Skimmianin

Planta Med. 2011 Sep;77(14):1644-7.

A new quinoline epoxide from the Australian plant Drummondita calida.[Pubmed: 21472648]

METHODS AND RESULTS:
A drug discovery program aimed at identifying new antimalarial leads from a prefractionated natural product library has resulted in the purification of a new quinoline alkaloid, (2' R)-2',3'-epoxy- N-methylatanine (1), along with eight known natural products, Skimmianin, γ-fagarine, maculosidine, evolitrine, dictamnine, pteleine, N-methylatanine, and werneria chromene.
CONCLUSIONS:
Compound 1 displayed 74 % inhibition at 80 µM against a chloroquine -resistant Plasmodium falciparum strain (Dd2).

Parasitology. 2011 Sep;138(10):1224-33.

Leishmanicidal effect of Spiranthera odoratíssima (Rutaceae) and its isolated alkaloid skimmianine occurs by a nitric oxide dependent mechanism.[Pubmed: 21810308 ]

Leishmaniasis is one of the neglected diseases. High cost, systemic toxicity, and diminished efficacy due to development of resistance by the parasites has a negative impact on the current treatment options. Thus, the search for a new, effective and safer anti-leishmanial drug becomes of paramount importance. Compounds derived from natural products may be a better and cheaper source in this regard. This study evaluated the in vitro anti-leishmanial activity of Spiranthera odoratíssima (Rutaceae) fractions and isolated compounds, using promastigote and amastigote forms of different Leishmania species.
METHODS AND RESULTS:
J774 A.1 macrophage was used as the parasite host cell for the in vitro assays. Evaluations of cytoxicity, nitric oxide (NO), interleukin-10 and in silico analysis were carried out. In vitro experiments showed that the fruit hexanic fraction (Fhf) and its alkaloid Skimmianine (Skm) have a significant (P<0·001) effect against L. braziliensis. This anti-L. braziliensis activity of Fhf and Skm was due to increased production of NO and attenuation of IL-10 production in the macrophages at concentrations ranging from 1·6 to 40·0 μg/ml.
CONCLUSIONS:
The in silico assay demonstrated significant interaction between Skm and amino acid residues of NOS2. Skm is thus a promising drug candidate for L. braziliensis due to its potent immunomodulatory activity.

Inflamm Res. 2013 Apr;62(4):367-76.

Anti-inflammatory effect of quinoline alkaloid skimmianine isolated from Ruta graveolens L.[Pubmed: 23344232 ]

The present study evaluates the anti-inflammatory effect of the quinoline alkaloid Skimmianine (Skimmianin,SKM), isolated from Ruta graveolens L., against carrageenan-induced acute inflammation.
METHODS AND RESULTS:
SKM at a dose of 5.0 mg/kg body weight was found to be the minimal concentration for maximal edema inhibition. Carrageenan suspension was administered into the sub-plantar tissue of the right hind paw 1 h after SKM and diclofenac (20 mg/kg) administration (i.p.). Paw edema was determined 3 h after carrageenan administration. The rats were then killed and mRNA expressions of TNF-α and IL-6, levels of PGE2 and TBARS, activities of COX-2, 5-LOX, SOD, catalase, glutathione peroxidase (GPx) and myeloperoxidase (MPO) and the level of nitrite were measured. SKM treatment resulted in a decrease in the mRNA levels of TNF-α and IL-6, which are upstream events of the inflammatory cascade. The levels of PGE2 and NO and the activities of COX-2 and 5-LOX were also significantly reduced after SKM treatment. Neutrophil infiltration, lipid peroxidation and associated oxidative stress in the paw tissue were reduced following SKM treatment.
CONCLUSIONS:
These results support the anti-inflammatory properties of Skimmianine and its multi-targeted mechanism of action, suggesting its potential therapeutic efficacy in various inflammatory diseases.

Medicinal Chemistry Research, 2012 , 21 (6) :722-725.

Skimmianine, a furoquinoline alkaloid from Zanthoxylum nitidum as a potential acetylcholinesterase inhibitor[Reference: WebLink]

Skimmianine (Skimmianin,1), a newly discovered strong acetylcholinesterase (AChE) inhibitor, along with nine weakly or no active compounds, toddalolactone (2), dictamnine (3), γ-fagarine (4), magnolone (5), (−)-(S)-edulinine (6), zanthodioline (7), edulitine (8), 5,6,7-trimethoxycoumarin (9), and haplopine (10) have been isolated from Zanthoxylum nitidum (Z. nitidum).
METHODS AND RESULTS:
Skimmianine (1) inhibited 50% of AChE activity at the concentrations of 8.6 ± 0.7 μg/ml when the IC50 value of Physostigmine as a standard was 0.013 ± 0.002 μg/ml. Antiacetylcholinesterase activity of Skimmianine (1) was also supported by TLC bioautographic assay.
CONCLUSIONS:
The structure activity relationship on the anti-acetylcholinesterase activity of the quinoline moiety is also discussed in this article.

J Auton Pharmacol. 1994 Oct;14(5):365-74.

Skimmianine and related furoquinolines function as antagonists of 5-hydroxytryptamine receptors in animals.[Pubmed: 7829541]

1. Skimmianine, kokusaginine and confusameline, three furoquinolines extracted from the leaves of Evodia merrillii (Rutaceae), were investigated to characterize their selective effects on subtypes of 5-hydroxytryptamine (5-HT) receptors.
METHODS AND RESULTS:
2. In the isolated membranes of rat cerebrocortex, using [3H]-5-HT and [3H]-ketanserin as radioligands, Skimmianine and the two other furoquinolines displaced radioligand bindings in a concentration-dependent manner. Lower concentrations were required to affect [3H]-ketanserin binding than [3H]-5-HT binding in the order Skimmianine > kokusaginine > confusameline. 3. Furoquinolines inhibited 5-HT-induced contraction mediated by 5-HT2 receptors in the presence of methiothepin in rat isolated aorta. Also, the combination of furoquinolines with ketanserin showed an additive antagonism. 4. These furoquinolines were inactive on the 5-carboxamidotryptamine-induced relaxation of guinea-pig ileum, a 5-HT1-mediated event. However, 5-HT-induced contraction via 5-HT2 receptors was reduced by these furoquinolines in a way similar to that in blood vessels. 5. The failure of these compounds to affect the 5-HT-induced Bezold-Jarisch-like reflex in anaesthetized rats, the major 5-HT3-mediated action, ruled out an action on 5-HT3 receptors.
CONCLUSIONS:
6. The results obtained suggest that three furoquinoline alkaloids may act on 5-HT receptors in animals, more selectively to the 5-HT2 subtype, in the order of Skimmianine > kokusaginine > confusameline.

Acta Crystallographica, 2010 , 59 (10) :o1503-o1505.

Redetermination of skimmianine: A new inhibitor against the Leishmania APRT enzyme[Reference: WebLink]

The title compound Skimmianin(alternative names 7,8-dimethoxydictammine and 4,7,8-trimethoxyfuro[2,3-b]quinoline), C14H13NO4, is a natural product extracted from Adiscanthus fusciflorus (Rutaceae).
METHODS AND RESULTS:
Our biochemical tests show that it has inhibitory activity against the enzyme adenine phosphoribosyltransferase (APRT) from Leishmania, a tropical parasite causing endemic disease in poor countries. It crystallizes in the centrosymmetric space group P2(1)/c, with one molecule in the asymmetric unit, and has at least two C-H...O intermolecular interactions, leading to the formation of centrosymmetric dimers.