMH) in Experimental Animals. Biomol. Ther. 2015, 23, 471–478. [Google Scholar] [CrossRef]
  132. Lokeshkumar, B.; Sathishkumar, V.; Nandakumar, N.; Rengarajan, T.; Madankumar, A.; Balasubramanian, M.P. Chemopreventive effect of myrtenal on bacterial enzyme activity and the development of 1,2-dimethyl hydrazine-induced aberrant crypt foci in Wistar Rats. J. Food Drug Anal. 2016, 24, 206–213. [Google Scholar] [CrossRef]
  133. Trytek, M.; Paduch, R.; Pięt, M.; Kozieł, A.; Kandefer-Szerszeń, M.; Szajnecki, Ł.; Gromada, A. Biological activity of oxygenated pinene derivatives on human colon normal and carcinoma cells. Flavour Fragr. J. 2018, 33, 428–437. [Google Scholar] [CrossRef]
  134. Dragomanova, S. Pharmacological, Toxicological and Neurobiological Studies of Myrtenal—A Bicyclic Monoterpenoid of Natural Origin. Ph.D. Thesis, Institute of Neurobiology at Bulgarian Academy of Sciences, Sofia, Bulgaria, 2020. Available online: https://ras.nacid.bg/api/reg/FilesStorage?key=6b37588e-6c9b-4708-bb22-e5872dca6bd3&mimeType=application/pdf&fileName=Authoreferate%20S%20Dragomanova.pdf&dbId=1 (accessed on 15 September 2020).
  135. Guimarães, A.G.; Quintans, J.S.; Quintans-Júnior, L.J. Monoterpenes with Analgesic Activity—A Systematic Review. Phytother. Res. 2013, 27, 1–15. [Google Scholar] [CrossRef]
  136. Silva, R.O.; Salvadori, M.S.; Sousa, F.B.M.; Santos, M.S.; Carvalho, N.S.; Sousa, D.P.; Gomes, B.S.; Oliveira, F.A.; Barbosa, A.L.R.; Freitas, R.M.; et al. Evaluation of the anti-inflammatory and antinociceptive effects of myrtenol, a plant-derived monoterpene alcohol, in mice. Flavour Fragr. J. 2014, 29, 184–192. [Google Scholar] [CrossRef]
  137. Hosseinzadeh, H.; Khoshdel, M.; Ghorbani, M. Antinociceptive, Anti-inflammatory Effects and Acute Toxicity of Aqueous and Ethanolic Extracts of Myrtus communis L. Aerial Parts in Mice. J. Acupunct. Meridian Stud. 2011, 4, 242–247. [Google Scholar] [CrossRef]
  138. Li, W.-X.; Qian, P.; Guo, Y.-T.; Gu, L.; Jurat, J.; Bai, Y.; Zhang, D.-F. Myrtenal and β-caryophyllene oxide screened from Liquidambaris Fructus suppress NLRP3 inflammasome components in rheumatoid arthritis. BMC Complement. Med. Ther. 2021, 21, 242. [Google Scholar] [CrossRef] [PubMed]
  139. Hailu, E.; Engidawork, E.; Asres, K. Essential Oil of Myrtus communis L. Produces a Non-Sedating Anxiolytic Effect in Mice Models of Anxiety. Ethiop. Pharm. J. 2011, 29, 1–12. [Google Scholar] [CrossRef]
  140. Akefe, I.; Nyan, E.; Adegoke, V.; Lamidi, I.; Ameh, M.; Chidiebere, U.; Ubah, S.; Ajayi, I. Myrtenal improves memory deficits in mice exposed to radiofrequency-electromagnetic radiation during gestational and neonatal development via enhancing oxido-inflammatory, and neurotransmitter functions. Heliyon 2023, 9, e15321. [Google Scholar] [CrossRef] [PubMed]
  141. Tancheva, L.P.; Lazarova, M.I.; Alexandrova, A.V.; Dragomanova, S.T.; Nicoletti, F.; Tzvetanova, E.R.; Hodzhev, Y.K.; Kalfin, R.E.; Miteva, S.A.; Mazzon, E.; et al. Neuroprotective Mechanisms of Three Natural Antioxidants on a Rat Model of Parkinson’s Disease: A Comparative Study. Antioxidants 2020, 9, 49. [Google Scholar] [CrossRef]
  142. Dragomanova, S.; Pavlov, S.; Marinova, D.; Hodzev, Y.; Petralia, M.C.; Fagone, P.; Nicoletti, F.; Lazarova, M.; Tzvetanova, E.; Alexandrova, A.; et al. Neuroprotective Effects of Myrtenal in an Experimental Model of Dementia Induced in Rats. Antioxidants 2022, 11, 374. [Google Scholar] [CrossRef]
  143. Kaufmann, D.; Dogra, A.K.; Wink, M. Myrtenal inhibits acetylcholinesterase, a known Alzheimer target. J. Pharm. Pharmacol. 2011, 63, 1368–1371. [Google Scholar] [CrossRef]
  144. Concepción, O.; Belmar, J.F.; de la Torre, A.; Muñiz, F.M.; Pertino, M.W.; Alarcón, B.; Ormazabal, V.; Nova-Lamperti, E.; Zúñiga, F.A.; Jiménez, C.A. Synthesis and Cytotoxic Analysis of Novel Myrtenyl Grafted Pseudo-Peptides Revealed Potential Candidates for Anticancer Therapy. Molecules 2020, 25, 1911. [Google Scholar] [CrossRef]
  145. Garberová, M.; Potočňák, I.; Tvrdoňová, M.; Bago-Pilátová, M.; Bekešová, S.; Kudličková, Z.; Samoľová, E.; Kešeľáková, A.; Elečko, J.; Vilková, M. Spectral, structural, and pharmacological studies of perillaldehyde and myrtenal based benzohydrazides. J. Mol. Struct. 2023, 1271, 134112. [Google Scholar] [CrossRef]
  146. Koziol, A.; Stryjewska, A.; Librowski, T.; Salat, K.; Gawel, M.; Moniczewski, A.; Lochynski, S. An Overview of the Pharmacological Properties and Potential Applications of Natural Monoterpenes. Mini-Reviews Med. Chem. 2014, 14, 1156–1168. [Google Scholar] [CrossRef]
  147. Barreto, R.S.S.; Albuquerque-Júnior, R.L.C.; Araújo, A.A.S.; Almeida, J.R.G.S.; Santos, M.R.V.; Barreto, A.S.; DeSantana, J.M.; Siqueira-Lima, P.S.; Quintans, J.S.S.; Quintans-Júnior, L.J. A Systematic Review of the Wound-Healing Effects of Monoterpenes and Iridoid Derivatives. Molecules 2014, 19, 846–862. [Google Scholar] [CrossRef]
  148. Marchese, A.; Orhan, I.E.; Daglia, M.; Barbieri, R.; Di Lorenzo, A.; Nabavi, S.F.; Gortzi, O.; Izadi, M.; Nabavi, S.M. Antibacterial and antifungal activities of thymol: A brief review of the literature. Food Chem. 2016, 210, 402–414. [Google Scholar] [CrossRef]
  149. Wojtunik-Kulesza, K.A.; Kasprzak, K.; Oniszczuk, T.; Oniszczuk, A. Natural Monoterpenes: Much More than Only a Scent. Chem. Biodivers. 2019, 16, e1900434. [Google Scholar] [CrossRef] [PubMed]
  150. Dheer, D.; Singh, D.; Kumar, G.; Karnatak, M.; Chandra, S.; Prakash Verma, V.; Shankar, R. Thymol Chemistry: A Medicinal Toolbox. Curr. Bioact. Compd. 2019, 15, 454–474. [Google Scholar] [CrossRef]
  151. Stephane, F.F.Y.; Jean Jules, B.K. Terpenoids as Important Bioactive Constituents of Essential Oils [Internet]. In Essential Oils—Bioactive Compounds, New Perspectives and Applications; IntechOpen: London, UK, 2020. [Google Scholar] [CrossRef]
  152. Coêlho, M.L.; Islam, M.T.; da Silva Oliveira, G.L.; de Alencar, M.V.O.B.; de Oliveira Santos, J.V.; dos Reis, A.C.; da Mata, A.M.O.F.; Paz, M.F.C.J.; Docea, A.O.; Calina, D.; et al. Cytotoxic and Antioxidant Properties of Natural Bioactive Monoterpenes Nerol, Estragole, and 3,7-Dimethyl-1-Octanol. Adv. Pharmacol. Pharm. Sci. 2022, 2022, 8002766. [Google Scholar] [CrossRef]
  153. Wang, J.; Sintim, H.O. Dialkylamino-2,4-dihydroxybenzoic Acids as Easily Synthesized Analogues of Platensimycin and Platencin with Comparable Antibacterial Properties. Chem. Eur. J. 2011, 17, 3352–3357. [Google Scholar] [CrossRef]
  154. Suslov, E.; Ponomarev, K.; Rogachev, A.; Pokrovsky, M.; Pokrovsky, A.; Pykhtina, M.; Beklemishev, A.; Korchagina, D.; Volcho, K.; Salakhutdinov, N. Compounds Combining Aminoadamantane and Monoterpene Moieties: Cytotoxicity and Mutagenic Effects. Med. Chem. 2015, 11, 629–635. [Google Scholar] [CrossRef]
  155. Ponomarev, K.Y.; Suslov, E.V.; Zakharenko, A.L.; Zakharova, O.D.; Rogachev, A.D.; Korchagina, D.V.; Zafar, A.; Reynisson, J.; Nefedov, A.A.; Volcho, K.P.; et al. Aminoadamantanes containing monoterpene-derived fragments as potent tyrosyl-DNA phosphodiesterase 1 inhibitors. Bioorg. Chem. 2018, 76, 392–399. [Google Scholar] [CrossRef] [PubMed]
  156. Luzina, O.; Filimonov, A.; Zakharenko, A.; Chepanova, A.; Zakharova, O.; Ilina, E.; Dyrkheeva, N.; Likhatskaya, G.; Salakhutdinov, N.; Lavrik, O. Usnic Acid Conjugates with Monoterpenoids as Potent Tyrosyl-DNA Phosphodiesterase 1 Inhibitors. J. Nat. Prod. 2020, 83, 2320–2329. [Google Scholar] [CrossRef]
  157. Gonda, T.; Szakonyi, Z. Stereoselective Synthesis and Application of Bi-and Trifunctional Monoterpene-based Compounds. Ph.D. Thesis, Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary, 2018. Available online: http://doktori.bibl.u-szeged.hu/9832/1/Gonda20Timea20disszertacio.pdf (accessed on 10 July 2023).
  158. Gonda, T.; Bérdi, P.; Zupkó, I.; Fülöp, F.; Szakonyi, Z. Stereoselective Synthesis, Synthetic and Pharmacological Application of Monoterpene-Based 1,2,4- and 1,3,4-Oxadiazoles. Int. J. Mol. Sci. 2017, 19, 81. [Google Scholar] [CrossRef]
  159. Teplov, G.; Suslov, E.; Zarubaev, V.; Shtro, A.; Karpinskaya, L.; Rogachev, A.; Korchagina, D.; Volcho, K.; Salakhutdinov, N.; Kiselev, O. Synthesis of New Compounds Combining Adamantanamine and Monoterpene Fragments and their Antiviral Activity Against Influenza Virus A (H1N1) pdm09. Lett. Drug Des. Discov. 2013, 10, 477–485. [Google Scholar] [CrossRef]
  160. Li-Zhulanov, N.S.; Zaikova, N.P.; Sari, S.; Gülmez, D.; Sabuncuoğlu, S.; Ozadali-Sari, K.; Arikan-Akdagli, S.; Nefedov, A.A.; Rybalova, T.V.; Volcho, K.P.; et al. Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity. Antibiotics 2023, 12, 818. [Google Scholar] [CrossRef] [PubMed]
  161. Ponomarev, K.; Pavlova, A.; Suslov, E.; Ardashov, O.; Korchagina, D.; Nefedov, A.; Tolstikova, T.; Volcho, K.; Salakhutdinov, N. Synthesis and analgesic activity of new compounds combining azaadamantane and monoterpene moieties. Med. Chem. Res. 2015, 24, 4146–4156. [Google Scholar] [CrossRef]
  162. Ponomarev, K.; Morozova, E.; Pavlova, A.; Suslov, E.; Korchagina, D.; Nefedov, A.; Tolstikova, T.; Volcho, K.; Salakhutdinov, N. Synthesis and Analgesic Activity of Amines Combining Diazaadamantane and Monoterpene Fragments. Med. Chem. 2017, 13, 773–779. [Google Scholar] [CrossRef]
  163. Dragomanova, S.; Andonova, V.; Lazarova, M.; Munkuev, A.; Suslov, E.; Volcho, K.; Salakhutdinov, N.; Stefanova, M.; Gavrilova, P.; Uzunova, D.; et al. Memory-improving effects of myrtenal-adamantane conjugates. J. Chem. Technol. Metall. 2023, 58, 627–634. Available online: https://journal.uctm.edu/node/j2023-3/JCTM_2023_58_26_23-11_pp627-634.pdf (accessed on 20 August 2023).
  164. Dragomanova, S.; Lazarova, M.; Munkuev, A.; Suslov, E.; Volcho, K.; Salakhutdinov, N.; Bibi, A.; Reynisson, J.; Tzvetanova, E.; Alexandrova, A.; et al. New Myrtenal–Adamantane Conjugates Alleviate Alzheimer’s-Type Dementia in Rat Model. Molecules 2022, 27, 5456. [Google Scholar] [CrossRef] [PubMed]
Life 13 02086 g001
Figure 1. Some bioactive monoterpenes and monoterpenoids.
Figure 1. Some bioactive monoterpenes and monoterpenoids.
Life 13 02086 g001
Life 13 02086 g002
Figure 2. Some monoterpenoids with antiparkinsonian activity (1–4).
Figure 2. Some monoterpenoids with antiparkinsonian activity (1–4).
Life 13 02086 g002
Life 13 02086 g003
Figure 3. Structure of (−) and (+)-Myrtenal.
Figure 3. Structure of (−) and (+)-Myrtenal.
Life 13 02086 g003
Life 13 02086 g004
Figure 4. Established mechanisms of antidiabetic activity of myrtenal.
Figure 4. Established mechanisms of antidiabetic activity of myrtenal.
Life 13 02086 g004
Life 13 02086 g005
Figure 5. Established mechanisms of antitumor activity of myrtenal.
Figure 5. Established mechanisms of antitumor activity of myrtenal.
Life 13 02086 g005
Life 13 02086 g006
Figure 6. Established mechanisms of neuroprotective activity of myrtenal.
Figure 6. Established mechanisms of neuroprotective activity of myrtenal.
Life 13 02086 g006
Life 13 02086 g007
Figure 7. Structures of biologically active myrtenal-derived compounds (5–12).
Figure 7. Structures of biologically active myrtenal-derived compounds (5–12).
Life 13 02086 g007
Life 13 02086 g008
Figure 8. Therapeutic potentials of myrtenal derivatives.
Figure 8. Therapeutic potentials of myrtenal derivatives.
Life 13 02086 g008
Table 1. Myrtenal-containing medicinal plants and other natural sources.
Table 1. Myrtenal-containing medicinal plants and other natural sources.
Natural SourcePlant PartReference
Artemisia spp.leaves, stems, and flowers/fruits[106]
Coriandrum sativumseed oil[107]
Cuminum cyminumessential oil[108,109]
Curcuma amada, Curcuma aromaticaessential oil[110]
Glycyrrhiza glabraroot essential oil[111]
Helianthus annuusflower heads[112]
Hyssopus officinalisessential oil[113]
Juglans regialeaf essential oil[114]
Laurus nobilisleaves[111]
Lavandula spp.essential oil[115]
Ledum palustreessential oil[116]
Myrtus communisessential oil[117]
Origanum majorana, Origanum vulgareessential oil[118]
Peumus boldusflower[111]
Piper nigrumfruit[111]
Propolis-[119]
Rosmarinus officinalisessential oil[120]
Thymus spp. essential oil[121]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Dragomanova, S.; Andonova, V.; Volcho, K.; Salakhutdinov, N.; Kalfin, R.; Tancheva, L. Therapeutic Potential of Myrtenal and Its Derivatives—A Review. Life 2023, 13, 2086. https://doi.org/10.3390/life13102086

AMA Style

Dragomanova S, Andonova V, Volcho K, Salakhutdinov N, Kalfin R, Tancheva L. Therapeutic Potential of Myrtenal and Its Derivatives—A Review. Life. 2023; 13(10):2086. https://doi.org/10.3390/life13102086

Chicago/Turabian Style

Dragomanova, Stela, Velichka Andonova, Konstantin Volcho, Nariman Salakhutdinov, Reni Kalfin, and Lyubka Tancheva. 2023. "Therapeutic Potential of Myrtenal and Its Derivatives—A Review" Life 13, no. 10: 2086. https://doi.org/10.3390/life13102086

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop