Conformation Analysis and Stereodynamics of Symmetrically ortho-Disubstituted Carvacrol Derivatives.

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.

Structure and Conformational Mobility of OLED-Relevant 1,3,5-Triazine Derivatives.

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.

Discovery of novel indole-based aroylhydrazones as anticonvulsants: Pharmacophore-based design.

A number of novel melatonin derivatives, containing aroylhydrazone moieties, were synthesized and explored in vivo for anticonvulsant activity, neurotoxicity in ICR mice as well as in-vitro for cytoxicity and oxidative stress in rats. The structures and configurations were confirmed by NMR, FTIR, HRMS and crystal X-ray diffraction method. For selection of potent structures for synthesis a pharmacophore model was used. Two compounds 3e, with a 2-furyl moiety fragment and 3f with 2-thienyl fragment, showed a potency in maximal electroshock (MES) test (ED50 = 50.98 mg kg-1, PI > 5.88 and ED50 = 108.7 mg kg-1; PI > 2.76), respectively, higher than melatonin (ED50 = 160.3 mg kg-1, PI > 1.87). The compounds 3c, 3e, 3f and 3i suppressed psychomotor seizures in the 6 Hz test and 3c was the most potent with higher ED50 = 13.98 mg kg-1 and PI of > 21.46 compared to that of melatonin (ED50 = 49.76 mg kg-1 and PI of > 6.03) in mice. None of the compounds displayed neurotoxicity in the rota-rod test. The novel melatonin derivatives exerted weak cytotoxic effects while 3f showed the lowest hepatoxic effects comparable to that of the positive control melatonin in rats. The high affinities to the elucidated pharmacophore model of the novel melatonin compounds derived from the inclusion of aroylhydrazone moiety in the indole scaffold yielded suitable candidates with anticonvulsant activity in the MES and 6 Hz test of psychomotor seizures.

Anti-enteroviral activity of new MDL-860 analogues: Synthesis, in vitro/in vivo studies and QSAR analysis.

A series of 60 nitrobenzonitrile analogues of the anti-viral agent MDL-860 were synthesized (50 of which are new) and evaluated for their activity against three types of enteroviruses (coxsackievirus B1, coxsackievirus B3 and poliovirus 1). Among them, six diaryl ethers (20e, 27e, 28e, 29e, 33e and 35e) demonstrated high in vitro activity (SI > 50) towards at least one of the tested viruses and very low cytotoxicity against human cells. Compound 27e possesses the broadest spectrum of activity towards all tested viruses in the same way as MDL-860 does. The most active derivatives (27e, 29e and 35e) against coxsackievirus B1 were tested in vivo in newborn mice experimentally infected with 20 MLD50 of coxsackievirus B1. Compound 29e showed promising in vivo activity (protection index 26% and 4 days lengthening of mean survival time). QSAR analysis of the substituent effects on the in vitro cytotoxicity (CC50) and anti-viral activity of the nitrobenzonitrile derivatives was carried out and adequate QSAR models for the anti-viral activity of the compounds against poliovirus 1 and coxsackievirus B1 were constructed.

Ru-Catalyzed Isomerization of Achmatowicz Derivatives: A Sustainable Route to Biorenewables and Bioactive Lactones.

A Ru-catalyzed isomerization of Achmatowicz derivatives that opens unexplored routes to diversify the biogenic furanic platform is reported. The mechanistic insights of this formally redox-neutral intramolecular process were studied computationally and by deuterium labeling. The transformation proved to be a robust synthetic tool to achieve the synthesis of bioderived-monomers and a series of 4-keto-δ-valerolactones that further enabled the development of a flexible strategy for the synthesis of acetogenins. A concise and protective group-free asymmetric total synthesis of two natural products, namely, (S,S)-muricatacin and the (S,S)-L-factor, is also described.

Thiol-ene coupling reaction achievement and monitoring by "in situ" UV irradiation NMR spectroscopy.

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 R h 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.

An 1H NMR- and MS-Based Study of Metabolites Profiling of Garden Snail Helix aspersa Mucus.

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.