Search

Background: In the era of resistance, the design and search for new "small" molecules with a narrow spectrum of activity that target a protein or enzyme specific to a certain bacterium with high selectivity and minimal side effects remains an urgent problem of medicinal chemistry. In this regard, we developed and successfully implemented a strategy for the search for new hybrid molecules, namely, the not broadly known [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines. They can act as "building blocks" and allow for the introduction of certain structural motifs into the desired final products in order to enhance the antistaphylococcal effect. Methods: The "one-pot" synthesis of the latter is based on the conversion of substituted 4-hydrazinoquinazolines or substituted 2-aminobenzonitriles and carboxylic acid derivatives to the target products. The possible molecular mechanism of the synthesized compounds (DNA gyrase inhibitors) was investigated and discussed using molecular docking, and their further study for antistaphylococcal activity was substantiated. Results: A significant part of the obtained compounds showed high antibacterial activity against Staphylococcus aureus (MIC: 10.1–62.4 µM) and 5-bromo-2-(3-(furan-3-yl)-1H-1,2,4-triazol-5-yl)aniline and 5-fluoro-2-(3-(thiophen-3-yl)-1H-1,2,4-triazol-5-yl)aniline, with MICs of 5.2 and 6.1 µM, respectively, approaching the strength of the effect of the reference drug, "Ciprofloxacin" (MIC: 4.7 µM). The conducted SAR and ADME analyses confirm the prospects of the further structural modification of these compounds. The obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antimicrobial activity and deserve further structural modification and detailed study as effective antistaphylococcal agents. The SAR analysis revealed that the presence of a cycloalkyl or electron-rich heterocyclic fragment in the third position of the triazole ring was essential for the antibacterial activity of the obtained compounds. At the same time, the introduction of a methyl group into the aniline moiety led to an enhancement of activity. The introduction of halogen into the aniline fragment has an ambiguous effect on the level of antistaphylococcal activity and depends on the nature of the substituent in the third position. Conclusions: Obtained [2-(3-R-1H-[1,2,4]-triazol-5-yl)phenyl]amines reveal significant antistaphylococcal activity and deserve for further detailed study as effective antibacterial agents. [ABSTRACT FROM AUTHOR]

The present work is devoted to the in silico study of 2-(3-R-1H-1,2,4-triazol-5-yl)anilines as potential inhibitors of EGFR (epidermal growth factor receptor) and RET (rearranged during transfection)-, which play a significant role in regulating the physiological cycle of non-small cell lung cancer. The well-known docking software AutoDock Vina was used for the study. The seven studied compounds and two standard drugs (vandetanib and gefitinib) were docked to the crystal structures of EGFR and RET proteins. It was found that among the newly investigated substances, 2-(3-(indolyl-2)-1H-1,2,4-triazol-5-yl)aniline (a5) has the highest affinity towards EGFR and RET with the binding energy of --9.7 and --8.7 kcal/mol, respectively. Visualization of the molecular docking results of this compound using the Discovery Studio software showed that it is characterized by similar to standard ligands location in the active sites of the enzymes, stable hydrogen bonds and π-stacking interactions, which are provided by the presence of indole and aniline fragments in the molecule. Thus, we have identified a new effective ligand that can be used as a "base" molecule for further fragment-oriented design using molecular hybridization methodology (fragment fusion, coupling or extension methods) or structural modification by introducing "pharmacophore" groups into the molecule. Summarizing the above screening results, we can say that 2-(3-R-1H-1,2,4-triazol-5- yl)anilines require further careful consideration as effective tyrosine kinase inhibitors for the search for promising anticancer agents for the treatment of non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

Present review is critical analysis of recently published data devoted to the search of the novel anti-inflammatory agents among substituted and condensed quinazolines. It has been shown that anti-inflammatory activity is typical for various quinazoline-containing compounds including substituted quinazolin-4-ones, quinazolin-4-amines, condensed and spiro-condensed quinazolines. The features of target compounds synthesis were systematized and discussed. It was shown that synthesis of quinazoline-containing anti-inflammatory agents in most of cases based on modification of anthranilic acid derivatives, substituted 2-aminobenzonitriles or isatoic anhydride. Particular attention was paid to the discussion of 2-azaheterylanilines as original initial compounds for synthesis of condensed quinazolines with promising anti-inflammatory activity. The mechanisms of quinazolines biological activity have been presented and discussed as well. It has been shown that described compounds can effect on COX- 1, COX-2, LOX-15, NO, PGE2, IL-1b, IL-6, TNF-α and other typical for anti-inflammatory agents' biomolecular targets. For some series of compounds, the structure-biological activity relationships were discussed. The data presented in review substantiates the reasonability of the search of new highly effective and low-toxic drugs with antiinflammatory activity among quinazoline containing compounds. [ABSTRACT FROM AUTHOR]

Tetrazoles are found broad applications in numerous fields such as in medicine, biochemistry, pharmacology, and in industry. Considering our continued interest in new azaheterocycles based on β-ketosulfones in this work a threecomponent heterocyclization of dihydro-2H-thiopyran-3(4H)-one-1,1-dioxide, 1H-tetrazol-5-amine, and aromatic aldehydes under microwave irradiation was studied. Regardless of the reaction conditions, 5-aryl-7,8,9,10- tetrahydro-5H-tetrazolo[1,5-a]thiopyrano[3,2-d]pyrimidine 6,6-dioxides were isolated as sole reaction products in good to excellent yields. To the best of our knowledge mentioned azaheterocycles are novel and previously not reported heterocyclic ensemble. Proposed structures were confirmed by spectral methods. Considering druglikeness we can conclude that compounds match parameters for Lipinski, Ghose, Veber, Egan and Muegge rules, and also correspond to the V class of acute toxicity. In silico screening of the biological profile of new derivatives showed adequate ADMET properties along with high (60 % and more) probability levels of activity against such pathogens/diseases as Candida albicans, Alphis gossypii, Tripomastigote Chagas, Tcruzi amastigota, Tcruzi epimastigota etc. [ABSTRACT FROM AUTHOR]

This work is dedicated to the 85th anniversary of the birthday of an outstanding scientist, professor, doctor of chemical sciences, honored worker of science and technology of Ukraine Lilia Ivanovna Kas'yan. L.I. Kasyan graduated from Odesa State University (1960). In 1965, she graduated from the Department of Organic Chemistry of Dnipropetrovsk University (1965). In 1970, she defended her candidate's thesis (PhD equivalent) «Synthesis and study of some epoxides of the bicyclo[2.2.1]heptane family», and in 1990 she defended her doctoral thesis (D.Sc. habilitation) «Epoxides of the alicyclic family. Stereochemistry, reactivity, and methods of synthesis». Since 1991, he has been a professor at the Department of Organic Chemistry at the Dnipropetrovsk State University (now Oles Honchar Dnipro National University). Her scientific works concerned the chemistry of epoxides of the alicyclic family, the study of their reactivity and the development of methods of synthesis. She headed the scientific school for the study of epoxy compounds. Based on her fundamental research many epoxy-containing compositions have been developed for chemical industry. A recognized specialist in the synthesis, stereochemistry and spectroscopy of cage-like compounds, including chemical agents with biological (pesticide and pharmacological) activity. Author of more than 500 scientific papers, including 4 books (monographs). She paid great attention to the creative education of young people, for a long time she headed the work with the student scientific society of the Department of Chemistry. More than 20 student scientific works performed under her supervision received the highest awards at regional and state contests, 17 PhD theses were defended. [ABSTRACT FROM AUTHOR]