Design, Synthesis, and Photophysical Properties of 5-Aminobiphenyl Substituted [1,2,4]Triazolo[4,3-c]- and [1,2,4]Triazolo[1,5-c]quinazolines.

Two series of novel [1,2,4]triazolo[4,3-c]- and [1,2,4]triazolo[1,5-c]quinazoline fluorophores with 4'-amino[1,1']-biphenyl residue at position 5 have been prepared via Pd-catalyzed cross-coupling Suzuki-Miyaura reactions. The treatment of 2-(4-bromophenyl)-4-hydrazinoquinazoline with orthoesters in solvent-free conditions or in absolute ethanol leads to the formation of [4,3-c]-annulated triazoloquinazolines, whereas [1,5-c] isomers are formed in acidic media as a result of Dimroth rearrangement. A 1D-NMR and 2D-NMR spectroscopy, as well as a single-crystal X-ray diffraction analysis, unambiguously confirmed the annelation type and determined the molecular structure of p-bromophenyl intermediates and target products. Photophysical properties of the target compounds were investigated in two solvents and in the solid state and compared with those of related 3-aryl-substituted [1,2,4]triazolo[4,3-c]quinazolines. The exclusion of the aryl fragment from the triazole ring has been revealed to improve fluorescence quantum yield in solution. Most of the synthesized structures show moderate to high quantum yields in solution. Additionally, the effect of solvent polarity on the absorption and emission spectra of fluorophores has been studied, and considerable fluorosolvatochromism has been stated. Moreover, electrochemical investigation and DFT calculations have been performed; their results are consistent with the experimental observation.

Synthesis of 4-Aminopyrazol-5-ols as Edaravone Analogs and Their Antioxidant Activity.

One of the powerful antioxidants used clinically is Edaravone (EDA). We synthesized a series of new EDA analogs, 4-aminopyrazol-5-ol hydrochlorides, including polyfluoroalkyl derivatives, via the reduction of 4-hydroxyiminopyrazol-5-ones. The primary antioxidant activity of the compounds in comparison with EDA was investigated in vitro using ABTS, FRAP, and ORAC tests. In all tests, 4-Amino-3-pyrazol-5-ols were effective. The lead compound, 4-amino-3-methyl-1-phenylpyrazol-5-ol hydrochloride (APH), showed the following activities: ABTS, 0.93 TEAC; FRAP, 0.98 TE; and ORAC, 4.39 TE. APH and its NH-analog were not cytotoxic against cultured normal human fibroblasts even at 100 µM, in contrast to EDA. According to QM calculations, 4-aminopyrazolols were characterized by lower gaps, IP, and η compared to 4-hydroxyiminopyrazol-5-ones, consistent with their higher antioxidant activities in ABTS and FRAP tests, realized by the SET mechanism. The radical-scavenging action evaluated in the ORAC test occurred by the HAT mechanism through OH bond breaking in all compounds, directly dependent on the dissociation energy of the OH bond. All the studied compounds demonstrated the absence of anticholinesterase activity and moderate inhibition of CES by some 4-aminopyrazolols. Thus, the lead compound APH was found to be a good antioxidant with the potential to be developed as a novel therapeutic drug candidate in the treatment of diseases associated with oxidative stress.

Direct C-H/C-H Coupling of the Azoloannulated Pteridines with Electron Rich (Hetero)Aromatic Compounds.

The methods for modification of azoloannulated pteridines with (hetero)aromatic nucleophiles using a nucleophilic substitution of hydrogen (SNH) methodology have been developed in this work. Stable intermediate σH-adducts, as well as products of an unexpected intramolecular rearrangement of diadducts, have been isolated and characterized. The potential of the proposed approach for obtaining donor-acceptor systems, in which the pteridine fragment of the molecule acts as an acceptor, was demonstrated. The main photophysical properties of the obtained D-A compounds have been studied.

A New Family of Fused Azolo[1,5-a]pteridines and Azolo[5,1-b]purines.

The nitration of azolo[1,5-a]pyrimidin-7-amines with several nitration agents (such as acetic nitric anhydride, nitronium tetrafluoroborate, and a mixture of concentrated nitric acid and sulfuric acid) has been investigated. It has been shown that, depending on the conditions, the nitration of pyrazolopyrimidin-7-amines bearing electron-withdrawing groups in the pyrazole ring leads to nitration products in the pyrimidine and/or pyrazole ring. The nitration of triazolo[1,5-a]pyrimidin-7-amines with "nitrating mixture" has been optimized, thus allowing us to obtain a series of 6-nitro[1,2,4]triazolo[1,5-a]pyrimidin-7-amines, followed by their reduction into the corresponding [1,2,4]triazolo[1,5-a]pyrimidin-6,7-diamines (yields 86-89%). The latter have been subjected to heterocyclization by a variety of electrophilic compounds (such as CS2, glyoxal, triethyl orthoformate) with the formation of five- or six-membered annulated cycles.