Synthesis and Biological Activity of Chromeno[3,2-c]Pyridines

Abstract

The review summarizes all synthetic methodologies for the preparation of chromeno[3,2-c]pyridines and chromeno[3,2-c]quinolines. The proposed approaches are systemized based on ways for the construction of the heterocyclic system. The presence of these compounds in nature and their bioactivity are also discussed. Natural products with an annelated chromeno[3,2-c]pyridine fragment are well-known and a number of alkaloids derived from this system as a key core have been recently isolated. These compounds demonstrate antimicrobial, antivirus, and cytotoxic activities, making chromeno[3,2-c]pyridine structural motifs promising for medicinal chemistry.

1. Introduction

Quinoline, pyridine, chromene, and especially its derivatives chromones, represent privileged scaffolds and occupy a unique place in the field of synthetic and medicinal chemistry due to their wide spectrum of biological activities [1,2,3,4,5,6,7,8,9,10,11,12]. The combination of these heterocyclic systems in a single molecule promises to open up new opportunities for finding desirable properties and thus encourages the scientific community to develop methods for constructing such fused hybrids. Indeed, chromenopyridines are a structurally diverse class of compounds with a wide range of biological activities that are increasing in presence in pharmaceuticals. Moreover, studies show that they can be applied as dyestuffs [13,14,15], luminescence intensifiers [16], and fluorescent dyes [17]. An analysis of data from the literature has revealed that for over the past three decades, a number of reviews on chromenopyridines have been published [18,19,20], but to our surprise, chromeno[3,2-c]pyridines and chromeno[3,2-c]quinolines have not been completely covered; so far, only scattered examples have been described in some of them [21,22]. Here, we try to summarize all synthetic methodologies and present the results of our survey.

2. Recently Isolated Natural Chromeno[3,2-c]Pyridines and Their Bioactivities

Natural products with an annelated chromeno[3,2-c]pyridine fragment are well-known and were discovered long ago [23,24,25,26,27,28,29,30,31,32]. However, surprisingly, alkaloids derived from the chromeno[3,2-c]pyridine system as a key core were not been isolated until the twenty-first century. Only in recent decades have papers devoted to the isolation and identification of chromeno[3,2-c]pyridines alkaloid begun to appear. Thus, in 2002, Paune et al. disclosed and characterized a novel series of tricyclic natural product-derived metallo-β-lactamase inhibitors. Among three natural products isolated from the fungus Chaetomium funicola, there was an alkaloid with the unique chromeno[3,2-c]pyridine nucleus. The first representative of the new class was labeled as SB236049. The biological test of SB236049 revealed inhibitory activity towards the Bacillus cereus II and Bacteroides fragilis CfiA metallo-β-lactamases [33] (Figure 1).

Later in 2013, Gan et al. succeeded in isolating another alkaloid with the chromeno[3,2-c]pyridine core–7-hydroxy-8-methoxy-3-methyl-10-oxo-10H-chromeno[3,2-c]-pyridine-9-carboxylic acid 1 from the cultures of Penicillium sp. I09F 484 (Figure 1) [34]. The alkaloid displayed inhibitory activity against New Delhi metallo-β-lactamase 1 with IC₅₀ values of 87.9 μM, but it did not reveal antimicrobial, antiviral, and cytotoxic activities at a concentration of 10 μM. The authors also proposed the biosynthetic pathway, suggesting that the chromeno[3,2-c]pyridine moiety was generated by a common biosynthesis strategy from a heptaketide precursor (Scheme 1).

In 2017, when analyzing metabolites from the mangrove endophytic fungus Diaporthe phaseolorum SKS019 obtained from holy mangrove (Acanthus ilicifilius), Cui et al. separated and identified four previously unknown alkaloids of this type. The new chromeno[3,2-c]pyridine alkaloids, labeled as Diaporphasines A–D, were tested on five tumor cell lines, but unfortunately, they exhibited no significant inhibitory activity [35]. More recently, the Diaporphasine series has been extended, with Diaporphasine E isolated by Phutthacharoen et al. from a mycelial extract of a saprotrophic fungus Lachnum sp. IW157 growing on the common reed grass Phragmites communis (Figure 1) [36]. Diaporphasines E revealed potent cytotoxicity against the tested cell lines L929 and KB3.1 with IC₅₀ values of 0.9 and 3.7 μM.

Chromeno[3,2-c]pyridine, named Phomochromenones C (Figure 2), was isolated from metabolites of the endophytic fungus Phomopsis sp. HNY29-2B, which was derived from the mangrove plant Acanthus ilicifolius Linn [37]. Later Phomochromenones C was also separated from the culture of Phomopsis asparagi DHS-48 from the Chinese mangrove Rhizophora mangle [38] and the marine-derived fungus Diaporthe sp. XW12–1 [39].

In 2021–2022, scientific groups from China published a series of papers devoted to isolation and identification of chromenopyridine alkaloids from different species of Thalictrum. Thus, Yang et al. reported on the isolation of three previously unknown chromeno[3,2-c]pyridine alkaloids 2–4 from the whole plants of Thalictrum scabrifolium. The compounds were tested and showed antirotavirus activity (Figure 3, line 1) [40]. Later, and from the same species, Yin et al. managed to obtain two more natural chromeno[3,2-c]pyridines 5–6, which possessed high antibacterial activity against 12 microbial strains isolated from the saliva of smokers (Figure 3, line 2) [41].

Chromeno[3,2-c]pyridines 7–8, isolated by Hu et al. from the whole plants of Thalictrum finetii, exhibited high antirotavirus activity (Figure 3, line 3) [42].

Exploring the whole plants of Thalictrum microgynum, Wu et al. succeeded in isolating two new alkaloids 9–10, comprising chromeno[3,2-c]pyridine skeleton in their structures. The obtained chromeno[3,2-c]pyridines showed anti-tobacco mosaic virus (anti-TMV) activity [43] (Figure 3, line 4).

In 2023, Wu et al., screening metabolites obtained from the cigar-tobacco-leaf-derived endophytic fungi Aspergillus lentulus, isolated two known chromeno[3,2-c]pyridine alkaloids (Figure 3, compound 4 and compound 9). The anti-TMV activities test of compound 4 revealed its high anti-TMV activities with inhibition rate of 38.5% [44].

3. Synthetic Ways to Chromeno[3,2-c]Pyridines and Chromeno[3,2-c]Quinolines

3.1. Construction of Chromene Fragment

3.1.1. Synthesis Based on Cyclization of Pyridyl(Quinolyl) Phenyl Ethers

The first suggested synthetic ways towards chromeno[3,2-c]pyridines were based on the cyclization of pyridyl phenyl ethers decorated with appropriate groups—cyano, ester, carboxylic acid, etc. In 1955, Kruger et al. realized the synthesis of chromeno[3,2-c]pyridine 14 via the cyclization of cyanopyridyl phenyl ether [45]. A four-step sequence commenced with a condensation of 4-chloro-3-nitropyridine with phenol to give intermediate 3-nitropyridyl phenyl ether 11. Reduction of the nitro-group of 11 to amine 12, followed by diazotation and cyanation, afforded cyanopyridyl phenyl ether 13. The final cyclization of it under the action of H₂SO₄ at 195 °C led to the target chromeno[3,2-c]pyridine 14 in 10% yield (Scheme 2).

In 1970, Bloomfield et al. showed that ester decorated phenyl pyridyl ether were also appropriate for furnishing the chromene fragment and realized a successful attempt at cyclization of ether 16 [46]. Obtained by treatment of the 4-chloroquinolines 15 with phenol at 160 °C, phenyl ethers 16 readily cyclized in hot polyphosphoric acid to give chromeno[3,2-c]quinolines 17 in 58–82% yield (Scheme 3).

Later, in 1975, employing 4-phenoxynicotinic acid 20 as a substrate, Villani et al. succeeded in achieving chromeno[3,2-c]pyridine 14 in 91% yield through the cyclization stage, which was carried out under the action of PPA (Scheme 4) [47]. The synthesis of the desired 4-phenoxynicotinic acid required four steps and included the interaction of the starting 4-nitro-3-picoline 1-oxide and phenol, resulting in the formation of ether 18, which was N-deoxygenated to give pyridyl ether 19. Oxidation of the latter with aqueous KMnO₄ led to the desired substrate 20.

In 1999, Khodair et al. also exploited this strategy [48]. Phenyl pyridyl ethers 23, derived from 4-chloro-3-nitro substituted quinolones 21 and corresponding salicylic acids or salicylaldehydes 22, underwent cyclization in benzene under reflux to produce chromeno[3,2-c]quinolines 24 (Scheme 5). It was also shown that the cyclization could be realized as a one-pot process.

In their research, Okada et al. took 3-trifluoroacetyl-4-quinolyl ethers 26 as a substrate for cyclization to obtain chromeno[3,2-c]quinolones 27 bearing a trifluoromethyl group in high yields. The required precursors 26 were synthesized by a two-step sequence including trifluoroacylation of 4-dimethylaminoquinoline followed by an exchange reaction with phenols 25. The cyclization of compound 26 with trifluoromethansulfonic acid (TFSA) proceeded smoothly at room temperature to give the final product 27 (Scheme 6) [49].

In 2017, Hong et al. suggested an efficient method to assemble the chromeno[3,2-c]quinoline core based on a one-pot oxidative O-arylation, Pd⁰-catalyzed C(sp³)-H arylation sequence [50]. In situ, generated from arylols 28 and trivalentaryl iodine reagents 29, without isolation ethers 30 underwent Pd⁰-catalyzed C(sp³)-H arylation to give the target products 31 in good yields (54–80%) (Scheme 7). The cyclization step occurred exclusively at the sterically less hindered position when methyl and ethyl groups were both present on the aryl ring of the iodine reagent, and tolerated both electron-donating and electron-withdrawing groups on the 6-position of the quinoline ring.

Recently, Kardile et al. returned to the idea of the cyclization of pyridyl phenyl ether having a carboxylic acid group and performed a six-step synthesis of chromeno[3,2-c]quinolines 33, starting from 4-bromoaniline and malonic acid (Scheme 8). The final cyclization step of ether 32 was carried out under trifluoroacetic anhydride in a mixture of THF/DCM (1:1) at 0 °C—room temperature to afford the target compound 33 in 81% yield. Further, compound 33 produced a series of chromeno[3,2-c]quinolines 34 by reaction with Grignard reagent [51].

Chen et al. also resorted to the cyclization of pyridyl phenyl ether as a methodology of the synthesis of chromeno[3,2-c]pyridine 39 necessary for their research on the discovery of novel chronic hepatitis B virus cccDNA reducers [52]. The target chromeno[3,2-c]pyridine 39 was obtained through Cu-catalyzed O-arylation between methyl 4,6-dicholonicotinate 36, derived from the corresponding acid 35, and 2-fluorophenol followed by the hydrolysis of intermediate ester 37, and the cyclization of the resultant ether 38 under the action of sulfuric acid at 100 °C (Scheme 9). The successive substitution of chlorine atom with pyrrolidine and K₃PO₄ as a base gave compound 40.

3.1.2. Synthesis Based on Morpholine Enamine

One of the most promising and simple synthetic pathways towards chromeno[3,2-c]pyridines is a condensation of heterocyclic morpholine enamines with salicylaldehydes. This approach was first proposed by Sliwa et al. in 1977 [53]. A condensation of morpholine enamine with salicylaldehyde in boiling hexane followed by the direct oxidation of intermediate 41 with chromium trioxide-pyridine afforded chromeno[3,2-c]pyridine 42 in 35% yield. When refluxed in xylene in the presence of palladium-charcoal, compound 42 underwent debenzylation and aromatization to give 14, which was reduced by lithium aluminum hydride to 10H-chromeno[3,2-c]pyridine 43 (Scheme 10).

Ten years later, the authors expanded their idea and showed that condensation could be realized between heterocyclic morphine enamine 44 and β-ketoester 45 when heated in xylene. In addition, the resulting octahydro derivative 46 could undergo partial or complete aromatization, leading to either chromeno[3,2-c]pyridine 47 or chromeno[3,2-c]pyridine 14 (Scheme 11) [54].

Later, the above-mentioned methodology was successfully applied by other scientific groups to create a series of differently substituted chromeno[3,2-c]pyridines 51–52 (Scheme 12) [55,56,57,58]. It was shown that the reaction features simplicity of performance and is tolerant to both electron-donating and electron-withdrawing groups. Moreover, it was found that when heated in o-xylene in the presence of TsOH, intermediate 50 was converted into chromeno[3,2-c]pyridines in moderate yields. Some of the obtained chromeno[3,2-c]pyridines 51 were chemically modified to increase the diversity of the class for biological tests [56,57,58]. Several derivatives showed multifaceted profiles of promising anti-Alzheimer’s disease properties and well-balanced multitarget inhibitory activity. Inhibitory activities against monoamine oxidase A and B (MAO A and B), acetyl- and butyrylcholinesterase (AChE and BChE), and anti-aggregation activity against β-amyloid were demonstrated. One of the compounds, a potent and selective inhibitor of human MAO B (IC50 = 0.89 μM), was shown to be a safe neuroprotector in a human neuroblastoma cell line (SH-SY5Y), improving viability impaired by Aβ1–42 and prooxidant damage.

3.1.3. Synthesis Based on Intramolecular Cyclization via Nucleophilic Substitution of Halogen

In 1971, Harnisch used an electrophilic substitution/nucleophilic substitution sequence of reactions for the synthesis of dye 57 possessing the chromeno[3,2-c]pyridine fragment [14]. The starting 4-chloroquinoline-3-caraldehyde 55 and N,N-dimethyl-3-aminophenol 56 underwent cyclization in glacial acetic acid under reflux to give dye 57 in 80% (Scheme 13). Later, the same principle for the synthesis of dyes and fluorescent markers was applied by other scientific groups [17].

In 1988, Marsais et al. also employed nucleophilic substitution of halogen atom as the final step for the construction of chromeno[3,2-c]pyridine synthon. To activate the halogen atom and facilitate the nucleophilic substitution, 4-fluoropyridine was submitted to metalation with LDA and o-anisaldehyde to give secondary alcohol 58, which when oxidized by MnO₂ afforded 4-fluoropyridine 59, activated by 3-carbonyl moiety. Intramolecular cyclization of the latter occurred in boiling pyridinium chloride, providing chromeno[3,2-c]pyridine 14 in 80% yield (Scheme 14) [59].

While exploring the synthesis of azafluorenones through Pd-catalyzed intramolecular arylation of diarylketones bearing a halogen at the 2-position in one of the aryl groups, Marquise et al. observed that under the suggested conditions (2-chlorophenyl)(2-methoxypyridin-3-yl)methanone 60 preferably underwent an intramolecular cyclization, resulting in the formation of chromeno[3,2-c]pyridine 61, which was the only product of the reaction (Scheme 15) [60].

3.1.4. Synthesis Based on Chromene-3-Thiocarboxamide

In 2001, El-Sayed obtained a series of chromeno[3,2-c]pyridines 62 from chromene-3-thiocarboxamides 61. The substrates 61 reacted with oxalyl chloride in the presence of triethylamine in dioxane at room temperature to give chromeno[3,2-c]pyridines 62 in good yields, whereas the conversion of chromene 61 into compound 64 required more rigid conditions and proceeded in two steps. Alkylation of thiocarboxamide fragment with bromomalononitrile and the sequent intramolecular cyclization of the resultant chromene 63 in refluxing DMSO afforded chromeno[3,2-c]pyridine 64 in 67% yield (Scheme 16) [61].

In a later paper, it was demonstrated that the interaction of 2-imino-chromen-3-thiocarboxamide 65 with malononitrile in EtOH in the presence of piperidine went through a cascade of reactions leading to the final compound 67 in 64% yield (Scheme 17). The process occurred at room temperature, but when the temperature was raised to boiling EtOH, another pathway was preferable, resulting in chromeno[2,3-b]pyridine [62].

3.1.5. Synthesis Based on Knoevenagel Condensation/Michael Addition Sequence

In 2015, Kumar et al. reported an efficient synthesis of a series of novel chromeno[3,2-c]pyridines 72 via Michael addition/intramolecular O-cyclization/elimination cascade [63]. 3,5-((E)-arylidene)-1-alkylpiperidin-4-ones 70, derived by Knoevenagel condensation of two molecules of aryl aldehyde 69 and N-alkyl(benzyl)piperidone 68, reacted with cyclic 1,3-diketones 71 in acetic acid under reflux to afford chromeno[3,2-c]pyridines 72 in excellent yields (Scheme 18). The process tolerates aldehydes bearing electron-withdrawing or electron-donating groups in the aryl rings. It is worth noting that the attempt to find conditions suitable to carry out a three-component reaction starting from the corresponding piperidones, aryl aldehydes, and cyclohexane-1,3-diones failed; instead of the targeted chromenopyridine derivatives, xanthene was formed.

In 2016, while working on a three-component strategy towards dibenzo[b,h][1,6]naphthyridine from aryl aldehydes 73, 3-(arylamino)cyclohex-2-enone 74 and 4-hydroxyquinolinone 75, Wang et al. developed an efficient method for the synthesis of chromeno[3,2-c]quinolones 77 [64]. It was observed that a three-component reaction of the starting compounds 73, 74, and 75, catalyzed by TsOH and heated to 140 °C in ionic liquid, provided chromeno[3,2-c]quinolones 77 in high yields. The temperature value and the presence of TsOH appeared to be crucial; without them, the final cyclization did not occur. As it was in the previous example, the reaction starts with the Knoevenagel condensation of aryl aldehyde 73 and 4-hydroxyquinolinone 75; the resulting quinolone-2,4-dione 76 undergoes consecutive Michael addition, protonation, secondary Michael addition, and deamination (Scheme 19). Interestingly, again, the idea to use dimedone instead of 3-(arylamino)cyclohex-2-enone 74 in a three-component reaction failed.

Recently Kamali et al. managed to select conditions and starting material suitable for a three-component reaction with dimedone and proposed a facile, one-pot three-component synthesis towards chromeno[3,2-c]pyridine-1,9-diones 81 [65]. The chromeno[3,2-c]pyridine system was built up through a SnCl₂·2H₂O-mediated sequence of Knoevenagel condensation/Michael addition/Knoevenagel condensation form 4-hydroxypyridine-2-ones 78, aldehydes 79, and dimedone in ethanol at 70 °C (Scheme 20). The mechanism of the transformation resembles the examples depicted in previous Scheme 19. Despite all the advantages of the reaction (environmentally friendly, mild conditions, operational simplicity, high yields), it featured a drawback as it could only be realized for aromatic aldehydes.

The similar strategy based on Knoevenagel condensation/Michael addition sequence was successfully applied to the synthesis of benzo[5,6]chromeno[3,2-c]quinolones 83. By taking arylglyoxal monohydrates 82, quinoline-2,4-dione, and β-naphthol as starting materials, Orang et al. succeeded in developing a TsOH-catalyzed one-pot, three-component reaction [66,67]. The reaction occurred in a water/EtOH mixture (2:1) under reflux to give compounds 83 in 88–92% yields. It is believed that the process commences with the TsOH-catalyzed in situ generation of arylglyoxal, followed by Knoevenagel condensation with quinoline-2,4-dione. The key step of the construction of chromene fragment is Michael addition of β-naphthol, then the subsequent O-cyclization and the elimination furnish formation of benzo[5,6]chromeno[3,2-c]quinolones 83 (Scheme 21).

3.1.6. Miscellaneous

In 2022, Yang et al. published a paper on a methodology for the efficient construction of β-enamino diketones 86 through the DABCO-catalyzed, CH₃NO₂-mediated three-component reaction of 1,3-cyclodiketones 84, furfurals 85, and allylamine in reflux toluene. Further, the obtained compounds 86 were successfully converted to chromeno[3,2-c]quinolines 87 via bromination with NBS [68]. The transformation presumably commences with the bromination of the double bond on the epoxyisoindole of β-enamino diketones 86 with NBS to produce cyclic brominium ion A. The succinimide anion, resulting from the bromination, takes a proton from β-enamino nitrogen, followed by electron delocalization to give zwitterion B. The succeeding rotation of the C−C single bond between quinoline-2,4-dione and epoxyisoindole moieties of B favors the cyclic brominium fragment for the final intramolecular S_N2 ring opening of the cyclicbromonium ion by the alkoxide anion to afford the cyclized product 87 (Scheme 22). The authors also showed that compounds 87 could be diastereoselectively reduced by NaBH₄ to chromeno[3,2-c]quinolones 88.

3.2. Construction of Pyridine Fragment

3.2.1. Synthesis Based on Ethyl Coumarin-3-Carboxylate

In 1980, Briet et al. released a patent describing the synthesis and antidepressant activity of a series of chromeno[3,2-c]pyridines 92, among which the hit compound was lortalamine [69]. The chromeno[3,2-c]pyridine system was constructed in a two-step procedure from ethyl coumarin-3-carboxylates 89 and 1-alkyl-4-piperidones 90. The Michael addition of N-substituted 4-piperidones 90 to coumarin derivatives 89 and the subsequent cleavage of the resultant adduct by ammonia, generated from ammonium acetate or primary amines 91, occurred when the reaction mixtures were heated with or without an alcohol solvent. The following treatment with boiling concentrated hydrochloric acid caused cyclization to give the final product 92 (Scheme 23). It was demonstrated that when the treatment was realized by cold concentrated hydrochloric acid β-ketoesters 93 were isolated, which successfully underwent decarboxylation when heated in sodium bicarbonate. Some N-benzyl substituted chromenopyridines 92 went through debenzylation to afford NH-chromonemopyridines. Later, it was shown that NH-chromonemopyridines could be obtained using N-Boc-4-piperidone [70].

Different groups of chemists undertook attempts to carry out the asymmetric synthesis of lortalamine or its analogs. Three papers appeared describing the syntheses of enantiomers [71,72,73]. All these syntheses were based on the methodology previously described in the patent.

3.2.2. Synthesis Based on 3-Carbonylchromones

In 1988, Ghosh et al. synthesized several chromenopyridines from 2-(2-dimethylaminoethenyl)chromones 95 derived by methylenation of 2-methyl 3-carbonyl chromones 94 with N,N-dimethylformamide dimethyl acetal (DMFDA). When reacted with N-nucleophiles, chromones 95 underwent 1,6-addition-elimination sequence leading to enamines 96; further, they were cyclized in acetic acid at the reflux to give chromeno[3,2-c]pyridines 97, 98, or 99. Chromenopyridine N-acetylinide 97 was converted into compound 98 in boiling ethylene glycol with 70–80% yields (Scheme 24) [74].

In another study, Ghosh et al. chose 3-carbonyl chromones 100 as the substrates for condensation with DMFDA. The obtained chromones 101 were submitted into reactions with N-nucleophiles in refluxing ethanol and, depending on the nature of the nucleophile, chromeno[3,2-c]pyridines 102 or chromeno[3,2-c]pyridinium salts 103 were formed. The formation of 102 was accompanied by phenyl pyridyl ketone 104 (Scheme 25) [75].

In 1990, Rajagopal et al. accomplished the synthesis of fluorescent 2,3-fused couramin derivatives, including chromeno[3,2-c]pyridines 107 and 108 [76]. 3-Carboxamide derivative 105, derived from 4-diethylaminosalicylaldehyde and cyanoacetamide, reacted with p-nitrobenzylcyanide or benzimidazo-2-acetonitrile 106 in DMF under reflux in the presence of pyridines as a catalyst, giving chromeno[3,2-c]pyridines 107 in 60% and 65% yield, respectively (Scheme 26). When refluxed in DFA with esters or cyanoacetamide 108, the starting coumarin 105 was converted into chromeno[3,2-c]pyridines 109 in 30–70% yields (Scheme 26).

In 2008, Plaskon et al. described the synthesis of 7H-chromeno[3,2-c]quinoline-7-ones 111 employing a TMSCl-promoted cyclization of 3-formylchromone with various anilines 110 (Scheme 27) [77]. On heating a solution of 3-formylchromone with anilines 110 in the presence of TMSCl in DMF at 100 °C, chromeno[3,2-c]quinolines 111 were obtained in 39–67% yields. The authors proved that the anilines 110 with substituents, which withdraw electrons from the ortho-position or increase electron density on the nitrogen-favored formation of chromeno[3,2-c]quinolones 111; otherwise the cyclization did not occur.

In 2012, an unusual way for constructing a chromeno[3,2-c]pyridine framework was found by Wittstein et al., who were the first to demonstrate that conjugated N-phenyl-C-chromonyl nitrones 112 behaved as 1,5-dipoles. Synthesized by the condensation of 3-formyl chromones with phenylhydroxylamine, N-phenyl nitrones 112 reacted with zwitterionic allenoate 113, in situ generated from triphenylphosphine and DMAD, to give chromeno[3,2-c]pyridines 114 (Scheme 28) [78]. The transformation proceeds via [5+3] cycloaddition followed by rearrangement with the elimination of Ph₃PO and 6π-electrocyclization to give the final compound 114. It is noteworthy that N-substituents of nitrones 112 displayed an unusual control over the pathway of the transformations. Thus, N-alkyl substituted nitrones 112 with zwitterionic allenoate 113 provided an expected [3+2] cycloadducts instead of the formation of chromenopyridine synthon.

Another interesting way of building up chromeno[3,2-c]pyridine moiety starting from formylchromone was revealed by Bandyopadhyay et al. The Ugi adduct chromones 119, synthesized from 3-formylchromone 115, o-haloanilines 116, isocyanides 117, and carboxylic acids 118, underwent a ligand-free Pd-catalyzed intramolecular C-arylation at the C-2 or C-3 position of the chromone with the o-halophenyl group to give compound 120 instead of C–N coupling between the o-halophenyl and the amide NH group. The reaction proceeded under an argon atmosphere with PdCl₂ as a catalyst, KOAc, and DMF at 100–110 °C (Scheme 29) [79].

3.2.3. Synthesis Based on Diels-Alder Reaction

In their ongoing research focusing on the search for substances with antituberculous activity, Sriram et al. synthesized a series of chromeno[3,2-c]pyridines 124 using a one-pot two-step process. The first step involved a MW-promoted condensation of 3-formyl chromone with 2-amino-3-methylpyridine or 2-amino-3,5-dibromopyridine 121, which was followed by MW-indium triflate-assisted hetero-Diels-Alder reaction of intermediate Schiff bases 122 and N-(prop-2-yn-1-yl)arylamides 123. The target compounds were isolated in good yields (Scheme 30) [80]. Some of these substances showed preliminary in-vitro and in vivo activity against Mycobacterium tuberculosis H37Rv (MTB) and multidrug-resistant M. tuberculosis (MDR-TB).

The possibility of exploiting the [4+2]-cycloaddition reactions of o-quinone methides with electron-rich olefines in the construction of the chromeno[3,2-c]pyridine system was demonstrated by Popova et al. [81]. The heating of 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)morpholine 126 with Mannich bases of isoflavones 125 in toluene, followed by the treatment with formic acid in isopropanol, led to the formation of pyrano[2′,3′:5,6]chromeno[3,2-c]pyridine 129 (Scheme 31A). It is believed that the sequence of reactions begins with the generation of the o-quinone methide intermediate 127, which undergoes the hetero-Diels–Alder reaction with 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)morpholine 126 to give unstable adducts 128, the hydrolysis of which completes the transformation, giving the targeted system 129. It is worth mentioning that a ring–chain tautomerism of the ketone and hemiketal forms was observed for the synthesized compounds 129. The same idea was successfully applied for the synthesis of furo [2′,3′:5,6]chromeno[3,2-c]pyridin-3(2H)-one 131 from 6-hydroxy-7-dimethylaminomethylaurones 130 (Scheme 31B).

3.2.4. Miscellaneous

In 2004, Abdelkhalik et al. described the synthesis of thiophene-fused chromeno[3,2-c]pyridine 134 from benzo[h]thieno[3,4-c]chromene 132 [82]. The starting compound 132 reacted with DMAD in reflux xylene to produce chromeno[3,2-c]pyridine 134, a product of addition and subsequent water elimination. The authors also showed that the same compound 134 (in 82% yield) could be obtained through the cyclization of thienopyridine 133, derived from the interaction of benzo[h]theino [3,4-c]chromene 132 with DMAD in DMF at reflux, when it was heated in xylene (Scheme 32).

In 2012, Yan et al. reported on a direct synthesis of chromeno[3,2-c]pyridines 138 via a domino three-component reaction [83]. Based on the fact that N-unsubstituted aryl aldimines would act as nucleophiles in the Michael addition reaction with 3-(1-alkynyl)chromones 135 and could cause further transformations, a new effective cascade reaction was developed. NH-aldimines 137, in situ generated by condensation of the corresponding aldehydes 136 with ammonium acetate, reacted with 3-(1-alkynyl)chromones 135 to give chromeno[3,2-c]pyridines 138 in 21–85% yield. The process occurred in DMF at 100 °C and was tolerant to a wide range of aryl aldehydes 136 and formaldehyde, whereas the use of both enolizable and α,β-unsaturated aldehydes led to complicated results. The plausible mechanism suggested that the domino process begins with the Michael addition of aldimine 137 to 3-(1-alkynyl)chromones 135 to give pyrone A, the subsequent cleavage of pyrone ring produces intermediate B, which undergoes intermolecular cyclization followed by 6π-electrocyclization and dehydration to end with the formation of the final product 138 (Scheme 33).

In 2014, Hamada et al. reported the efficient synthesis of fused heterocycles through an acid-promoted cascade cyclization process of aryl group-substituted propargyl alcohol derivatives 139 with a p-hydroxybenzylamine unit [84]. Using phenol derivatives 139 as substrates, they obtained chromeno[3,2-c]pyridine 140 in moderated yield. The cascade cyclization commences with an acid-promoted intramolecular ipso-Friedel-Crafts alkylation of phenol derivatives 139; the subsequent rearomatization-promoted C–C bond cleavage gives an iminium cation A, which goes through aza-Prins reaction, and the final 6-membered ring cyclization of the resulting allyl cation B affords chromeno[3,2-c]pyridine product 140 (Scheme 34).

Investigating the substrate scope of Pd(II)-catalyzed tandem C–H alkenylation/C–O cyclization reactions in o-hydroxyphenyl decorated flavone derivatives, Kim et al. demonstrated that the revealed process was flexible and could be successfully applied for N-sulfonyl derivative 141 [85]. Flavone 141 reacted with n-butyl acrylate at 120 °C in t-BuOH in the presence of Pd(acac)₂ as a catalyst, Cs₂CO₃ as a base, and Al₂O₃ as an additive, to afford chromeno[3,2-c]quinoline 142 in 62% yield (Scheme 35).

An interesting example of a one-pot synthesis of a novel series of chromenopyridodiazepinone 144 with chromeno[3,2-c]pyridine moiety was suggested by Bouchama et al. [86]. The synthesis was based on the nucleophilic addition of ethane-1,2-diamine to (E,E)-3-[3-(2-hydroxyphenyl)-3-oxoprop-1-en-1-yl]-2-styrylchromones 143 and proceeded at room temperature under mild conditions. Chromenopyridodiazepinone 144 resulted from a tandem process involving the Michael addition of one amine group of ethane-1,2-diamine, the subsequent intramolecular heterocyclization through a 1,6-conjugate addition, and the final imine condensation (Scheme 36).

In 2019, Kumar et al. described an approach towards chromeno[3,2-c]quinolones 147 from 2-(2-aminophenyl)chromen-4-ones 145 through a Fe^III-catalyzed imine formation/C-C coupling/oxidation cascade [87]. The starting substrates 145 interacted with aromatic aldehydes 146, bearing both electron-donating and electron-withdrawing groups, in the presence of FeCl₃ as a catalyst in nitrobenzene under an argon atmosphere (Scheme 37). It is suggested that the key step of the formation of the target system is the electrophilic attack of the chromone ring followed by oxidative aromatization.

While optimizing conditions for a tree-component reaction for the synthesis of indole-substituted chromenopyridines, Kulikova et al. revealed that carrying out reactions of salicylic aldehydes 148 and N-methylpiperidone 149 in EtOH in the presence of L-proline as a catalyst leads to the formation of hexahydrochromenopyridines 150 in 69–76% yields (Scheme 38) [58]. The products precipitated from the reaction mixtures and were isolated by filtration. According to the X-ray data, compounds 150 are formed diastereoselectively and have hydroxyl groups in a relative trans-configuration and the azadecalin system of annulated two non-aromatic six-membered cycles in a cis-configuration. It was demonstrated that L-proline played a crucial role in the stereoselectivity; thus, when the same reactions were performed without the additive, a series of chromeno[3,2-c]pyridines 151 with trans-configuration of the fused azadecalin system were obtained.

A simple and interesting way for the synthesis of chromeno[3,2-c]pyridines 154 was suggested by Kawai et al. The starting pyrano[4,3-b]chromen-1,10-dione, derived through acylation of pyran-2-one with 2-fluorobenzoyl chloride and the consequent rearrangement and aromatic nucleophilic substitution caused by the treatment of resultant ester 152 with KCN, Et₃N, and 18-crown-6, reacted with primary amines 153 in the presence of acetic acid at 110 °C in trifluoroethanol to provide N-substituted chromeno[3,2-c]pyridines 154 in 16–32% yields (Scheme 39) [88].

4. Biological Activity of Chromeno[3,2-c]Pyridines

Natural and synthetically prepared chromeno[3,2-c]pyridines demonstrate a wide range of biological activities. The available data is summarized in Table 1.

Comparing the biological activity of other chromenopyridines [89,90] with chromeno[3,2-c]pyridines clearly demonstrates that the latter has promising potential for treating neurodegenerative diseases [56,57,58,69]. At the same time, the antimicrobial and antibacterial activities of these compounds are similar to other chromenopyridines [91,92,93]. However, the antivirus activity was described only for chromeno[3,2-c]pyridines. Some chromenopyridines can be used as non-steroidal anti-inflammatory drugs [94,95,96]. Unfortunately, chromeno[3,2-c]pyridines have not been tested for these purposes yet.

Chromeno [2,3-b]pyridines and chromeno [4,3-b]pyridines possess high antiproliferative properties [97,98,99,100,101]. However, the anticancer properties of chromeno[3,2-c]pyridines do not look very promising now, but the development of their chemistry can produce novel substances, demonstrating better results in this field. For example, the introduction of indole fragments increases their potential.

In our opinion, we assume that chromeno[3,2-c]pyridine are at the beginning of their stardom, and the further evolution of the chemistry of chromeno[3,2-c]pyridines should be focused on the synthesis of multitarget compounds, having both anti-neurodegenerative and antioxidant properties. These aims may be achieved by the introduction of substituents that have described antioxidant activities. Another productive approach implies the synthesis of binary compounds containing two scaffolds chromeno[3,2-c]pyridine and, for example, tacrine, indole, etc., which are bonded by linkers [102,103].

Table 1

Information on biological activity of chromeno[3,2-c]pyridines.

Chemical Structure	Clinical Use	Concentration of Compound	Year–Author–Lit
SB236049	inhibitory activity towards the Bacillus cereus II and Bacteroides fragilis CfiA metallo-β-lactamases	IC50 values of 0.3 μM and 2 μM	In 2002, Paune et al. [33]isolated from the fungus Chaetomium funicola
	the alkaloid displayed inhibitory activity against New Delhi metallo-β-lactamase	IC50 value of 87.9 μM	In 2013, Gan et al. [34]isolated cultures of Penicillium sp. I09F 484
	cytotoxicity against the tested cell lines L929 and KB3.1	IC50 values of 0.9 and 3.7 μM	In 2023, Phutthacharoen et al. [36]isolated by Phutthacharoen et al. from a mycelial extract of a saprotrophic fungus Lachnum sp. IW157 growing on the common reed grass Phragmites communis
	antirotavirus activity	TI values of 18.3, 23.7, and 19.2 therapeutic index(TI)—CC50/EC50.CC50: mean (50%) value of cytotoxic concentration; EC50: mean (50%) value of effective concentration	In 2021–2022, Yang et al. [40]isolated from plants of Thalictrum scabrifolium
	antibacterial activity against 12 microbial strains isolated from the saliva of smokers	antibacterial activity in the range of 11.1 to 35.3 mm	In 2022, Yin et al. [41]isolated from plants of Thalictrum scabrifolium
	antirotavirus activity	TI values of 19.7 and 17.1 therapeutic index(TI)—CC50/EC50.CC50: mean (50%) value of cytotoxic concentration; EC50: mean (50%) value of effective concentration	In 2022, Hu et al. [42]isolated from plants of Thalictrum finetii
	anti-tobacco mosaic virus (anti-TMV) activity	IC50 value of 29.3 μM	In 2023, Wu et al. [44]plants of Thalictrum microgynum
	efficacy in significantly reducing chronic hepatitis B virus (HBV) antigens, DNA, and intrahepatic cccDNA levels	IC50 value of 0.51 μM	In 2022, Chen et al. [52]
	inhibitors of the human isoforms of MAO A	IC50 value of 4.4 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO B and AChE.	IC50 values of 2.23 μM and 3.22 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO B and AChE.	IC50 values of 4.98 μM and 17.3 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO B	IC50 value of 0.89 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO B and AChE	IC50 values of 1.15 μM and 23.0 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO A, MAO B, and AChE	IC50 values of 7.1 μM, 2.08 μM and 3.43 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO B and BChE	IC50 values of 2.81 μM and 3.87 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO A, MAO B and AChE	IC50 values of 1.14 μM, 4.91 μM, and 2.05 μM	In 2020, Purgatorio et al. [57]
	inhibitors of the human isoforms of MAO A	IC50 value of 1.18 μM	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO A and B	IC50 values of 0.703 μM and 7.88 μM	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO B	IC50 value of 0.626 μM	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO B and ChE (AChE and BChE).	IC50 values of 0.510 μM, 6.78 μM, and 4.42 μM	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO Bthe tumor growth inhibitory activity assayed in three cell lines (i.e., MCF-7, HCT116, and SK-OV-3)	IC50 value of 7.3 μMIC50 value of 4.8 μM (MCF-7)IC50 value of 8.62 μM (HCT116)IC50 value of 14.7 μM (SK-OV-3)	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO Bthe tumor growth inhibitory activity assayed in three cell lines (i.e., MCF-7, HCT116 and SK-OV-3)	IC50 value of 4.72 μMIC50 value of 6.62 μM (MCF-7)IC50 value of 18.6 μM (HCT116)IC50 value of 22.3 μM (SK-OV-3)	In 2023, Kulikova et al. [58]
	inhibitors of the human isoforms of MAO B the tumor growth inhibitory activity assayed in three cell lines (i.e., MCF-7, HCT116 and SK-OV-3)	IC50 value of 3.51 μMIC50 value of 4.83 μM (MCF-7)IC50 value of 9.40 μM (HCT116)IC50 value of 11.3 μM (SK-OV-3)	In 2023, Kulikova et al. [58]
	antidepressant activity	Lortalamine is a potent NET inhibitor with a potency higher than imipramine (13 fold) and desipramine (5 fold)	In 1980, Briet et al. [69], in 1985, Depin et al. [104], in 2006, Ding et al. [105]
	activity against Mycobacterium tuberculosis H37Rv (MTB) and multidrug-resistant M. tuberculosis (MDR-TB).	IC50 value of 50.69 μM	In 2010, Sriram et al. [80]

5. Conclusions

Chromeno[3,2-c]pyridines and their derivatives are promising heterocyclic systems due to their biological properties. We reviewed the literature, which reported various protocols for the efficient synthesis of chromeno[3,2-c]pyridine core. Synthetic methods for chromenopyridines based on the formation of both chromene and pyridine moiety are described. Various factors affecting the yield, temperature, substituents, and solvent effects are also discussed.

The analysis of biological data clearly demonstrates the great potential of chromeno[3,2-c]pyridine core for medicinal chemistry. We hope that this review will be useful for the synthesis of new biologically active compounds having antiviral, antibacterial, antituberculous, and cytotoxic activities, inhibitory activity against MAO, AChE, BChE, and anti-aggregation activity against β-amyloid.

Acknowledgments

This paper has been supported by the RUDN University Strategic Academic Leadership Program.

Conflicts of Interest

The authors declare no conflicts of interest.

Footnotes

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.

Figures, Schemes and Table

Figure 1. Natural chromeno[3,2-c]pyridines.

Scheme 1. A proposed the biosynthetic pathway towards chromeno[3,2-c]pyridine moiety.

Figure 2. Natural chromeno[3,2-c]pyridine.

Figure 3. Natural chromeno[3,2-c]pyridines.

Scheme 2. The first suggested synthetic ways towards chromeno[3,2-c]pyridines.

Scheme 3. Synthesis of chromeno[3,2-c]quinolines 17.

Scheme 4. Cyclisation of 4-phenoxynicotinic acid 20 towards chromeno[3,2-c]pyridine 14.

Scheme 5. Synthesis of chromeno[3,2-c]quinolines 24.

Scheme 6. Cyclisation of 3-trifluoroacetyl-4-quinolyl ethers 26.

Scheme 7. An efficient method to chromeno[3,2-c]quinolines 31.

Scheme 8. Synthesis of chromeno[3,2-c]quinolines 33 and 34.

Scheme 9. Synthesis of chromeno[3,2-c]pyridine 39.

Scheme 10. A construction of chromeno[3,2-c]pyridine core based on condensation of morpholine enamine and salicylaldehyde.

Scheme 11. Synthesis of chromeno[3,2-c]pyridine 14 starting form β-ketoester 45.

Scheme 12. Synthesis of a series of chromeno[3,2-c]pyridines via condensation of enamines 48 and salisylaldehydes 49.

Scheme 13. Synthesis of dye 57.

Scheme 14. Synthesis of chromeno[3,2-c]pyridine 14 via nucleophilic substitution.

Scheme 15. Intramolecular cyclization of (2-chlorophenyl)(2-methoxypyridin-3-yl)methanone 60.

Scheme 16. Synthesis of a series of chromeno[3,2-c]pyridines 62 from chromene-3-thiocarboxamides 61.

Scheme 17. Synthesis of chromeno[3,2-c]pyridine 67.

Scheme 18. Michael addition/intramolecular O-cyclization/elimination cascade.

Scheme 19. An efficient method for the synthesis of chromeno[3,2-c]quinolones 77.

Scheme 20. One-pot three-component synthesis towards chromeno[3,2-c]pyridines 81.

Scheme 21. The synthesis of benzo[5,6]chromeno[3,2-c]quinolones 83.

Scheme 22. Synthesis of chromeno[3,2-c]quinolones 87 and 88.

Scheme 23. Synthesis of a series of chromeno[3,2-c]pyridines 92.

Scheme 24. Synthesis of chromenopyridines from 2-(2-dimethylaminoethenyl)chromones 95.

Scheme 25. Use of chromones 101 in construction of chromeno[3,2-c]pyridine core.

Scheme 26. Synthesis of fluorescent chromeno[3,2-c]pyridines 107 and 108.

Scheme 27. A TMSCl-promoted cyclization of 3-formylchromone with various anilines 110.

Scheme 28. Synthesis of chromeno[3,2-c]pyridines 114 via 5+3] cycloaddition.

Scheme 29. Intramolecular C-arylation in Ugi adduct chromones 119.

Scheme 30. Synthesis of a series of chromeno[3,2-c]pyridines 124.

Scheme 31. [4+2]-cycloaddition in the construction of the chromeno[3,2-c]pyridines 129 (A) and 131 (B).

Scheme 32. Synthesis of thiophene-fused chromeno[3,2-c]pyridine 134.

Scheme 33. Synthesis of chromeno[3,2-c]pyridines 138 via a domino three-component reaction.

Scheme 34. An acid-promoted cascade cyclization of aryl group-substituted propargyl alcohol derivatives 139.

Scheme 35. Pd(II)-catalyzed tandem C–H alkenylation/C–O cyclization in the synthesis of chromeno[3,2-c]quinoline 142.

Scheme 36. Synthesis of chromenopyridodiazepinone 144 with chromeno[3,2-c]pyridine moiety.

Scheme 37. Synthesis of chromeno[3,2-c]quinolones 147 via a FeIII-catalyzed imine formation/C-C coupling/oxidation cascade.

Scheme 38. Stereochemistry in the synthesis of hexahydrochromenopyridines 150 and 151.

Scheme 39. Synthesis of chromeno[3,2-c]pyridines 154.

References

1. Benny, A.T.; Arikkatt, S.D.; Vazhappilly, C.G.; Kannadasan, S.; Thomas, R.; Leelabaiamma, M.S.N.; Radhakrishnan, E.K.; Shanmugam, P. Chromone, A Privileged Scaffold in Drug Discovery: Developments in the Synthesis and Bioactivity. MRMC; 2022; 22, pp. 1030-1063. [DOI: https://dx.doi.org/10.2174/1389557521666211124141859]

2. Verma, N.; Sood, P.; Singh, J.; Jha, N.K.; Rachamalla, M.; Dua, K. Chromene and its Importance: Chemistry and Biology. The Role of Chromenes in Drug Discovery and Development; Kumar Dash, A.; Kumar, D. Bentham Science Publishers: Sharjah, United Arab Emirates, 2023; pp. 1-16.

3. Keri, R.S.; Budagumpi, S.; Pai, R.K.; Balakrishna, R.G. Chromones as a privileged scaffold in drug discovery: A review. Eur. J. Med. Chem.; 2014; 78, pp. 340-374. [DOI: https://dx.doi.org/10.1016/j.ejmech.2014.03.047] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24691058]

4. Pisani, L.; Catto, M.; Muncipinto, G.; Nicolotti, O.; Carrieri, A.; Rullo, M.; Stefanachi, A.; Leonetti, F.; Altomare, C. A twenty-year journey exploring coumarin-based derivatives as bioactive molecules. Front. Chem.; 2022; 10, 1002547. [DOI: https://dx.doi.org/10.3389/fchem.2022.1002547] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36300022]

5. Madhav, H.; Jameel, E.; Rehan, M.; Hoda, N. Recent advancements in chromone as a privileged scaffold towards the development of small molecules for neurodegenerative therapeutics. RSC Med. Chem.; 2022; 13, pp. 258-279. [DOI: https://dx.doi.org/10.1039/D1MD00394A]

6. Kumar Dash, A.; Kumar, D. The Role of Chromenes in Drug Discovery and Development; Bentham Science Publishers: Sharjah, United Arab Emirates, 2023.

7. Carosati, E.; Ioan, P.; Micucci, M.; Broccatelli, F.; Cruciani, G.; Zhorov, B.S.; Chiarin, A.; Budriesi, R. 1,4-Dihydropyridine Scaffold in Medicinal Chemistry, The Story So Far And Perspectives (Part 2): Action in Other Targets and Antitargets. CMC; 2012; 19, pp. 4306-4323. [DOI: https://dx.doi.org/10.2174/092986712802884204]

8. Welsch, M.E.; Snyder, S.A.; Stockwell, B.R. Privileged scaffolds for library design and drug discovery. Curr. Opin. Chem. Biol.; 2010; 14, pp. 347-361. [DOI: https://dx.doi.org/10.1016/j.cbpa.2010.02.018]

9. Bräse, S. Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis, Evaluation; Royal Society of Chemistry: Cambridge, UK, 2015.

10. Costantino, L.; Barlocco, D. Privileged Structures as Leads in Medicinal Chemistry. CMC; 2006; 13, pp. 65-85. [DOI: https://dx.doi.org/10.2174/092986706775197999]

11. Chiacchio, M.A.; Iannazzo, D.; Romeo, R.; Giofrè, S.V.; Legnani, L. Pyridine and Pyrimidine Derivatives as Privileged Scaffolds in Biologically Active Agents. CMC; 2020; 26, pp. 7166-7195. [DOI: https://dx.doi.org/10.2174/0929867325666180904125400]

12. Nazhand, A.; Durazzo, A.; Lucarini, M.; Romano, R.; Mobilia, M.A.; Izzo, A.A.; Santini, A. Human health-related properties of chromones: An overview. Nat. Prod. Res.; 2020; 34, pp. 137-152. [DOI: https://dx.doi.org/10.1080/14786419.2019.1678618]

13. Hammond, P.R.; Atkins, R.L. 2-Keto-4-trifluoromethyl-9-methyl-6,7,8,9-tetrahydro-2H-pyrano [3,2-g] quinoline, an efficient, stable laser dye. J. Heterocycl. Chem.; 1975; 12, 1061. [DOI: https://dx.doi.org/10.1002/jhet.5570120553]

14. Harnisch, H. Über 4-Chlor-7-dimethylamino-1-methyl-chinolon-(2)-aldehyd-(3), II. Justus Liebigs Ann. Chem.; 1971; 751, pp. 155-158. [DOI: https://dx.doi.org/10.1002/jlac.19717510118]

15. Atkins, R.L.; Bliss, D.E. Substituted coumarins and azacoumarins. Synthesis and fluorescent properties. J. Org. Chem.; 1978; 43, pp. 1975-1980. [DOI: https://dx.doi.org/10.1021/jo00404a028]

16. Fujimoto, A.; Sakurai, A.; Iwase, E. The Sensitization of Rare Earth Ion Luminescence in Dilute Solutions by [1]Benzopyrano[3,4-c]pyridine-4,5(3H)-dione Derivatives. Bull. Chem. Soc. Jpn.; 1976; 49, pp. 809-810. [DOI: https://dx.doi.org/10.1246/bcsj.49.809]

17. Arden-Jacob, J.; Frantzeskos, J.; Kemnitzer, N.U.; Zilles, A.; Drexhage, K.H. New fluorescent markers for the red region. Spectrochim. Acta Part A Mol. Biomol. Spectrosc.; 2001; 57, pp. 2271-2283. [DOI: https://dx.doi.org/10.1016/S1386-1425(01)00476-0]

18. Mandal, T.K.; Kuznetsov, V.V.; Soldatenkov, A.T. Chemistry of pyrido[c]coumarins (review). Chem. Heterocycl. Compd.; 1994; 30, pp. 867-887. [DOI: https://dx.doi.org/10.1007/BF01165023]

19. Ramazani, A.; Kiani, M.T.; Rezayati, S. A Review on the Syntheses and Applications of the 5H-chromeno[2,3- b]pyridines. Lett. Org. Chem.; 2023; 20, pp. 28-53. [DOI: https://dx.doi.org/10.2174/1570178619666220818151151]

20. Elinson, M.N.; Ryzhkova, Y.E.; Ryzhkov, F.V. Multicomponent design of chromeno[2,3-b]pyridine systems. Russ. Chem. Rev.; 2021; 90, 94. [DOI: https://dx.doi.org/10.1070/RCR4972]

21. Nunez-Vergara, J.L.; Squella, J.A.; Navarrete-Encina, A.P.; Vicente-García, E.; Preciado, S.; Lavilla, R. Chromenopyridines: Promising Scaffolds for Medicinal and Biological Chemistry. Curr. Med. Chem.; 2011; 18, pp. 4761-4785. [DOI: https://dx.doi.org/10.2174/092986711797535272]

22. Resende, D.I.S.P.; Durães, F.; Maia, M.; Sousa, E.; Pinto, M.M.M. Recent advances in the synthesis of xanthones and azaxanthones. Org. Chem. Front.; 2020; 7, pp. 3027-3066. [DOI: https://dx.doi.org/10.1039/D0QO00659A]

23. Johns, S.R.; Lamberton, J.A.; Sioumis, A.A.; Wunderlich, J.A. Alkaloids of a new type from Elaeocarpus polydactylus Schl. (family elaeocarpaceae). Chem. Commun.; 1968; 6, pp. 290-291. [DOI: https://dx.doi.org/10.1039/c19680000290]

24. Johns, S.; Lamberton, J.; Sioumis, A.; Willing, R. Elaeocarpus alkaloids. I. The structures of (±)-elaeocarpine, (±)-isoelaeocarpine, and (±)-isoelaeocarpicine, three new indolizidine alkaloids from Elaeocarpus polydactylus. Aust. J. Chem.; 1969; 22, 775. [DOI: https://dx.doi.org/10.1071/CH9690775]

25. Johns, S.; Lamberton, J.; Sioumis, A. Elaeocarpus alkaloids. II. (+)-Elaeocarpiline and (-)-isoelaeocarpiline, new indolizidine alkaloids from Elaeocarpus dolichostylis. Aust. J. Chem.; 1969; 22, 793. [DOI: https://dx.doi.org/10.1071/CH9690793]

26. Johns, S.R.; Lamberton, J.A.; Sioumis, A.A.; Suares, H.; Willing, R.I. The structures and absolute configurations of seven alkaloids from Elaeocarpus sphaericus. J. Chem. Soc. D; 1970; 13, pp. 804-805. [DOI: https://dx.doi.org/10.1039/c29700000804]

27. Johns, S.; Lamberton, J.; Sioumis, A.; Suares, H.; Willing, R.I. Elaeocarpus alkaloids. IV. The alkaloids of Elaeocarpus sphaericus. Aust. J. Chem.; 1971; 24, 1679. [DOI: https://dx.doi.org/10.1071/CH9711679]

28. Ray, A.B.; Chand, L.; Pandey, V.B. Rudrakine, a new alkaloid from Elaeocarpus ganitrus. Phytochemistry; 1979; 18, pp. 700-701. [DOI: https://dx.doi.org/10.1016/S0031-9422(00)84309-5]

29. Katavic, P.L.; Venables, D.A.; Forster, P.I.; Guymer, G.; Carroll, A.R. Grandisines C−G, Indolizidine Alkaloids from the Australian Rainforest Tree Elaeocarpus grandi s. J. Nat. Prod.; 2006; 69, pp. 1295-1299. [DOI: https://dx.doi.org/10.1021/np060179c]

30. Katavic, P.L.; Venables, D.A.; Rali, T.; Carroll, A.R. Indolizidine Alkaloids with δ-Opioid Receptor Binding Affinity from the Leaves of Elaeocarpus fuscoides. J. Nat. Prod.; 2007; 70, pp. 872-875. [DOI: https://dx.doi.org/10.1021/np060607e]

31. Zhou, C.; Wang, X.; Mo, J.; Zhang, J.; Gan, L.S. Optical Resolution and Structure Determination of New Indolizidine Alkaloids from Elaeocarpus sphaericus. Helv. Chim. Acta; 2011; 94, pp. 347-354. [DOI: https://dx.doi.org/10.1002/hlca.201000200]

32. Hong, W.; Zhang, Y.; Yang, J.; Xia, M.Y.; Luo, J.F.; Li, X.N.; Wang, Y.H.; Wang, J.S. Alkaloids from the Branches and Leaves of Elaeocarpus angustifolius. J. Nat. Prod.; 2019; 82, pp. 3221-3226. [DOI: https://dx.doi.org/10.1021/acs.jnatprod.8b01027]

33. Payne, D.J.; Hueso-Rodríguez, J.A.; Boyd, H.; Concha, N.O.; Janson, C.A.; Gilpin, M.; Bateson, J.H.; Cheever, C.; Niconovich, N.L.; Pearson, S. et al. Identification of a Series of Tricyclic Natural Products as Potent Broad-Spectrum Inhibitors of Metallo-β-Lactamases. Antimicrob. Agents Chemother.; 2002; 46, pp. 1880-1886. [DOI: https://dx.doi.org/10.1128/AAC.46.6.1880-1886.2002]

34. Gan, M.; Liu, Y.; Bai, Y.; Guan, Y.; Li, L.; Gao, R.; He, W.; You, X.; Li, Y.; Yu, L. et al. Polyketides with New Delhi Metallo-β-lactamase 1 Inhibitory Activity from Penicillium sp. J. Nat. Prod.; 2013; 76, pp. 1535-1540. [DOI: https://dx.doi.org/10.1021/np4000944] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/23972215]

35. Cui, H.; Yu, J.; Chen, S.; Ding, M.; Huang, X.; Yuan, J.; She, Z. Alkaloids from the mangrove endophytic fungus Diaporthe phaseolorum SKS019. Bioorg. Med. Chem. Lett.; 2017; 27, pp. 803-807. [DOI: https://dx.doi.org/10.1016/j.bmcl.2017.01.029] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28119026]

36. Phutthacharoen, K.; Khalid, S.J.; Schrey, H.; Ding, M.; Huang, X.; Yuan, J.; She, Z. Diaporphasines E and F: New Polyketides from the Saprotrophic Fungus Lachnum sp. IW157 Growing on the Reed Grass Phragmites communis. ACS Omega; 2023; 8, pp. 41689-41695. [DOI: https://dx.doi.org/10.1021/acsomega.3c05984]

37. Ding, B.; Wang, Z.; Xia, G.; Huang, X.; Xu, F.; Chen, W.; She, Z. Three New Chromone Derivatives Produced by Phomopsis sp. HNY29-2B from Acanthus ilicifolius Linn. Chin. J. Chem.; 2017; 35, pp. 1889-1893. [DOI: https://dx.doi.org/10.1002/cjoc.201700375]

38. Wei, C.; Sun, C.; Feng, Z.; Zhang, X.; Xu, J. Four New Chromones from the Endophytic Fungus Phomopsis asparagi DHS-48 Isolated from the Chinese Mangrove Plant Rhizophora mangle. Mar. Drugs; 2021; 19, 348. [DOI: https://dx.doi.org/10.3390/md19060348]

39. Xing, D.-X.; Song, X.-S.; Pan, W.-C.; Cui, H.; Zhao, Z.X. New chromone compounds from the marine derived fungus Diaporthe sp. XW12-1. Fitoterapia; 2023; 164, 105384. [DOI: https://dx.doi.org/10.1016/j.fitote.2022.105384]

40. Hu, Q.F.; Wu, F.; Zhou, T.; Zhou, M.; Zhu, Y.N.; Cai, B.B.; Liu, M.X.; Li, M.F.; Yang, G.Y.; Li, Y.K. Three New Anti-Rotavirus Chromeno[3,2-c]pyridines from the Whole Plant of Thalictrum scabrifolium. Heterocycles; 2021; 102, 1810. [DOI: https://dx.doi.org/10.3987/COM-21-14505]

41. Yin, G.-Y.; Zhu, Y.-N.; Wu, F.; Mi, Q.L.; Shi, J.Q.; Gao, Q.; Zhu, L.C.; Zhou, T.; Li, J.; Liu, X. et al. Two New Antibacterial Chromeno[3,2-c]Pyridine Alkaloids from Whole Plants of Thalictrum scabrifolium. Chem. Nat. Compd.; 2022; 58, pp. 506-510. [DOI: https://dx.doi.org/10.1007/s10600-022-03722-w]

42. Hu, Q.-F.; Zhang, L.-F.; Liu, M.-X.; Cai, B.-B.; Li, Y.; Zhou, T.; Li, M.-F.; Wang, H.-S.; Xu, Y.; Kong, W.-S. et al. Two New Chromeno[3,2-c]Pyridine Derivatives from the Whole Plants of Thalictrum finetii and Their Antirotavirus Activity. Chem. Nat. Compd.; 2022; 58, pp. 511-515. [DOI: https://dx.doi.org/10.1007/s10600-022-03720-y]

43. Wu, Y.-P.; Lin, Z.-L.; Zhao, G.-K.; Zhou, M.; Yao, H.; Zhang, G.H.; Li, W.; Yang, G.Y.; Li, Y.K.; Hu, Q.F. et al. Two New Anti-Tobacco Mosaic Virus Alkaloids from the Whole Plants of Thalictrum microgynum. Chem. Nat. Compd.; 2022; 58, pp. 699-703. [DOI: https://dx.doi.org/10.1007/s10600-022-03771-1]

44. Wu, Y.-P.; Zhao, G.-K.; Liu, Z.-Y.; Tan, T.; Li, Z.M.; Zhou, M.; Yao, H.; Li, Y.K.; Wang, W.G.; Hu, Q.F. et al. Antiviral Chromone Alkaloids from the Cigar Tobacco Leaves Derived Endophytic Fungus Aspergillus lentulus. Chem. Nat. Compd.; 2023; 59, pp. 721-725. [DOI: https://dx.doi.org/10.1007/s10600-023-04096-3]

45. Kruger, S.; Mann, F.G. Xanthones and thioxanthones. Part VI. The preparation and properties of 9-thia-3-aza-anthrone. J. Chem. Soc.; 1955; pp. 2755-2763. [DOI: https://dx.doi.org/10.1039/jr9550002755]

46. Bloomfield, D.G.; Partridge, M.W.; Vipond, H.J. Cyclic amidines. Part XXIII. Dibenzo[b,h][1]benzopyrano[2,3,4-de][1,6]naphthyridines and their molecular orientation in carcinogenesis. J. Chem. Soc. C; 1970; pp. 2647-2653. [DOI: https://dx.doi.org/10.1039/j39700002647] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/5532410]

47. Villani, F.J.; Mann, T.A.; Wefer, E.A.; Hannon, J.; Larca, L.L.; Landon, M.J.; Spivak, W.; Vashi, D.; Tozzi, S. Benzopyranopyridine derivatives. 1. Aminoalkyl derivatives of the azaxanthenes as bronchodilating agents. J. Med. Chem.; 1975; 18, pp. 1-8. [DOI: https://dx.doi.org/10.1021/jm00235a001]

48. Khodair, A.I.; Abbasi, Μ.M.A.; Ibrahim, E.-S.I.; Soliman, A.H.; El-Ashry, E.S.H. Synthesis of substituted quinolines and heterocyclo[x,y-c]quinolines by the nucleophilic substitution and rearrangements of 4-chloro-2-methyl-3-nitroquinolines. Heterocycl. Commun.; 1999; 5, pp. 577-584. [DOI: https://dx.doi.org/10.1515/HC.1999.5.6.577]

49. Okada, E.; Hatakenaka, M.; Kuratani, M.; Mori, T.; Ashida, T. A Facile and Convenient Synthetic Method for Fluorine-Containing Dibenzo[b,h][1,6]naphthyridines, Thiochromeno[3,2-c]quinolines, and Chromeno[3,2-c]quinolines. Heterocycles; 2014; 88, 799. [DOI: https://dx.doi.org/10.3987/COM-13-S(S)57]

50. Hong, F.; Lu, N.; Lu, B.; Cheng, J. Synthesis of Fused Heterocycles via One-pot Oxidative O-Arylation, Pd-Catalyzed C(sp³)-H Arylation. Adv. Synth. Catal.; 2017; 359, pp. 3299-3303. [DOI: https://dx.doi.org/10.1002/adsc.201700761]

51. Kardile, R.A.; Sarkate, A.P.; Borude, A.S.; Mane, R.S.; Lokwani, D.K.; Tiwari, S.V.; Azad, R.; Burra, P.V.L.S.; Thopate, S.R. Design and synthesis of novel conformationally constrained 7,12-dihydrodibenzo[b,h][1,6] naphthyridine and 7H-Chromeno[3,2-c] quinoline derivatives as topoisomerase I inhibitors: In vitro screening, molecular docking and ADME predictions. Bioorg. Chem.; 2021; 115, 105174. [DOI: https://dx.doi.org/10.1016/j.bioorg.2021.105174]

52. Chen, D.; Tan, X.; Chen, W.; Liu, Y.; Li, C.; Wu, J.; Zheng, J.; Shen, H.C.; Zhang, M.; Wu, W. et al. Discovery of Novel cccDNA Reducers toward the Cure of Hepatitis B Virus Infection. J. Med. Chem.; 2022; 65, pp. 10938-10955. [DOI: https://dx.doi.org/10.1021/acs.jmedchem.1c02215]

53. Sliwa, H.; Cordonnier, C. Synthesis of new fundamental heterocycles. Part VII. Synthesis of 2-azaxanthene. J. Heterocycl. Chem.; 1977; 14, pp. 169-170. [DOI: https://dx.doi.org/10.1002/jhet.5570140136]

54. Cordonnier, G.; Sliwa, H. A new route to 6-azachromones. An improved synthesis of 2-azaxanthone. J. Heterocycl. Chem.; 1987; 24, pp. 111-115. [DOI: https://dx.doi.org/10.1002/jhet.5570240123]

55. Kulikova, L.N.; Borisov, R.S.; Voskressensky, L.G. Ring opening in 1,2,3,4-tetrahydrochromeno[3,2-c]pyridines under the action of electron-deficient alkynes. Mendeleev Commun.; 2017; 27, pp. 640-641. [DOI: https://dx.doi.org/10.1016/j.mencom.2017.11.035]

56. Makhaeva, G.F.; Boltneva, N.P.; Lushchekina, S.V.; Rudakova, E.V.; Serebryakova, O.G.; Kulikova, L.N.; Beloglazkin, A.A.; Borisov, R.S.; Richardson, R.J. Synthesis, molecular docking, and biological activity of 2-vinyl chromones: Toward selective butyrylcholinesterase inhibitors for potential Alzheimer’s disease therapeutics. Bioorg. Med. Chem.; 2018; 26, pp. 4716-4725. [DOI: https://dx.doi.org/10.1016/j.bmc.2018.08.010]

57. Purgatorio, R.; Kulikova, L.N.; Pisani, L.; Catto, M.; Candia, M.; Carrieri, A.; Cellamare, S.; De Palma, A.; Beloglazkin, A.A.; Raesi, G.R. et al. Scouting around 1,2,3,4-Tetrahydrochromeno[3,2-c]pyridin-10-ones for Single- and Multitarget Ligands Directed towards Relevant Alzheimer’s Targets. ChemMedChem; 2020; 15, pp. 1947-1955. [DOI: https://dx.doi.org/10.1002/cmdc.202000468]

58. Kulikova, L.N.; Purgatorio, R.; Beloglazkin, A.A.; Tafeenko, V.A.; Reza, R.G.; Levickaya, D.D.; Sblano, S.; Boccarelli, A.; de Candia, M.; Catto, M. et al. Chemical and Biological Evaluation of Novel 1H-Chromeno[3,2-c]pyridine Derivatives as MAO Inhibitors Endowed with Potential Anticancer Activity. Int. J. Mol. Sci.; 2023; 24, 7724. [DOI: https://dx.doi.org/10.3390/ijms24097724]

59. Marsais, F.; Trécourt, F.; Bréant, P.; Quéguiner, G. Directed lithiation of 4-halopyridines: Chemoselectivity, regioselectivity and application to synthesis. J. Heterocycl. Chem.; 1988; 25, pp. 81-87. [DOI: https://dx.doi.org/10.1002/jhet.5570250112]

60. Marquise, N.; Harford, P.J.; Chevallier, F.; Roisnel, T.; Dorcet, V.; Gagez, A.-L.; Sablé, S.; Picot, L.; Thiéry, V.; Wheatley, A.E.H. et al. Synthesis of azafluorenones and related compounds using deprotocupration–aroylation followed by intramolecular direct arylation. Tetrahedron; 2013; 69, pp. 10123-10133. [DOI: https://dx.doi.org/10.1016/j.tet.2013.09.030]

61. El-sayed, A.M.; Abd Allah, O.A. Synthetic and biological studies on coumarin hydrazone derivatives. Phosphorus Sulfur Silicon Relat. Elem.; 2001; 170, pp. 75-86. [DOI: https://dx.doi.org/10.1080/10426500108040586]

62. El-Sayed, A.M. The Synthesis of Some New Fused and Substituted Chromenes. Phosphorus Sulfur Silicon Relat. Elem.; 2006; 181, pp. 2709-2723. [DOI: https://dx.doi.org/10.1080/10426500600864221]

63. Sumesh, R.V.; Malathi, A.; Ranjith Kumar, R. A facile tandem Michael addition/O-cyclization/elimination route to novel chromeno[3,2-c]pyridines. Mol. Divers.; 2015; 19, pp. 233-249. [DOI: https://dx.doi.org/10.1007/s11030-015-9576-4]

64. Shen, J.-C.; Jin, R.-Z.; Yuan, K.; Zhang, M.M.; Wang, X.S. A Green Synthesis of Fused Polycyclic 5H-Chromeno[3,2-c]quinoline-6,8(7H,9H)-dione Derivatives Catalyzed by TsOH in Ionic Liquids. Polycycl. Aromat. Compd.; 2016; 36, pp. 758-772. [DOI: https://dx.doi.org/10.1080/10406638.2015.1053502]

65. Kamali, M.; Keramat Pirolghor, F. One-pot three-component synthesis of novel chromeno[3,2-c]pyridine-1,9(2H)-diones by using S_NC_L2·2H₂O as catalyst. J. Heterocycl. Chem.; 2022; 59, pp. 655-663. [DOI: https://dx.doi.org/10.1002/jhet.4404]

66. Orang, N.S.; Soltani, H.; Ghiamirad, M.; Sabegh, M.A. Para toluenesulfonic acid-catalyzed one-pot, three-component synthesis of benzo[5,6]chromeno[3,2-c]quinoline compounds in aqueous medium. Heterocycl. Commun.; 2021; 27, pp. 90-99. [DOI: https://dx.doi.org/10.1515/hc-2020-0128]

67. Sadeghpour Orang, N.; Ghiami Rad, M.; Soltani, H.; Ahmadi Sabegh, M. Synthesis and evaluation of the antibacterial activity of benzo [5,6] chromeno[3,2-c] quinoline derivatives. Int. J. Mol. Clin. Microbiol.; 2022; 12, pp. 1713-1721. [DOI: https://dx.doi.org/10.22034/ijmcm.2022.694299]

68. Chithanna, S.; Yang, D.-Y. Intramolecular Diels–Alder Cycloaddition of Furan-Derived β-Enamino Diketones: An Entry to Diastereoselective Synthesis of Polycyclic Pyrano[3,2- c ]quinolin-5-one Derivatives. J. Org. Chem.; 2022; 87, pp. 5178-5187. [DOI: https://dx.doi.org/10.1021/acs.joc.1c03163] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35380043]

69. Briet, P.; Berthelon, J.-J.; Depin, J.-C. Antidepressant Substituted Hexahydro Benzopyrano [3,2-c] Pyridines. U.S. Patent; 4,201,783, 6 May 1980.

70. Lin, K.-S.; Ding, Y.-S. Synthesis and C-11 labeling of three potent norepinephrine transporter selective ligands ((R)-nisoxetine, lortalamine, and oxaprotiline) for comparative PET studies in baboons. Bioorg. Med. Chem.; 2005; 13, pp. 4658-4666. [DOI: https://dx.doi.org/10.1016/j.bmc.2005.04.062]

71. Munari, I.; Traldi, P.; Biala, J.; Czarnocki, Z. Characterization of stereoisomeric alkaloids by electrospray ionization tandem mass spectrometry. Rapid Comm. Mass. Spectrom.; 2001; 15, pp. 889-892. [DOI: https://dx.doi.org/10.1002/rcm.309]

72. Biała, J.; Czarnocki, Z.; Maurin, J.K. Diastereoselective synthesis of lortalamine analogs. Tetrahedron Asymmetry; 2002; 13, pp. 1021-1023. [DOI: https://dx.doi.org/10.1016/S0957-4166(02)00232-X]

73. Pawłowska, J.; Krawczyk, K.K.; Wojtasiewicz, K.; Maurin, J.K.; Czarnocki, Z. (S)-(−)-α-Methylbenzylamine as chiral auxiliary in the synthesis of (+)-lortalamine. Monatsh. Chem.; 2009; 140, pp. 83-86. [DOI: https://dx.doi.org/10.1007/s00706-008-0017-2]

74. Ghosh, C.K.; Pal, C.; Maiti, J.; Sarkar, M. Benzopyrans. Part 23. Nitrogen heterocycles fused with or linked to 1-benzopyran from 3-acyl-2-methyl-1-benzopyran-4-one. J. Chem. Soc. Perkin Trans.; 1988; 1, 1489. [DOI: https://dx.doi.org/10.1039/p19880001489]

75. Ghosh, C.K.; Karak, S.K.; Patra, A. Benzopyrans. Part 47. Reactions of 3-(β-Dimethylaminoacryloyl)-1-benzopyran-4-one with Some Nitrogen Nucleophiles. ChemInform; 2005; 36, chin.200517040. [DOI: https://dx.doi.org/10.1002/chin.200517040]

76. Rajagopal, R.; Shenoy, V.U.; Padmanabhan, S.; Sequeira, S.; Seshadri, S. Synthesis of fluorescent 2, 3-fused coumarin derivatives. Dye. Pigment.; 1990; 13, pp. 167-175. [DOI: https://dx.doi.org/10.1016/0143-7208(90)80016-I]

77. Plaskon, A.S.; Ryabukhin, S.V.; Volochnyuk, D.M.; Gavrilenko, K.S.; Shivanyuk, A.N.; Tolmachev, A.A. Synthesis of Quinolines from 3-Formylchromone. J. Org. Chem.; 2008; 73, pp. 6010-6013. [DOI: https://dx.doi.org/10.1021/jo800950y]

78. Wittstein, K.; García, A.; Schürmann, M.; Kumar, K. Exploring α-Chromonyl Nitrones as 1,5-Dipoles. Synlett; 2012; 2012, pp. 227-232. [DOI: https://dx.doi.org/10.1055/s-0031-1290070]

79. Ghosh, J.; Biswas, P.; Maiti, S.; Sarkar, T.; Drew, M.G.B.; Bandyopadhyay, C. Ligand-free palladium-catalyzed intramolecular arylation of chromones: An expedient synthesis of 1-benzopyrano[3,2-c]quinolines. Tetrahedron Lett.; 2013; 54, pp. 2221-2225. [DOI: https://dx.doi.org/10.1016/j.tetlet.2013.02.057]

80. Sriram, D.; Yogeeswari, P.; Dinakaran, M.; Banerjee, D.; Bhat, P.; Gadhwal, S. Discovery of novel antitubercular 2,10-dihydro-4aH-chromeno[3,2-c]pyridin-3-yl derivatives. Eur. J. Med. Chem.; 2010; 45, pp. 120-123. [DOI: https://dx.doi.org/10.1016/j.ejmech.2009.09.033]

81. Popova, A.V.; Mrug, G.P.; Kondratyuk, K.M.; Bondarenko, S.P.; Frasinyuk, M.S. New Heterocyclic Pyrano[2′,3′:5,6]Chromeno[3,2-c]Pyridin-4-Ones and Furo[2′,3′:5,6]Chromeno[3,2-c]Pyridin-3(2H)-Ones Synthesized Via a Hetero-Diels–Alder Reaction. Chem. Nat. Compd.; 2016; 52, pp. 1000-1004. [DOI: https://dx.doi.org/10.1007/s10600-016-1846-6]

82. Abdelkhalik, M.M.; Negm, A.M.; Elkhouly, A.I.; Elnagdi, M.H. Studies with condensed amino-thiophenes: Further investigation of reactivity of amino-thieno-coumarines and amino-thieno-benzo[h]coumarines toward electron-poor olefins and acetylenes. Heteroat. Chem.; 2004; 15, pp. 502-507. [DOI: https://dx.doi.org/10.1002/hc.20047]

83. Yan, J.; Cheng, M.; Hu, F.; Hu, Y. Direct Synthesis of Functional Azaxanthones by Using a Domino Three-Component Reaction. Org. Lett.; 2012; 14, pp. 3206-3209. [DOI: https://dx.doi.org/10.1021/ol3013099]

84. Yokosaka, T.; Shiga, N.; Nemoto, T.; Hamada, Y. Construction of Divergent Fused Heterocycles via an Acid-Promoted Intramolecular ipso-Friedel–Crafts Alkylation of Phenol Derivatives. J. Org. Chem.; 2014; 79, pp. 3866-3875. [DOI: https://dx.doi.org/10.1021/jo500308y]

85. Kim, Y.; Moon, Y.; Kang, D.; Hong, S. Synthesis of heterocyclic-fused benzopyrans via the Pd(II)-catalyzed C–H alkenylation/C–O cyclization of flavones and coumarins. Org. Biomol. Chem.; 2014; 12, pp. 3413-3422. [DOI: https://dx.doi.org/10.1039/C4OB00180J]

86. Bouchama, A.; Hassaine, R.; Talhi, O.; Taibi, N.; Mendes, R.F.; Paz, F.A.A.; Bachari, K.; Silva, A.M.S. Diastereoselective One-Pot Tandem Synthesis of Chromenopyridodiazepinones through 1,4- and 1,6-Aza-Conjugate Additions/Heterocyclizations. Synlett; 2018; 29, pp. 885-889. [DOI: https://dx.doi.org/10.1055/s-0037-1609201]

87. Kumar, T.U.; Roy, D.; Bhattacharya, A. Iron(III) catalyzed direct C–H functionalization at the C-3 position of chromone for the synthesis of fused chromeno-quinoline scaffolds. Tetrahedron Lett.; 2019; 60, pp. 1895-1898. [DOI: https://dx.doi.org/10.1016/j.tetlet.2019.06.024]

88. Kawai, S.; Takashima, S.; Ando, M.; Shintaku, S.; Takeda, S.; Otake, K.; Ito, Y.; Fukui, M.; Yamamoto, M.; Shoji, Y. et al. Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs. Chem. Pharm. Bull.; 2023; 71, pp. 859-878. [DOI: https://dx.doi.org/10.1248/cpb.c23-00488] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/38044139]

89. Unangst, P.C.; Capiris, T.; Connor, D.T.; Heffner, T.G.; MacKenzie, R.G.; Miller, S.R.; Pugsley, T.A.; Wise, L.D. Chromeno[3,4-c]pyridin-5-ones:  Selective Human Dopamine D4 Receptor Antagonists as Potential Antipsychotic Agents. J. Med. Chem.; 1997; 40, pp. 2688-2693. [DOI: https://dx.doi.org/10.1021/jm970170v] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/9276014]

90. Oset-Gasque, M.J.; González, M.P.; Pérez-Peña, J.; García-Font, N.; Romero, A.; del Pino, J.; Ramos, E.; Hadjipavlou-Litina, D.; Soriano, E.; Chioua, M. et al. Toxicological and pharmacological evaluation, antioxidant, ADMET and molecular modeling of selected racemic chromenotacrines {11-amino-12-aryl-8,9,10,12-tetrahydro-7H-chromeno[2,3-b]quinolin-3-ols} for the potential prevention and treatment of Alzheimer’s disease. Eur. J. Med. Chem.; 2014; 74, pp. 491-501.

91. Dawane, B.S.; Konda, S.G.; Bodade, R.G.; Bhosale, R.B. An efficient one-pot synthesis of some new 2,4-diaryl pyrido[3,2-c]coumarins as potent antimicrobial agents. J. Heterocycl. Chem.; 2010; 47, pp. 237-241. [DOI: https://dx.doi.org/10.1002/jhet.234]

92. Patel, A.A.; Lad, H.B.; Pandya, K.R.; Patel, C.V.; Brahmbhatt, D.I. Synthesis of a new series of 2-(2-oxo-2H-chromen-3-yl)-5H-chromeno[4,3-b]pyridin-5-ones by two facile methods and evaluation of their antimicrobial activity. Med. Chem. Res.; 2013; 22, pp. 4745-4754. [DOI: https://dx.doi.org/10.1007/s00044-013-0489-4]

93. Patel, M.A.; Bhila, V.G.; Patel, N.H.; Patel, A.K.; Brahmbhatt, D.I. Synthesis, characterization and biological evaluation of some pyridine and quinoline fused chromenone derivatives. Med. Chem. Res.; 2012; 21, pp. 4381-4388. [DOI: https://dx.doi.org/10.1007/s00044-012-9978-0]

94. Li, Z.; Mu, G.; Chen, W.; Gao, L.; Jhanji, V.; Wang, L. Comparative Evaluation of Topical Pranoprofen and Fluorometholone in Cases with Chronic Allergic Conjunctivitis. Cornea; 2013; 32, 579. [DOI: https://dx.doi.org/10.1097/ICO.0b013e318265684b]

95. Makino, H.; Saijo, T.; Ashida, Y.; Kuriki, H.; Maki, Y. Mechanism of Action of an Antiallergic Agent, Amlexanox (AA-673), in Inhibiting Histamine Release from Mast Cells: Acceleration of cAMP Generation and Inhibition of Phosphodiesterase. Int. Arch. Allergy Appl. Immunol.; 2009; 82, pp. 66-71. [DOI: https://dx.doi.org/10.1159/000234292] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/2433225]

96. Maeda, A.; Tsuruoka, S.; Kanai, Y.; Endou, H.; Saito, K.; Miyamoto, E.; Fujimura, A. Evaluation of the interaction between nonsteroidal anti-inflammatory drugs and methotrexate using human organic anion transporter 3-transfected cells. Eur. J. Pharmacol.; 2008; 596, pp. 166-172. [DOI: https://dx.doi.org/10.1016/j.ejphar.2008.08.023]

97. Banerjee, S.; Wang, J.; Pfeffer, S.; Ma, D.; Pfeffer, L.M.; Patil, S.A.; Li, W.; Miller, D.D. Design, Synthesis and Biological Evaluation of Novel 5H-Chromenopyridines as Potential Anti-Cancer Agents. Molecules; 2015; 20, pp. 17152-17165. [DOI: https://dx.doi.org/10.3390/molecules200917152] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26393554]

98. Oliveira-Pinto, S.; Pontes, O.; Lopes, D.; Sampaio-Marques, B.; Costa, M.D.; Carvalho, L.; Gonçalves, C.S.; Costa, B.M.; Maciel, P.; Ludovico, P. et al. Unravelling the anticancer potential of functionalized chromeno[2,3-b]pyridines for breast cancer treatment. Bioorg. Chem.; 2020; 100, 103942. [DOI: https://dx.doi.org/10.1016/j.bioorg.2020.103942] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32450388]

99. Mulakayala, N.; Rambabu, D.; Raja, M.R.; Chaitanya, M.; Kumar, C.S.; Kalle, A.M.; Krishna, G.R.; Reddy, C.M.; Rao, M.V.B.; Pal, M. Ultrasound mediated catalyst free synthesis of 6H-1-benzopyrano[4,3-b]quinolin-6-ones leading to novel quinoline derivatives: Their evaluation as potential anti-cancer agents. Bioorg. Med. Chem.; 2012; 20, pp. 759-768. [DOI: https://dx.doi.org/10.1016/j.bmc.2011.12.001]

100. Thapa, P.; Jun, K.-Y.; Kadayat, T.M.; Park, C.; Zheng, Z.; Magar, T.B.T.; Bist, G.; Shrestha, A.; Na, Y.; Kwon, Y. et al. Design and synthesis of conformationally constrained hydroxylated 4-phenyl-2-aryl chromenopyridines as novel and selective topoisomerase II-targeted antiproliferative agents. Bioorg. Med. Chem.; 2015; 23, pp. 6454-6466. [DOI: https://dx.doi.org/10.1016/j.bmc.2015.08.018]

101. Hamama, W.S.; Ibrahim, M.E.; Metwalli, A.E.; Zoorob, H.H. New synthetic approach to coumarino[4,3-b]pyridine systems and potential cytotoxic evaluation. Med. Chem. Res.; 2014; 23, pp. 2615-2621. [DOI: https://dx.doi.org/10.1007/s00044-013-0859-y]

102. Tian, S.; Huang, Z.; Meng, Q.; Liu, Z. Multi-target drug design of anti-alzheimer’s disease based on tacrine. Mini Rev. Med. Chem.; 2021; 21, pp. 2039-2064. [DOI: https://dx.doi.org/10.2174/1389557521666210212151127]

103. Sameem, B.; Saeedi, M.; Mahdavi, M.; Shafiee, A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem.; 2017; 128, pp. 332-345. [DOI: https://dx.doi.org/10.1016/j.ejmech.2016.10.060]

104. Depin, J.C.; Betbeder-Matibet, A.; Bonhomme, Y.; Muller, A.J.; Berthelon, J.-J. Pharmacology of lortalamine, a new potent non-tricyclic antidepressant. Arzneim. Forsch.; 1985; 35, pp. 1655-1662.

105. Ding, Y.S.; Lin, K.S.; Logan, J. PET imaging of norepinephrine transporters. Curr. Pharm. Des.; 2006; 12, pp. 3831-3845. [DOI: https://dx.doi.org/10.2174/138161206778559687] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17073682]