[show abstract][hide abstract] ABSTRACT: Searching for new anti-inflammatory agents, we have prepared a series of potential COX-2 inhibitors, 1-(4,6-dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-Δ(2)-pyrazolines (3) and 1-(4,6-dimethylpyrimidin-2-yl)-3-trifluoromethylpyrazoles (4), by refluxing 2-hydrazino-4,6-dimethylpyrimidine (1) with a number of trifluoromethyl-β-diketones (2) in ethanol. Further dehydration of compounds (3) to the corresponding 1-(4,6-dimethylpyrimidin-2-yl)-5-trifluoromethylpyrazoles (5) was also achieved. Fifteen of these compounds were screened for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay. While all the compounds exhibited significant anti-inflammatory activity (47-76%) as compared to indomethacin (78%), 3-trifluoromethylpyrazoles (4) were found to be the most effective agents (62-76%). To rationalize this anti-inflammatory activity, docking experiments molecular dynamics simulations were performed to study the ability of these compounds to bind into the active site of the COX-2 enzyme.
European journal of medicinal chemistry 10/2013; 70C:350-357. · 3.27 Impact Factor
[show abstract][hide abstract] ABSTRACT: Considering that guanidine-based derivatives are good DNA minor groove binders, we have theoretically studied, using the Polarizable Continuum Model (PCM) mimicking water solvation, the complexes formed by the biologically relevant guanidinium cation and the DNA and RNA nucleobases (adenine, guanine, cytosine, thymine and uracil). The interactions established within these complexes both by hydrogen bonds and by cation-π interactions, have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches. Moreover, maps of electron density difference have been produced to understand the cation-π complexes. Finally, the NICS and 3D NICS maps of the cation-π complexes have been studied to understand the effect of the guanidinium cation on the aromaticity of the nucleobases.
The Journal of Physical Chemistry B 09/2013; · 3.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: We present the crystal structures of the chloride salts of the mono-guanidinium 1 (–CH2CH2– linker) and the bis-isouronium 2 (–O– linker) that have been resolved by us indicating that these compounds are diprotonated in the solid state as informed by the counterions positions. To determine the pK
a values of these compounds as well as those of their analogues 3 (mono-2-aminoimidazolinium with a –CH2CH2– linker) and 4 (mono-guanidinium with a –O– linker), the corresponding UV–Vis titrations were carried out. Thus, in aqueous solution compounds 1, 3 and 4 were present as mono-cationic species while derivative 2 was a bis-cation.
[show abstract][hide abstract] ABSTRACT: The N-aryl- and N-acylguanidine structural motifs are essential for the function of several important classes of molecules, including pharmaceuticals, catalysts and natural products. Compounds combining both motifs can exist as different isomers due to tautomerism within the guanidine subunit, E/Z isomerism with reference to the guanidine double bond, and conformational isomerism. This complex phenomenon results in unresolved broad signal NMR spectra that strongly complicate the characterisation of these derivatives. Hence, the present study examines isomerism in N,N′-bis-aryl-N′′-acylguanidines using low temperature NMR spectroscopy in tandem with Density Functional Theory (DFT), Natural Bond Analysis (NBO) and the Gauge-Invariant Atomic Orbital (GIAO) approach for calculating the NMR chemical shifts associated with each isomer. It was found that the structural preference of these compounds is strongly influenced by intramolecular hydrogen bond (IMHB) effects.
New Journal of Chemistry 06/2013; · 2.97 Impact Factor
[show abstract][hide abstract] ABSTRACT: Considering the strong DNA minor-groove binding observed for our previous series of di-aromatic symmetric and asymmetric guanidinium and 2-aminoimidazolinium derivatives, we report now the synthesis of new aminoalkyl derivatives of di-aromatic guanidines with potential as DNA minor groove binders and antiprotozoal activity. The preparation of these aminoalkyl derivatives (12a-e; 13a-e; 14a-c,e; 15a-e; 16a-e) is presented as well as their affinity for DNA which was evaluated by means of DNA thermal denaturation experiments. Finally, the antiprotozoal activity of most of these aminoalkyl-minor groove binders was evaluated in vitro against Trypanosoma brucei rhodesiense (8 compounds) and Plasmodium falciparum (18 compounds). The O-linked derivatives 13c and 14c showed 100nanomolar activities against P. falciparum, whereas for T. b. rhodesiense all compounds tested showed micromolar activity. Some of the derivatives prepared seem to exert the antimalarial activity by binding to the DNA minor groove whereas other set of compounds could exert this antimalarial activity by inhibiting the parasite dihydrofolate reductase, for example.
Journal of Medicinal Chemistry 01/2013; · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: Searching for new anti-inflammatory agents, we have prepared a series of potential COX-2 inhibitors, 1-(4,6-dimethylpyrimidin-2-yl)-5-hydroxy-5-trifluoromethyl-Δ2-pyrazolines (3) and 1-(4,6-dimethylpyrimidin-2-yl)-3-trifluoromethylpyrazoles (4), by refluxing 2-hydrazino-4,6-dimethylpyrimidine (1) with a number of trifluoromethyl-β-diketones (2) in ethanol. Further dehydration of compounds (3) to the corresponding 1-(4,6-dimethylpyrimidin-2-yl)-5-trifluoromethylpyrazoles (5) was also achieved. Fifteen of these compounds were screened for their anti-inflammatory activity using the carrageenan-induced rat paw edema assay. While all the compounds exhibited significant anti-inflammatory activity (47-76%) as compared to indomethacin (78%), 3-trifluoromethylpyrazoles (4) were found to be the most effective agents (62-76%). To rationalize this antiinflammatory activity, docking experiments molecular dynamics simulations were performed to study the ability of these compounds to bind into the active site of the COX-2 enzyme.
European Journal of Medicinal Chemistry 01/2013; · 3.50 Impact Factor
[show abstract][hide abstract] ABSTRACT: Regioselectivity in the intramolecular Heck reaction of a series of N-sulfonyl-2,5-dihydro-3-substituted pyrroles was studied. These substrates are unbiased in terms of the formed ring size of the new heterocycle. Results indicate that high levels of regioselectivity are observed under a range of conditions, and that there is an underlying propensity for carbon-carbon bond formation at the most hindered end of the alkene. For two examples (3-Me and 3-tBu), DFT calculations were performed and indicate that in both cases, the modelled transition state for carbopalladation is energetically lower for the experimentally preferred isomer.
[show abstract][hide abstract] ABSTRACT: Evidence suggests that depression is associated with an increase in the high-affinity conformation of the α2-adrenoceptors in human brain. Such enhanced α2-adrenoceptor activity could explain the deficit in central noradrenergic transmission described in the aetiology of depression. Thus, administration of α2-adrenoceptor antagonists augments noradrenaline levels and provides an effective therapeutic approach for the treatment of depressive disorders. In previous studies, we have characterized three new synthesized guanidine and 2-aminoimidazoline aromatic derivatives (8b, 17b and 20b) as α2-adrenoceptor antagonists that are able to increase extracellular concentration of noradrenaline in rat brain. The purpose of the present study was to evaluate the in vivo antidepressant-like properties of these three new α2-adrenoceptor antagonists. For that aim, compounds were tested on the tail suspension test (TST) and forced swim test (FST), two classically widely-used behavioural paradigms for the evaluation of antidepressant-like activity. Compound 8b significantly reduced the immobility time at 10, 20 and 40 mg/kg doses in both TST and FST. Compound 17b reduced the immobility time at 40 mg/kg in both TST and FST. Compound 20b showed a significant decrease in the immobility time at 20 mg/kg in the TST. As drugs of reference, fluoxetine induced a significant antidepressant-like effect in both TST and FST, while mirtazapine induced a significant antidepressant-like effect only in the FST. Additionally, none of the tested compounds increased locomotor activity or displayed anxiolytic-like properties. These results suggest that these new synthesized α2-adrenoceptor antagonists may be useful as potential antidepressant drugs.
[show abstract][hide abstract] ABSTRACT: A divergent strategy for the synthesis of 1-aryl- and 2-aryl-2-iminoimidazolidines is presented. Cyclization of N-Boc-N′-aryl-N′′-(2-hydroxyethyl)guanidines in the presence of methanesulfonyl chloride and triethylamine or sodium hydride at 0 °C affords the corresponding 2-iminoimidazolidines in good yields.
[show abstract][hide abstract] ABSTRACT: A theoretical study of the possible protonation sites of simple molecules formed by C, N, Si, P, B and Al that present a triple
bond between those atoms has been carried out. The calculations performed include MP2 and CCSD(T) methods with the aug-cc-pVTZ
basis set. The nature of the protonated species has been analyzed with the Atoms In Molecules methodology.
[show abstract][hide abstract] ABSTRACT: In this paper we report the design and synthesis of a new family of asymmetric peptide linked diaromatic dications as potent DNA minor groove binders. These peptide-linked compounds, with a linear core, displayed a much larger affinity than other guanidinium-like derivatives from the same series with curved cores. As a first screening, the DNA affinity of these structures was evaluated by means of thermal denaturation experiments, finding that the nature of the cation (guanidinium vs 2-aminoimidazolinium) significantly influenced the binding strength. Their binding affinity was assessed by implementing further biophysical measurements such as surface plasmon resonance and circular dichroism. In particular, it was observed that compounds 6, 7, and 8 displayed both a strong binding affinity and significant selectivity for AT oligonucleotides. In addition, the thermodynamics of their binding was evaluated using isothermal titration calorimetry, indicating that the binding is derived from favorable enthalpic and entropic contributions.
Journal of Medicinal Chemistry 04/2012; 55(9):4397-406. · 5.61 Impact Factor
[show abstract][hide abstract] ABSTRACT: We have theoretically studied, using PCM–water solvation, the cation–π and π–π complexes established by the biologically relevant 5-substituted 2-pyridinylguanidinium derivatives and electron-rich and electron-depleted aromatic systems (benzene and (hexafluoro)benzene). In condensed phase using PCM–water and M06-2X/6-311++G(d,p) different cation–π and π–π complexes were found. The interactions established within these complexes have been analyzed by means of the Atoms in Molecules and Natural Bond Orbital approaches and electron density difference maps have been calculated. Finally, the effect of the cation–π and π–π complexation on the aromaticity of pyridine, benzene and hexafluorobenzene was evaluated by calculating the corresponding aromaticity indexes, NICS0, 1 and 2 as well as the NICS on the 0.001 a.u. isodensity surface.
[show abstract][hide abstract] ABSTRACT: The synthesis and conformational analysis of a series of pyridin-2-yl guanidine derivatives using NMR, X-ray crystallography, and B3LYP/6-31+G** theoretical studies are reported. A remarkable difference was observed in the (1)H NMR spectra of the guanidinium salts as compared with their N,N'-di-Boc protected and neutral analogues. This difference corresponds to a 180° change in the dihedral angle between the guanidine/ium moiety and the pyridine ring in the salts as compared to the Boc-protected derivatives, a conclusion that was supported by theoretical studies, X-ray data, and NMR analysis. Moreover, our data sustain the existence of two intramolecular hydrogen-bonding systems: (i) between the pyridine N1 atom and the guanidinium protons in the salts and (ii) within the tert-butyl carbamate groups of the Boc-protected derivatives. To verify that the observed conformational control arises from these intramolecular interactions, a new series of N-Boc-N'-propyl-substituted pyridin-2-yl guanidines were also prepared and studied.
The Journal of Organic Chemistry 11/2011; 76(22):9216-27. · 4.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Abinitio calculations have been used to study the conformational potential surface of sulfamide, by considering the S—N bond rotations and the nitrogen inversion processes. The lowest energy conformation (b) is found for a cis–trans arrangement of the amino groups, although conformations with cis–cis (a), trans–trans (c), and near staggered (c′) arrangements lie close in energy. Nitrogen inversion barriers are very low, and consequently one may expect forms b and c′ to be the only ones present in the gas phase. Conformer a is very polar, its dipole moment being twice that of b, so it may be favored in condensed media or in polar-solvent solutions. The relative stability of the different isomers is governed by interactions between the amino protons and between the nitrogen lone pairs. Our results show that d–π backbonding, involving the d orbitals on sulfur, is responsible for the multiple bond character of the S—O linkage, but is very small in the S—N interactions. The role of the sulfur d-orbital exponent, when a 6-31G* basis is used, is analyzed on a series of model compounds containing SII, SIV, and SVI. Although the inclusion of d functions on sulfur is crucial to describing correctly the bonding in sulfamide, the results obtained do not change appreciably if a second set of d functions is centered on sulfur. Nevertheless, only when polarization functions are also included for first-row atoms is the description of the system reliable. Keywords: sulfamide, inversion and rotational barriers, sulfur d-functions.
Canadian Journal of Chemistry 02/2011; 67(12):2227-2236. · 0.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: The reaction between aryl or heteroarylhydrazines with fluorinated β-diketones (CF3COCH2COR) yields a variety of 3-, 5-, and 3,5-trifluoromethylpyrazoles and 5-trifluoromethyl-5-hydroxy-Δ2-pyrazolines. Twenty-one of such compounds have been isolated and identified by 13C and 19F NMR. Together with the results from the literature they provide a comprehensive overview of the reaction. Semi-empirical calculations at the PM3 level have been used to rationalize these results. The outcome that emerges seems to be that the dehydration of a pair of 3,5-dihydroxypyrazolidines kinetically controls the isomer formed.Key words: hydrazines, 1,3-diketones, pyrazolines, pyrazoles, PM3 calculations.
Canadian Journal of Chemistry 02/2011; 78(8):1109-1120. · 0.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: We present a new and concise method for the preparation of asymmetrical N,N′-disubstituted guanidines starting from thiourea via the reaction of N-Boc-protected N′-alkyl/aryl substituted thioureas with an amine in the presence of mercury(II) chloride and triethylamine.
Tetrahedron Letters - TETRAHEDRON LETT. 01/2011; 52(32):4117-4119.
[show abstract][hide abstract] ABSTRACT: We have theoretically studied, in gas phase and using PCM-water solvation, the complexes established by the biologically relevant guanidinium cation and simple aromatic systems (benzene, naphthalene and pyridine). In gas phase only hydrogen bonded complexes were obtained, whereas using PCM-water different cation–π complexes for the three aromatic systems were found. The interactions established within these complexes have been analyzed by means of the atoms in molecules and natural bond orbital approaches. Finally, experimental evidence of the cation–π interactions created by guanidinium was found in the crystal structure of N-(5-methylpyridin-2-yl)guanidinium chloride, which was also theoretically analyzed.Graphical abstractView high quality image (58K)Highlights► We study pi–cation interactions. ► We analyze interactions established by the guanidinium cation. ► Stacking interactions formed by simple aromatic systems are examined. ► Computations are performed using the Truhlar DFT functional. ► The N-(5-methylpyridin-2-yl)guanidinium chloride crystal structure is presented.
Chemical Physics Letters 01/2011; 511:129-134. · 2.15 Impact Factor