Vitor F. Ferreira

Synthesis, Biological Activity, and Molecular Modeling Studies of 1H-1,2,3-Triazole Derivatives of Carbohydrates as α-Glucosidases Inhibitors

A class of drugs in use for treating type II diabetes mellitus (T2D), typified by the pseudotetrasaccharide acarbose, act by inhibiting the alpha-glucosidase activity present in pancreatic secretions and in the brush border of the small intestine. Herein, we report the synthesis of a series of 4-substituted 1,2,3-triazoles conjugated with sugars, including D-xylose, D-galactose, D-allose, and D-ribose. Compounds were screened for alpha-glucosidase inhibitory activity using yeast maltase (MAL12) as a model enzyme. Methyl-2,3-O-isopropylidene-beta-D-ribofuranosides, such as the 4-(1-cyclohexenyl)-1,2,3-triazole derivative, were among the most active compounds, showing up to 25-fold higher inhibitory potency than the complex oligosaccharide acarbose. Docking studies on a MAL12 homology model disclosed a binding mode consistent with a transition-state-mimicking mechanism. Finally, the actual pharmacological potential of this triazole series was demonstrated by the reduction of postprandial blood glucose levels in normal rats. These compounds could represent new chemical scaffolds for developing novel drugs against T2D.

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.

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.

3-Arylamino and 3-Alkoxy-nor-β-lapachone Derivatives: Synthesis and Cytotoxicity against Cancer Cell Lines

Several 3-arylamino and 3-alkoxy-nor-beta-lapachone derivatives were synthesized in moderate to high yields and found to be highly potent against cancer cells SF295 (central nervous system), HCT8 (colon), MDA-MB435 (melanoma), and HL60 (leukemia), with IC(50) below 2 microM. The arylamino para-nitro and the 2,4-dimethoxy substituted naphthoquinones showed the best cytoxicity profile, while the ortho-nitro and the 2,4-dimethoxy substituted ones were more selective than doxorubicin and similar to the precursor lapachones, thus emerging as promising new lead compounds in anticancer drug development.

Cytotoxic, Trypanocidal Activities and Physicochemical Parameters of nor-β-Lapachone-based 1,2,3-Triazoles

The cytotoxicities of five nor-²-lapachone-based 1,2,3-triazoles and the precursor azidonaphthoquinone were assayed against six neoplasic cancer cell lines: SF-295 (central nervous system), HCT-8 (colon), MDAMB-435 (melanoma), HL-60 (leukaemia), PC-3 (prostate) and B-16 (murine melanoma). IC50 values ranging from 0.43 to 9.48 µM were obtained. 3-(4-(1-hydroxycyclohexyl)-1H-1,2,3-triazol-1yl)-2,2-dimethylnaphtho[1,2-b]furan-4,5-dione proved highly cytotoxic to MDAMB-435, with IC50 even lower than the one from doxorubicin (positive control). In an attempt to correlate physicochemical parameters (reduction potentials and calculated log P) with cytotoxic activity, electrochemical studies were conducted in acetate buffer, pH 4.5, using a vitreous carbon electrode and calculated log P values were obtained. Despite the absence of a structural conjugative interaction between the two systems (quinone and triazole), the heterocyclic group was found to influence the voltammetric behaviour, as indicated by anodic shifts in the reduction potentials. No correlation was found between EpIc and cytotoxicity. In contrast, a comparison of EpIc with previously reported trypanocidal activities reconfirmed the trend for higher activity coupled with better quinone electrophilicity (> EpIc).A leading term in the correlation of cytoxicity, despite the absence of a linear correlation, was the calculated log P: the lower the lipophilicity, the lower the cytoxicity (> IC50).

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.