Maria Cecília B. V. de Souza

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

Antiplatelet properties of novel N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone derivatives

This paper describes the design, synthesis and pharmacological evaluation of new N-acylhydrazone (NAH) compounds, belonging to the N-substituted-phenyl-1,2,3-triazole-4-acylhydrazone class (2a-p). Classical heteroaromatic ring bioisosterism strategies were applied to the previously reported N-phenylpyrazolyl-4-acylhydrazone derivative 1, elected as lead-compound due to its important anti-aggregating profile on arachidonic acid induced platelet aggregation (IC(50)=24+/-0.5 micro M), from which emerge this new series 2. These new compounds 2a-p were readily synthesized, characterized and tested on platelet aggregation assays induced by collagen (5 micro g/mL), ADP (5 micro M) and arachidonic acid (100 micro M) in rabbit citrated platelet-rich plasma. Compounds 2b, 2d, and 2h were found to be the most potent, exhibiting a significant antiplatelet activity on arachidonic acid- and collagen-induced platelet aggregation. In addition, these new antiplatelet agents are free of gastric ulcerogenic effect and presented discrete anti-inflammatory and analgesic properties. The N-para-chlorophenyltriazolyl-4-acylhydrazone compound 2h produced the highest inhibitory effect on collagen (IC(50)=21.6+/-0.4 micro M) and arachidonic acid-induced platelet aggregation (IC(50)=2.2+/-0.06 micro M), suggesting that the nature of the substituent on the phenyl ring of the N-heteroaromatic system of NAH moiety may be an important structural requirement for the improvement of antiplatelet activity, in comparison with lead-series 1.

Synthesis, HIV-RT inhibitory activity and SAR of 1-benzyl-1H-1,2,3-triazole derivatives of carbohydrates.

This paper describes the synthesis of several 1-benzyl-1H-1,2,3-triazoles attached to different carbohydrate templates and their in vitro inhibitory profile against HIV-1 reverse transcriptase. In addition a theoretical comparison of the most active compounds with other classical antivirals was also performed. Our results showed 2a, 2d and 2g as the most active compounds that inhibited the HIV-1 reverse transcriptase catalytic activity with cytotoxicity lower than AZT and SI higher than DDC and DDI. The overall theoretical analysis of the molecular descriptors of 2a, 2d and 2g revealed that their HOMO energy is similar to other antivirals in use (AZT, DDC, DDI and 3TC) and together with the volume may contribute for the biological profile as they may allow new interactions with the target. In fact the 1,2,3-triazole compounds presented more lipophilicity and higher molecular volume and weight than the antivirals studied, which suggested that these features might not only contribute for new interactions with the HIV-RT but also influence the specificity and consequently the low cytoxicity profile of these compounds. Thus these data point them as promising leading compounds for generating new anti-HIV-RT compounds.

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.

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.

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).

A new and efficient procedure for preparing 1,2,3-triazoles

Abstract 1,2,3-Triazoles are readily accessible in moderate to good yields by a diazo transfer reaction with β-amino-α,β-unsaturated ketones or esters and tosyl or mesyl azide reagent. In this methodology the nitrogen atoms N-2 and N-3 of the triazole ring are derived from diazo transfer reagent and nitrogen atom N-1 is derived from the appropriate enamine.

Oxyrane derivative of α-lapachone is potent growth inhibitor of Trypanosoma cruzi epimastigote forms

The investigation of trypanocidal effects against Trypanosoma cruzi and cytotoxicity in VERO cell line of several oxyranes structurally related to β-lapachone, nor-β-lapachone, α-lapachone, and 4-methoxy-1,2-naphthoquinone is described. It was found that the oxyranes 10 derived from α-lapachone showed an approximately the same trypanocidal activity of β-lapachone. In addition, all the oxyranes showed less cytotoxicity than the corresponding naphthoquinones.

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.