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Publisher Copyright: © 2023 The Authors A series of quaternary ammonium fluoroquinolones was obtained by exhaustive methylation of the amine groups present at the 7-position of fluoroquinolones, including ciprofloxacin, enoxacin, gatifloxacin, lomefloxacin, and norfloxacin. The synthesized molecules were tested for their antibacterial and antibiofilm activities against Gram-positive and Gram-negative human pathogens, i.e. Staphylococcus aureus and Pseudomonas aeruginosa. The study showed that the synthesized compounds are potent antibacterial agents (MIC values at the lowest 6.25 μM) with low cytotoxicity in vitro as assessed on the BALB 3T3 mouse embryo cell line. Further experiments proved that the tested derivatives are able to bind to the DNA gyrase and topoisomerase IV active sites in a fluoroquinolone-characteristic manner. The most active quaternary ammonium fluoroquinolones, in contrast to ciprofloxacin, reduce the total biomass of P. aeruginosa ATCC 15442 biofilm in post-exposure experiments. The latter effect may be due to the dual mechanism of action of the quaternary fluoroquinolones, which also involves disruption of bacterial cell membranes. IAM-HPLC chromatographic experiments with immobilized artificial membranes (phospholipids) showed that the most active compounds were those with moderate lipophilicity and containing a cyclopropyl group at the N1 nitrogen atom in the fluoroquinolone core.

A series of novel fluoroquinolone-Safirinium dye hybrids was synthesized by means of tandem Mannich-electrophilic amination reactions from profluorophoric isoxazolones and antibiotics bearing a secondary amino group at position 7 of the quinoline ring. The obtained fluorescent spiro fused conjugates incorporating quaternary nitrogen atoms were characterized by H-1 NMR, IR, MS, and elemental analysis. All the synthetic analogues (3a-h and 4a-h) were evaluated for their in vitro antimicrobial, bactericidal, and antibiofilm activities against a panel of Gram positive and Gram-negative pathogenic bacteria. The most active Safirinium Q derivatives of lomefloxacin (4d) and ciprofloxacin (4e) exhibited molar-based antibacterial activities comparable to the unmodified drugs and displayed considerable inhibitory potencies in E. coli DNA gyrase supercoiling assays with IC50 values in the low micromolar range. Zwiterionic hybrids were noticeably less lipophilic than the parent quinolones in micellar electrokinetic chromatography (MECK) experiments. The tests performed in the presence of phenylalanine-arginine-beta-naphthylamide (PA beta N) or carbonyl cyanide m-chlorophenylhydrazone (CCCP) revealed that the conjugates are to some extent subject to bacterial efflux and cellular accumulation, respectively. Moreover, the hybrids did not exhibit notable cytotoxicity towards the HEK 293 control cell line and demonstrated low propensity for resistance development, as exemplified for compounds 3g and 4b. Finally, molecular docking experiments revealed that the synthesized compounds were able to bind in the fluoroquinolone-binding mode at S. aureus DNA gyrase and S. pneumoniae topoisomerase IV active sites. (C) 2019 Elsevier Masson SAS. All rights reserved.

A series of inexpensive and water-soluble fluorescent dihydro-[1,2,4]triazolo [4,3-a]pyridin-2-ium-carboxylates (Safirinium dyes) have been synthesized and characterized by UV–Vis, IR, 1H- and 13C NMR spectroscopic techniques as well as by single crystal X-ray analysis. Significantly lower fluorescence quantum yields were determined in aprotic polar solvent (DMF). The photophysical properties of zwitterions and hydrochlorides were rationalized theoretically. A combined experimental and DFT/TD-DFT study of absorption and emission spectra have been performed. The calculations were carried out within the vertical non-equilibrium approximation or the state-specific approach using conventional (APFD, B3LYP and PBE0) and long-range-corrected hybrid functionals (CAM-B3LYP and ωB97XD) by means PCM and SMD solvation models. We have found that global hybrid functionals (GH) fail for charge transfer excited states in which charge is moved from the substituent to the heteroaromatic system, while the long range corrected functionals deliver consistent estimates, especially within the state-specific PCM modeling framework. The long-range-corrected hybrid functionals (RSH) were also found to be the most efficient in reproducing the emissive properties of the dyes.

A new Au(III) complex was synthesized from an amidrazone derivative and HAuCl4. Cyclization of amidrazone moiety lead to the 1,2,4-triazolo[1,5a]pyridine ring system, followed by Au(III) chelation. The crystal and molecular structure of the final compound was studied by single crystal X-ray diffraction as well as by 1H 13C and 1H 15N HMQC- and HMBC-NMR spectroscopy, which resulted in the assignment of all detected signals. This species was tested in vitro as an antibacterial and antiproliferative agent. It exhibited good antibacterial activity against Staphylococcus aureus and was proved to be more potent than amoxicillin against Bacillus subtilis and the drug resistant strain of Klebsiella pneumoniae. In contrast, its antiproliferative properties against cancer cell lines A549, HT-29, MV-4-11 and MCF-7 were relatively low.

Mass spectrometry methods are commonly used in the identification of peptides and biomarkers. Due to a relatively low abundance of proteins in biological samples, there is a need for the development of novel derivatization methods that would improve MS detection limits. Hence, novel fluorescent N–hydroxysuccinimide esters of dihydro-[1,2,4]triazolo[4,3-a]pyridin-2-ium carboxylates (Safirinium P dyes) have been synthesized. The obtained compounds, which incorporate quaternary ammonium salt moieties, easily react with aliphatic amine groups of peptides, both in solution and on the solid support; thus, they can be applied for derivatization as ionization enhancers. Safirinium tagging experiments with ubiquitin hydrolysate revealed that the sequence coverage level was high (ca. 80%), and intensities of signals were enhanced up to 8-fold, which proves the applicability of the proposed tags in the bottom–up approach. The obtained results confirmed that the novel compounds enable the detection of trace amounts of peptides, and fixed positive charge within the tags results in high ionization efficiency. Moreover, Safirinium NHS esters have been utilized as imaging agents for fluorescent labeling and the microscopic visualization of living cells such as E. coli Top10 bacterial strain.

Currently, rapid evaluation of the physicochemical parameters of drug candidates, such as lipophilicity, is in high demand owing to it enabling the approximation of the processes of absorption, distribution, metabolism, and elimination. Although the lipophilicity of drug candidates is determined using the shake flash method (n-octanol/water system) or reversed phase liquid chromatography (RP-LC), more biosimilar alternatives to classical lipophilicity measurement are currently available. One of the alternatives is immobilized artificial membrane (IAM) chromatography. The present study is a continuation of our research focused on physiochemical characterization of biologically active derivatives of isoxazolo[3,4-b]pyridine-3(1H)-ones. The main goal of this study was to assess the affinity of isoxazolones to phospholipids using IAM chromatography and compare it with the lipophilicity parameters established by reversed phase chromatography. Quantitative structure–retention relationship (QSRR) modeling of IAM retention using differential evolution coupled with partial least squares (DE-PLS) regression was performed. The results indicate that in the studied group of structurally related isoxazolone derivatives, discrepancies occur between the retention under IAM and RP-LC conditions. Although some correlation between these two chromatographic methods can be found, lipophilicity does not fully explain the affinities of the investigated molecules to phospholipids. QSRR analysis also shows common factors that contribute to retention under IAM and RP-LC conditions. In this context, the significant influences of WHIM and GETAWAY descriptors in all the obtained models should be highlighted.

This review is aimed to provide extensive survey of quinolones and fluoroquinolones for a variety of applications ranging from metal complexes and nanoparticle development to hybrid conjugates with therapeutic uses. The review covers the literature from the past 10 years with emphasis placed on new applications and mechanisms of pharmacological action of quinolone derivatives. The following are considered: metal complexes, nanoparticles and nanodrugs, polymers, proteins and peptides, NO donors and analogs, anionic compounds, siderophores, phosphonates, and prodrugs with enhanced lipophilicity, phototherapeutics, fluorescent compounds, triazoles, hybrid drugs, bis-quinolones, and other modifications. This review provides a comprehensive resource, summarizing a broad range of important quinolone applications with great utility as a resource concerning both chemical modifications and also novel hybrid bifunctional therapeutic agents. Graphical abstract

A series of new linear trisubstituted N1-acylamidrazones have been investigated using a variety of analytical techniques and theoretical calculations to check the influence of the type of N1-acyl substituent on the resonance forms and conformational behavior in the solid state and in solution. The 1D- and 2D-NMR experiments, supported by computational studies, revealed that in solution all amidrazones exhibit conformational syn/anti isomerism that results from the hindered rotation around the amide bond. In the case of the propenoic acid derivative, the ROESY, HSQC, and HMBC experiments proved a third equilibrium structure that corresponds to the planar ylide form. The SC XRD data confirmed that the compounds tend to exist as Z-anti conformers of their hydrazone-amide tautomeric species in the solid state. The carboxyl-amide heterosynthon is favoured provided that the carboxyl group is not involved in the intramolecular hydrogen bonding. Interestingly, after replacement of the cyclic C1-substituent by the smaller propanoic acid unit, which results in lower steric hindrance, both syn and anti conformers can exist. Furthermore, in the former case both the neutral molecules and zwitterions are present in the single crystal. The relative stability of the distinct crystal forms was examined using TG-DSC methods supplemented with cohesive energy calculations (CRYSTAL). The results indicate that the unsolvated forms are stable in a wide range of temperatures; however, inclusion of solvent molecules makes them prone to cyclization at higher temperatures. This paper reports the first observation of temperature-induced cyclization of N1-acylamidrazone to its cyclic triazole derivative in the solid state.

The reaction of bidentate 1-(pyridin-2-yl)-2,3,7,8-tetrahydro-1H-imidazo[2,1-b][1,3,5]triazepin-5(6H)-one ligands (3a–g) with copper(II) chloride, carried out at ambient temperature in aqueous EtOH or DMF, led to the formation of corresponding complexes 4 of type [Cu(L)(Cl)2], which in the presence of water and excess of Cu2+ ions provided copper(II) complexes (5) of tridentate N1-[1-(pyridin-2-yl)imidazolidin-2-ylidene]ethane-1,2-diamine ligands of the formula {[Cu(L)(μ-Cl)]2Cl2}n. Structures of the selected complexes 4 and 5 were confirmed by single crystal X-ray crystallography. The mechanism of the observed copper(II)-assisted hydrolysis of cyclic ureas 3 was elucidated with the aid of quantum chemical calculations.

We have used isoxazolo[3,4-b]pyridin-3(1H)-one and isoxazolo[3,4-b]quinolin-3(1H)-one as "masked" heterocyclic hydroxylamines to generate Paal-Knorr intermediates of the Trofimov pyrrole synthesis. The previously inaccessible intermediates, trapped by ethyl propiolate, were obtained by reacting corresponding isoxazolones with 4-fold excess of ethyl propiolate under basic conditions at ambient temperature, and characterized by means of IR and NMR spectroscopic data as well as by single crystal X-ray analysis. Quantum chemical calculations of a [3,3]sigmatropic rearrangement of the N,O-divinyl hydroxylamines to corresponding imino-aldehydes (Paal-Knorr intermediates) revealed that this reaction proceeds via chairlike transition state and is exothermic.

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm&mdash, partial least squares (GA-PLS)&mdash, was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones.

The title compound, 2,2’-[(1,4-dimethoxy-1,4-dioxobutane-2,3-diylidene)bis(azanylylidene)]bis(quinoline-3-carboxylic acid) was synthesized from isoxazolo[3,4-b]quinolin-3(1H)-one and dimethyl acetylenedicarboxylate (DMAD) via a double aza-Michael addition followed by [1,3]-H shifts. The product was characterized by infrared and nuclear magnetic resonance spectroscopy, as well as elemental analysis and high-resolution mass spectrometry (HRMS). The proposed reaction mechanism was rationalized by density functional theory (DFT) calculations.

The lipophilicity of a molecule is a well-recognized as a crucial physicochemical factor that conditions the biological activity of a drug candidate. This study was aimed to evaluate the lipophilicity of isoxazolo[3,4-b]pyridine-3(1H)-ones and their N1-substituted derivatives, which demonstrated pronounced antifungal activities. Several methods, including reversed-phase thin layer chromatography (RP-TLC), reversed phase high-performance liquid chromatography (RP-HPLC), and micellar electrokinetic chromatography (MEKC), were employed. Furthermore, the calculated logP values were estimated using various freely and commercially available software packages and online platforms, as well as density functional theory computations (DFT). Similarities and dissimilarities between the determined lipophilicity indices were assessed using several chemometric approaches. Principal component analysis (PCA) indicated that other features beside lipophilicity affect antifungal activities of the investigated derivatives. Quantitative-structure-retention-relationship (QSRR) analysis by means of genetic algorithm—partial least squares (GA-PLS)—was implemented to rationalize the link between the physicochemical descriptors and lipophilicity. Among the studied compounds, structure 16 should be considered as the best starting structure for further studies, since it demonstrated the lowest lipophilic character within the series while retaining biological activity. Sum of ranking differences (SRD) analysis indicated that the chromatographic approach, regardless of the technique employed, should be considered as the best approach for lipophilicity assessment of isoxazolones.

Lipophilicity is a vital physicochemical parameter of a molecule, which affects several biological processes such as absorption, tissue distribution, and pharmacokinetic properties. In this study, evaluation of lipophilicities of a series of novel fluoroquinolone-Safirinium dye hybrids using chromatographic and computational methods is presented. Fluoroquinolone-Safirinium dye hybrids have been synthesized as new dual-acting hydrophilic antibacterial agents. Reversed phase thin-layer chromatography and micellar electrokinetic chromatography experiments were carried out. Furthermore, logP values of the target structures were predicted by means of different software platforms and algorithms. In order to assess similarities and dissimilarities of the obtained lipophilicity indexes, cluster analysis and sum of ranking differences were performed. The significant differences of calculated logP values (&alpha, = 0.05, p &lt, 0.001) indicated that an experimental approach is necessary for lipophilicity prediction of this class of antibiotics. Chromatographic data indicated that the newly synthesized hybrid (fluoro)quinolone-based quaternary ammonium derivatives show less lipophilic character than the parent (fluoro)quinolones. Additionally, the chromatographically obtained lipophilicity indexes were evaluated for possible application in quantitative retention&ndash, activity relationships. The established lipophilicity models have the potential to predict antimicrobial activities of a series of quaternary (fluoro)quinolones against Bacillus subtilis, Escherichia coli, and Proteus vulgaris.

A series of 1-[(imidazolidin-2-yl)imino]-1H-indole analogues of hypotensive α2-AR agonists 1-[(imidazolidin-2-yl)imino]-1H-indazoles, was synthesized and tested in vitro for their activities at α1- and α2-adrenoceptors as well as imidazoline I1 and I2 receptors. The most active 1-[(imidazolidin-2-yl)imino]-1H-indoles displayed high or moderate affinities for α1- and α2-adrenoceptors and substantial selectivity for α2-adrenoceptors over imidazoline-I1 binding sites. The in vivo cardiovascular properties of indole derivatives 3 revealed that substitution at C-7 position of the indole ring may result in compounds with high cardiovascular activity. Among them, 7-fluoro congener 3g showed the most pronounced hypotensive and bradycardic activities in this experiment at a dose as low as 10 μg/kg i.v. Metabolic stability of the selected compounds of type 3 were determined using both in vitro and in silico approaches. The results indicated that these compounds are not vulnerable to rapid first phase oxidative metabolism. This article is protected by copyright. All rights reserved.

Background Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1 H -indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1 H -imidazol-2-yl)methyl]-1 H -indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I 1 -imidazoline receptors and the lowest α 2 /I 1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α 2 -adrenergic and I 1 -imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α 2 -adrenergic and/or I 1 -imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. Methods Anesthetized rats were infused iv with the tested compounds and selective α 2 -adrenoceptor antagonist, RX821002, or nonselective α 2 -adrenergic/I 1 -imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. Results Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. Conclusion Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α 2 -adrenergic and I 1 -imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I 1 -imidazoline receptors than by the α 2 -adrenergic ones.

Mass spectrometry methods are commonly used in the identification of peptides and biomarkers. Due to a relatively low abundance of proteins in biological samples, there is a need for the development of novel derivatization methods that would improve MS detection limits. Hence, novel fluorescent N&ndash, hydroxysuccinimide esters of dihydro-[1,2,4]triazolo[4,3-a]pyridin-2-ium carboxylates (Safirinium P dyes) have been synthesized. The obtained compounds, which incorporate quaternary ammonium salt moieties, easily react with aliphatic amine groups of peptides, both in solution and on the solid support, thus, they can be applied for derivatization as ionization enhancers. Safirinium tagging experiments with ubiquitin hydrolysate revealed that the sequence coverage level was high (ca. 80%), and intensities of signals were enhanced up to 8-fold, which proves the applicability of the proposed tags in the bottom&ndash, up approach. The obtained results confirmed that the novel compounds enable the detection of trace amounts of peptides, and fixed positive charge within the tags results in high ionization efficiency. Moreover, Safirinium NHS esters have been utilized as imaging agents for fluorescent labeling and the microscopic visualization of living cells such as E. coli Top10 bacterial strain.

Proteinogenic amino acids were derivatized via coupling reactions with N-hydroxysuccinimide esters of Safirinium dyes. The obtained compounds were fully characterized by 1H and 13C NMR, IR, and ESI-MS spectral techniques. Elemental analysis, as well as the crystal structure analysis of exemplary compounds, were performed. The absorption and fluorescent properties of the obtained derivatives have been systematically investigated. The optical properties and very good water solubility allowed for the development of a simple method for the determination of exemplary amino acids by means of micellar electrokinetic chromatography. Moreover, a new class of fluorescent peptide building blocks comprising a spiro-conjugated Safirinium-proline system was obtained. Due to the presence of a permanent positive charge, Safirinium-amino acid dervatives are potential candidates for signal enhancers in MS proteomic analysis. The applicability of the examined ionization tags in signal enhancement and peptide sequencing was proved. The obtained results provide an experimental basis for the development of a new approach for trace amino acids, peptides, and proteins detection by means of absorption, fluorescence, and mass spectrometry.

Nowadays, fluoroquinolones (FQs) constitute one of the most important classes of antibiotics. FQs are used to treat infections caused by Gram-positive and Gram-negative species. A set of fluoroquinolone–Safirinium dye hybrids has been synthesized in our laboratory as potential new dual-action antibacterial agents. In the present study we have evaluated how such a modification influences the affinity of FQs to phospholipids. The immobilized artificial membrane (IAM) high-performance liquid chromatography (IAM-HPLC) was used as a tool for the determination of phospholipids partitioning. The obtained results indicate that the fluoroquinolone–Safirinium dye hybrids, especially the SafiriniumP conjugates, display significantly lower affinity to phospholipids than the parent FQs. Despite the fact that the hybrid structures comprise a quaternary nitrogen atom and hence are permanently charged, the attractive electrostatic interactions between the solutes and negatively charged phospholipids do not occur or occur at a lesser extent than in the case of the unmodified FQs. Since affinity of FQs to phospholipids involves molecular mechanism, which is not entirely determined by lipophilicity, assessment of phospholipid partitioning should be considered at the early stage of the development of new FQ antibiotics.

A series of 2-imino-2H-chromen-3-yl-1,3,5-triazine compounds 5&ndash, 12, which are namely hybrids of 2,4-diamino-1,3,5-triazines and 2-imino-coumarins, was synthesized by reacting 2-(4,6-diamine-1,3,5-triazin-2-yl)acetonitriles 1&ndash, 4 with 2-hydroxybenzaldehydes. After this, upon heating in aqueous DMF, 2-imino-2H-chromen-3-yl-1,3,5-triazines 10 and 12 were converted into the corresponding 2H-chromen-3-yl-1,3,5-triazines 13 and 14, which are essentially hybrids of 2,4-diamino-1,3,5-triazines and coumarins. The in vitro anticancer activity of the newly prepared compounds was evaluated against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO and RT-4. The greatest cytotoxic activity displayed 4-[7-(diethylamino)-2-imino-2H-chromen-3-yl]-6-(4-phenylpiperazin-1-yl)-1,3,5-triazin-2-amine (11, IC50 in the range of 1.51&ndash, 2.60 &mu, M).

A variety of substituted isoxazolo[3,4-b]quinolin-3(1H)-ones incorporating an ambident amidine functionality was synthesized by a two-step procedure starting from the corresponding 2-chloroquinoline-3-carboxylic acids. Alkylation and acylation reactions carried out in DMF solution in the presence of Et3N occurred preferentially on the available σ lone pair of the pyridine-type N1 nitrogen atom of the most stable 9H-oxo tautomer. The use of sodium hydroxide in place of Et3N led to isoxazolone ring cleavage with the formation of alkyl 2-(alkoxy(alkyl)amino)quinoline-3-carboxylates. The electronic structure of the three possible N1-oxo, N9-oxo and 3-hydroxy tautomeric forms, and the NaOH-induced cleavage of the isoxazolone ring were studied theoretically with use of the B3LYP/6-31+G* density functional method and SM8 (DMF) solvation model. The synthesized N1-alkyl and N1-acyl derivatives of isoxazolo[3,4-b]quinolin-3(1H)-one were evaluated for their in vitro antifungal activity against 19 pathogenic yeast-like fungal strains.

This review summarizes the synthesis of quinolines and acridines by the reactions of anionically activated 2-(perfluoroalkyl)anilines. Mechanistic studies including isolation of the intermediate aza-ortho-xylylene are discussed.

The electronic structure and prototropic tautomerism of 4,6-dimethylisoxazolo[3,4-b]pyridin-3(1H)-one (1) were studied theoretically with use of the B3LYP/6-31G* and ωB97X-D/6-31G* density functional methods and SM8 (H2 O, DMF) solvation models. Compound 1, which is a weak acid with a pK a of 6.9, undergoes regioselective alkylation and sulfonylation under basic reaction conditions to give a series of N1-substituted products 2a–i. Later compounds were evaluated in vitro for antibacterial activity with the use of 68 strains of aerobic and anaerobic bacteria, including 12 reference strains.

The heterocyclic hydroxylamine-O-sulfonates constitute a novel family of formal O-substituted hydroxyguanidines and hydroxyamidines that serve as functional precursors to a variety of fused heterocyclic ring systems incorporating N-N, N-O, N-S, or N-N+ moiety. They are readily accessible from the reaction of 2-chloroazoles, 2-chloroazines, and 2-chlorodiazines with hydroxylamine-O-sulfonic acid. They have a rich chemistry exemplified by tandem reactions, such as nucleophilic addition-electrophilic amination, nucleophilic addition-electrophilic 5-endo-trig cyclization or fluorogenic Mannich-electrophilic amination reaction. The heterocyclic hydroxylamine-O-sulfonates have significant potential for use in synthesis of anticancer, antiviral, and antimicrobial agents. The newly discovered fluorogenic reaction and fluorescent dyes (Safirinium-P and Safirinium-Q) have found applications in fluorescent detection and labeling.

Treatment of 2-(perfluoroalkyl)aniline with 2-tolylmagnesium bromide or chloride or their substituted analogs yields an acridine containing a shorter perfluoroalkyl group at the 9 position and devoid of the methyl group of the Grignard substrate. Interestingly, no acridine is produced in an attempted reaction with aryl magnesium bromide without the ortho methyl group. With 2-fluoro-6-methylphenylmagnesium bromide the methyl group is eliminated and the fluorine is retained in the acridine product. Results of the mechanistic studies strongly suggest that loss of the methyl group occurs as methanol during air oxidation and hydrolysis of the intermediate products during aqueous workup.

Tandem fluorogenic reaction: A new platform for the direct, selective and sensitive detection of formaldehyde and/or secondary aliphatic amines, based on a tandem Mannich-electrophilic amination reaction, is described. Biological applications of hydrophilic, water-soluble fluorescent 2,2-dialkyl-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-2-ium-8-carboxylates (Safarinium P probes) are exemplified by labeling of the amine-containing Ac-AKF-NH2 peptide and Bacillus subtilis spores in aqueous solution.

A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile—compound 12 can be regarded as a dual 5-HT7/5-HT2AR ligand, and 13 as a multi-receptor (5-HT7, 5-HT2A, 5-HT6 and D2) agent.

The reaction of 6-chloropurine (1) with fourfold excess of hydroxylamine-O-sulfonic acid (HOSA) provided (Z)-1H-purin-6-ylideneaminooxysulfonic acid (2) which can be regarded as a secondary metabolite of ultimate mutagen 6-hydroxylaminopurine (6-HAP). A similar reaction of 1 with twofold excess of HOSA gave a mixture of the substrate and the betaine product which co-crystallized from DMF-methanol-water in the form of complex 3 that proved to be a 1:1 complex 1·2 with offset face-to-face π-stacking interactions between purine rings.

2-Aryl(arylsulfony1)-6,7-dihydro-2H-imidazo[2,1-c][1,2,4]triazol-3(5H)-ones and 3-arylimino-6,7-dihydroimidazo[2,1-c][1,2,4]thiadiazoles have been synthesized by intramolecular nucleophilic substitution reactions at the electron-deficient sp(2) nitrogen atom of 2-(hydroxyimino)imidazolidine O-sulfonate. The displacement of the sulfate leaving group by both nitrogen and sulfur anionic nucleophiles proceeds exothermically by in-plane S(N)2 sigma nucleophilic substitution.

This paper reports the crystal structure of 4-dimethylaminopyridinium N-[2,4,6-triisopropylphenyl)sulfonyl]carbamoylide. The the X-ray diffraction results are compared with theoretical models derived from ab initio Hartree–Fock and density functional B3LYP calculations. The stability of 4-dimethylaminopyridinium N-arylsulfonylcarbamoylides is discussed in terms of phenyl ring substitution with application of ab initio, DFT and MP2 theories. Carbonyl group frequencies, atomic charges and dipole moments are presented for representative 4-dimethylaminopyridinium N-arylsulfonylcarbamoylides.

In this Letter, we describe the synthesis of several bis(thiocarbamoyl) disulfides that present interesting intramolecular S⋯N and S⋯S interactions. In one case, crystals suitable for X-ray characterization have been obtained. The non-covalent interactions have been studied analyzing the crystal structure and by means of high level density functional theory (DFT) calculations (RI-PB86/TZVP) using both ‘atoms-in-molecules’ (AIM) and natural bond orbital (NBO) analyses.

2-Alkoxyiminoimidazolidines 2–3 react with acetylene dicarboxylates and ethyl phenylpropiolate to give 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones C , which subsequently undergo a sterically induced multihetero-retro-ene fragmentation to give imidazo[1,2-a]pyrimidin-5(1H)-ones 4–7 together with formaldehyde or benzaldehyde. On the other hand, a similar reaction of 2–3 with ethyl propiolate gives corresponding 8-alkoxy-imidazo[1,2-a]pyrimidin-5(3H)-ones 8–10 . The unsubstituted imidazo[1,2-a]pyrimidin-5(1H)-one 11 can be prepared by retro-ene reaction of 9 upon prolonged heating in refluxing ethanol. A direct synthetic approach to 1-formyl-7-phenyl-imidazo[1,2-a]pyrimidine-5(1H)-one 14 is reported using DMF/sulfonyl chloride as a new Vilsmeier-type N-formylating reagent.

The treatment of 2-(trifluoromethyl)aniline with 2,6-dimethylphenylmagnesium bromide yields 1-methyl-9-(2,6-dimethylphenyl)acridine by the formal reaction of one equivalent of the aniline and two equivalents of the Grignard reagent. Interestingly, one of the methyl groups is eliminated during the reaction, and the product contains three methyl groups only. In a similar way, the reaction of 2-(trifluoromethyl)aniline with 2-ethylphenylmagnesium bromide furnishes 9-(2-ethylphenyl)acridine devoid of one ethyl group. The mechanism is discussed.

This review includes 129 fused heterocyclic systems (6:5:6) with at least one ring junction nitrogen atom. Crystallographic and spectroscopic data have been surveyed, reactivity has been described with differentiation of fully conjugated and nonconjugated rings, and synthetic methods have been classified by the number of atoms in each reacting component. Biologically active compounds have been reviewed.

The reaction of 2-(perfluoroethyl)aniline and its higher perfluoroalkyl analogues with an arylmagnesium bromide substituted with a methyl or ethyl group at the ortho position furnishes an acridine containing a shorter perfluoroalkyl group at the 9-position and devoid of the methyl or ethyl group of the Grignard reagent. Yields are in the range of 46–93 %. The intermediary of a substituted aza-ortho-xylylene has been postulated for related transformations in the literature previously, but this intermediate product has never been isolated. As part of this work, the labile product E-27 (half-life of 6 h at 23°C) was isolated for the first time and characterized by infrared spectroscopy, electron impact mass spectrometry, fast atom bombardment mass spectrometry, and 1H NMR. Experimental evidence was also obtained regarding the elimination of the ortho-alkyl group of the Grignard reagent during the course of the reaction as an alcohol.

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles have been identified as selective imidazoline I 2 /α 2 -adrenoceptor ligands. 4-Methyl ( 2 ) and 4-chloro ( 4 ) derivatives display I 2 affinity at nanomolar concentration ( K i = 4.4 and 17.7 nM, respectively) and high I 2 /α 2 selectivity ratio = 4226 and 5649, respectively. An evidence has been obtained that p K a value influences considerably the I 2 /α 2 -selectivity ratio of this class of imidazoline I 2 receptor ligands.