Heterocyclic Residues Research Articles

An oxidative photocyclization approach to the synthesis of Securiflustra securifrons alkaloids.

Securines and securamines are cytotoxic alkaloids that contain reactive alkene and heterocyclic residues embedded in skeletons comprising four to six oxidized rings. This structural complexity imparts a rich chemistry to the isolates but has impeded synthetic access to the structures in the nearly three decades since their isolation. We present a flexible route to eight isolates that exemplify the three skeletal classes of metabolites. The route proceeds by the modular assembly of the advanced azides 38 and 49 (13 steps, 6 to 10% yield), sequential oxidative photocyclizations, and late-stage functional group manipulations. With this approach, the targets were obtained in 17 to 19 steps, 12 to 13 purifications, and 0.5 to 3.5% overall yield. The structure of an advanced intermediate was elucidated by microcrystal electron diffraction (MicroED) analysis. The route will support structure-function and target identification studies of the securamines.

Specific Fluorescent Probes for Imaging DNA in Cell-Free Solution and in Mitochondria in Living Cells.

New styryl dyes consisting of N-methylpyridine or N-methylquinoline scaffolds were synthesized, and their binding affinities for DNA in cell-free solution were studied. The replacement of heterocyclic residue from the pyridine to quinoline group as well as variation in the phenyl part strongly influenced their binding modes, binding affinities, and spectroscopic responses. Biological experiments showed the low toxicity of the obtained dyes and their applicability as selective dyes for mitochondria in living cells.

Benzthiophenes containing a 2-amino-ethyl fragment: synthesis, antibacterial, antiprotozoal and fungistatic activity

Benzthiophenes containing a 2-aminoethyl fragment were synthesized, at the NCRSRVI branch of FSBSC Federal Rostov Agrarian Scientific Center, and their antibacterial, antiprotozoal, and fungistatic activities were studied. We synthesized compounds based on 1-(2-chloroaryl)-3,4-dihydroisoquinolines by base-catalyzed nucleophilic substitution of an atom for a mercapto group containing an electron-withdrawing substituent, followed by recycling to the corresponding benzthiophenes, developed by us for the first time. Fifteen benzthiophene derivatives containing a 2-aminoethyl fragment have been synthesized. The starting compounds for the synthesis of benzothiophenes (compounds 1-6) showed a relatively weak activity against all the cultures studied. Only hydrazide 5 in terms of antiprotozoal activity corresponds to the level of chloroquine and is 4 times more active than amprolium. The formation of a benzothiophene ring significantly changes the activity of the compounds. Thus, compounds 14 and 15 (arylurea derivatives) have a noticeable fungistatic activity, although all other structures presented in this study are completely inactive against Penicillium italicum. It is also necessary to note the high antibacterial activity of compounds 14 and 15 against both gram-positive and gram-negative bacteria, which allows us to conclude that the search for active structures in the series of urea analogues 14 and 15 is promising. The azabenzthiophene derivative 11 showed the highest antiprotozoal activity, exceeding the indicator of chloroquine by 2 times and that of amprolium by 6 times. It should be assumed that the synthesis of analogues of compound 11 with other heterocyclic residues instead of the benzimidazole core (pyridine, imidazole, quinoxaline, pyrimidine) can lead to an increase in both antiprotozoal and (for the corresponding ureas) antibacterial activity. Analysis of the results of studying the biological activity of new compounds also showed that a high level of protistocidal activity (31.25-7.8 ?g/ml) was found in three compounds of the benzthiophene series: 5, 8, 11; average level (125-62.5 mcg/ml) - in five substances: 1, 4, 10, 14, 15. The antibacterial activity of the studied benzthiophene derivatives was manifested to a greater extent in relation to Gram-positive bacteria: twelve substances inhibited the growth of St. aureus All-Russian Collection of Microorganisms B-128. Five compounds were active against Gram-negative bacteria (E. coli All-Russian Collection of Microorganisms B-820). Combined antiprotozoal and antibacterial activity was found in compounds 1, 4, 5, 9, 10, 11, 14 and 15.

Mechanism of hydride abstraction in the electrocyclic phototransformation of heterostilbene

A new mechanism of hydride abstraction in the course of a photochemical electrocyclic reaction of heterostilbene in aqueous solution is reported. The study of electrocyclic transformations of heterostilbenes containing different types of heterocyclic residues revealed that the herein estimated mechanism of hydride abstraction is common for heterostilbene photochemical electrocyclization through the formation of new CN bond.

Heterocyclic Resveratrol Analogs: Synthesis and Physiological Activity. Part 2: Analogs Obtained by the Replacement of Ethylene Fragments with Heterocyclic Residues

Heterocyclic Resveratrol Analogs: Synthesis and Physiological Activity. Part 2: Analogs Obtained by the Replacement of Ethylene Fragments with Heterocyclic Residues

Molecular Docking of Cyanine and Squarylium Dyes with NSP15 Endoribonuclease of the SARS-CoV-2 Coronavirus

The ongoing spread of the COVID-19 coronavirus infection requires us to find new tools and methods for detecting and studying the infection and preventing morbidity (new analytical procedures and tests). With the aim of developing probes for the detection of SARS-CoV-2 coronavirus by modeling in silico (molecular docking), the noncovalent binding of cyanine and squarylium dyes with different molecular charges and different types of heterocyclic residues and substituents (42 compounds in total) with different variants of the NSP15 endoribonuclease of the SARS-CoV-2 coronavirus (COVID-19) of the original (wild) type and mutant types is studied. The interaction energies and spatial configurations of the dye molecules in complexes with NSP15 are determined. Some dyes with negative values of the total energy of the complex Etot are promising for further practical study as probes for coronavirus.

Highly regioselective and stereoselective photodimerization of azine-containing stilbenes in neat condition: An efficient synthesis of novel cyclobutanes with heterocyclic substituents

We have developed a visible light promoted reaction of intermolecular [2 + 2] cycloaddition of heterostilbene molecules containing a phenyl ring with OMe donor groups and a 6-membered nitrogen-containing ring as an acceptor, which proceeds under mild conditions in water at room temperature. The corresponding cyclobutane derivatives were synthesized with yields of up to 57%. The efficiency of this photoreaction depends on the nature of the heterocyclic residue and the concentration of heterostilbenes. The mild reaction conditions and the absence of additives facilitate the reaction. This work provides a convenient and gentle method for the preparation of cyclobutanes.

Sequences of Acretocins, Peptaibiotics Containing the Rare 1-Aminocyclopropanecarboxylic Acid, from Acremonium crotocinigenum CBS 217.70.

Sequences of Acretocins, Peptaibiotics Containing the Rare 1-Aminocyclopropanecarboxylic Acid, from Acremonium crotocinigenum CBS 217.70.

Self-sorting processes in a stimuli-responsive supramolecular systems based on cucurbituril, cyclodextrin and bisstyryl guests

We report a four-component mixture comprising bisstyryl dyes, HP-β-CD and CB[7] that undergoes self-sorting in aqueous solution based on ion–dipole, electrostatic, charge–transfer interactions, as well as the hydrophobic effect. The formation of 1:1 and 1:2 complexes between the bisstyryl guests and HP-β-CD, CB[7] has been confirmed by optical and NMR spectroscopy as well as ESI-MS data. The studied supramolecular systems are stimuli responsive. Thus, protonation of bisstyryl dye based on pyridine heterocyclic residue leads to the destruction of its complexes with HP-β-CD. Whereas, complex of the bisstyryl dye with CB[7] based on N-methylpyridinium moiety can be replaced by Ba2+ cation. The work demonstrates that HP-β-CD and CB[7] are molecular containers suitable for the creation of stimuli-responsive and self-sorting systems.

Silylated iminophosphonates: Novel reactive synthons for the preparation of fluorinated aminophosphonates and aminophosphonic acids

A convenient synthetic approach towards previously unknown N- and N,O-silylated α-iminophosphonates bearing fluoroalkyl groups at the imine C atom was developed. The synthetic potential of the compounds was demonstrated by their easy functionalization and the straightforward preparation of biorelevant aminophosphonates and free aminophosphonic acids with heterocyclic residues in the α-position.

Synthesis of 3-(furyl)acrylates containing several phosphonate groups

Isomeric (diethoxyphosphorylmethyl)furoyl phosphonates react with ethoxycarbonylmethylenetriphenylphosphorane to form 3-[(diethoxyphosphorylmethyl)fyryl]-3-(diethoxyphosphoryl)acrylates with trans-location of phosphonate and ester groups regardless of the structure of heterocyclic residue. 2,5-Bis(diethoxyphosphorylmethyl)-3-furoyl phosphonate and 4,5-bis(diethoxyphosphorylmethyl)-2-furoyl phosphonate prepared from the corresponding acid chlorides via the Arbuzov reaction behave analogously. The dependence of coupling costants JPP and JPC on the location of phosphorus-containing substituents in the furan ring of these compounds is analyzed.

Synthesis of (benzimidazol-2-yl)aniline derivatives as glycogen phosphorylase inhibitors

A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC50 values in the 400–600μM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC50 324μM and 357μM, respectively) with stronger effect than the p-tolyl analogue 8.

Deciphering molecular aspects of interaction between anticancer drug mitoxantrone and tRNA

Mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione) is a synthetically designed antineoplastic agent and structurally similar to classical anthracyclines. It is widely used as a potent chemotherapeutic component against various kinds of cancer and possesses lesser cardio-toxic effects with respect to naturally occurring anthracyclines. In the present study, we have investigated the binding features of mitoxantrone–tRNA complexation at physiological pH using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, circular dichroism (CD) spectroscopy, isothermal titration calorimetry, and UV–visible absorption spectroscopic techniques. FTIR analysis reveals that mitoxantrone interacts mainly with heterocyclic base residues of tRNA along with slight external binding with phosphate–sugar backbone. In particular, mitoxantrone binds at uracil (C=O) and adenine (C=N) sites of biomolecule (tRNA). CD spectroscopic results suggest that there is no major conformational transition in native A-form of tRNA upon mitoxantrone–tRNA adductation except an intensification in the secondary structure of tRNA is evident. The association constant calculated for mitoxantrone–tRNA association is found to be 1.27 × 105 M−1 indicating moderate to strong binding affinity of drug with tRNA. Thermodynamically, mitoxantrone–tRNA interaction is an enthalpy-driven exothermic reaction. Investigation into drug–tRNA interaction can play an essential role in the rational development of RNA targeting chemotherapeutic agents, which also delineate the structural–functional relationship between drug and its target at molecular level.

ChemInform Abstract: General Photoinduced Sequential Electrocyclization/[1,9]‐Sigmatropic Rearrangement/Ring‐Opening Reaction of Diarylethenes.

A novel and efficient photochemical transformation of diarylethenes comprising a five-membered heterocyclic ring and phenyl moiety is described. This reaction provides a simple method for the preparation of functionalized naphthalene derivatives via photorearrangement reaction of diarylethenes, and the process is characterized by high efficiency that was determined by NMR monitoring. Some mechanistic aspects of this process have been also explored. It was found that the reaction includes tandem transformation of three basic processes: the photocyclization of the hexatriene system, [1,9]-sigmatropic rearrangement, and heterocyclic ring opening. Diarylethenes with different heterocycle moieties (thiophene, benzo[b]thiophene, furan, indole, imidazole, thiazole, oxazole, pyrazole) have been involved into this process, and the target naphthalenes with good yields have been obtained. The opportunity for use in the transformation of diarylethenes with different heterocyclic residues permits synthesis of naphthalenes with desired functional groups. The general character and high efficiency of the reaction promise that the transformation can be an effective synthetic route for the annulation of benzene rings to various aromatic systems, including heterocycles.

General Photoinduced Sequential Electrocyclization/[1,9]-Sigmatropic Rearrangement/Ring-Opening Reaction of Diarylethenes.

A novel and efficient photochemical transformation of diarylethenes comprising a five-membered heterocyclic ring and phenyl moiety is described. This reaction provides a simple method for the preparation of functionalized naphthalene derivatives via photorearrangement reaction of diarylethenes, and the process is characterized by high efficiency that was determined by NMR monitoring. Some mechanistic aspects of this process have been also explored. It was found that the reaction includes tandem transformation of three basic processes: the photocyclization of the hexatriene system, [1,9]-sigmatropic rearrangement, and heterocyclic ring opening. Diarylethenes with different heterocycle moieties (thiophene, benzo[b]thiophene, furan, indole, imidazole, thiazole, oxazole, pyrazole) have been involved into this process, and the target naphthalenes with good yields have been obtained. The opportunity for use in the transformation of diarylethenes with different heterocyclic residues permits synthesis of naphthalenes with desired functional groups. The general character and high efficiency of the reaction promise that the transformation can be an effective synthetic route for the annulation of benzene rings to various aromatic systems, including heterocycles.

Cytotoxic activity of rearranged drimane meroterpenoids against colon cancer cells via down-regulation of β-catenin expression.

Colorectal cancer has emerged as a major cause of death in Western countries. Down-regulation of β-catenin expression has been considered a promising approach for cytotoxic drug formulation. Eight 4,9-friedodrimane-type sesquiterpenoids (1–8) were acquired using the oxidative potential of Verongula rigida on bioactive metabolites from two Smenospongia sponges. Compounds 3 and 4 contain a 2,2-dimethylbenzo[d]oxazol-6(2H)-one moiety as their substituted heterocyclic residues, which is unprecedented in such types of meroterpenoids. Gauge-invariant atomic orbital NMR chemical shift calculations were employed to investigate stereochemical details with support of the application of advanced statistics such as CP3 and DP4. Compounds 2 and 8 and the mixture of 3 and 4 suppressed β-catenin response transcription (CRT) via degrading β-catenin and exhibited cytotoxic activity on colon cancer cells, implying that their anti-CRT potential is, at least in part, one of their underlying antineoplastic mechanisms.

Synthesis and spectral properties of merocyanine dyes based on polynitrofluorenes

The di-, tetra- and hexamethinemerocyanines derived from di-, tri- and tetranitrofluorene, containing heterocyclic indolylidene residue were synthesized and their absorption spectra in the solvents of different polarity were investigated. A quantum-chemical analysis of the electronic structure of the synthesized merocyanines was performed and the types of electronic transitions in their molecules were calculated using DFT and TDDFT methods with the B3LYP/6-31G(d,p) basis. It was shown that with increasing electronacceptor properies of the fluorene core the electronic structure of the merocyanines can change from a neutral polyene to an ideal polymethine, which significantly affects the position, intensity and shape of the absorption bands, as well as vinylene shifts and deviations.

Conformational Properties of Secondary Amino Acids: Replacement of Pipecolic Acid by N‐Methyl‐L‐alanine in Efrapeptin C

The efrapeptins, a family of naturally occurring peptides with inhibitory activities against ATPases, contain several α,α-disubstituted α-amino acids such as α-aminoisobutyric acid (Aib) or isovaline (Iva) besides pipecolic acid (Pip), β-Ala, Leu, Gly, and a C-terminal heterocyclic residue. Secondary α-amino acids such as proline are known to stabilize discrete conformations in peptides. A similar influence is ascribed to N-alkyl α-amino acids. We synthesized two efrapeptin C analogs with replacement of Pip by N-methyl-L-alanine (MeAla) using a combination of solid- and solution-phase techniques in a fragment-condensation strategy to compare the conformational bias of both secondary amino acids. The solution conformation was investigated by vibrational circular dichroism (VCD) to probe whether the analogs adopt a 310 -helical conformation. The MeAla-containing analogs [MeAla(1,3) ]efrapeptin C and [MeAla(1,3,11) ]efrapeptin C inhibit ATP hydrolysis by the A3 B3 complex of A1 A0 -ATP synthase from Methanosarcina mazei Gö1.

Imidazole‐ and Benzimidazole‐Based Inhibitors of the Kinase IspE: Targeting the Substrate‐Binding Site and the Triphosphate‐Binding Loop of the ATP Site

AbstractThe enzymes of the mevalonate‐independent biosynthetic pathway to isoprenoids are attractive targets for the development of new drug candidates, in particular against malaria and tuberculosis, because they are present in major human pathogens but not in humans. Herein, the structure‐based design, synthesis, and biological evaluation of a series of inhibitors featuring a central imidazole or benzimidazole scaffold for the kinase IspE from E. coli, a model for the corresponding malarial enzyme, are described. Optimization of the binding preferences of the hydrophobic sub‐pocket at the substrate‐binding site allowed IC50 values in the lower micromolar range to be reached. Structure–activity relationship studies using a 1,2‐disubstituted imidazole central core revealed that alicyclic moieties fit the sub‐pocket better than acyclic aliphatic and aromatic residues. The phosphate‐binding region in the ATP‐binding site of IspE, a neutral glycine‐rich loop, was addressed for the first time by an additional vector attached to the central core. Polar functional groups, such as trifluoromethyl or nitriles, were introduced to undergo orthogonal dipolar interactions with the amide groups in the loop. Alternatively, small hydrogen‐bond‐accepting heterocyclic residues, capable of binding to the convergent NH groups in the loop, were explored. The biological data showed slightly improved inhibitory potency in some cases and confirmed the challenges in addressing, with gain in binding affinity, the highly water‐exposed sections of enzyme active sites, such as the glycine‐rich loop of IspE.

Synthesis and study of anti-bacterial activity of complexes of diallyldisulphide from garlic

Background: The development of bacterial resistance to available antibiotics and increasing incidence of multiresistant bacterial infections in hospitals and in the community has necessitated the search for new antibacterial agents to treat the bacterial infection. It has long been known that metal ions are involved in biological processes of life through bonding to the heteroatoms of the heterocyclic residues of biological molecules i.e., proteins, enzymes and nucleic acids etc. The behavior of the disulfide group as a donor in transition metal complexes has not been subjected to such detailed study as a number of other donor groups. Aim: The Diallyldisulphide is one of the main constituents of Allium sativum (Garlic). The antibacterial and antifungal activity of the Garlic is due to the presence of sulphur containing compounds. The aim of the present work was to synthesize metal complexes with Diallyldisulphide. Materials and Methods: Complexation reactions between the Diallyldisulphide and the metal ions were carried out at three different pH i.e. acidic (pH 3), neutral (pH 7) and alkaline (pH 10) using three different ratios of metal ligand namely 1:1, 1:2, 1:3, respectively. Complex formation with the ligand and all the metals took place at pH 10, indicating that complexes were stable at this pH. Studies with different metal: ligand ratio showed that in case of silver the complexation took place at 1:1 ratio. In case of divalent metals, the appropriate ratio of metal: ligand was 1:2. The structures of the new complexes obtained were determined by spectroscopic methods. Results and Discussion: Synthesized complexes were investigated for antimicrobial activity against Staphylococcus aureus, Pseudomonas aeruginosa, Klebsiella pneumoniae and E.coli. Diallyldisulphide-silver complex exhibited significant antibacterial activity (MIC 100 μg/ mL), and was found to be effective against selected organisms. The results concluded that the metal complexes are better antibacterial agents as compared to the silversulphadiazine. Key words: Antibacterial activity, complexes, diallyldisulphide, garlic, minimum inhibitory concentration