Furoquinoline Alkaloids: Insights into Chemistry, Occurrence, and Biological Properties

Furoquinoline alkaloids exhibit a diverse range of effects, making them potential candidates for medicinal applications. Several compounds within this group have demonstrated antimicrobial and antiprotozoal properties. Of great interest is their potential as acetylcholinesterase inhibitors and anti-inflammatory agents in neurodegenerative diseases. The promising biological properties of furoquinoline alkaloids have motivated extensive research in this field. As a result, new compounds have been isolated from this group of secondary metabolites, and numerous pharmacological studies have been conducted to investigate their activity. It is crucial to understand the mechanisms of action of furoquinoline alkaloids due to their potential toxicity. Further research is required to elucidate their mechanisms of action and metabolism. Additionally, the exploration of derivative compounds holds significant potential in enhancing their pharmacological benefits. In vitro plant cultures offer an alternative approach to obtaining alkaloids from plant material, presenting a promising avenue for future investigations.


Introduction
Furoquinoline alkaloids, derived from anthranilic acid, possess a furoquinoline backbone and are commonly found in the Rutaceae family.Notable alkaloids belonging to this group include dictamnine, skimmianine, kokusaginine, and γ-fagarine.Research has revealed that certain furoquinoline alkaloids exhibit pharmacological properties, including antibacterial, antifungal, antiviral, mutagenic, cytotoxic, antiplatelet, and enzymeinhibitory effects [1].The promising biological properties of furoquinoline alkaloids have driven extensive research into this compound group, leading to the discovery of new compounds and comprehensive pharmacological investigations.Given their potential toxicity, understanding the mechanisms of action of furoquinoline alkaloids is of the utmost importance.Additionally, exploring alternative methods, such as plant biotechnology, to obtain these metabolites has been an area of research interest.This study aims to provide a review of current research on furoquinoline alkaloids and prospects for future exploration.The review encompasses comprehensive searches of available databases such as Scopus, Google Scholar, Web of Science, MEDLINE-PubMed, BioMed Central, and Embase.

Biogenesis, Chemical Structure, and Occurrence of Furoquinoline Alkaloids
Furoquinoline alkaloids belong to the class of organic heterotricyclic compounds.Their distinctive chemical structure comprises the quinoline and furan rings.The quinoline ring is formed through a biosynthetic condensation process involving anthranilic acid and acetic acid, possibly in conjunction with one or both of the coenzyme-A derivatives.Alternatively, the condensation between anthranilic acid and a derivative of cinnamic acid can serve as a starting point, as demonstrated in tracer experiments with Ruta angustifolia.After the formation of the quinoline ring, in the case of furoquinoline alkaloids, furan rings are generated from isoprenoid-substituted compounds.Once 2,4-dihydroxyquinoline is formed, a dimethylallyl group attaches to the C-3 position.It is conceivable that the dimethylallyl group is initially added to the C-4 oxygen and subsequently migrates to C-3 [2].

Pharmacological Properties
Furoquinoline alkaloids demonstrate multidirectional pharmacological activity.These compounds exhibit antimicrobial, antiprotozoal, antispasmodic, and anti-inflammatory effects.They also possess antiosteoporosis properties and antiplatelet aggregation effects.Additionally, they can influence enzymatic activity, such as the potent antiacetylcholinesterase activity observed in skimmianine (2).Furthermore, these alkaloids often exhibit cytotoxic effects, making them potentially useful in the treatment of certain cancers.However, it is important to note that they can also have mutagenic properties.A well-known example is the alkaloid dictamnine (1), which has been documented to have mutagenic and genotoxic effects.

Antifouling Activity
The exploration of novel, environmentally friendly antifouling agents has revealed the potential of certain furoquinoline alkaloids.Kokusaginine (8) and flindersiamine (35) derived from Balfourodendron riedelianum demonstrated notable antifouling activity in tests conducted with mussel Mytilus edulis platensis [41].

Anticholinesterase and Neuroprotective Activity
Skimmianine (2) shows potential in the treatment of Alzheimer's disease due to its ability to inhibit acetylcholine esterase (AChE) and the production of nitric oxide (NO), which can influence inflammation within the nervous tissue [1].The neuroprotective effect of skimmianine may also be attributed to its ability to inhibit neuroinflammation in LPS-activated microglia by targeting the NF-κB activation pathway [49].Furoquinoline alkaloids extracted from the leaves of Evodia lepta were evaluated for their cholinesterase (ChEs)-inhibitory activity.Kokusaginine (8) and melineurine (28) exhibited the highest activity against AChE and BChE, respectively [51].Evolitrine (18) significantly affected neurite growth mediated by nerve growth factor in PC12 cells (EC50 3.8 µg/mL), and thus it may have potential application in the treatment of Alzheimer's disease [26].

Antiosteoporosis Activity
Dictamnine (1) has emerged as a promising therapeutic agent for the treatment of osteoporosis.This compound effectively mitigates osteoclast formation and demonstrates efficacy in alleviating OVX-induced osteoporosis [53].

Antinociceptive Action
Choisyine (58) exhibits antinociceptive activity in animal models.Studies have revealed that the cholinergic pathway plays a role in mediating its antinociceptive effects [31,54].

Anti-Anaphylactoid Activity
Dictamnine (1) demonstrated anti-anaphylactoid activity in a mouse model of hind paw extravasation.It is suggested that dictamnine may act through the MrgX2 receptor located on mast cells, making it a promising candidate for an effective anti-anaphylactic compound [55].

Hepatoprotective Activity
Hepatoprotective effects against DL-galactosamine-induced damage in WB-F344 cells and inhibitory effects on the LPS-induced NO production of the compounds found in Clausena emarginata were investigated.γ-Fagarine (3) showed hepatoprotective effects against DL-galactosamine-induced toxicity [15].

Discussion
Natural compounds are a promising group that can be used to search for new, effective drugs in the treatment of many diseases.Furoquinoline alkaloids belong to a very large group of quinoline alkaloids and attract the attention of many researchers.The development of laboratory techniques, including methods of metabolite isolation, means that new compounds are still being isolated.The basic structure of this group of alkaloids consists of a furoquinoline ring.The compounds occur in the form of aglycones; however, there has also been a report of a glycoside form of the alkaloid, namely clausenaside F (27) [26].An interesting form comprises dimeric combinations of furoquinoline alkaloids such as anstifolines A (59) and B (60) [32].
For many years, plants used in folk herbal medicine have been intensively studied.They are often endemic and very rare species.This research aimed, among other goals, at examining the chemical composition and medicinal properties of plants.Biological research most often concerns extracts from various parts of plants, and the individual compounds that are part of the extract are less frequently studied.There is still much to explore in this field.Of the furoquinoline alkaloids isolated so far, only some have been analyzed for their biological activity.Well-documented healing properties are only noted for the most common alkaloids, such as dictamin, skimmianine, or γ-fagarine.Less common alkaloids, or alkaloids occurring in small amounts, do not have a sufficiently documented biological effect [26].
Furoquinoline alkaloids are a group of compounds found mainly in the Rutaceae family.However, there are reports of the occurrence of this type of alkaloid also in another family known for its medicinal properties-Apiaceae.This creates new possibilities of exploitation for researchers [3].
Discovering new molecular structures is extremely important in the search for new drugs.The molecular structures of natural compounds can provide valuable clues for drug design.A very good example of such an application is the discovery of febrifugin, triptanthrin, and their analogues, with significant antimalarial activity.New classes of compounds have allowed the huge expansion of research into malaria therapy [26].
Furoquinoline alkaloids exhibit diverse effects, making them potential candidates for medicinal use.Many compounds in this group demonstrate antimicrobial and antiprotozoal activity [23,56].The use of furoquinoline alkaloids as inhibitors of AChE and anti-inflammatory agents in neurodegenerative diseases is particularly interesting [26].Furoquinoline alkaloids show great potential for cytotoxic and anticancer activity [57][58][59].However, it is important to note that alkaloids can also have toxic effects.Studies on the toxicity of individual alkaloids are scarce and concern only a few selected compounds.Dictamnine, in particular, is well known for its phototoxic and photomutagenic properties [60].γ-Fagarine induced sister chromatid exchange in human lymphocytes.γ-Fagarine, skimianine, and dictamnine showed strong mutagenic activity in S. typhimurium strains TA98 and TA100, but showed relatively little or no activity in the corresponding R-factorfree strains TA1538 and TA1535.Furoquinoline alkaloids can be activated as mutagenic metabolites by cytochrome P450 and cytochrome P448 and possibly a flavin-containing monooxygenase [20].
To address this, exploring the synthesis of derivatives from native alkaloids with improved therapeutic profiles and reduced toxicity is an interesting approach.The modification of dictamnine allowed fluorinated analogues with improved cardiac effects to be obtained.The mechanism of their action might be related to epinephrine α receptors, the M-receptor, and the calcium channel receptor [61].Derivatives of cocusaginine and flindersiamine, the primary alkaloids isolated from the bark of Balfourodendron riedelianum, have shown superior in vitro activity against Trypanosoma cruzi compared with positive controls [62].
As climate change and diminishing crop areas pose challenges in obtaining plant metabolites from field crops, plant biotechnology offers an alternative solution.In vitro plant cultures provide a means to produce valuable plant metabolites independent of environmental conditions and seasonal constraints.Furoquinoline alkaloids can be produced in vitro.Species of the genus Ruta have been found to contain alkaloids such as γ-fagarine and skimmianine in culture [63,64].The use of innovative biotechnological technologies enables the increased production of secondary metabolites and biomass through the utilization of temporary immersion bioreactors.In in vitro cultures of Ruta montana carried out in Plantform TM bioreactors, the highest content of γ-fagarine and skimmianine was 305.4 mg/100 g DM and 233.7 mg/100 g DM, respectively [65].In turn, in in vitro cultures of Ruta chalepensis carried out in RITA ® bioreactors, the highest content of γ-fagarine and skimmianine was 186.8 mg/100 g DM and 291.6 mg/100 g DM, respectively [66].

Conclusions
Furoquinoline alkaloids exhibit a diverse range of therapeutic properties, such as antimicrobial, antiprotozoal, and anti-inflammatory effects.Furthermore, their ability to inhibit acetylcholinesterase makes them potential candidates for the treatment of neurodegenerative diseases, such as Alzheimer's disease.
Although some mechanisms of action of these compounds are well known, there is still a considerable amount of research needed to understand their mechanisms of action and metabolism.Additionally, exploring the development of derivatives holds significant promise in enhancing their pharmacological effects.The discussed group of compounds may contribute to the development of new drugs in the future through targeted pharmacological modeling and synthetic modification.
To source alkaloids from plant material, in vitro plant cultures offer an alternative to traditional field crops and can serve as a valuable method for alkaloid production.Obtaining natural compounds from plants can be associated with many problems related to both field cultivation and harvesting from natural sites.An alternative may be the use of in vitro plant cultures.Research on in vitro cultures should be aimed at maximizing the production of selected secondary metabolites.Plant biotechnology offers many opportunities in this field.In addition to manipulating the composition of the medium, different lighting conditions, elicitation with biotic and abiotic elicitors, as well as the addition of precursors of metabolic pathways can be used.This approach opens up opportunities for the efficient and controlled production of these compounds, paving the way for further studies and applications in various fields of research.

Table 1 .
Selected alkaloids with examples of plants in which furoquinoline alkaloids occur and their main biological activity.