The design and synthesis of analogs of natural products can be a valuable source of medicinal preparations for the pharmaceutical industry. In the present study, the structural elucidation of eleven derivatives of 2,4-dihalogeno substituted synthetic analogues of the natural compound carvacrol was carried out by means of NMR experiments, and of another thirteen by DFT calculations. By selective NOE experiments and the irradiation of CH signals of the isopropyl group, individual conformers were assigned as syn and anti. By comparing GIAO/B3LYP/6-311++G(d,p)-calculated and experimentally measured vicinal 3JCH spin-spin constants, this assignment was confirmed. An unusual relationship is reported for proton-carbon vicinal couplings: 3JCH (180°) < 3JCH (0°). The conformational mobility of carvacrols was studied by 2D EXSY spectra. The application of homonuclear decoupling technique (HOBS) to these spectra simplifies the spectra, improves resolution without reducing the sensitivity, and allows a systematic examination of the rotational barrier of all compounds via their CH signals of the isopropyl group in a wider temperature interval. The rate constants of the isopropyl rotation between syn and anti conformers were determined and the corresponding energy barriers (14–17 kcal/mol) were calculated. DFT calculations of the energy barriers in carvacrol derivatives allowed the determination of the steric origin of the restricted isopropyl rotation. The barrier height depends on the size of the 2- and 4-position substituents, and is independent of the derivatization of the OH group.

The tautomeric properties of favipiravir were investigated experimentally for the first time by using molecular spectroscopy (UV–Vis absorption, fluorescence and NMR), as well as DFT quantum–chemical calculations. According to the obtained results, the enol tautomer is substantially more stable in most of the organic solvents. In the presence of water, a keto form appears to be favored due to the specific solute–solvent interactions. Upon the addition of alkaline-earth-metal ions, deprotonation and complexation occurred simultaneously, giving the formation of 2 : 1 ligand : metal complexes. According to the theoretical simulations, the metal ion is captured between the carbonyl groups as a result of the size–fit effect.

A series of OLED-relevant compounds, consisting of 1,3,5-triazine core linked to various aromatic arms by amino group, has been synthesized and characterized. The studied compounds exist in solution as a mixture of two conformers, a symmetric propeller and asymmetric conformer, in which one of the aromatic arms is rotated around the C-N bond. At temperatures below −40 °C, the VT NMR spectra in DMF-d7 are in a slow exchange regime, and the signals of two conformers can be elucidated. At temperatures above 100 °C, the VT NMR spectra in DMSO-d6 are in a fast exchange regime, and the averaged spectra can be measured. The ratio of symmetric and asymmetric conformers in DMF-d7 varies from 14:86 to 50:50 depending on the substituents. The rotational barriers of symmetric and asymmetric conformers in DMF-d7 were measured for all compounds and are in the interval from 11.7 to 14.7 kcal/mol. The ground-state energy landscapes of the studied compounds, obtained by DFT calculations, show good agreement with the experimental rotational barriers. The DFT calculations reveal that the observed chemical exchange occurs by the rotation around the C(1,3,5-triazine)-N bond. Although some of the compounds are potentially tautomeric, the measured absorption and emission spectra do not indicate proton transfer neither in the ground nor in the excited state.

Studies of the rotational barrier energy of the amide bond using quantum computing and nuclear magnetic resonance (NMR) are focused mainly on its use as a model of the peptide bond. The results of these studies are valuable not only in terms of the fundamental conformational properties of amide bonds, but also in the design of molecular machines, which have recently attracted interest. We investigate the fluxionality of the amide and enamide bonds of compound 3-[(E)-(dimethylamino)methylidene]-1,1-dimethylurea using advanced dynamic NMR experiments and a theoretical evaluation of the density functional theory (DFT) calculation. The dynamic NMR study shows restricted rotation around the amide group (16.4 kcal/mol) and a very high barrier around the enamine group (18.6 kcal/mol). In a structurally similar compound, (E)-3-(dimethylamino)-N,N-dimethylacrylamide (N atom is replaced by CH), the amide barrier is 12.4 kcal/mol and the enamine barrier is 11.7 kcal/mol. The DFT studies of both compounds reveal the electronic origin of this phenomenon. Theoretical calculations reveal the origin of the higher enamine barrier. The better delocalization of the lone pair of electrons on the end nitrogen atom into the antibonding orbital of the neighboring C-N double bond leads to the better stabilization of the ground state, and this leads to a greater increase in the enamine barrier.

Alzheimer’s disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone (3a–r) or sulfonyl hydrazone (5a–l) fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds (3c and 3d) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system. Compound 3n, possessing two indole scaffolds, showed the highest activity against butyrylcholinesterase (BChE) and a high selectivity index (SI = 47.34), as well as a pronounced protective effect in H2O2-induced oxidative stress in SH-SY5Y cells. Moreover, compounds 3c, 3d, and 3n showed low neurotoxicity against malignant neuroblastoma cell lines of human (SH-SY5Y) and murine (Neuro-2a) origin, as well as normal murine fibroblast cells (CCL-1) that indicate the in vitro biocompatibility of the experimental compounds. Furthermore, compounds 3c, 3d, and 3n were capable of penetrating the blood–brain barrier (BBB) in the experimental PAMPA-BBB study. The molecular docking showed that compound 3c could act as a ligand to both MT1 and MT2 receptors, as well as to AchE and BchE enzymes. Taken together, those results outline compounds 3c, 3d, and 3n as promising prototypes in the search of innovative compounds for the treatment of AD-associated neurodegeneration with oxidative stress. This study demonstrates that hydrazone derivatives with melatonin and donepezil are appropriate for further development of new AChE/BChE inhibitory agents.

Breast cancer (BC) is the second leading cause of cancer death in women, with more than 600,000 deaths annually. Despite the progress that has been made in early diagnosis and treatment of this disease, there is still a significant need for more effective drugs with fewer side effects. In the present study, we derive QSAR models with good predictive ability based on data from the literature and reveal the relationships between the chemical structures of a set of arylsulfonylhydrazones and their anticancer activity on human ER+ breast adenocarcinoma and triple-negative breast (TNBC) adenocarcinoma. Applying the derived knowledge, we design nine novel arylsulfonylhydrazones and screen them in silico for drug likeness. All nine molecules show suitable drug and lead properties. They are synthesized and tested in vitro for anticancer activity on MCF-7 and MDA-MB-231 cell lines. Most of the compounds are more active than predicted and show stronger activity on MCF-7 than on MDA-MB-231. Four of the compounds (1a, 1b, 1c, and 1e) show IC50 values below 1 μM on MCF-7 and one (1e) on MDA-MB-231. The presence of an indole ring bearing 5-Cl, 5-OCH3, or 1-COCH3 has the most pronounced positive effect on the cytotoxic activity of the arylsulfonylhydrazones designed in the present study.

BACKGROUND:Alzheimer's disease (AD) and Multiple sclerosis (MS) lead to neurodegenerative processes negatively affecting millions of people worldwide. Their treatment is still difficult and practically incomplete. One of the most commonly used drugs against these neurodegenerative diseases is 4-aminopyridine. However, its use is confined by the high toxicity.OBJECTIVES:The aim of this work is to obtain new peptide derivatives of 4-aminopyridine with decreased toxicity compared to 4-aminopyridine.METHODS:Synthesis was conducted in solution using a consecutive condensation approach. The new derivatives were characterized by melting points, NMR, and Mass spectra. Important ADME (absorption, distribution, metabolism, and excretion) properties have been studied in silico using ACD/Percepta v.2020.2.0 software. Acute toxicity was determined in mice according to a Standard protocol. All new derivatives were tested in vitro for cytotoxic activity in a panel of human (HEP-G2, BV-173) and murine (NEURO 2A) tumor cell lines via a standard MTT-based colorimetric method. β-secretase inhibitory activity was determined by applying the fluorescent method.RESULTS:New derivatives of 4-aminopyridine containing analogues of the β-secretase inhibitory peptide (Boc-Val-Asn-Leu-Ala-OH) were obtained. The in vivo toxicity of the tested compounds was found to be as high as 1500 mg/kg. Cell toxicity screening against tumor cell lines of different origins showed negligible growth-inhibitory effects of all investigated 4-aminopyridine analogues.CONCLUSION:Synthesis of new peptide derivatives of 4-aminopyridine is reported. Acute toxicity studies revealed a ca. 150 times lower toxicity of the new compounds as compared to 4-aminopyridine that may be ascribed to their peptide fragment.

Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives 3a–d and sulfonyl hydrazones 5a–k were synthesized. They were characterized by 1H-NMR, 13C NMR, and HRMS. Mycobacterium tuberculosis strain H37Rv was used to assess their antimycobacterial activity. All compounds demonstrated significant minimum inhibitory concentrations (MIC) from 0.07 to 0.32 µM, comparable to those of isoniazid. The cytotoxicity was evaluated using the standard MTT-dye reduction test against human embryonic kidney cells HEK-293T and mouse fibroblast cell line CCL-1. 4-Hydroxy-3-methoxyphenyl substituted 1,2,3-thiadiazole-based hydrazone derivative 3d demonstrated the highest antimycobacterial activity (MIC = 0.0730 µM) and minimal associated cytotoxicity against two normal cell lines (selectivity index SI = 3516, HEK-293, and SI = 2979, CCL-1). The next in order were sulfonyl hydrazones 5g and 5k with MIC 0.0763 and 0.0716 µM, respectively, which demonstrated comparable minimal cytotoxicity. All compounds were subjected to ADME/Tox computational predictions, which showed that all compounds corresponded to Lipinski’s Ro5, and none were at risk of toxicity. The suitable scores of molecular docking performed on two crystallographic structures of enoyl-ACP reductase (InhA) provide promising insight into possible interaction with the InhA receptor. The 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives and sulfonyl hydrazones proved to be new classes of lead compounds having the potential of novel candidate antituberculosis drugs.

The Alzheimer's disease leads to neurodegenerative processes and affecting negatively million people worldwide. The treatment of the disease is still difficult and incomplete in practice. Galanthamine is one of the most commonly used drugs against the illness. The main aim of this work is design and synthesis of new derivatives of galanthamine comprising peptide moiety as well as study of their β-secretase inhibitory activity and the anti-aggregating effect. All new derivatives of galanthamine containing analogues of Leu-Val-Phe-Phe (Aβ17-Aβ20) were synthesized in solution using fragment and consecutive condensation approaches. The new derivatives were characterized by melting points, NMR, and HPLC/MS. They were tested in vitro for β-secretase inhibition activity by means of fluorescent method and were investigated in vitro for anti-aggregation activity on sheep platelet-rich plasma. Although the new compounds do not contain a structural element responsible for the β-secretase inhibition, five of them show high or good β-secretase inhibitory activity between 19.98 and 51.19% with IC50 between 1.95 and 5.26 nM. Four of the new molecules were able to inhibit platelet aggregation between 55.0 and 90.0% with IC50 between 0.69 and 1.36 µM. Four of the compounds were able to inhibit platelet aggregation and two of them have high anti-aggregating effects.

Despite the widely studied anticancer activity of metal complexes of various hydantoin derivatives, reports on biological properties of dithiohydantoin complexes are limited to only few. Main challenge is determination of their structure, since no crystallographic data are available for metal complexes of dithiohydantoins. Herein, we describe the synthesis and structure of Pt(II) complexes of two spiro-5-(2,4-dihiohydantoins) with large and potentially intercalating aromatic rings, namely 3',4'-dihydro-2H,2'H,5H-spiro[imidazolidine-4,1'-naphthalene]-2,5-dithione and spiro-(fluorene-9,4'-imidazolidine)-2',5'-dithione. The anticancer activity of all compounds were tested against HL-60, BV-173, and K-562 tumor cell lines. Single-crystal X-ray analysis was performed for the spiro-(benzocyclohexane-4'-imidazolidine)-2',5'-dithione, whereas all other compounds were characterized by integrated approach of spectroscopic (IR and solid-state NMR) and theoretical (DFT) studies. The analysis of the data suggested Pt2L4 composition of the complexes with bridging N boolean AND S coordination of four ligand molecules and two Pt(II) centers of square planar geometry. Polymeric structure in the solid state was also presumed. The complexes showed modest to moderate anticancer activity as compared to cisplatin and the chronic myeloid leukemia derived BV-173 proved to be the most responsive tumor model.

Two novel, 7-hydroxyquinoline based, Schiff bases have been synthesized and their spectral properties have been investigated by combined use of optical and NMR spectroscopy and theoretical DFT calculations. The results indicate that 8-((phenylimino)methyl)quinolin-7-ol exists as a mixture of enol and two keto tautomers in solution, while 8-(((pentarfluorophenyl)imino)methyl)quinolin-7-ol is presented as a single enol form. Upon irradiation, in both compounds, through excited state intramolecular proton transfer mechanism, a rotation around the Cquin-CH bond occurs, indicating that they are suitable to be used as bistable switches. The back relaxation is faster comparing to the theoretical expectations, due to the additional flexibility around the azomethine bond. As a result of forming complexes with the acidic counter ion, no intramolecular rotation happens upon protonation with trifluoroacetic acid.

Two new bis-carbene (Pd(NHC)(2)Cl-2 and Pd(NHC)(NHC`)Br-2) complexes derived from substituted 1,8-naphthalimides were synthesized. All complexes were fully characterized by NMR spectra, which indicate trans orientation of the NHC ligands. H-1 and C-13 NMR spectra of complex Pd(NHC)(2)Cl-2 are influenced by existence of trans-syn and trans-anti rotamers. The dynamic behaviour in solution of the complex Pd(NHC)(2)Cl-2 was studied by H-1 NMR spectra in the temperature range of 293-403 K. The rotational barrier is experimentally estimated to 20 kcal/mol at 298 K. The DFT calculations reproduce the experimental data very well. The analysis of DFT calculations suggests electronic origin of the restricted rotation around Pd-C carbene bond. The electron-donating properties of reported system are situated between unsaturated and saturated five-membered ring NHC ligands. (C) 2021 Elsevier B.V. All rights reserved.

A novel rotary switch, overcoming the disadvantages of hydrazone based switches with competitive proton acceptor sub-rotors, has been designed. The new compound contains a pyridyl ring and a COOH group as sub-rotors, which provides engagement of the pyridyl nitrogen atom and leads to the existence of a single isomer in the ground state. The availability of acidic functionality in the rotor creates conditions for excited state intramolecular proton transfer (ESIPT), which exhibits anti-Kasha behavior.

The paper reports on the facile and convenient synthesis of a series of novel 2,5-substituted 1,3,4-oxadiazoles 3af and that of aroylhydrazone-based molecular hybrids 5a-g from readily available starting materials. The structure of the compounds was confirmed by IR, 1H NMR, 13C NMR and HRESI-MS spectral data. The toxicological potential of the compounds was evaluated by monitoring the synaptosomal viability and the levels of reduced glutathione in rat brain synaptosomes, isolated by Percoll gradient. The neuroprotective effects were assessed in vitro in a model of 6-hydroxydopamine-induced neurotoxicity. Administered alone, at a concentration of 40 mu M, most of the 1,3,4-oxadiazole derivatives and all of the hydrazone derivatives exhibited weak statistically significant neurotoxic effects, compared to the control. Two of the compounds from the novel oxadiazoles 3a and 3d did not have any toxicity. In a model of 6-OHDA-induced oxidative stress, again 3a and 3d and all aroylhydrazone derivatives 5a-g revealed statistically significant neuroprotective effect by preserving the synaptosomal viability and the level of reduced glutathione, against the toxic agent. Some of the compounds may have neuroprotective effects due to possible stabilization of the synaptosomal membrane and/or because of the preserved reduced glutathione. Additionally, all the compounds display a good predicted ADME profile.

The properties of several hydrazon-diketone rotary switches with OH groups in the stators (2-(2-(2-hydroxy-4-nitrophenyl)hydrazono)-1-phenylbutane-1,3-dione, 2-(2-(2-hydroxyphenyl)hydrazono)-1-phenylbutane-1,3-dione and 2-(2-(4-hydroxyphenyl)hydrazono)-1-phenylbutane-1,3-dione) were investigated by molecular spectroscopy (UV-Vis and NMR), DFT calculations (M06-2X/TZVP) and X-ray analysis. The results show that, when the OH group is in ortho position, the E' and Z' isomers are preferred in DMSO as a result of a stabilizing intermolecular hydrogen bonding with the solvent. The availability, in addition, of a nitro group in para position increases the possibility of deprotonation of the OH group in the absence of water. All studied compounds showed a tendency towards formation of associates. The structure of the aggregates was revealed by theoretical calculation and confirmed by X-ray analysis.

In this study, the possibilities of a new "in situ" LED UV illumination NMR spectroscopic technique for performing an initiator-free thiol-ene "click" coupling reaction of an allyl-functionalized poly(allyl glycidyl ether) (PAGE) prepolymer with a number of mono- and di-oligo polyethylene glycol (PEG) thiols is demonstrated. The state-of-the-art setup constructed with LEDs as UV light sources that illuminate through optical fibers directly into an NMR testing tube at a fixed wavelength of 365 nm is appropriate for various polymeric materials and biologically active substances. The selected experimental protocol uses a series of periods of irradiation and dark periods, thus providing opportunities to conduct an effective thiol-ene "click" reaction and simultaneously study the kinetics of the photochemical reaction with the exposure time, as well as macromolecular association directly in a solution applying the whole types of NMR methods: from conventional 1H or 13C NMR to diffusion NMR spectroscopy (DOSY). In addition, the molecular mass characteristics of the prepared copolymers were studied by gel-permeation chromatography (GPC). The observed differences in the reaction rates as well as in the size of species formed (the corresponding hydrodynamic radiuses Rh of aggregates) as a result of the coupling process of parent PAGE prepolymers and model PEG thiols were thoroughly discussed and the reaction pathway proposed.

In a search of effective ligands for asymmetric catalysis (-)-galantamine has been selected as a complex chiral framework for the synthesis of four novel diphenylphosphino-benzenecarboxamides. Their application in Pd-catalyzed asymmetric allylic alkylation proceeded with excellent conversion and moderate enantioselectivity due to the conformational flexibility of the galantamine derived compounds. To get insights into their molecular structure and conformational behaviour in solution a combination of experimental NMR methods and theoretical DFT calculations has been employed. The ligands exist as four conformers due to restricted rotation around the amide bond and due to flexibility of the 2,3,4,5 tetrahydro-1H-azepine ring. The experimentally measured barriers of C-N rotation (17.1 divided by 17.7 kcal/mol) are higher than the barriers of observed exchange process in azepine ring (13.7 divided by 14.0 kcal/mol). Their BOC precursors exist in solution as two conformers due to restricted rotation around the carbamate C-N bond. The experimentally measured barrier is lower than the amide barriers in ligands (16.1 divided by 16.5 kcal/mol). (C) 2020 Elsevier B.V. All rights reserved.

Metabolic profiling based on 1H nuclear magnetic resonance (NMR) spectroscopy was applied with the aim to investigate the functional role of the metabolites in lyophilized mucus from the garden snail Helix aspersa. Twenty metabolites were unambiguously identified by 1H, 1D TOCSY, 2D J-resolved, 2D COSY, and 2D HSQC NMR spectra with water suppression. The metabolic profiles of two fractions with low molecular weight (Mw < 1 kDa and Mw < 3 kDa) are very similar. Metabolites with known antioxidant, antibacterial, and antimicrobial activity were detected by NMR metabolic analysis of mucus samples from Helix aspersa. Some of them were confirmed by mass spectrometric analysis. The primary structure of several peptides was identified in low molecular weight fractions (Mw < 1 kDa) by tandem mass spectrometry.

The E/Z switching mechanism of the rotary switch ethyl-2-(2-(quinolin-8-yl)hydrazono)-2-(pyridin-2-yl)acetate was studied by NMR, UV–Vis, and ultrafast spectroscopy and modeled by advanced quantum-chemical calculations. Three possible mechanisms were considered theoretically: out-of-plane rotation, in-plane inversion and proton transfer. Neither of them correctly describes the experimental data by using implicit solvation. Taking into account the existence of water in the used solvents, which influence the measured rate constants, an explicit solvation was attempted in the quantum-chemical calculations. According to a simplified model, the water molecules form a wire, being able to transfer the proton from Z to E form of the switch. This leads to substantially lower transition states and corresponds to the experimentally observed rate constants. This information shines new light on the mechanism of isomerization in the rotary switches and on the understanding of the mechanism of hydrazone tautomerism as a whole.

Two new 4-OH coumarin based rotary switches, containing fixed carbonyl groups in the rotor, have been synthesized and their properties have been studied by combined use of DFT calculations and molecular spectroscopy (UV–Vis absorbance and emission, NMR). It was found that the structure of the stator (naphthyl in 2 or quinolyl moiety in 3) and solvents polarity do not influence their azo-hydrazone tautomerism. Both compounds exist as keto (hydrazone) tautomers. The NMR data indicate a mixture of E (major) and Z (minor) keto form isomers in solution. The results are in very good agreement with ground state DFT calculations. The keto tautomers exhibit different emission behavior depending on the structure of the stators. Comparing to 2, more intensive emission and higher lifetime was observed in 3, where the formation of intramolecular hydrogen bonding of the hydrazone NH with the N atom of quinoline restricts the rotation of the stator. According to the spectral data and the TDDFT analysis the observed emission originates from the excitation of the keto tautomers and does not include excited state proton transfer. It was shown that the protonation is a suitable stimulus for E/Z switching in 2, where a possible mechanism is sketched. In the case of 3, the addition of acid leads to the protonation of the quinolyl nitrogen atom, which slightly affects the E/Z isomerization ratio.