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The alkaloid triacanthine was isolated from Gleditschia triacanthos and its di- and tribenzyl derivatives were synthesized. Both compounds are crystallized in the R-3 space group with same unit cell parameters. A channel is formed in the crystals, in which water molecules with large thermal parameters located on the c axis on H-bonds distances. In the dibenzyl derivative of triacanthine, the prenyl group is disordered in two positions in a ratio of 0.65:0.35, which makes it possible to fill voids in the crystal packing. The Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H…H (about 57.9% and 51.4% for di- and tribenzyl derivatives respectively) and H…C/C…H (around 14.9% and 19.2%) interactions.

This study investigated the positive inotropic andvasorelaxant activity ofDHQ-11, aconjugate of flavonoid dihydroquercetin with isoquinoline alkaloid 1-aryl-6,7-dimethoxy-1,2.3,4-tetrahydroisoquinoline.A study was performed using anterior papillary muscle removed from the left ventricle and thoracic aorta dissected from rats. DHQ-11 produceda concentration-dependent positive inotropic effect which was more potent than their parent compounds alone. The positive inotropic effect of conjugate DHQ-11was significantly attenuated by the β-adrenoreceptor inhibitor propranolol and L-type Ca2+ channel blocker nifedipine. Also,conjugate DHQ-11 markedly potentiated first post-rest responses indicating that it can modulate Ca2+ loading/release processes in the sarcoplasmic reticulum.These results suggest that positive inotropic effect produced by conjugate DHQ-11may be mediated through activation oftheβ-AR/AC/cAMP/PKA pathway that leads to increased Ca2+ influx and rises in Ca2+ loading/release in the SR, resulting in increased [Ca2+]i and enhanced contraction force. DHQ-11 significantly relaxed both high KCl- and phenylephrine-induced contractions of rat aortic rings whichwere significantly inhibited by lowering extracellular Ca2+ concentration and in the presence of verapamil.DHQ-11 significantly inhibited phenylephrine-induced contractions in a Ca2+-free medium, in the presence of verapamil. The vasorelaxant effect of the DHQ-11 was significantly reduced by the removal of endothelium and in the presenceof L-NAME and methylene blue as well as glibenclamide and TEA.These results suggest that the vasorelaxation produced by conjugate DHQ-11may be mediatedbyan endothelium-independent mechanism involving activation of KATP and BKCa channels and inhibition of L-type VDCCs and Ca2+ release from the sarcoplasmic reticulum and endothelium-dependent mechanism through activation of the NO/sGC/cGMP/PKG signaling pathway resulting in a decrease of intracellular Ca2+levels. These observations reveal that the conjugate DHQ-11 due to its high positive inotropic and vasorelaxant activity could be a promising compound for the design and development of new drugs for the treatment of heart failure.

Oxidation of the alkaloid skimmianine produced a formyl derivative that reacted with homoveratrylamine to give the product of nucleophilic ipso-substitution 3-formyl-4-(3,4-dimethoxyphenylethylamino)-7,8- dimethoxyquinolin-2-one. The presence of the formyl group in the latter stimulated its further ipso-substitution at the H atom in acidic solution to form 4-(3,4-dimethoxyphenylethylamino)-7,8-dimethoxyquinolin-2-one, the structure of which was confirmed by an X-ray crystal structure analysis.

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.

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.

The main residue and the solvent mol­ecule aggregate to discrete pairs via a classical O—H⋯O hydrogen bond, while non-classical C—H⋯O inter­actions lead to the formation of an extended network., Two potentially bioactive fragments, namely a tricyclic quinazoline derivative with an exocyclic alkene moiety and a substituted iso­quinoline, are coupled to give 3-{[6,7-dimeth­oxy-1-(4-nitro­phen­yl)-1,2,3,4-tetra­hydro­isoquinolin-2-yl]methyl­idene}-1,2,3,9-tetra­hydro­pyrrolo­[2,1-b]quinazolin-9-one. The target product crystallizes as a methanol solvate, C29H26N4O5·CH4O, and is E configured. The alternative Z isomer would necessarily imply either considerable twist about the central double bond or very unfavourable intra­molecular contacts between sterically more demanding substituents. The main residue and the co-crystallized solvent mol­ecule aggregate to discrete pairs via a classical O—H⋯O hydrogen bond with a distance of 2.8581 (7) Å between the methanol OH donor and the quinazolinone O=C acceptor.

5′-Nitro- (2) and 5′-aminodubamine (3) were sequentially synthesized from the alkaloid dubamine. Condensation of 3 with 15 aldehydes gave imines, reduction of which produced secondary amines. Studies of the cytotoxicities for HeLa and HEp-2 cells of the compounds at a concentration of 100 μM revealed several trends. The activity decreased significantly or disappeared at lower concentrations although compound 5o at concentrations of 1–10 μM was active for HEp-2 cells at the level of cisplatin.

Compounds 3a [1-(3′,4′-methylenedioxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] and 3b [1-(6′-bromo-3′,4′-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] demonstrated dose-dependent (5-75 μM) negative inotropic effects. Compound 5 [1,3-bis-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin- 1-yl)propane] demonstrated a two-phase inotropic effect. The experimental results and a literature analysis suggested that the negative inotropic effects of the tested compounds (3a, 3b, 5) could be due to their influences on the [Ca2+]i concentration through blocking of cardiomyocyte Na+- and Ca2+-channels. The positive inotropic effect of free base 5 could be related to modulation of cardiomyocyte muscarinic receptor activity.

Cyclization of α-benzoylamino-N-[2-(3,4-dimethoxyphenyl)ethyl]alkyl amides by POCl3 was studied. Spectral analyses and an X-ray crystal structure analysis found that the synthesized compounds contained 5,6-dihydroimidazo[5,1-a]isoquinoline cores.

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.

Amides were synthesized from N-benzoyl aliphatic α-amino acids and homoveratrylamine and screened for cytotoxicity.

N-phthaloyl derivatives of aliphatic α-amino acids were synthesized using phthalanhydride under standard conditions. The optimization reaction carried out by the thermal method to obtain the amides of these N-phthaloyl amino acids resulted in transimitted rather than amidation. The target amides of N-phthaloyl-α-amino acids were obtained by acylation of the amine with the corresponding acid chloroanhydrides in dichloromethane. These results were compared with the results of a similar acylation in a non-polar solvent (benzene). The dependence of the direction of the reaction on the duration of the acylation and the amount of amine used was established. The conditions for the formation of the corresponding N-phthaloyl-α-amino acid amides and asymmetric phthalic acid diamides were found. It is noteworthy that the formation of diamides is directly proportional to the equivalent amount of amine and the duration of the reaction, which makes it possible to purposefully control the synthesis in one reactor.

Acta crystallographica / E 77(1), 47-51 (2021). doi:10.1107/S2056989020016059, Published by International Union of Crystallography, Chester

Proceedings 62(1), 1-9 (2020). doi:10.3390/proceedings2020062001, The crystal structures of 4-(3,4-dimethoxyphenylethylamino)-methylidene-2,3,4,10-tetrahydro-1H-pyrido[2,1-b]-quinazolin-10-one (1) and 4-(3,4-methylene-dioxyphenylethylamino)-methylidene-2,3,4,10-tetrahydro-1H-pyrido[2,1-b]-quina-zolin-10-one hydrochloride (2) were studied by single crystal X-ray diffraction. Their molecular and crystal structures are described in the context of intra- and inter-molecular interactions and of stereoisomerism. The crystallographic study established mixed E, Z configuration about the C4=C12 bond for (1) and E configuration about the C4=C12 bond for (2). For molecular crystals, Hirshfeld surface analyses may provide insight into intermolecular interactions, and energy framework analyses allow one to quantify different contributions to the overall energy. These analyses were performed to pinpoint intermolecular interactions in (1) and (2). According to our results, the molecules are associated with intra- and intermolecular hydrogen bonds, C-H···$π$ and $π$-stacking interactions. The three-dimensional Hirshfeld surface analyses and two-dimensional fingerprint plots revealed that the structures are dominated by H···H, H···C/C···H and H···O/O···H contacts. The intermolecular energy analysis confirmed a significant contribution of dispersion to the stabilization of molecular packings in (1) and (2)., Published by Basel$nMDPI AG

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.

The structures and absolute configurations of the matrine-type alkaloids darvasine, leontalbine methyl iodide, albertamine, and deoxydarvasamine diperchlorate were established by X-ray crystal structure analyses. The structures of albertamine and darvasamine were revised as 14-hydroxymatrine and isosophoridine, respectively. Albertidine isolated from Leontice albertii was (+)-isomatrine.

Data from the CCDC were analyzed to prove that cis-matrine is a nonexistent quasi-diastereomer. The proposed existence of 32 enantiomeric pairs in nature (considering the N atoms as chiral centers) was incorrect.

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.

New conjugates of the quinolizidine alkaloids (–)-cytisine and thermopsin were synthesized by alkylating their 9-amino derivatives with 1,3-dimethyl-5-formyluracil. The cytotoxic properties of the synthesized conjugates against cell lines HEK293, HepG2, and Jurkat were studied. Screening identified the lead compound 5-{[(3-benzyl-8-oxo-1,3,4,5,6,8-hexahydro-2H-1,5-methanopyrido[1,2-a][1,5]diazocin-9-yl)amino]methyl}-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione, which suppressed metabolic activity of lymphoblastic leukemia cells with inhibitory concentration (IC50) 20.6 ± 2.1 μM (IC50 of reference compound 5-fluorouracil was 18.5 ± 3.3 μM).

The azido-Ugi reaction with natural alkaloid cytisine was investigated. It was demonstrated that the reaction could be performed with various carbonyls (both aldehydes and ketones) and isocyanides. The transformation proceeded under mild conditions in methanol using TMSN3 as a source of hydrazoic acid to give target tetrazole derivatives of cytisine in up to 98% yield. The diastereoselectivity of this reaction was studied using both aliphatic and aromatic aldehydes. A family of tetrazole derived cytisine compounds was prepared. Selective deprotection of tetrazoles was elaborated to synthesize the corresponding NH-tetrazoles.

3-Formyl- and 3-bromo-N-methylcytisine derivatives of the alkaloid N-methylcytisine from Thermopsis alterniflora were synthesized. Their structures were established using NMR spectroscopy and X-ray crystal structure analyses. The crystal structure of 3-formyl-N-methylcytisine perchlorate involves two protonated cations mutually bonded by a bifurcated N–H…O H-bond. A Br…O donor–acceptor interaction is observed in the crystal of 3-bromo-N-methylcytisine.

The antibacterial and antifungal activity against gram-positive and gram-negative bacteria and Candida albicans fungal strain for alkyltetrahydroisoquinoline derivatives were evaluated. It was established, that 1,11-bis(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)undecan shows pronounced antibacterial properties against all the microorganism strains and strong antifungal activity against Candida albicans with greater inhibition area than the reference drug. IC50 value of the compound is 2,1±0,1 μg/ml, LD50 value is 324,9±18,2 mg/kg.

The reaction of dihydroquercetin monosuccinate with ammonia, a series of alkylamines, and amino-derivatives of heterocyclic compounds including nitroxyl radicals and alkaloids produced the corresponding ionic conjugates, the water solubility of which was 1–2 orders of magnitude greater than that of dihydroquercetin with retention of the high antioxidant activity.

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.

Two bis(tetrahydroisoquinoline) derivatives of undecane were synthesized from brassylic acid and 3,4-dimethoxy-(or methylenedioxy-)phenylethylamine. It was shown that 4a and 4b were highly cytotoxic for cancer-cell cultures and less toxic to healthy cells and exhibited noticeable antimicrobial activity against Gram-positive and Gram-negative bacteria and fungal strain Candida albicans. The antifungal activity of 4a exceeded that of the reference drug nystatin.

The new cytisine derivatives N-(3′-β-bromoethoxy-4′-methoxy-2′-bromobenzyl)cytisine and N-[2′-bromo-4′-methoxy-3′-(β-cytisinylethoxy)benzyl]cytisine were prepared from cytisine, substituted benzaldehyde, and dibromoethane. The structures of the synthesized compounds were established using IR, mass, and PMR spectral data.

Bischler–Napieralski cyclization of amides synthesized from homoveratrylamine and malonic and succinic acids produced N-(3,4-dimethoxy-β-phenylethyl)-succinimide, 1,1-bis-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)methane, cleavage products, and several intermediates, the structures of which were confirmed using IR and NMR spectral data and x-ray crystal structure analysis.

Mannich reaction of dihydroquercetin with a series of 1-aryl-6,7-dimethoxytetrahydroisoquinolines synthesized heterocyclic mono-and di-substituted conjugates of dihydroquercetin and N-hydroxymethyl isoquinoline derivatives.

Pyrido- and [1, 4]-oxazinoisoquinolines, bis-tetrahydroisoquinolines, the alkaloid corydaldine, cleavage products, and a series of intermediates were prepared from homoveratrylamine and dibasic acids (glutaric and diglycolic) using a Bischler–Napieralski reaction. Their structures were confirmed using IR and NMR spectra and an x-ray crystal structure analysis.

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.

New hydroxyethyl derivatives of 1-aryltetrahydroisoquinoline alkaloids and diisoquinoline were prepared using a Pictet–Spengler reaction.

Bis-tetrahydroisoquinolines were prepared from homoveratrylamine and phthalic acids using a Bischler–Napieralski reaction. Their structures were confirmed by IR and NMR spectral data.

1-Alkyltetrahydroisoquinolines were prepared by a Bischler–Napieralski reaction starting from homoveratrylamine and monobasic acids. Their structures were confirmed by IR and NMR spectral data.

The Diels–Alder adducts of the quinolizidine alkaloids N-methylcytisine, (−)-leontidine, and (−)-thermopsine with N-phenylmaleimide have been synthesized. The structures and absolute configurations of the new asymmetric centers of the products were determined by NMR spectroscopy experiments, QC-calculations, and X-ray data.

Spin-labeled cytisine derivatives containing stable pyrrolidine and piperidine nitroxyl radicals were synthesized by acylation and alkylation of the secondary amine. Toxicological studies showed that introduction of the nitroxyl group decreased significantly the general toxicity.

Three alkaloids of the cryptostylin series and 20 monomolecular and 3 bimolecular 1-aryltetrahydroisoquinoline derivatives were prepared using the Picte–Spengler reaction.

The possibility of using the alkaloid cytisine to synthesize N12-cytisinylethoxy derivatives of isoflavonoids and their analogs was studied. A series of substituted 7-(N12-cytisinylethoxy)isoflavones containing chromone and cytisine fragments connected through a linker were synthesized.

An oxazine ring was annelated to benzopyran-4-one and benzopyran-2-one cores by reacting 7-hydroxyisoflavones and 7-hydroxycoumarins with lupinylamine and formalin. The new derivatives 9,10-dihydro- 4H,8H-chromeno(8,7-e)(1,3)oxazin-4-one and 9,10-dihydro-2H,8H-chromeno(8,7-e)(1,3)oxazin-2-one containing a lupinine moiety in the 9-position were prepared. The presence of a hydroxyl in lupinine enabled several esters of carboxylic and dicarboxylic acids (3-5) with antiviral, antitumor, hepatoprotective, antituberculosis, anticholinesterase, and anesthetic properties (6, 7) to be prepared from it. A series of new derivatives of 4-aminoquinoline that included a lupinylamine moiety (2) exhibited antimalarial activity (8). Salts of lupinine with 3- or 4-azomethinebenzoic acids were also synthesized (9). Several azomethines of lupinylamine (10) and its phosphorylated derivatives (11) were prepared. The goal of the present work was to introduce the lupinine moiety into natural flavonoids and their analogs because the combination in one molecule of two natural heterocyclic groups could facilitate the manifestation of properties important for practical use. The appropriate ratio of substrate, amine, and formaldehyde in the presence of a basic catalyst under Mannich reaction conditions is known to form derivatives of 3,4-dihydro-1,3-benzoxazines as a result of electrophilic substitution (12-14). We considered it interesting to study the reaction features of flavonoids with lupinylamine and formalin. Heating formononetin (3a) (15), 7-hydroxy-2-methoxyisoflavone (3b) (16) and its 2-methyl derivative 3d (17), and 7-hydroxy-2-methylisoflavone (3c), which was isolated from Glycyrrhiza glabra (18), with an equivalent amount of 2 and a two-fold excess of formalin in propan-2-ol in the presence of a catalytic amount of 4-(dimethylamino)pyridine (DMAP) produced derivatives of 9,10-dihydro-4H,8H-chromeno(8,7-e)(1,3)oxazin-4-one (4a-d) in satisfactory yields without preliminary preparation of N,N-bis-(hydroxymethyl)amine. Thus, we synthesized several new derivatives 4a-d containing a lupinine moiety in the 9-position as a result of simultaneous C- and O-aminomethylation of the benzopyran-4-one core. 3-Arylcoumarins, certain representatives of which were isolated from plant material, are flavonoids according to their biogenetic origin. We studied the reaction features of 3-aryl-7-hydroxycoumarins (5a-c) with 2 and formalin. Like for the 7-hydroxyisoflavones, the Mannich reaction occurred with satisfactory yield without preliminary preparation of N,N-bis

Aminomethylation of natural 7-hydroxyisoflavones and their analogs by the alkaloid (−)cytisine was studied. Substituted 8-(cytisin-12-yl)methyl-7-hydroxyisoflavones were synthesized.

In vitro leishmanicidal activity of 16 N-benzylcytisine derivatives has been evaluated using Leishmania donovani axenic amastigotes. In general, halogen (bromo-, chloro-) derivatives appeared to be more toxic against parasites than their parent compounds. Quantum-chemical calculations helped to recognize certain patterns in the structure of frontier orbitals related to bioactivity of compounds. Thus, the presence of halogen atom is shown to have a significant effect on both distribution and the energy of LUMOs thereby on potent activity that was also confirmed by Quantitative-Structure Activity Relationship (QSAR) analysis. Experimentally and theoretically observed structure-cytotoxicity relationships are described.

Recyclization of N 12-cytisinylethoxy derivatives of natural isoflavonoids and their analogs through the action of hydroxylamine was studied. Substituted 4-aryl-5-(2-hydroxyphenyl)isoxazoles containing cytisine and isoxazole fragments were synthesized. The structures of the synthesized compounds were established using 2D NMR spectroscopy.