Anna C. Cunha

RECENT ADVANCES IN THE SYNTHESIS OF PYRROLES

.......................................................................... INTRODUCTION ........ 413 I. ADVANCES IN THE CLASSICAL METHODS ...................................................................... . 4 14 .................................. 414 1. Knorr Pyrrole Synthesis .............................................. 2. Paal-Knorr Pyrrole Synthesis ......................................................... 3. Hantzsch Pyrrole Synthesis and Related Reactions ................................................... 11. ZAV’YALOV PYRROLE SYNTHESIS ........ 111. BARTON-ZARD PYRROLE SYNTHESIS AND RELATED REACTIONS ..................... 425 IV. PYRROLES FROM l93-DICARBONYL COMPOUNDS .................. ............ 429 V. MULTIPLE-COMPONENT REACTIONS ............................................................... 432 VI. SYNTHESES OF PYRROLES FROM ALKYNYL COMPOUNDS ................................... 436 W. OTHER REACTIONS ....................................................................... VIII. CONCLUSION ..... ...................................................................... REFERENCES ........................................ ................................................................. 446

Antiviral evaluation of N-amino-1,2,3-triazoles against Cantagalo virus replication in cell culture

This paper describes the antiviral evaluation of new N-amino-1,2,3-triazole derivatives, 1-(substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid ethyl esters, 3 and 1-(4-substituted-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazides, 4, on Cantagalo virus replication. 1-(4-Fluoro-phenylamino)-5-methyl-1H-[1,2,3]-triazole-4-carboxylic acid hydrazide, 4e, exhibited a significant antiviral effect. Characterization of all compounds was confirmed by IR, (1)H and (13)C spectroscopies and elemental analysis. In addition, molecular structure of 4e was also reported.

Design, synthesis and pharmacological profile of novel dopamine D2 receptor ligands.

The present study describes the synthesis and pharmacological profile of three novel heterocyclic compounds originally designed, on the basis of bioisosterism, as dopamine D2 receptor ligands: 1-[1-(4-chlorophenyl)-1H-pyrazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-579), 1-phenyl-4-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperazine (LASSBio-580) and 1-[1-(4-chlorophenyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-581). Binding studies performed on brain homogenate indicated that all three compounds bind selectively to D2 receptors. In addition, electrophysiological studies carried out in cultured hippocampal neurons suggested that LASSBio-579 and 581 act as D2 agonists, whereas LASSBio-580 acts as a D2 antagonist.

Synthesis, antiplatelet and in silico evaluations of novel N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides

This paper describes the synthesis, antiplatelet and theoretical evaluations of 10 N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (2a-j). These compounds were synthesized, characterized and screened for their in vitro antiplatelet profile against human platelet aggregation using arachidonic acid, adrenaline and ADP as agonists. Among NAH derivatives 2a-j, the compounds 2a, 2c, 2e, 2g and 2h were the most promising molecules with significant antiplatelet activity.

New Families of Hetero-tri-spin 2p−3d−4f Complexes: Synthesis, Crystal Structures, and Magnetic Properties

In this work we report the synthesis, crystal structures, and magnetic behavior of 2p-3d-4f heterospin systems containing the nitroxide radical 4-azido-2,2,6,6-tetramethylpiperidine-1-oxyl radical (N3tempo). These compounds were synthesized through a one-pot reaction by using [Cu(hfac)2], [Ln(hfac)3] (hfac = hexafluoroacetylacetonate, Ln = Dy(III), Tb(III) or Gd(III)), and the N3tempo radical. Depending on the stoichiometric ratio used, the synthesis leads to penta- or trimetallic compounds, with molecular formulas [Cu3Ln2(hfac)8(OH)4(N3tempo)] (Ln = Gd, Tb, Dy) and [CuLn2(hfac)8(N3tempo)2(H2O)2] (Ln = Gd, Dy). The magnetic properties of all compounds were investigated by direct current (dc) and alternating current (ac) measurements. The ac magnetic susceptibility measurements of Tb(III)- and Dy(III)-containing compounds of both families revealed slow relaxation of the magnetization, with magnetic quantum tunneling in zero field.

Synthesis, antitubercular activity, and SAR study of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides

Tuberculosis treatment remains a challenge that requires new antitubercular agents due to the emergence of multidrug-resistant Mycobacterium strains. This paper describes the synthesis, the antitubercular activity and the theoretical analysis of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazides (8a-b, 8e-f, 8i-j and 8n-o) and new analogues (8c-d, 8g-h, 8l-m and 8p-q). These derivatives were synthesized in good yields and some of them showed a promising antitubercular profile. Interestingly the N-acylhydrazone (NAH) 8n was the most potent against the Mycobacterium tuberculosis H37Rv strain (MIC=2.5 μg/mL) similar to or better than the current drugs on the market. The theoretical structure-activity relationship study suggested that the presence of the furyl ring and the electronegative group (NO(2)) as well as low lipophilicity and small volume group at R position are important structural features for the antitubercular profile of these molecules. NMR spectra, IR spectra and elemental analyses of these substances are reported.

Crystallographic and computational study of 1-(arylamino)-1,2,3-triazole-4-carbohydrazides

The crystallography of mono-p-substituted derivatives of 1-(arylamino)-1,2,3-triazole-4-carbohydrazides, 1 (X = H), 2 (F), 3 (Cl) and 4 (Br), and a 2,5-dichloro (5) analogue, shows the molecular structures to be similar. Distinct hydrogen bonding patterns based on N–H⋯N and N–H⋯O are observed in their crystal structures with 1, having two independent molecules comprising the asymmetric unit, displaying one pattern, 2 and 5 another, and 3 and 4 yet another. Geometry optimisation calculations indicate that any conformational differences in the solid state do not persist in the gas-phase and that no influence of the substituents is seen on the geometric parameters. A natural population analysis, for both experimental and optimised structures, shows that the charge on the triazole-N3 atom is at a maximum for 1, as opposed to 2–5, an observation correlated with its distinctive packing based around a supramolecular synthon not seen in the other structures. For the molecules having electronegative substituents, molecular electrostatic potentials show that the energies of the amine-H4n atoms are reduced for 2 and 5, compared to 3 and 4. A further distinction in 2–5 is indicated by the Hirshfeld surface analysis which highlights the importance of π⋯π interactions in 2 and 5, i.e. with the more electronegative substituents. Clearly, there is interplay between various factors but all correlated with the influence of the electronegativity of the substituent(s).

Aryl-substituents moderate the nature of hydrogen bonds, N–H⋯N versus N–H⋯O, leading to supramolecular chains in the crystal structures of N-arylamino 1,2,3-triazole esters

Structural analysis reveals the presence of supramolecular chains in a series of eight N-arylamino 1,2,3-triazole esters, which differ only in the nature of the substituent (Y) of the terminal aryl ring. In each of 1 (Y = 4-H), 3 (4-Cl), 4 (4-Br), 5 (4-I) and 6 (4-OMe), the chains are sustained by N–H⋯N hydrogen bonding. In 2 (Y = 4-F) and 8 (Y = 2,5-Cl2), the chains are mediated by alternating N–H⋯N and N–H⋯O hydrogen bonding, whereas in 7 (Y = 4-NO2) the chain is sustained by N–H⋯O hydrogen bonding only. While the differences in the adopted supramolecular motifs are qualitatively correlated with the electronegativity of the Y substituents, no quantitative correlations could be made with the electronic structures of the theoretical gas-phase molecules. Two distinct patterns of crystal packing are observed, with the first of these being based on the inter-digitation of layers, comprised of supramolecular chains and connections of the type C–X⋯π(aryl) between them for 3–5 and 8; only weak off-set edge-to-edge π⋯π interactions were noted in the case of 1. A common feature of the zigzag chains in these crystal structures was a syn-disposition of successive aryl rings along the axis of propagation. The remaining structures adopted three-dimensional architectures where the Y substituents of the anti-disposed aryl rings participated in F⋯H (2) or C–H⋯O (6 and 7) interactions. A detailed analysis of the Hirshfeld surfaces and fingerprint plots for 1–8 enabled a comparison of the intermolecular interactions involved in constructing the disparate supramolecular architectures. In the structures featuring N–H⋯N hydrogen bonding leading to the supramolecular chain, the maximum contribution to the overall crystal packing was less than 20%. This increased to over 25% in the case where there was exclusive N–H⋯O hydrogen bonding in the chain.

Heterociclos 1,2,3-triazólicos: histórico, métodos de preparação, aplicações e atividades farmacológicas

The 1,2,3-triazole, known since the end of 19th century, is a very widely used heterocyclic system present in many synthetic substances and commercial pharmaceutical compounds. In fact, 1,2,3-triazoles show several applications in many areas especially as medicines against many diseases like cancer, AIDS, Parkinson and Alzheimer. Nowadays there is a large variety of known methods to obtain these heterocyclic compounds comprising mainly three synthetic routes. Nevertheless, there is no article that gives an objective overview of the synthetic methods for obtaining these kinds of azoheterocycles. This paper presents a brief history of this class of compounds, and a synthetic discussion concerning the main synthetic methods for its preparation, such as cyclization through hydrazones, concerted cycloadditon [2+3] and pseudopericyclic cyclization - and some others of restricted application, but also important. Finally, this paper also provides a brief overview on pharmacological applications of some 1,2,3-triazoles.

Nitroxides attenuate carrageenan-induced inflammation in rat paws by reducing neutrophil infiltration and the resulting myeloperoxidase-mediated damage

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) and other cyclic nitroxides have been shown to inhibit the chlorinating activity of myeloperoxidase (MPO) in vitro and in cells. To examine whether nitroxides inhibit MPO activity in vivo we selected acute carrageenan-induced inflammation on the rat paw as a model. Tempol and three more hydrophobic 4-substituted derivatives (4-azido, 4-benzenesulfonyl, and 4-(4-phenyl-1H-1,2,3-triazol-1-yl)) were synthesized, and their ability to inhibit the in vitro chlorinating activity of MPO and carrageenan-induced inflammation in rat paws was evaluated. All of the tested nitroxides inhibited the chlorinating activity of MPO in vitro with similar IC(50) values (between 1.5 and 1.8 μM). In vivo, the attenuation of carrageenan-induced inflammation showed some correlation with the lipophilicity of the nitroxide at early time points but the differences in the effects were small (<2-fold) compared with the differences in lipophilicity (>200-fold). No inhibition of MPO activity in vivo was evident because the levels of MPO activity in rat paws correlated with the levels of MPO protein. Likewise, paw edema, levels of nitrated and oxidized proteins, and levels of plasma exudation correlated with the levels of MPO protein in the paws of the animals that were untreated or treated with the nitroxides. The effects of the nitroxides in vivo were compared with those of 4-aminobenzoic hydrazide and of colchicine. Taken together, the results indicate that nitroxides attenuate carrageenan-induced inflammation mainly by reducing neutrophil migration and the resulting MPO-mediated damage. Accordingly, tempol was shown to inhibit rat neutrophil migration in vitro.