Chemical composition of Cinnamosma madagascariensis (Cannelaceae) essential oil and its larvicidal potential against the filariasis vector Culex quinquefasciatus Say

Madagascar flora is diverse and unique. Cinnamosma madagascariensis is an endemic species widely present in the forests of Madagascar. This plant has important traditional uses ranging from management of dementia, epilepsy, headache to malaria. Fewdata have been reported about the chemical composition of the essential oil, and no studies have been published on its bioactivity againstmosquitoes. Here,we focus on the chemical composition of essential oils extracted from C. madagascariensis stem bark and leaves, and their larvicidal potential against the filariasis vector Culex quinquefasciatus. GC-MS analysis revealed differences between the chemical volatile profiles of leaves and bark oils. In the former, linalool (30.1%), limonene (12.0%), myrcene (8.9%) and α-pinene (8.4%) were the major constituents, while in the latter β-pinene (33.3%), α-pinene (19.3%) and limonene (12.0%) were the most representative compounds. Acute toxicity experiments conducted on larvae of the filariasis vector C. quinquefasciatus led to LC50 of 61.6 μL L−1 and 80.1 μL L−1 for the bark and the leaf essential oils, respectively. Overall, the chance to use compounds from the C. madagascariensis bark and leaf essential oils against filariasis vectors seems promising, since they are effective at moderate doses and could be an advantageous alternative to build newer and safer mosquito control tools. To the best of our knowledge, this is the first report about the chemical composition of C. madagascariensis essential oils

SYNTHESIS AND PHARMACOLOGICAL CHARACTERIZATION OF RIBOSE-MODIFIED ADENOSINE DERIVATIVES AS P1 RECEPTOR LIGANDS

Adenosine, the natural ligand of P1 receptors, is implicated in the control of many physiological and pathological conditions such as inflammation, pain, cardiovascular and central nervous system (CNS) diseases.1 P1 receptors belong to the large family of GPCR receptors and are divided in four subtypes: A1, A2A, A2B and A3 adenosine receptors (ARs). Even though a large number of P1 ligands have been synthesized and characterized byin vitro and in vivo pharmacological studies, only very few of them are commercially available. Modifications at the ribose moiety and substitution at the N6-position of adenosine, lead to adenosine derivatives endowed with increased potency at A1 or A3AR. Our previous SAR studies showed that the replacement of OH at 5’-position of the ribose moiety of N6-substituted adenosine derivatives by a chlorine improved A1AR potency and selectivity versus A3AR, with 5′-chloro-5′-deoxy-N6-(±)-(endo- norborn-2-yl)-adenosine (5′Cl5′d-(±)-ENBA) as one of the most potent and selective A1AR agonists,2 while a 5’-C-ethyl-tetrazolyl moiety maintained the A1AR potency, but restored high A3AR affinity, leading to very potent dual A1AR and A3AR ligands.3 Interestingly, both modifications at 5’-position of adenosine derivatives brought to human A3AR antagonism. In order to further explore the structural determinants of this class of P1 ligands, a new series of ribose- modified N6-substituted adenosine derivatives was synthesized and their pharmacological profile was assayed. The results of this study will be discussed.References 1. Jacobson KA, Muller CE, Neuropharmacology 2015, doi: 10.1016/J.neuropharm.2015.12.001. 2. (a) Franchetti, P.; Cappellacci, L.; Vita, P.; Petrelli, R.; Lavecchia, A.; Kachler, S.; Klotz, K.-N.; Marabese, I.; Luongo, L.; Maione, S.; Grifantini, M. J. Med. Chem. 2009, 52, 2393−2406. (b) Luongo, L.; Petrelli, R.; Gatta, L.; Giordano, C.; Guida, F.; Vita, P.; Franchetti, P.; Grifantini, M.; De Novellis, V.; Cappellacci, L.; Maione, S. Molecules 2012, 17, 13712−13726. (c) Luongo, L.; Guida, F.; Imperatore, R.; Napolitano, F.; Gatta, L.; Cristino, L.; Giordano, C.; Siniscalco, D.; Di Marzo, V.; Bellini, G.; Petrelli, R.; Cappellacci, L.; Usiello, A.; de Novellis, V.; Rossi, F.; Maione, S. Glia 2014, 62, 122−132. 3. Petrelli, R.; Torquati, I.; Kachler, S.; Luongo, L.; Maione, S.; Franchetti, P.; Grifantini, M.; Novellino, E.; Lavecchia, A.; Klotz, K.-N-; Cappellacci, L. J. Med. Chem. 2015, 58, 2560-2566

An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis

Among natural products, sesquiterpenes have showed promising inhibitory effects against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing the human African trypanosomiasis (HAT). Smyrnium olusatrum (Apiaceae), also known as Alexanders or wild celery, is a neglected horticultural crop characterized by oxygenated sesquiterpenes containing a furan ring. In the present work we explored the potential of its essential oils obtained from different organs and the main oxygenated sesquiterpenes, namely isofuranodiene, germacrone and β-acetoxyfuranoeudesm-4(15)-ene, as inhibitors of Trypanosoma brucei. All essential oils effectively inhibited the growth of parasite showing IC50 values of 1.9-4.0 g/mL. Among the main essential oil constituents, isofuranodiene exhibited a significant and selective inhibitory activity against T. brucei (IC50 of 0.6 g/mL, SI = 30), with β-acetoxyfuranoeudesm-4(15)-ene giving a moderate potentiating effect. These results, albeit preliminary, shed light into the possible application of isofuranodiene as anti-protozoal agent to be included in combination treatments aimed not only at curing patients but also at preventing the diffusion of this HAT

Essential oils from Smyrnium olusatrum L. (Apiaceae) as a potential source of trypanocidal compounds

Plant-borne sesquiterpenes are considered as promising natural inhibitors against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing the human African trypanosomiasis (HAT). Smyrnium olusatrum L. (Apiaceae), also known as Alexanders or wild celery, is an overlooked vegetable characterized by oxygenated sesquiterpenes1. Among them, isofuranodiene, germacrone and β-acetoxyfuranoeudesm-4(15)-ene are the most abundant in the plant essential oil. In the present work, we investigated the antitrypanosomal activity of S. olusatrum essential oils obtained from different parts and the isolated sesquiterpenes, namely isofuranodiene, germacrone and β-acetoxyfuranoeudesm-4(15)-ene. The quali-quantitative composition of essential oils was investigated by gas chromatography coupled to mass-spectrometry (GC-MS). All essential oils reduced the growth of T. brucei with IC50 values of 1.9-4.0 g/ml. Among the isolated compounds, isofuranodiene showed a significant and selective inhibitory effect against T. brucei (IC50 of 0.6 g/ml, SI = 30), with β-acetoxyfuranoeudesm-4(15)-ene giving a moderate synergistic effect2. These results, albeit preliminary, shed light on the potential application of isofuranodiene as antitrypanosomal drug to be used for prophylactic and curative purposes against HAT

An overlooked horticultural crop, Smyrnium olusatrum, as a potential source of compounds effective against African trypanosomiasis

Among natural products, sesquiterpenes have shown promising inhibitory effects against bloodstream forms of Trypanosoma brucei, the protozoan parasite causing human African trypanosomiasis (HAT). Smyrnium olusatrum (Apiaceae), also known as Alexanders or wild celery, is a neglected horticultural crop characterized by oxygenated sesquiterpenes containing a furan ring. In the present work we explored the potential of its essential oils obtained from different organs and the main oxygenated sesquiterpenes, namely isofuranodiene, germacrone and \u3b2-acetoxyfuranoeudesm-4(15)-ene, as inhibitors of Trypanosoma brucei. All essential oils effectively inhibited the growth of parasite showing IC50 values of 1.9\u20134.0 \u3bcg/ml. Among the main essential oil constituents, isofuranodiene exhibited a significant and selective inhibitory activity against T. brucei (IC50 of 0.6 \u3bcg/ml, SI = 30), with \u3b2-acetoxyfuranoeudesm-4(15)-ene giving a moderate potentiating effect. These results shed light on the possible application of isofuranodiene as an antiprotozoal agent to be included in combination treatments aimed not only at curing patients but also at preventing the diffusion of HAT

Identification of highly effective antitrypanosomal compounds in essential oils from the Apiaceae family

The Apiaceae family encompasses aromatic plants of economic importance employed in foodstuffs, beverages, perfumery, pharmaceuticals and cosmetics. Apiaceae are rich sources of essential oils because of the wealth of secretory structures (ducts and vittae) they are endowed with. The Apiaceae essential oils are available on an industrial level because of the wide cultivation and disposability of the bulky material from which they are extracted as well as their relatively cheap price. In the fight against protozoal infections, essential oils may represent new therapeutic options. In the present work, we focused on a panel of nine Apiaceae species (Siler montamon, Sison amomum, Echinophora spinosa, Kundmannia sicula, Crithmum maritimum, Helosciadium nodiforum, Pimpinella anisum, Heracleum sphondylium and Trachyspermum cunmi) and their essential oils as a model for the identification of trypanocidal compounds to be used as alternative/integrative therapies in the treatment of Human African trypanosomiasis (HAT) and as starting material for drug design. The evaluation of inhibitory effects of the Apiaceae essential oils against Trypanosoma brucei showed that some of them (E. spinosa, S. amomum, C. maritimwn and H. nodifloruin) were active, with EC50 in the range 2.7-10.7 mu g/mL. Most of these oils were selective against T. brucei, except the one from C. maritimum that was highly selective against the BALB/3T3 mammalian cells. Testing nine characteristic individual components (a-pinene, sabinene, alpha-phellandrene, p-cymene, limonene, beta-ocimene, gamma-terpinene, terpinolene, and myristicin) of these oils, we showed that some of them had much higher selectivity than the oils themselves. Terpinolene was particularly active with an EC50 value of 0.035 mu g/rnL (0.26 mu M) and a selectivity index (SI) of 180. Four other compounds with EC50 in the range 1.0-6.0 mu g/mL (7.4-44 mu M) had also good SI: a-pinene (> 100), beta-ocimene (> 91), limonene (> 18) and sabinene ( > 17). In conclusion, these results highlight that the essential oils from the Apiaceae family are a reservoir of substances to be used as leading compounds for the development of natural drugs for the treatment of HAT

Essential oils from Smyrnium olusatrum and their major components as potential mosquitocidal and trypanocidal agents

Smyrnium olusatrum L., also known as Alexanders or wild celery, is a celery-scented biennial herb belonging to the Apiaceae family and distributed in the Mediterranean area where it grows on hedgerows, hedged banks, sea cliffs, quarries and railway embankments, from sea level to 800 m of altitude [1]. Since Roman age the plant has been used as both a vegetable and for medicinal uses. After a long period of cultivation, the use of S. olusatrum was abandoned due to the introduction of common celery (Apium graveolens L.) in the Middle Ages [1]. Owing to the abundance of secretory structures like ducts and vittae [2], S. olusatrum is a rich source of essential oils. Their chemical composition has been extensively investigated by our group [1-4] and revealed the furan ring-containing sesquiterpenes as the marker compounds. Among the main compounds, isofuranodiene, germacrone and 1β-acetoxyfurano-4(15)-eudesmene were the most representative ones (Fig. 1). Recently, essential oils have been considered as new therapeutic options to combat protozoal infections [5] as well as effective and eco-friendly tools to control highly invasive mosquito vectors [6,7]. On this basis, we have assayed the S. olusatrum essential oils and its main components (i.e. isofuranodiene, germacrone and 1β-acetoxyfurano-4(15)-eudesmene) for larvicidal effects on Culex quinquefasciatus, the vector of lymphatic filariasis, and for inhibitory effects on Trypanosoma brucei, the protozoan parasite responsible for Human African trypanosomiasis. The essential oil of S. olusatrum flowers exhibited acute toxicity on C. quinquefasciatus larvae, with germacrone and isofuranodiene being involved in the effect displayed. As concerning T. brucei, the S. olusatrum essential oils showed good inhibitory effects and selectivity, with the sample from fruits being the most active, and isofuranodiene and 1β-acetoxyfurano-4(15)-eudesmene as the main contributors to the effect on protozoal cell. These results, although preliminary, encourage further studies in the attempt to find a new application of S. olusatrum secondary metabolites as natural insecticides and antiprotozoal agents

Mexican sunflower (Tithonia diversifolia, Asteraceae) volatile oil as a selective inhibitor of Staphylococcus aureus nicotinate mononucleotide adenylyltransferase (NadD)

Tithonia diversifolia, well-known as Mexican sunflower, is an invasive shrub growing in tropical areas of South America, Asia and Africa where it is used as a traditional medicine, ornamental plant and green biomass to improve soil fertility. Given the traditional uses in the treatment of skin infections, we have first analysed the chemical composition and the antimicrobial effects of the essential oil hydrodistilled from inflorescences of T. diversifolia. For the purpose the inhibition zones against a panel of pathogens were measured by the agar diffusion method. In addition, we evaluated the inhibitory effects on several NaMN/NMN adenylyltransferases, which are essential enzymes for NAD biosynthesis in most bacterial pathogens, and also tested the inhibition on the mammalian orthologue enzymes as a promising way to identify novel natural antibiotics. To complete the screening of biological effects, the antioxidant capacity and antiproliferative effects on human tumor cells were evaluated using the DPPH, ABTS, FRAP, and MTT methods. Results showed that T. diversifolia essential oil was mostly active against Staphylococcus aureus with a halo of 14 mm. The essential oil selectively inhibited in vitro the pure NAD biosynthetic enzyme NadD from S. aureus (IC50 of ~60 μg/mL), with basically none or only minor effects on mammalian orthologue enzymes. Finally, the essential oil displayed significant cytotoxic effects on A375, MDA-MB 231, HCT 116 and T98G tumor cells with IC50 values of 3.02, 3.79, 3.46 and 12.82 μg/mL, respectively, and noticeable radical scavenging activity on DPPH and ABTS radicals, with IC50 values of 108.8 and 41.7 μg/mL, respectively