Biological Activity of Naturally Derived Naphthyridines

Marine and terrestrial environments are rich sources of various bioactive substances, which have been used by humans since prehistoric times. Nowadays, due to advances in chemical sciences, new substances are still discovered, and their chemical structures and biological properties are constantly explored. Drugs obtained from natural sources are used commonly in medicine, particularly in cancer and infectious diseases treatment. Naphthyridines, isolated mainly from marine organisms and terrestrial plants, represent prominent examples of naturally derived agents. They are a class of heterocyclic compounds containing a fused system of two pyridine rings, possessing six isomers depending on the nitrogen atom’s location. In this review, biological activity of naphthyridines obtained from various natural sources was summarized. According to previous studies, the naphthyridine alkaloids displayed multiple activities, i.a., antiinfectious, anticancer, neurological, psychotropic, affecting cardiovascular system, and immune response. Their wide range of activity makes them a fascinating object of research with prospects for use in therapeutic purposes.


Introduction
The natural environment abounds in substances with multiple biological properties that have become an inspiration and basis for modern drugs. Since prehistoric times, secondary metabolites especially in the form of plant materials have been used for therapeutic purposes [1]. Nowadays, thanks to chemical sciences development, natural derivatives can be isolated from terrestrial and marine sources as multi-component extracts or single compounds. This provides a possibility to explore their properties, from chemical structures and general mechanisms of action to more specialized molecular targets.
Naphthyridines are a class of heterocyclic compounds that are also referred to in the chemical literature as "benzodiazines" or "diazanaphthalenes", due to possessing a fused system of two pyridine rings. There are six positional isomers with different locations of nitrogen atoms (Figure 1).
The compounds containing the naphthyridine scaffold are found in natural products (plants and marine organisms) or can be obtained synthetically. The properties and synthesis of 1,8-isomer derivatives were most often described, mainly due to nalidixic acid (1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid), which was discovered by G. Lesher in 1962 [2] and introduced into treatment in 1967 as an antibacterial drug. In the last several decades, scientists' interest in naphthyridines has been growing due to their broad spectrum of biological activity. In this review, biological activity of naphthyridines derived exclusively from the natural environment is presented. Many of them revealed significant bioactivity and this article may encourage researchers to further the investigation of these chemical compounds. 2. Naturally Occurring Naphthyridine Derivatives 2.1. 1,5-Naphthyridine Derivatives 1,5-Naphthyridine natural products are represented primarily by canthinone-type alkaloids. A major member of the group, canthin-6-one 1 (Figure 2), is isolated primarily from plants-the Rutaceae and Simaroubaceae families, but also from fungi [3]. The immunomodulatory activity of the compound has been determined. In rats with druginduced colitis, canthin-6-one 1 reduced the production of pro-inflammatory mediators TNF-α (tumor necrosis factor α), IL-1β (interleukin-1β), IL-12p70 (interleukin-12p70), and VEGF (vascular endothelial growth factor). Moreover, it diminished oxidative stress in colon tissues [4]. Moreover, canthin-6-one 1 has been studied for its anticancer properties. Normally, cell death determines system homeostasis and prevents excessive proliferation and accumulation of defective cells. Major mechanisms of cell death comprise programmed apoptosis and autophagy, and traumatic necrosis. In cancer cells, cell death is disturbed due to genetic abnormalities. Restoration of a proper cell cycle together with generating cell damage in tumor tissues are key targets for anticancer compounds.
Canthin-6-one 1 was shown to activate apoptosis and necrosis in Kasumi-1human myeloid leukemia cells, with cell cycle arrest at G0/G1 and G2, respectively, at 7 µM and 45 µM. The agent also induced cancer cells differentiation, a process which could potentially lead to the conversion of neoplastic cells into normal [5].
1,5-Naphthyridine alkaloids were isolated also from Leitneria floridana, a species of shrub, commonly known as corkwood, which is distributed in the southern regions of the United States. Leitneria floridana-derived 1-methoxycanthin-6-one 9 appeared to exert an effect against HIV (Human Immunodeficiency Virus) with an EC 50 value of 0.26 g/mL [11]. Beside antiviral properties, the compound displayed anticancer potency and was shown to induce cellular apoptosis by activation of c-Jun N-terminal kinase [12].
Picrasma quassioides, a genus of tree commonly growing in temperate regions of southern Asia, revealed to be the source of another natural naphthyridine agents. Jiao et al. isolated novel 1,5-naphthyridine alkaloids from Picrasma quassioides Bennet [15]. The compounds were determined as quassidine E 12 and canthin-16-one-14-butyric acid 13 ( Figure 3). The novel agents 12 and 13 reduced the production of pro-inflammatory mediators: NO, IL-6, and TNF-α in LPS-induced RAW 264.7 cells, with IC 50 values in the range of 20.51-66.96 µM [15].  Natural products-cimiciduphytine 14 and eburnane derivatives 15 ( Figure 4)-were evaluated as natural painkillers and antihypertensive agents, which could be used in cerebral circulation disturbance therapy [16].

1,6-Naphthyridine Derivatives
Aaptos, a widely-known genus of marine sponges, is considered as a prominent natural source of 1,6-naphthyridines. Aaptos was firstly described by Gray in 1867 [17]. The genus is represented by nearly 29 species that can be found in shallow waters of coastal areas all over the world. Since the 1980s, Aaptos has been extensively researched due to being the source of at least 62 secondary metabolites with diverse biological activities [18].
Aaptamine (8,9-dimethoxy-1H-benzo[de] [1,6]naphthyridine) 16 ( Figure 5) isolated by Nakamura et al. [19] in 1982 from Aaptos aaptos became the first, maternity representative of aaptamines family. The anticancer activity of the compound 16 has been extensively researched. Aaptamine exhibited notable cytotoxic effects in vitro against H1299 and A549 non-small cell lung cancer [20], HeLa cervical cancer [21], and CEM-SS T-lymphoblastic leukemia cell lines [22], with IC 50 values ranging from 10.47 to 15.03 µg/mL. Moreover, aaptamine 16 displayed a potent anticancer effect in mice carrying human hepatocellular carcinoma HCC-LM3 xenografts with downregulation of SOX9 and Ki67 expression [23]. The agent 16 has been detected to intercalate into DNA [24], upregulate p21 expression, and induce apoptosis in cancer cells in a p53-independent manner [23,25]. Aaptamine 16 expressed the ability to interfere specifically with p53 and c-myc network in NT2 human embryonal carcinoma cell line [26]. Gong et al. [20] performed further investigation of the mechanism of aaptamine 16 action in non-small cell lung cancer cell lines. The agent 16 displayed antiproliferative properties with inhibition of cancer cells growth and clonogenicity in a dose-dependent manner. Aaptamine induced G1 cell cycle arrest with a reduction of CDK2 (Cyclin-dependent kinase 2), CDK4 (Cyclin-dependent kinase 4), Cyclin D1, and Cyclin E levels, and also interfered with the PI3K/AKT/GSK3b (phosphatidylinositol-3 kinase/protein kinase B/glycogen synthase kinase 3 beta) axis. It could potentially diminish the process of metastasis and tumor invasion due to downregulation of MMP-7 (matrix metalloproteinase-7) and MMP-9 (matrix metalloproteinase-9) expression [20]. Beside anticancer activity, aaptamine 16 was shown to block α-adrenoceptors in vascular smooth muscles [27]. Hence, it could be considered a antihypertensive agent. Moreover, the compound 16 has been reported to display antiviral activity against HIV-1 [24] and anti-amoebic effect towards Acanthamoeba castellanii [28]. Aaptamine 16 selectively blocked the type A MAO (Monoamine Oxidase) [29], an enzyme which is overexpressed in the brain during major depression episodes. Therefore, aaptamine 16 could be useful in depression therapy. Aaptamine 16 demonstrated a wide range of activity, nevertheless its derivatives surpassed the effect of parental agent. There are several studies comparing properties of parent aaptamine 16 with its derivatives demethyl(oxy)aaptamine 17 and isoaaptamine 18 ( Figure 5). Dyshlovoy et al. [30] investigated anticancer properties of these compounds 16-18, isolated from Aaptos. Evaluation of cytotoxicity on human cancer cell lines (THP-1 human leukemia monocytic, HeLa cervical cancer, SNU-C4 colorectal carcinoma, SK-MEL-28 human melanoma, MDA-MB-231 breast cancer) in MTS assay confirmed significant anticancer potency of aaptamines 16-18, and aaptamine analogues exerted impressively higher activity than the parent compound. All the agents 16-18 induced apoptosis in THP-1 cell line, and the effect was also more significant for demethyl(oxy)aaptamine 17 and isoaaptamine 18. The study confirmed p53-independent cell cycle arrest induced by these compounds 16-18. The agents 16-18 were also shown to prevent cancerogenesis induced by epidermal growth factor at low, non-toxic concentrations in the JB6 P+ Cl41 murine epidermal cell line. The mechanism of prevention is independent from the transcription of AP-1 (activator protein-1) and NF-κB.
Wu et al. [31] investigated the cytotoxicity of aaptamine 16, demethyl(oxy)aaptamine 17, and isoaaptamine 18 on breast cancer cell lines. The derivatives 17 and 18 also presented higher activity than parent compound 16. Isoaaptamine 18 exerted the highest effect on T-47D (IC 50 = 30.13 µM), meanwhile demethyl(oxy)aaptamine 17 was the most potent on MCF-7 (IC 50 = 23.11 µM) and MDA-MB-231 (IC 50 = 19.34 µM) cell lines. Isoaaptamine 18, chosen for further research as the most prominent alkaloid (84.74%) in the active fraction isolated from sponge Aaptos sp., presented short-term and long-term antiproliferative properties. The compound 18 inhibited XIAP (X-linked inhibitor of apoptosis protein) expression, and due to caspases 3 and 7 activation and cleavage of PARP (Poly ADPribose polymerase), induced apoptotic cell death in cancer cells. Cytotoxic properties of isoaaptamine 18 have also been based on autophagy induction, disruption to mitochondrial function, and over-generating reactive oxygen species. The role of isoaaptamine 18 as a significant apoptosis inducer on THP-1 cells was confirmed by Shubina et al. [32]. The compound 18 exerted the highest activity among tested aaptamine analogues.
Matrine 30 ( Figure 10) is considered as one of the most principal and widely studied Sophora alkaloid, and the number of publications regarding the compound are constantly growing. Molecular mechanisms of matrine 30 antitumor activity have been considerably researched. Recent studies confirmed the antineoplasm effect of matrine on MCF-7 breast cancer and A549 non-small cell lung cancer cell lines by inhibiting AKT/mTOR axis [38,39]. Additionally, it reduced tumor growth of ovarian cancer cells in vivo by inducing the expression of ERK and JNK (c-Jun N-terminal kinase) pathways [40]. Matrine 30 also exerted a significant effect in drug-resistant tumors by inducing apoptosis and inhibiting efflux-pump activity [41,42]. Beside anticancer properties, matrine 30 exerted cardioprotective effects towards cardiomyocyte damage during hyperglycemia and sepsis [43,44]. Moreover, matrine 30 properties of protecting liver function resulted in several clinical trials. Intramuscular injections of matrine 30 caused improvement of condition in patients treated for chronic Hepatitis type B and patients suffering from primary hepatic carcinoma after trans-artery chemo-embolization [45,46]. Compound 30 was also reported to decrease total bilirubin level and improve survival rates in liver transplant recipients [47]. Matrine 30 is also considered a promising candidate as an immunosuppressive drug due to inhibiting autoimmune response in experimental models of multiple sclerosis [48,49]. It also exerts antiviral activity [50,51]. Extract isolated from the seeds of Sophora alopecuroides matrine 30, sophocarpine 31 and sophoramine 32 ( Figure 10), with contents, respectively, of 32.85%, 26.55%, and 6.91%, have alleviated morphine withdrawal in patients [52]. Moreover, these alkaloids 30-33 displayed strong antitumor properties. Matrine 30, sophoridine 33 ( Figure 10), and sophocarpine 31 exerted potent cytotoxic activity against HL-60 human leukemia, U937 human myeloid leukemia, K562 human erythroleukemia, EC109 esophageal squamous cell carcinoma, A549 non-small cell lung cancer, and HepG2 hepatocellular carcinoma cell lines, with IC 50 values in the range of 1.21-12.86 mM [53]. Matrine 30 and sophocarpine 31 decreased cachexia symptoms (induced by colon carcinoma) in mice, and the mechanism of action was related to the suppression of TNF-α and IL-6 production [54]. Additionally, sophoramine 32 and sophocarpine 31 displayed antinematicidal activity against Bursaphelenchus xylophilus, pine trees parasite, and it was observed that degree of unsaturation in the -lactam ring correlated with the strength of antinematicidal activity [55].
Sophora alkaloids were also reported to exhibit immunosuppressive properties. Alopecines A-E 44-48 ( Figure 14), isolated from the seeds of Sophora alopecuroides, were assessed toward inhibiting proliferation of Concanavalin A-induced T lymphocytes and LPSinduced B cells [59].
Alopecine D 47 exerted the most potent effect, with IC 50 = 3.98 µM for inhibiting proliferation of T lymphocytes and 3.74 µM for B lymphocytes (SI ratios respectively 8.0 and 8.5).
Pan et al. [60] evaluated antiviral activity of 16 natural alkaloids, obtained from rhizomes of Sophora tonkinensis.

1,7-Naphthyridine Derivatives
Bisleuconothine A 54 (Figure 16), determined as 1,7-naphthyridine alkaloid, was derived from the bark of Leuconotis griffithii-a species of plant with native distribution in southern Asia [61]. The agent 54 was shown to exert antineoplasm potency by inhibiting WNT signaling pathway, and to induce G0/G1 cell cycle arrest in cancer cells. It displayed significant antiproliferative properties against SW480, HCT116, HT29, and SW620 colon cancer cells in vitro (IC 50 values respectively 2.74, 3.18, 1.09, and 3.05 µM), and reduced tumor growth in mice carrying HCT116 Xenograft [62]. Research conducted by Wong et al. [63] in A549 non-small cell lung cancer and MCF-7 breast cancer cell lines showed that bisleuconothine A 54 ows its cytostatic properties to inducing autophagosome formation. Additionally, the compound 54 could also play a protective role in periodontitis. Bisleuconothine A 54 was determined to reduce RANKL expression and diminish periodontal tissue infiltration by pro-inflammatory polymorphonuclear cells [64].
Streptomyces albogriseolus is a mangrove bacterium species, widely known for producing aminoglycoside antibiotics neomycin B and neomycin C. Streptomyces albogriseolus has also been reported to be the source of 1,7-naphthyridine compound, 1-N-methyl-3methylamino-[N-butanoic acid-3 -(9 -methyl-8 -propen-7 -one)-amide]-benzo[f ] [1,7]  Some indolo [2,6]naphthyridine alkaloids were obtained from plants of Erythrina spp. The seeds of these tropical trees contain erythrina alkaloids of varying degrees of toxicity. Some of them are used by indigenous peoples for medicinal purposes. They have an effect on the central nervous system and exhibit hypnotic, curare-like effects and neuromuscular inhibition, as well as sedative and hypotensive activity [68,69].
Calycanthine 59 ( Figure 19) was the first alkaloid isolated from the plants Calycanthaceae [75]. Calycanthine 59 was also isolated from Meratia praecox [76]. Toxic doses of calycanthine 59 cause excitation in mice, rats, and rabbits. After injection, calycanthine hydrochloride induces hyperglycaemia in rabbits and lowers blood pressure in cats or dogs [77]. Calycanthine 59 acts on peripheral motor nerves to cause muscle weakness associated in lower animals. In mammals, calycanthine causes seizures. The alkaloid 59 is also a strong depressant on the heart. It was reported that the anticonvulsant effect of calycanthine 59 is mainly caused by the inhibition of the release of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid) [78]. Gordin [75] isolated a second alkaloid, isocalycanthine 60 ( Figure 19), from the seeds of Chimonanthus genus. This tetradehydroisomer of calycanthine was also isolated from the leaves of Psychotria colorata, the plant used in folk medicine to relieve pain [79], and from Psychotria forsteriana [80].

Tetracyclic Alkaloids
The extract of the plant Alangium lamarckii has been used by Indians to treat many human disorders [103]. In Thailand, it is useful in the treatment of asthma, coughs, hemorrhoids, diarrhea; and in India to treat leprosy, fever, or as an anthelmintic agent [104,105]. Pakrashi et al. [106,107]    Kitahara et al. [111] synthesized eupomatidines 1-3 84-86 and evaluated their antifungal activity against Candida albicans, Paecilomyces variotii, and Trichophyton mentagrophytes. Eupomatidine-1 84 exhibited activity against those tree fungi with EC 50 values of 50 µg/mL, 6.25 µg/mL, and 0.4 µg/mL, respectively. Eupomatidine-2 85 and eupomatidine-3 86 were active only toward T. mentagrophytes with EC 50 values 3.1 µg/mL and 6.25 µg/mL, respectively. Khan et al. [112] evaluated eupomatidine-1 84 against over a dozen Gram-positive and Gram-negative bacteria strains, a protozoan and nine fungi. This alkaloid 84 turned out to be much better than the applied standard (ketoconazole and griseofulvin), both in terms of scope and level of antifungal activity. Eupomatidine-1 84 showed comparable antimicrobial activity to chloramphenicol. Imbiline-1 87 (Figure 26) was also isolated from a large tree Duguetia hadrantha and then evaluated for its antimalarial and antimicrobial activity [113]. Imbiline-1 87 showed a weak antimalarial potency, but it was more active against chloroquine-resistant than chloroquine-sensitive Plasmodium falciparum clones. Imbiline-1 87 was found to be inactive against C. albicans, C. neoformans, and S. aureus. This alkaloid 87 exhibited cytotoxic activity in vitro against human malignant melanoma and human ovary carcinoma cell lines with IC 50 values of 2 µg/mL and 5 µg/mL, respectively [113].
Sampangines 92-96 ( Figure 27) also are tetracyclic alkaloids containing the 2,7 -naphthyridine scaffold. Sampangine 92 was isolated first from the stem bark of plant Cananga odorata by Rao et al. [114]. 3-Methoxy derivative 93 was isolated from Cleistopholis patens by Liu et al. [115]. Sampangine 92 and 3-methoxysampangine 93 were also isolated from Duguetia hadrantha and then evaluated for their antimalarial, antifungal, and cytotoxic potency [115]. Both alkaloids 92-93 exhibited activity against P. falciparum with no cytotoxicity toward VERO cells. Sampangine 92 showed cytotoxicity to human malignant melanoma with IC 50 = 0.37 µg/mL and inhibited cell aggregation (MIC < 0.15 µg/mL) [113]. Sampangine 92 isolated from the stem bark of Anaxagorea dolichocarpa by Lucio et al. [116] demonstrated antitumor activity against human leukemic strains with IC 50 values of 10.15-11.80 µg/mL. Sampangine 92 and 11-methoxysampangine 94 isolated from the roots of Ambavia gerrardii were evaluated for their antiproliferative activity [117]. Alkaloids 92 and 94 showed strong activity against human non-small cell lung cancer cell line with IC 50 values of 0.57-0.58 µM, but sampangine 92 was more active against human ovarian cancer cell line (IC 50 = 0.60 µM) than its 11-methoxy derivative 94 (IC 50 = 10.30 µM) [117]. Research by scientists under Kluza [118] directions has shown that sampangine 92 induces apoptosis in HL-60 cells. In low concentrations, it caused G1 arrest and at the same time induced mitochondrial hyperpolarization. At higher concentrations, it elicited mitochondrial depolarization [118]. The treatment of human leukemia cells with sampangine 92 (40 µM) induced apoptosis due to an oxidative stress [119]. The ability of sampangine 92 to produce reactive oxygen species was confirmed by using an in vitro biochemical assay, and the participation of this alkaloid 92 in binding and damaging DNA was excluded [120].
Calliactine 114 (Figure 31) was the first pyridoacridine derivative that was obtained. This alkaloid 114 was isolated from the sea anemone Calliactis parasitica in 1940 by E. Lederer et al. [135]. Since then, about a 100 pyridoacridine analogs have been found in many marine organisms. They have been isolated from ascidians, sponges, anemone, and certain mollusks. Most pyridoacridine derivatives were reported to possess significant pharmacological activities, including anticancer, antimicrobial, and antiparasitic activities [136][137][138][139].
Methylsulfanyl derivative of cystodytine J was isolated from the tunicate Diplosoma sp. by Charyulu et al. and named diplamine 130 [147]. Diplamine 130 and its isomer isodiplamine 131 ( Figure 34) were also isolated from the ascidian Lissoclinum notti and were tested for their cytotoxicity against murine leukemia, human colon tumor, and nonmalignant African Green Monkey kidney cell lines. Diplamine 130 was more cytotoxic towards BSC-1 cells than isodilamine 131. Diplamine 130 turned out to be a stronger topoisomerase II inhibitor than etoposide and showed the ability to intercalate into DNA [142]. Diplamines 130-131 also exhibited moderate antimicrobial activity towards Bacillus subtilis, Escherichia coli, Candida albicans, and Trichophyton mentagrophytes [143]. Diplamine B 132 was isolated from the ascidian Lissoclinum badium and tested by immunoblotting for its effects on cellular p53 and Hdm2 in the tert-immortalized human retinal pigment epithelial cells (the potency was similar to proteasome inhibitor N-acetyl-leucyl-leucylnorleucinal) [148].
The dependence of the activity of diplamine derivatives 130-132 on the type of substituents in the pyridoacridine scaffold is presented in Table 2. Another pyridoacridine alkaloid containing thiomethyl substituents-varamine A 133, veramine B 134, lissoclin A 135, and lissoclin B 136 ( Figure 35)-was isolated from the ascidian Lissoclinum sp. [149,150]. Varamines 133-134 showed cytotoxicity towards L-1210 murine leukemia cells with IC 50 values of 0.03 and 0.05 µg/mL, so they proved to be more toxic than cystoditines, which have the same skeleton but without the thiomethyl group [150]. Norsegoline 137 (Figure 36) was isolated from tunicate Eudistoma sp. [151,152]. Einat et al. [153] evaluated the inhibitory effect of norsegoline on the growth of myeloid progenitors obtained from bone marrow and peripheral blood of chronic myelogenous leukemia (CML) patients. Norsegoline 137 showed antiproliferative activity and may be an effective agent for use in removing ex vivo Philadelphia-positive cells from peripheral blood of CML patients in conjunction with autologous bone marrow transplantation [153]. Kim et al. [154] isolated a brominated alkaloid pantherinine 138 ( Figure 36) from the ascidian Aplidium pantherinum, which showed cytotoxic activity against murine leukemia cells (ED 50 = 4.5 µg/mL).
Kuanoniamine D 144 exhibited affinity to A1-and A2A-adenosine receptors (K i values of 2.94 and 13.7 µM, respectively), and all derivatives showed moderate affinity to benzodiazepine binding sites of GABA-A receptors [157]. Dehydrokuanoniamine F 149 showed cytotoxic activity toward the SW480 colon cancer cell line with IC 50 values of 3.30 µM [158].
Shermilamines are alkaloids with the 3-thiomorpholinone ring fused to pyridoacridine scaffold ( Figure 45). These alkaloids 187-190 were first isolated from the tunicate Trididemnum sp. [183,184], and later also from the ascidian Cystodytes sp. [142,185]. Shermilamines A 187 and B 188 exhibited cytotoxicity to murine leukemia cells. Shermilamine B 188 showed in vitro cytotoxic activity against KB cells with IC 50 = 5 µg/mL, and human colon tumor cells with IC 50 = 13.8 µM [156]. Shermilamines B and C 188-189 inhibit topoisomerase II and have the ability to intercalate into calf thymus DNA [142]. Shermilamine B 188 and N-deacetylshermilamine 190 were evaluated for their antibacterial activity against E. coli and M. luteus, but they were found to be less potent than reference gentamicin [138].

Hepta-and Oxacyclic Pyridoacridine Derivatives
Eilatin 191 is a symmetrical, heptacyclic alkaloid containing two pyridoacridine moieties ( Figure 46). This alkaloid 191 was isolated from the tunicate Eudistoma sp. [151,152] and also from the ascidians Cystodytes sp. and Polysyncraton echinatum [142,169]. Eilatin 191 showed in vitro antiproliferative activity against the human colon tumor cell line and the human embryonic kidney cell line [176]. It also inhibited topoisomerase II and intercalated into DNA [142]. Eilatin 191 has two sets of nitrogen atoms capable of metal ion chelation. Complexes of eilatin-Ru(II) exhibited strong anti-HIV activity [186].

Naphthyridines Molecular Mechanisms of Action-What Do We Know?
Naturally occurring naphthyridines are characterized by diverse mechanisms of action. Some of their biomolecular activities have been discovered, nevertheless there is still much to explore in this field.
The compounds modulate neurotransmission by affinity to GABA A and MAO A receptors, and inhibiting AchE activity [29,157,174].
Natural naphthyridines antiinfectious properties were widely screened against many infectious species [6,8,111,112,178]. However, molecular mechanisms of their action are still poorly researched and described. This issue is an interesting target for deeper research.
Natural naphthyridines have an extensive background of preliminary research, which is a solid foundation for molecular studies. Further investigations are still needed.

Conclusions
The natural environment, including marine and terrestrial organisms, should be considered as a rich source of bioactive substances. Naturally-derived naphthyridines, isolated mostly from sea species and terrestrial plants, have been shown as potent chemical compounds with multidirectional activity. Natural naphthyridines are most abundantly represented by 1,6-and 2,7-naphthyridine isomeric forms. Until now, research studies revealed their impressive antimicrobial [6,8,177], antifungal [6,8,111,112], and antimycobacterial [10,178] effects, and some of them displayed activity superior or comparable to those presented by chloramphenicol [112], amphotericin B [115], and rifampin [124]drugs used in standard therapeutic regimens. Moreover, naphthyridines were shown to present significant properties including antiinfectious: antiviral [11,24,50,51], antiparasitic [9,176], and antimalarial [113]; anticancer [5,6,23,35]; influencing cardiovascular system: hypotensive [16,27], cardioprotective [43,44]; neurological: sedative [94], analgesic [15], anticonvulsant [78], stimulating neuritogenesis [188]; psychotropic: antianxiety [97], antidepressant [29,97]; and affecting immune system: anti-inflammatory [7,56,57], immunosuppressant [48][49][50]. The spectrum of activity of naturally-derived naphthyridines is wide, thus these compounds are undeniably fascinating subjects of research. An undoubted advantage of naphthyridines is their wide availability thanks to the possibility of obtaining them both from natural sources and synthetically. The versatility of naphthyridines is expressed by the occurrence of multiple activities within a single compound. Moreover, many of the representatives are considered as safe and nontoxic, and constitute a great alternatives for standard therapies [9,48]. We strongly believe that this work will contribute to further exploration of naphthyridine derivatives-their natural sources and bioactive properties-and will result in the use of these chemical compounds for therapeutic purposes in the future.