Relationship between the Crystal Structure and Tuberculostatic Activity of Some 2-Amidinothiosemicarbazone Derivatives of Pyridine

Tuberculosis remains one of the most common diseases affecting developing countries due to difficult living conditions, the rapidly increasing resistance of M. tuberculosis strains and the small number of effective anti-tuberculosis drugs. This study concerns the relationship between molecular structure observed in a solid-state by X-ray diffraction and the 15N NMR of a group of pyridine derivatives, from which promising activity against M. tuberculosis was reported earlier. It was found that the compounds exist in two tautomeric forms: neutral and zwitterionic. The latter form forced the molecules to adopt a stable, unique, flat frame due to conjugation and the intramolecular hydrogen bond system. As the compounds exist in a zwitterionic form in the crystal state generally showing higher activity against tuberculosis, it may indicate that this geometry of molecules is the “active” form.

Tautomers of the Orotate Anion Have Anti-Inflammatory Effects in the Correction of Drug-Induced Hepatitis in Rats

The purpose of this paper was to conduct a comparative experimental study of the anti-inflammatory effects of tautomeric forms of orotic acid in the correction of drug-induced hepatitis in rats. Materials and Methods. A total of 40 rats (Rattus norvegicus Berk.) were randomly divided into 5 groups: control group (n = 10); intervention group with drug-induced hepatitis (n = 15); animals with drug-induced hepatitis who were injected with orotic acid (ОА) tautomers: initial oxo-form (n = 5), hydroxy-form (n = 5) and dihydroxyform (n = 5) at a dose of 0.5 g/kg body weight a day in the course of 14 days. The tautomers were obtained by mechanical activation in a planetary ball mill AGO-2C for 1 (hydroxy-form) and 6 (dihydroxyform) hours. In the blood of animals of all experimental groups, the content of leukocytes, granulocytes, lymphocytes, and monocytes was determined. Liver sections were stained with hematoxylin and eosin to assess the histo- and cytostructure of the tissues, and immunohistochemically using a set of monoclonal antibodies to detect the expression of the CD68+ macrophage marker. Results. It was found that when correcting drug-induced hepatitis with the hydroxy-form of OA, the severity of leuko- and monocytosis decreased and the number of lymphocytes was restored. The number of CD68+ macrophages with a pro-inflammatory phenotype decreased in the group receiving the hydroxy-form of OA (by a factor of 1.32; p = 0.019), but remained unchanged at the administration of oxo- and dihydroxy-forms of OA. The intensity of reaction product expression decreased by a factor of 1.5 in the group administered with the initial drug and by a factor of 1.9 in animals administered with mechanically activated drugs (p = 0.0001). Thus, the obtained data indicate a pronounced anti-inflammatory activity of the hydroxyform of OA, which can substantiate its use as a hepatoprotective agent. For citation: Pazinenko K.A., Chuchkova N.N., Smetanina M.V. Tautomers of the Orotate Anion Have Anti-Inflammatory Effects in the Correction of Drug-Induced Hepatitis in Rats. Journal of Medical and Biological Research, 2021, vol. 9, no. 4, pp. 366–373. DOI: 10.37482/2687-1491-Z074

Discovery of a novel glucuronan lyase system in Trichoderma parareesei

Glucuronan lyases (EC 4.2.2.14) catalyze depolymerization of linear β-(1, 4)-polyglucuronic acid (glucuronan). Only a few glucuronan lyases have been characterized until now, most of them originating from bacteria. Here we report the discovery, recombinant production, and functional characterization of the full complement of six glucuronan specific polysaccharide lyases in the necrotic mycoparasite Trichoderma parareesei . The enzymes belong to four different polysaccharide lyase families and have different reaction optima and glucuronan degradation profiles. Four of them showed endo-lytic action and two, TpPL8A and TpPL38A, displayed exo-lytic action. NMR revealed that the monomeric end-product from TpPL8A and TpPL38A underwent spontaneous rearrangements to tautomeric forms. Proteomic analysis of the secretomes from T. parareesei growing on pure glucuronan and lyophilized A. bisporus fruiting bodies, respectively, showed secretion of five of the glucuronan lyases and HPAEC-PAD analysis confirmed the presence of glucuronic acid in the A. bisporus fruiting bodies. By systematic genome annotation of more than 100 fungal genomes and subsequent phylogenetic analysis of the putative glucuronan lyases, we show that glucuronan lyases occur in several ecological and taxonomic groups in the fungal kingdom. Our findings suggest that a diverse repertoire of glucuronan lyases is a common trait among Hypocreales spp. with mycoparasitic and entomopathogenic lifestyles. IMPORTANCE This paper reports the discovery of a set of six complementary glucuronan lyase enzymes in the mycoparasite Tricoderma parareseei . Apart from the novelty of the discovery of these enzymes in T. parareesei, the key importance of the study is the finding that the majority of these lyases are induced when T. parareseei is inoculated on Basidiomycete cell walls that contain glucuronan. The study also reveals putative glucuronan lyase encoding genes in a wealth of other fungi that furthermore points at fungal cell wall glucuronan being a target C-source for many types of fungi. In a technical context, the findings may lead to controlled production of glucuronan oligomers for advanced pharmaceutical applications and pave the way for development of new fungal biocontrol agents.

DFT Study and Antiparasitic Activity of Some Azo Dyes Containing Uracil

In this study, for the first time, molecular modeling and antiparasitic activity studies were carried out on some azo dyes containing uracil, 6-amino-5-[(4-nitrophenyl) diazenyl] pyrimidine-2,4 (1H, 3H)-dione (dye I) and 6-amino-5-[(4-bromophenyl) diazenyl] pyrimidin-2,4 (1H, 3H)-dione (dye II), which were resynthesized using the same method in the literature and whose molecular structures were confirmed using FTIR and 1H-NMR methods. In molecular modeling study, all calculations were performed using DFT/B3LYP/6-311++G(d,p) method. The molecular structures of the possible tautomeric forms of dyes I and II were optimized, and their molecular total energies were calculated in the gas phase and DMSO solvent. IR and 1H-NMR spectral data of the possible tautomeric forms of dyes were obtained, and theoretical spectral data were compared with experimental ones. The evaluations show that, for both dyes, the spectral data of the imine-diketo-hydrazone form, which has the lowest energy and is hence determined to be the most stable form, are in agreement with the experimental ones. In antiparasitic activity study, dyes I and II were tested for the first time against parasites Leishmania infantum, Leishmania major, Leishmania tropica promastigotes, and Trichomonas vaginalis trophozoites. In vitro antileishmanial activities against Leishmania promastigotes were tested by microdilution broth assay with Alamar Blue in RPMI 1640 medium, and in vitro trichomonacidal activities against Trichomonas vaginalis parasite were tested using TYM medium. In tests, antileishmanial and trichomonacidal effects were determined by comparing the obtained minimum inhibitory concentration (MIC) and minimum lethal concentration (MLC) values with those obtained for standard drugs (amphotericin B and metronidazole, respectively).

Structure and IR Spectra of 3(5)-Aminopyrazoles and UV-Induced Tautomerization in Argon Matrix

The prototropic tautomerism in 3(5)-aminopyrazoles was investigated by matrix isolation infrared (IR) spectroscopy, supported by DFT(B3LYP)/6-311++G(d,p) calculations. In consonance with the experimental data, the calculations predict tautomer 3-aminopyrazole (3AP) to be more stable than the 5-aminopyrazole (5AP) tautomer (calculated energy difference: 10.7 kJ mol−1; Gibbs free energy difference: 9.8 kJ mol−1). The obtained matrix isolation IR spectra (in both argon and xenon matrices) were interpreted, and the observed bands were assigned to the tautomeric forms with help of vibrational calculations carried out at both harmonic and anharmonic levels. The matrix-isolated compound (in argon matrix) was then subjected to in situ broadband UV irradiation (λ > 235 nm), and the UV-induced transformations were followed by IR spectroscopy. Phototautomerization of the 3AP tautomer into the 5AP form was observed as the strongly prevalent reaction.

Microcirculatory Liver Bloodstream in Hyperhomocysteinemia and Administration of Tautomeric Forms of Orotic Acid

The aim of the study was to analyze the microvasculation of the liver in administration of tautomeric forms of orotic acid for a methionine-induced liver pathology to assess the efficacy of the modified drugs and the potentialof their clinical use.Material and methods. The study included 30 white outbred rats, that were simulated methionine induced hyperhomocysteinemia by the administration of methionine, dosage 0.15 g/100 g of the body we ight, via food during 4 weeks. Animals with hyperhomocysteinemia were divided into 4 groups: animals of group 1 received orotic acid (OA) in the initial form (oxo-tautomer), animals of group 2 received hydroxy–tautomer OA after mechanomodification for 1 hour, animals of group 3 received dihydroxy-tautomer OA after mechanomodification for 6 hours. Histological preparations of the liver were used to evaluate the area of hepatocytes; diameters and areas of the central vein, the interlobular vein and artery, the bile duct, and the Visotto coefficient were calculated.Results. Morphometric data of the hepatic microvascular bloodstream with simulated hyperhomocysteinemia evidenced a general increase in the diameter and area of blood vessels, changes affected the system of blood inflow and outflow at the organ level. Administration of OA had a normalizing effect on the liver bloodflow, but the effects were different: the most pronounced effect was detected in administration of the hydroxy-form of the preparation, this can be explained by a modificationin the dispersion of the preparation (without changing the crystal lattice), an increase in the rate of dissolution in water and aqueous solutions, an increasein the number of functionally active groups in the heterocycle of the hydroxy-form of OA. Thus, the hydroxy-tautomer of orotic acid had the greatest efficacy relating to vasodilation of microvessels of the liver bloodstream in hyperhomocysteinemia; the fact suggesting feasibility of its further study in the clinical environment.

Monoazo (Monohydrazone) pigments based on benzimidazolones

A series of azo pigments containing the benzimidazolone ring were introduced in the mid to late twentieth century as high-performance organic pigments in the yellow, orange, red, and brown shade areas. The structures of the commercial benzimidazolone azo pigments are derived from either the monoazoacetoacetanilide or monoazonaphtharylamide classical azo pigments systems and exist in the ketohydrazone tautomeric forms. The high-performance properties of the pigments have been attributed to a network of intermolecular hydrogen bonds involving the benzimidazolone group, and efficient molecular packing, as demonstrated by X-ray crystal structure determinations. The manufacturing processes leading to the pigments involve traditional diazotization and azo coupling reaction procedures, although they require special conditioning aftertreatments to optimize their performance. Although benzimidazolone azo pigments were initially developed for the coloration of plastics, they have probably had a greater impact on the paint industry. The application properties of the benzimidazolone azo pigments are discussed for individual products.

Exploring the octanol–water partition coefficient dataset using deep learning techniques and data augmentation

Today more and more data are freely available. Based on these big datasets deep neural networks (DNNs) rapidly gain relevance in computational chemistry. Here, we explore the potential of DNNs to predict chemical properties from chemical structures. We have selected the octanol-water partition coefficient (log P) as an example, which plays an essential role in environmental chemistry and toxicology but also in chemical analysis. The predictive performance of the developed DNN is good with an rmse of 0.47 log units in the test dataset and an rmse of 0.33 for an external dataset from the SAMPL6 challenge. To this end, we trained the DNN using data augmentation considering all potential tautomeric forms of the chemicals. We further demonstrate how DNN models can help in the curation of the log P dataset by identifying potential errors, and address limitations of the dataset itself.

The Two Faces of the Guanyl Radical: Molecular Context and Behavior

The guanyl radical or neutral guanine radical G(-H)• results from the loss of a hydrogen atom (H•) or an electron/proton (e–/H+) couple from the guanine structures (G). The guanyl radical exists in two tautomeric forms. As the modes of formation of the two tautomers, their relationship and reactivity at the nucleoside level are subjects of intense research and are discussed in a holistic manner, including time-resolved spectroscopies, product studies, and relevant theoretical calculations. Particular attention is given to the one-electron oxidation of the GC pair and the complex mechanism of the deprotonation vs. hydration step of GC•+ pair. The role of the two G(-H)• tautomers in single- and double-stranded oligonucleotides and the G-quadruplex, the supramolecular arrangement that attracts interest for its biological consequences, are considered. The importance of biomarkers of guanine DNA damage is also addressed.

Multiscale Modeling of Wobble to Watson–Crick-Like Guanine–Uracil Tautomerization Pathways in RNA

Energetically unfavorable Watson–Crick (WC)-like tautomeric forms of nucleobases are known to introduce spontaneous mutations, and contribute to replication, transcription, and translation errors. Recent NMR relaxation dispersion techniques were able to show that wobble (w) G•U mispair exists in equilibrium with the short-lived, low-population WC-like enolic tautomers. Presently, we have investigated the wG•U → WC-like enolic reaction pathway using various theoretical methods: quantum mechanics (QM), molecular dynamics (MD), and combined quantum mechanics/molecular mechanics (QM/MM). The previous studies on QM gas phase calculations were inconsistent with experimental data. We have also explored the environmental effects on the reaction energies by adding explicit water. While the QM-profile clearly becomes endoergic in the presence of water, the QM/MM-profile remains consistently endoergic in the presence and absence of water. Hence, by including microsolvation and QM/MM calculations, the experimental data can be explained. For the G•Uenol→ Genol•U pathway, the latter appears to be energetically more favorable throughout all computational models. This study can be considered as a benchmark of various computational models of wG•U to WC-like tautomerization pathways with and without the environmental effects, and may contribute on further studies of other mispairs as well.