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An efficient method for regioselective synthesis of C-7 Mannich bases of 6-hydroxyaurones was accomplished by the N,N-dialkylaminomethylation using aminals prepared from dimethylamine, dipropylamine, bis(2-methoxyethyl)amine, N-methylbutylamine, N-methylbenzylamine, morpholine, piperidine, and 1-methylpiperazine. Further transformation of 7-(N,N-dialkylamino)methyl group in these aurones led to formation of C-7 acetoxymethyl and methoxymethyl derivatives of 6-hydroxyaurones, some of which showed promising inhibition of PC-3 prostate cancer cell proliferation in the high nanomolar to low micromolar range that exceeded that of cisplatin. Compound 12c (R3 = Ac, Ar = 3,4-OMePh) displays 75% inhibition of PC-3 prostate cancer cells proliferation at 300 nM concentration.

The reactions of cytisine with glycidyl ethers of 3-arylcoumarins were studied. A series of cytisine–coumarin conjugates were synthesized via regiospecific opening of the oxirane ring by cytisine. Methods for conjugating anabasine and cytisine with 3-arylcoumarins through a but-2-ynyl linker via reactions of propargyl ethers of 7-hydroxy- and 6-hydroxy-3-arylcoumarins with the alkaloids were proposed.

Furo[3,2-g]neoflavones and furo[2,3-h]neoflavones modified by coumarin and (het)aroyl substituents were synthesized via reactions of 7-hydroxy-6(8)-acetyl(formyl)neoflavones with substituted phenacyl bromides, 2-bromacetylbenzofuran, and 4-chloromethylcoumarins.

Reactions of 7-hydroxy-2-methyl-8-formylisoflavone with 4-chloromethylcoumarins synthesized 8-(coumarin-4-yl)furo[2,3-h]chromones, which reacted with 2-bromoacetylbenzofuran to produce 8-(benzofuroyl)furo [2,3-h]chromone. Recyclization of the corresponding furochromones through the action of hydrazine hydrate gave 4-hydroxybenzofurans with pyrazole and coumarin or benzofuroyl substituents.

The reactions of cytisine with isoflavone glycidyl ethers were investigated. A series of cytisine–isoflavone conjugates were regioselectively synthesized via opening the oxirane ring by cytisine.

7-Hydroxy-8-methyl-4'-methoxy-6-formylisoflavone was synthesized from the 6-aminomethyl derivative of 7-hydroxychromone under modified Duff reaction conditions and underwent heterocyclization to form linear furo- and pyranochromones.

The over-accumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast glycogen synthase 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the UDP-glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure-activity relationship (SAR) profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.

Conjugates of natural and synthetic amino acids and 7-hydroxyisoflavone in which the amino-acid residue was bonded to the isoflavone through a hydroxyacetate linker were prepared using the activated ester method.

New coumarin-4-ylmethylphosphonates and coumarin-4-ylmethylphosphonic acids were synthesized and tested for antiviral activity.

The possibility of using the alkaloid anabasine in Mannich aminomethylation of coumarins was studied. Anabasine-coumarin conjugates in which the benzopyrone core was conjugated to anabasine through a methylene linker were synthesized.

This article provides generalized and systematic overview of data on the synthesis, stereoisomerism, and reactivity of aurones (2-benzylidenebenzofuran-3(2Н)-ones) published between the years 1910 and 2018. Analysis of the literature data shows that the most common precursors for the synthesis of aurones are 2'-hydroxychalcones, benzofuran-3(2Н)-ones, and 1-(2-hydroxyphenyl)-3-phenylprop-2-yn-1-ones. Reactions involving electrophiles, nucleophiles, as well as reduction reactions have been reviewed.

Reaction features of polyhydroxydeoxybenzoins and their heteroatomic analogs with succinic and glutaric anhydrides were studied and shown to be useful for synthesizing 3-(3-pyrazolyl)butyric acids and 4,11-dioxo-8,10,11,12-tetrahydro-4H,9H-pyrano[2,3-a]xanthene derivatives with a butyric acid moiety.

Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.

Structural data of chromone alkaloids and antibiotics related to them that were isolated from natural sources up to 2017 are systematized in this review. Information on their biological activity is given.

Aminomethylation of aurones was studied by using anabasine. The reaction in the case of 6-hydroxyaurones was shown to selectively provide 7-aminomethyl-6-hydroxyaurones, while 5-aminomethyl-6-hydroxy-7-methylaurones could be obtained by transamination of 5-dimethylaminomethyl derivatives of 6-hydroxy-7-methylaurones in the presence of anabasine.

Possible Mannich aminomethylation of isoflavone chromone rings was studied using the alkaloid anabasine. Anabasine-isoflavone conjugates in which the benzopyrone core was connected to anabasine through a methylene linker were synthesized.

Furo[2,3-h]chromone and pyrano[2′,3′:5,6]chromeno[4,3-b]pyridine derivatives were synthesized from 7-hydroxy-8-formylisoflavones, which were prepared from natural isoflavones using a Duff reaction, via reactions with bromoacetophenones and ethyl 3-aminocrotonate, respectively.

The regioisomeric 6-hydroxy-4-methyl- and 4-hydroxy-6-methylaurones were synthesized. Aminomethylation by the action of aminals of secondary amines was investigated. It was shown that the reaction proceeds selectively with the formation of 7-aminomethyl-6-hydroxy-4-methyl- and 5-aminomethyl-4-hydroxy-6-methylaurones, respectively. The use of an excess of the aminals allows to obtain 5,7-bis(aminomethyl) derivatives of 6-hydroxy-4-methylaurones.

Aminomethylation of 7-substituted 6-hydroxyaurones was studied using primary and secondary amines. In the case of 6-hydroxy-7-methylaurones, their 5-dialkylaminomethyl derivatives or 7-benzylidene-3,4-dihydro-2Н-furo[3,2-g][1,3]benzoxazin-6(7Н)-ones were formed. The aminomethylation reaction of 6,7-dihydroxyaurones produced only 5-aminomethyl derivatives.

Aminomethylation of the natural isoflavones afromosin and cladrastin and their 2-methyl derivatives was studied. Several new Mannich bases of 7-hydroxy-6-methoxyisoflavones were synthesized under Mannich reaction conditions using aminals of secondary amines.

Recyclization by hydrazine of furo[3,2-b]pyrano[2,3-f]chromen-4-ones, dipyrano[2,3-b:2,3-f]chromen4-ones, and pyrano[2,3-a]xanthen-4-ones derived from natural isoflavonoids and their analogs was studied. The reaction was shown to proceed selectively with opening of the chromone ring. Several substituted 4-arylpyrazoles containing furo[3,2-b]chromen-5-ol, pyrano[2,3-b]chromen-6-ol, and xanthen-8-ol fragments were synthesized.

6-(2-Methylthiazol-4-yl)-4-methylumbelliferone derivatives were synthesized from 4-(1,3-thiazol-4-yl)-1,3-benzenediols via a Pechmann reaction and were modified by acylation and aminomethylation.

Xanthine oxidase is a potential target for treatment of hyperuricemia and gout. In this study, a number of A- and B-ring carboxylated aurone derivatives were synthesized and evaluated for their ability to inhibit xanthine oxidase in vitro . According to the results obtained, two different ranges of inhibitory activity were observed. The aurones with carboxylic acid group at the 4′-position of B-ring were found to be potent inhibitors of the enzyme with IC 50 values in the low micromolar range. The effects of these compounds were about 50 fold higher than of A-ring modified aurones with carboxymethoxy group at the 6-position. The binding modes of the carboxylated aurones in the active site of xanthine oxidase were explained using molecular docking calculations.

A two-step synthesis of 6-(5-isoxazolyl)coumarins was developed. Recyclization of 7-hydroxychromones by hydroxylamine into 4-(5-isoxazolyl)-1,3-benzenediols followed by condensation with acetoacetic ester produced 6-(5-isoxazolyl)-4-methylumbelliferone derivatives with aryl and hetaryl substituents on the isoxazole ring.

Aminomethylation of 6-hydroxy- and 6-hydroxy-7-methylaurones by the alkaloid cytisine was studied. It was shown that the aminomethylation of the 6-hydroxyaurones occurred at the 7-position of the benzofuran ring and at the 5-position if the 7-position was occupied.

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

A reliable method for the synthesis of B-ring hydroxylated homoisoflavonoids and 3-hetarylmethyl chromones has been developed. The method involves an initial oxa-Diels-Alder reaction of ortho-quinone methides generated from aryl/hetaryl-substituted ortho-( N, N-dimethylaminomethyl)phenols with (2 E)-3-( N, N-dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones and the subsequent cascade of reactions. This synthetic strategy avoids conventional multistep protocols and does not require the protection of hydroxyl groups, thus allowing the facile synthesis of a library of various aromatic and heterocyclic analogues of naturally occurring homoisoflavonoids.

Cytisine-linked isoflavonoids (CLIFs) inhibited PC-3 prostate and LS174T colon cancer cell proliferation by inhibiting a peroxisomal bifunctional enzyme. A pull-down assay using a biologically active, biotin-modified CLIF identified the target of these agents as the bifunctional, peroxisomal enzyme, hydroxysteroid 17β-dehydrogenase-4 (HSD17B4). Additional studies with truncated versions of HSD17B4 established that CLIFs specifically bind the C-terminus of HSD17B4 and selectively inhibited the enoyl CoA hydratase but not the D-3-hydroxyacyl CoA dehydrogenase activity. HSD17B4 was overexpressed in prostate and colon cancer tissues, knocking down HSD17B4 inhibited cancer cell proliferation, suggesting that HSD17B4 is a potential biomarker and drug target and that CLIFs are potential probes or therapeutic agents for these cancers.

The behavior of flavonoid Mannich bases in inverse electron-demand hetero-Diels–Alder reactions was studied. Isoflavones and aurones were used as examples to show that their Mannich bases reacted with 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)morpholine through an elimination mechanism and subsequent cycloaddition to form derivatives of the new heterocyclic systems pyrano[2′,3′:5,6]chromeno[3,2-c]pyridin-4-one and furo[2′,3′:5,6]chromeno[3,2-c]pyridin-3(2H)-one.

The possibility of introducing a substituted aminomethyl group into ring B of an isoflavone via reductive amination was studied. Several novel 2′-aminomethyl derivatives of natural 7-hydroxy-3′,5′ -dimethoxyisoflavone and its 7-O-methoxy derivative were synthesized.

Aminomethylation of 6-hydroxyaurones with primary amines was used to synthesize 2-benzylidene-8,9-dihydro-7H-furo[2,3-f][1,3]-benzoxazin-3(2H)-one derivatives, while opening of 1,3-oxazine ring in the presence of acid gave secondary amines containing a 6-hydroxyaurone moiety. Acetylation of 2-benzylidene-8,9-dihydro-7H-furo[2,3-f][1,3]benzoxazin-3(2H)-ones was also accompanied by opening of 1,3-oxazine ring.

The reactivity of Mannich bases derived from 6- and 7-hydroxycoumarins was studied in inverse electron demand Diels–Alder reactions with enamines. The reactions were shown to proceed by a cycloaddition mechanism followed by transformation of hemiaminals and resulted in the formation of heterocyclic pyrano[2,3-a]xanthene, pyrano[2,3-b]xanthene, and pyrano[3,2-b]xanthene.

The reaction of aloperine with isoflavone glycidyl ethers was investigated. A series of alkaloid–isoflavonoid conjugates were synthesized via regioselective opening of the oxirane ring by aloperine.

A simple method of the synthesis of α-(3(5)-trifluoromethylpyrazol-5(3)-yl)-2-hydroxydeoxybenzoins by a chemoselective reaction of 2-(1,1,1-trifluoroacetonyl)chromones with hydrazine dihydrochloride was developed. This approach involves the initial attack of hydrazine at the carbonyl atom of the CF3C(O)CH2 group followed by the chromone ring opening at C-2 atom and subsequent cyclization to pyrazoles. Such synthetic strategy provides easy access to the novel type of pharmaceutically attractive 3-(trifluomethyl)pyrazole-deoxybenzoin hybrids in high yields.

A two-step synthesis of 6-(3-pyrazolyl)coumarins starting from 7-hydroxy(acetoxy)chromones was developed. It included their recyclization using hydrazine hydrate into 4-(3-pyrazolyl)-1,3-benzenediols followed by condensation with acetoacetic ester to produce 6-(3-pyrazolyl)-4-methylumbelliferone derivatives with aryl, aryloxy, and hetaryl substituents on the pyrazole ring.

Oximes of 2,4-dihydroxybenzophenones, 1-(2,4-dihydroxyphenyl)-2-phenylethanones, and 1-(2,4-di-hydroxyphenyl)-2-phenoxyethanones were dehydrated with 1,1'-carbonyldiimidazole, yielding 3-substi-tuted 6-hydroxy-1,2-benzisoxazoles, aminomethylation reactions of which were studied with various reagents.

The aminomethylation of hydroxylated isoflavones with 2-aminoethanol, 3-amino-1-propanol, 4-amino-1-butanol, and 5-amino-1-pentanol in the presence of excess formaldehyde led principally to 9-(2-hydroalkyl)-9,10-dihydro-4H,8H-chromeno[8,7-e][1,3]-oxazin-4-ones 4 and/or the tautomeric 7-hydroxy-8-(1,3-oxazepan-3-ylmethyl)-4H-chromen-4-ones 5. The ratio of these tautomers was dependent on solvent polarity, electronic effects of aryl substituents in the isoflavone and the structure of the amino alcohol. NMR studies confirmed the interconversion of tautomeric forms.

Chromones play an important role in the design and discovery of new pharmacologically active compounds. A large volume of reports dedicated to synthesis and study of properties of nitrogen-containing chromone derivatives show important role of chromone alkaloid-like compounds. The present review covers achievements in the field of synthesis of chromone aminomethyl derivatives as one of perspective scaffolds.

The possibility of using the alkaloid cytisine to synthesize N 12-cytisinylethoxy 3-arylcoumarin derivatives was studied. A series of substituted 3-aryl-7-(N 12-cytisinylethoxy)coumarins with the coumarin and cytisine moieties connected by a linker were synthesized.

The possibility of using the alkaloid aloperine for aminomethylation of a chromone ring was studied. A series of 8-(aloperin-12-yl)methyl-substituted isoflavone derivatives were synthesized.

Nitrosation and cyclization of 4-(3-aminothieno[2,3-b]pyridine-2-yl)-2H-chromen-2-ones 1 afforded substituted 6H-chromeno[3,4-c]pyrido[3',2':4,5]thieno[2,3-e]pyridazin-6-ones 2 that inhibited the intermediary filament protein, vimentin, at low micromolar concentrations. This inhibition promoted the secretion of Prostate Apoptosis Response-4 protein (Par-4), which selectively triggered apoptosis in prostate cancer cells such as CWR22Rv1, LNCaP-derivative C4-2B, PC-3 and its aggressive analog, PC-3 MM2.

The propensity of cyclic carboxylic anhydrides to undergo ring-opening was exploited in a reaction with 2'-hydroxy-α-heteroarylacetophenones leading to the formation of chromones. New simple method was developed for the synthesis of 2-(ω-carboxyalkyl)-3-heteroarylchromones without protecting either the phenolic or the carboxylic groups. Treatment with hydrazine led to the formation of 3(5)-(ω-carboxyalkyl)-5(3)-(2,4-dihydroxyphenyl)-4-heteroarylpyrazoles.