J. Mol. Struct. 1261, 132883 (2022)

DOI: 10.1016/j.molstruc.2022.132883

Determination of the tautomerism of albendazole desmotropes using solution and solid state NMR together with DFT theoretical calculations, both energies and chemical shifts

This paper reports a structural study of albendazole concerning the desmotropy of its amino and imino tautomers, ABZ-I and ABZ-II, mistakenly called polymorphs. Experimental NMR determination in solution, DMSO‑d6, HMPA-d18 and CF3CO2H, and in the solid state, CPMAS, together with DFT calculations, energies and NMR chemical shifts, has allowed to understand the complex problem of prototropy combined with rotation about the benzimidazole C2-N exocyclic group that explain the disorder problem of the S-propyl group. The structure of protonated albendazole, ABZH+, has also been studied. The role of the hybrid HF/DFT B3LYP computational method at the B3LYP/6–311++G(d,p) level has been determinant to solve the problems related to the structure of albendazole in the solid state and in solution and the barrier in solution of a phenomenon resulting either from annular tautomerism or from the rotation about the exocyclic Csingle bondN bond.

Tetahedron 74, 3937-3942 (2018)

DOI: 10.1016/j.tet.2018.02.041

The structure of fosfomycin salts in solution and in the solid state by nuclear magnetic resonance spectroscopy and DFT calculations

Two samples of fosfomycin salts, the calcium and the disodium ones, were used to record their NMR spectra both in solution and in the solid state. The existence of fosfomycin in a neutral and two ionized structures (mono and dianion) was considered to interpret the spectra that were solved using the GIAO calculated chemical shifts of the minimum energy conformations. Although the starting materials were dianions, the spectra in solution show the presence of monoanions.

Chem. Commun., 2016,52, 9652-9655

DOI: 10.1039/C6CC04566A

Highly solvatochromic and tunable fluorophores based on a 4,5-quinolimide scaffold: novel CDK5 probes

Novel 4,5-quinolimide-based fluorophores are more solvatochromic and red-shifted than known naphthalimide analogues. Conjugation of one of these fluorophores to a peptide derived from CDK5 kinase demonstrated its sensitivity for monitoring the interaction with its regulatory partner p25. Introduction of the quinolimide-labelled peptide into living glioblastoma cells probed the interaction with endogenous p25.

Comput. Theor. Chem. 1076, 101-108 (2016)

DOI: 10.1016/j.comptc.2015.12.007

The effect of cytosine methylation on its halogen-bonding properties

This study shows the influence of a 5-methyl substituent on the interaction between 1-methylcytosine, 1,5-dimethylcytosine, 1-methyluracil and 1-methylthymine and dichloride (Cl2) and fluorine chloride (ClF). The methyl derivatives were selected because of the important role played by a methyl group at position 5 of the pyrimidine ring on the biological properties of nucleobases. Besides binding energies obtained at the MP2/aug-cc-pVDZ level, a variety of theoretical methods were used to analyze the structures of the different minima obtained. A total of 116 complexes have been studied.

J. Mol. Struct. 1261, 132883 (2022)

DOI: 10.1016/j.ejmech.2015.07.013

Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1–3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains ofT. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies.

Eur. J. Med. Chem. 101, 806-817 (2015)

DOI: 10.1016/j.ejmech.2015.07.013

Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro

Diphenyl-based bis(2-iminoimidazolidines) are promising antiprotozoal agents that are curative in mouse models of stage 1 trypanosomiasis but devoid of activity in the late-stage disease, possibly due to poor brain penetration caused by their dicationic nature. We present here a strategy consisting in reducing the pKa of the basic 2-iminoimidazolidine groups though the introduction of chlorophenyl, fluorophenyl and pyridyl ring in the structure of the trypanocidal lead 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide (1). The new compounds showed reduced pKa values (in the range 1–3 pKa units) for the imidazolidine group linked to the substituted phenyl ring. In vitro activities (EC50) against wild type and resistant strains ofT. b. brucei (s427 and B48, respectively) were in the submicromolar range with four compounds being more active and selective than 1 (SI > 340). In particular, the two most potent compounds (3b and 5a) acted approximately 6-times faster than 1 to kill trypanosomes in vitro. No cross-resistance with the diamidine and melaminophenyl class of trypanocides was observed indicating that these compounds represent interesting leads for further in vivo studies.

ChemPhysChem, 16, 2226–2236 (2015)

DOI: 10.1002/cphc.201500139

Understanding the Aldo-Enediolate Tautomerism of Glycolaldehyde in Basic Aqueous Solutions

The biochemically important interconversion process between aldoses and ketoses is assumed to take place via 1,2-enediol or 1,2-enediolate intermediates, but such intermediates have never been isolated. The current work was undertaken in an attempt to detect the presence of the 1,2-enediol structure of glycolaldehyde in alkaline medium, actually a 1,2-enediolate, and to try to clarify the scarce data existing about both the formation of deprotonated enediol and the aldo-enediolate equilibrium. The Raman spectra of neutral and basic solutions were recorded as a function of time for eleven days. Several bands associated with the presence of the enediolate were observed in alkaline medium. Glycolaldehyde exists as three different structures in aqueous solution at neutral pH, that is, hydrated aldehydes, aldehydes and dimers, with a respective ratio of approximately 4:0.25:1. Additionally, the formation of Z-enediolate forms takes place at basic pH, together with an increase in the concentration of aldehyde species, such as 2-oxoethan-1-olate, and a decrease in the concentrations of the hydrated aldehyde and dimeric forms. The theoretical ratio of ≈1.5:1 for aldehyde:Z-enediolate reproduces the experimental Raman spectrum in basic medium, with an additional contribution of the previously mentioned ratio between the hydrated aldehyde and dimeric forms. Finally, Raman spectroscopy allowed us to monitor the enolization of this carbohydrate model and conclude that aldo-enediol tautomerism—formally aldo-enediolate—happens when a suitable amount of basic species is added.

Chem. Eur. J. 21, 2489-2500 (2015)


Experimental and Theoretical Studies on the Rearrangement of 2-Oxoazepane α,α-Amino Acids into 2'-Oxopiperidine β2,3,3-Amino Acids: An Example of Intramolecular Catalysis

Enantiopure β-amino acids represent interesting scaffolds for peptidomimetics, foldamers and bioactive compounds. However, the synthesis of highly substituted analogues is still a major challenge. Herein, we describe the spontaneous rearrangement of 4-carboxy-2-oxoazepane α,α-amino acids to lead to 2′-oxopiperidine-containing β2,3,3-amino acids, upon basic or acid hydrolysis of the 2-oxoazepane α,α-amino acid ester. Under acidic conditions, a totally stereoselective synthetic route has been developed. The reordering process involved the spontaneous breakdown of an amide bond, which typically requires strong conditions, and the formation of a new bond leading to the six-membered heterocycle. A quantum mechanical study was carried out to obtain insight into the remarkable ease of this rearrangement, which occurs at room temperature, either in solution or upon storage of the 4-carboxylic acid substituted 2-oxoazepane derivatives. This theoretical study suggests that the rearrangement process occurs through a concerted mechanism, in which the energy of the transition states can be lowered by the participation of a catalytic water molecule. Interestingly, it also suggested a role for the carboxylic acid at position 4 of the 2-oxoazepane ring, which facilitates this rearrangement, participating directly in the intramolecular catalysis.

PLoS ONE 9: e113841 (2014)

DOI: 10.1371/journal.pone.0113841

Adamantyl Analogues of Paracetamol as Potent Analgesic Drugs via Inhibition of TRPA1

Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.

Tetrahedon, 70, 2784-2795 (2014)


An experimental and theoretical study of the structure of Lamotrigine in its neutral and protonated forms: evidence of Lamotrigine enantiomers

The energies, geometries, and NMR chemical shifts have been calculated at the B3LYP/6-311++G(d,p) level for 17 structures of the anticonvulsant drug Lamotrigine and 29 structures of protonated Lamotrigine, including tautomers and E/Z isomers of the imino groups. The calculations were compared with solid state (X-ray and CPMAS NMR) and solution experimental results both reported in the literature and determined in this work. The conclusion is that Lamotrigine exists as the diamino tautomer and that its protonation takes place on the N2 atom. Using ABTE and/or deuterated ABTE as chiral solvating agent, it has been demonstrated for the first time by NMR in solution that Lamotrigine is a racemate of rapidly interconverting enantiomers. The crystal structure of two new solvated salts of Lamotrigine, both saccharinates, has been determined. Both salts present the same arrangement in chains of Lamotrigine and saccharinate joined by hydrogen bonds and stacking interactions. No isostructurality is present because of the different arrangement of the chains in both crystal structures.

New J. Chem., 38,529-538 (2014)

DOI: 10.1039/c3nj01076g

Carbohydrates in the gas phase: conformational preference of D-ribose and 2-deoxy-D-ribose

A full exploration of the conformational landscape of D-ribose and 2-deoxy-D-ribose monosaccharides in the gas phase has been performed using DFT methods (B3LYP and M06-2X). Open-chain, furanose and pyranose configurations have been examined. Up to 954 and 668 stable structures have been obtained for D-ribose and 2-deoxy-D-ribose. Among these structures, up to 35 and 22 have relative energies smaller than 5 kJ mol−1 with respect to the absolute minimum of each molecule, respectively. For D-ribose, pyranose in α- and β-forms is the most populated according to both functionals, the β-diastereoisomer being the most populated. For 2-deoxy-D-ribose, the α-pyranose form is in majority. The β/α relationship of pyranose forms presents different results for both functionals: for M06-2X it increases in D-ribose and decreases in 2-deoxy-D-ribose at 0 K with respect to the room temperature results, the opposite case occurring in B3LYP. Intramolecular weak interactions have been characterized using the AIM and NBO methodologies.

J. Mol. Struct. 1056-1057, 209-215 (2014)

DOI: 10.1016/j.molstruc.2013.10.040

A theoretical study of the structure and protonation of Palbociclib (PD 0332991)

The geometry, protonation and chemical shifts of the important new drug, Palbociclib (8-cyclopentyl-6-ethanoyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-d]pyrimidin-7(8H)-one), have been studied theoretically. The conclusion is that in the active site of its target enzyme, Palbociclib exists as a cation protonated on the nitrogen atom of the pyridine ring. The tautomerism of the neutral form in solution has also been determined indicating that it is a mixture of two imino tautomers in fast equilibrium.

J. Phys. Chem. B, 117, 14599–14614 (2013)

DOI: 10.1021/jp405121s

Conformational Preference and Chiroptical Response of Carbohydrates d-Ribose and 2-Deoxy-D-ribose in Aqueous and Solid Phases

This work targets the structural preferences of d-ribose and 2-deoxy-D-ribose in water solution and solid phase. A theoretical DFT (B3LYP and M06-2X) and MP2 study has been undertaken considering the five possible configurations (open-chain, α-furanose, β-furanose, α-pyranose, and β-pyranose) of these two carbohydrates with a comparison of the solvent treatment using only a continuum solvation model (PCM) and the PCM plus one explicit water molecule. In addition, experimental vibrational studies using both nonchiroptical (IR-Raman) and chiroptical (VCD) techniques have been carried out. The theoretical and experimental results show that α- and β-pyranose forms are the dominant configurations for both compounds. Moreover, it has been found that 2-deoxy-D-ribose presents a non-negligible percentage of open-chain forms in aqueous solution, while in solid phase this configuration is absent.

Struct. Chem. 24, 145-1151 (2013)


A theoretical investigation of the mechanism of formation of a simplified analog of the green fluorescent protein (GFP) from a peptide model

Theoretical calculations at the B3LYP/6-311++G(d,p) level have been carried out on the reaction path connecting a dipeptide to an imidazolinone as a model for the formation of GFP. In addition, we have studied the hydration effects on the processes, adding a water molecule to assist the cyclization. The solvent effects have been taken into account by introducing the monohydrated molecules into a solvent cavity with a polarized continuum model. Significant reductions of the energy barriers for the reaction path can be observed within the water-assisted processes. The solvent effects account for a barrier lowering of 4–5 kJ mol−1.

New J. Chem., 37, 1391-1401 (2013)

DOI: 10.1039/c3nj40921j

A silver complex of chloroquine: synthesis, characterization and structural properties

A new silver–chloroquine (CQ–Ag) complex [CQAgNO3, CQ = chloroquine, C18H26N3Cl] has been synthesized and characterized by using a combination of NMR (solution and solid-state), FTIR, molar conductivity and ESI/FT-ICR high resolution mass spectroscopy with DFT calculations. The CQ–Ag complex is formed by silver–CQ cations and nitrate counter anions, where the silver atoms are di-coordinated to chloroquines (CQ2Ag2+) through the quinoline sp2 N and diethylamino sp3 N nitrogen basic sites. These cations presumably form polymeric structures mainly as head–head catemers. The most important cationic fragments of the CQ–Ag complex, detected by ESI/FT-ICR, were CQAg+, CQ2Ag+, chloroquine singly (CQH+) and doubly protonated (CQH22+), whose formations are clearly favored by proton-displacement of the Ag+ cations.

Mol. Informat. 32, 363-376 (2013)

DOI: 10.1002/minf.201300008

Predicting pKa Values in Aqueous Solution for the Guanidine Functional Group from Gas Phase Ab Initio Bond Lengths

Here we applied a novel method to predict pKa values of the guanidine functional group, which is a notoriously difficult. This method, which was developed in our lab, uses only one ab initio bond length obtained at a low level of theory. The method is shown to work for drug molecules, delivers prediction errors of less than 0.5 log units, successfully treats tautomerisation in close relation with experiment, and demonstrates strong correlations with only a few data points. The high structural content of the ab initio bond length makes a given data set essentially divide itself into high correlation subsets. One then observes that molecules within a subset possess a common substructure. Each high correlation subset exists in its own region of chemical space. The high correlation subset method is explored with respect to this position in chemical space, in particular tautomerisation. The proposed method is able to distinguish between different tautomeric forms and the preferred tautomeric form emerges naturally, in agreement with experiment.

Carboh. Res. 372, 1-8 (2013)


Theoretical study of the mutarotation of erythrose and threose: acid catalysis

The acid catalysis of the mutarotation mechanism in the two aldotetroses, d-erythrose and d-threose, has been studied at B3LYP/6-311++G(d,p) computational level in gas phase and in solution employing the PCM–water model. The open-chain, the furanose and the connecting TS structures have been characterized. To study the enhancing effect of acid groups on the electrophilicity of the carbonyl carbon atom, four situations have been considered: (i) a classical Lewis acid as BH3; (ii) a classical hard-Pearson acid as Na+; (iii) classical Brønsted acids as H+ and H3O+; and (iv) a combined strategy using H3O+ and one bridge-H2O molecule as assistant in the proton transfer process. All the acidic groups reduce the activation energy with exception of the Na+, which can act, in some cases, as inhibitor. It is greatly reduced by the presence of Brønsted acids (iii) and through the combined strategy (iv). For this last mechanism, the electronic activation energies are between 12 and 43 kJ mol−1 in vacuum and between 13 and 25 kJ mol−1 in water solution, through the use of the PCM model.

Carbohyd. Res. 358, 96-105 (2012)

DOI: 10.1016/j.carres.2012.06.011

Conformational study of the open-chain and furanose structures of d-erythrose and d-threose

The chapter “Atropisomerism and axial chirality in heteroaromatic compounds” provides a summary of the present knowledge of this important topic. The structure of the chapter is: first a detailed description of the methods used to study atropisomerism, from X-ray diffraction to theoretical calculations (14 items), then the application to different compounds according to the nature of the central bond. Rotation about a C–C bond (5–5, 5–6 and 6–6 rings), rotation about a C–N bond (azoles, oxo- and thioxo-five-membered rings, azines), rotation about an N–N bond (5–5, 5–6 and 6–6 rings), rotation about ortho-ortho’-linked compounds, rotation about N-metal bonds, multiple rotations, to end with axial chiral synthesis. In conclusion, a phenomenon that was discovered in 1922 for diphenic acids and that was extended to heterocycles in 1931 by Adams shows eighty years later to be very active, being expected to grow in importance because it is related to asymmetric synthesis, to materials and to biological properties.

Carbohydr. Res. 346, 2933-2939 (2011)

DOI: 10.1016/j.carres.2011.10.013

Computational study of mutarotation in erythrose and threose

For the first time the mutarotation mechanism of furanose rings has been investigated, with and without solvent. The transformations from open-chain furanose to d-erythrose and d-threose have been studied at B3LYP/6-311++G(d,p) and G3MP2B3 levels, in vacuum and in solution through continuum solvation models. We studied the catalytic influence of one, two or three water molecules, as well as simplified models of carbohydrates, that is, methanol and 1,2-ethanediol. Water molecules significantly reduce the energy barrier of the hemiacetal formation occurring between the open-chain and furanose configurations. The energy barrier is optimally reduced by two water molecules. Methanol yields a smaller transition state barrier than the one obtained with a single water molecule. In contrast, 1,2-ethanediol does not provide a lower transition state compared to the barrier in the presence of two water molecules.

Arkivoc, ii, 127-147 (2010)


N-substituted-1,2,3-triazoles: synthesis, characterization and evaluation as cannabinoid ligands 

A series of new N1-, N2- and N3-substituted 1,2,3-triazole derivatives has been synthesized by cycloaddition of butyltin azide with substituted alkynes followed by a N-alkylation reaction. The regioisomers have been isolated and characterized using NMR techniques. GIAO/B3LYP calculations of the absolute shieldings have been performed to verify the assignments and so the structures have been unequivocally identified. The proportion in which the three isomers are obtained corresponds with the relative order of stability indicated by the energy values calculated at the B3LYP level.  CB1 cannabinoid receptor binding assays have been performed but none of the compounds showed significant activity

Eur. J. Med. Chem. 44, 1864-1869 (2009)

Doi: 10.1016/j.ejmech.2008.10.037

The structure of Rimonabant in the solid state and in solution: An experimental and theoretical study

The X-ray molecular structure of Rimonabant methanol solvate has been determined together with the 1H, 13C and 15N NMR spectra in acetone solution. B3LYP / 6-311++G(d,p) calculations have been performed out to determine two minimum energy conformations, on these geometries GIAO calculations were carried out to obtain the corresponding absolute shieldings that were compared with the experimental chemical shifts.

J. Mol. Struct. 920, 82-89 (2009)

Doi: 10.1016/j.molstruc.2008.10.020

Structural study of diarylazoles related to Rimonabant

The structures of three diarylazoles (two pyrazoles and one 1,2,4-triazole) related to Rimonabant have been determined by X-ray crystallography. The conformation of both aryl groups in the new structures is discussed with regard to other related compounds reported in the Cambridge Structural Database. The secondary structure of the three compounds is very different. Compound 2 forms a helix, compound 3 forms a structure with the hydrocarbon layers parallel and compound 4 crystallizes forming a double chain. In the solid state, the conformation of both aryl groups, the N-aryl and the C-aryl, was compared with similar compounds reported in the literature. GIAO calculations afford absolute shieldings that were compared with experimental chemical shifts.

Chem. Phys. Lett. 412, 97-100 (2005)

Doi: 10.1016/j.cplett.2005.06.104

A theoretical investigation of N–H⋯O═P hydrogen bonds through15N–31P and 1H–31P coupling constants

The Fermi contact terms corresponding to 3hJNP and 2hJHP for complexes involving N–H⋯O–P hydrogen bonds have been calculated at the EOM-CCSD level of theory. The N–H donors in these complexes are urea or two hydrogen isocyanide molecules, and the proton acceptor is . Experimentally measurable3hJNP values are predicted only for linear or nearly linear N–H⋯O═P hydrogen bonds. Computed 2hJHPvalues appear to be too small to detect the presence of these hydrogen bonds.

Org. Biomol. Chem., 3 , 366-371 (2005)

Doi: 10.1039/b415768k

Modelling protein-RNA interactions: an electron density study of the guanidinium and formate complexes with RNA bases 

The complexes formed by the double interaction established between RNA bases and guanidinium and formate ions, as a model for the interacting groups of arginine and glutamic or aspartic amino acid side chains, have been theoretically studied. A density functional theory method (B3LYP/6-31 + G**) has been used for this study. The range of interaction energies obtained allowed for a distinction between bidentate and bifurcate hydrogen bond interactions. The analysis of the electron density and the natural bond orbital analysis shows that these complexes are bound by double hydrogen bonds established between the donor and acceptor groups of guanidinium and formate respectively and those of the RNA bases. Comparisons are made with the results obtained in some previous theoretical and experimental studies.

Mag. Res. Chem. 42,712-714 (2004)

DOI: 10.1002/mrc.1409

The tautomerism of Omeprazole in solution: a 1H and 13C NMR study

The tautomerism of 5(6)-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinyl}-1H-benzimidazole (omeprazole) was determined in solution, KT = 0.59 in THF at 195 K, in favor of the 6-methoxy tautomer. The assignment of the signals was made by comparison with its two N-methyl derivatives in acetone-d6 and through theoretical calculations of the absolute shieldings (GIAO/DFT/6-311++G**).

Theochem 680, 191-198 (2004)


Theoretical study of peptide model dimers. Homo versus heterochiral complexes

The study of possible chiral recognition of a series of peptide models (For-Gly-NH2, For-Ala-NH2 and four of their fluoro substituted derivatives) has been carried out by means of DFT calculations. Homo (L,L) and heterochiral (L,D) dimers formed by hydrogen bond (HB) complexation have been considered. Initially, the conformational preferences of the monomers have been calculated and used to generate all the possible homo and heterochiral dimers. The energetic results show that in most cases, the β monomers are the most stable while in the dimers, the γ–γ complexes show the strongest interaction energies. In three of the four chiral cases studied, a heterochiral dimer is the most stable one. In addition, the electron density and nuclear shielding of the complexes have been studied.

J. Med. Chem. 47, 2939-2942 (2004)

Doi: 10.1021/jm031099y

Discovery of 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole, a Novel in Vivo Cannabinoid Antagonist Containing a 1,2,4-Triazole Motif

A new series of 1,2,4-triazoles have been prepared and the evaluation of their cannabinoid properties have been carried out. Compound 8 showed cannabinoid silent antagonist activity in mouse vas deferens and guinea pig ileum preparations and in vivo assays (cannabinoid tetrad) in mouse. It did not have intrinsic activity in these bioassays, and therefore, it did not behave as a partial agonist or an inverse agonist.

J. Phys. Chem. B 108, 3335-3341 (2004)

Doi: 10.1021/jp036901m

Modelling Protein-RNA interactions: An electron density study of the formamide and formic acid complexes with RNA Bases

The complexes formed by the double interaction established between the four RNA bases (adenine, cytosine, guanidine, and uracil) and formamide and formic acid as a model for the interacting groups of certain amino acid side chains have been theoretically studied. Density functional theory (B3LYP/6-31+G**) methods have been used for this study. The interaction energies obtained range between 10 and 19 kcal mol-1. The analysis of the electron density and the natural bond orbital analysis show that these complexes are bound by medium strength double hydrogen bonds established between the donor and acceptor groups of formamide and formic acid and those of the RNA bases. Comparisons are made with the results obtained in some experimental studies and the analysis of protein−RNA interactions databases.

ARKIVOC (xiv) 31-36 (2003)


Hydrogen bond acceptor properties of two radicals: nitric oxide molecule and hydrogen atom 

Two very significant, although for different reasons, radicals NO. and H. have been examined theoretically as hydrogen bond acceptors (HBA). Two acids have been studied as hydrogen bond donors (HBD), hydrogen fluoride and ammonium. Nitrogen oxide should be a nitrogen base towards both neutral and cationic acids as HBD. Atomic hydrogen, although a much weaker hydrogen-bonded base, should form stable complexes with the ammonium cation. A conclusion of this work is that DFT methods only work acceptably well for relatively strong HBs.

J. Phys. Chem. B, 107, 5306 -5310, (2003)

DOI: 10.1021/jp027662q

Interaction of Protein Backbone with Nucleic Acid Bases

A theoretical study of the hydrogen-bonded (HB) complexes between a protein model and nucleic acid bases (NAB) has been carried out. As protein models, N-formylglycinamide (For-Gly-NH2, 2-formylaminoacetamide), 1, in beta- and gamma-conformations and as NABs, the isolated ones, and the AU, GC dimers in the Watson-Crick (WC) disposition have been considered. Only those dispositions with a double HB between the protein model and the nucleic acid bases have been studied. The aromatic CH groups of the nucleic acids have been included as HB donor. The results indicate that the strongest HBs between the individual NAB and the protein models involve the atoms that participate in the formation of the WC dimers. In the trimeric complexes, no significant preference is obtained for the 1-AU trimers studied while in the 1-GC ones the complex where formylglycinamide interacts simultaneously with the carbonyl group of guanine and the amino of cytosine is favored. The electron density of the complexes has been analyzed using the atoms in molecules methodology, finding exponential relationships between the electron density and its Laplacian vs the bond distance. Finally, the effect in the nuclear chemical shielding due to the complexation has been explored. Exponential relationships have been found for the variation of the chemical shift of the 1H signal for the NH···O and NH···N interactions with the HB distance.

J. Phys. Chem. B, 107, 323-330(2003)

DOI: 10.1021/jp026684+

DNA Triplexes: A Study of Their Hydrogen Bonds

Since their discovery, DNA triplexes have received a large amount of interest because of their potential as viable strategy for control of gene expression and their formation with some specific drugs. For that reason, we have studied, by means of ab initio calculations, the structure of the bases of these DNA triplexes in terms of their interaction energies and electron densities for the different hydrogen bonds, which is one of the interactions that determine the structure and dynamics of nucleic acid molecules. A good agreement has been found with experimental results and previous calculations. In general, when a third base is added to a dimer, the strength of the hydrogen bonds of the dimer becomes modified provoking changes in their structures by increasing the distance in the major groove and decreasing the space in the minor groove.

Chem. Pharm. Bull., 51, 929-934 (2003)


Fentanyl and Its Analogue N-(1-Phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl] propanamide: 1H- and 13C-NMR Spectroscopy, X-Ray Crystallography, and Theoretical Calculations.

The oxalate salts and free bases of fentanyl and N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide, a new lead compound for long-acting analgesia, have been characterized by 1H- and 13C-NMR spectroscopy. The crystal structure of the hydrochloride of N-[1-(2-phenylethyl)-4-piperidyl]-N-(1-phenyl-4-pyrazolyl)propanamide monohydrate has been determined. Two centrosymmetrically related cations, joined through C(phenyl)-H…π contacts, encapsulate a large void that contains pairs of anions and bridged water molecules into a zero-dimensional (0D) supramolecular motif. The cations are linked to this framework via N+H…Cl contacts. GIAO/B3LYP calculations have been carried out to compare the experimental 13C chemical shifts with the absolute shieldings thus calculated. The protonation of both molecules takes place on the piperidine ring (axial protonation), as has been verified both in the solid state (X-ray) and in solution (NMR).

J. Am. Chem. Soc. 124, 6393-6397 (2002)

DOI: 10.1021/ja011755o

3hJ(15N-31P) Spin-Spin Coupling Constants across N-H···O-P Hydrogen Bonds 

Equation-of-motion coupled cluster singles and doubles (EOM-CCSD) calculations have been performed to evaluate three-bond 15N−31P coupling constants (3hJN-P) across N−H···O−P hydrogen bonds in model cationic and anionic complexes including NH4+:OPH, NH4+:OPH3, NH3:-O2PH2, NFH2:-O2PH2, and NF2H:-O2PH2. Three-bond coupling constants can be appreciable when the phosphorus is P(V), but are negligible with P(III). 3hJN-P values in complexes with cyclic or open structures are less than 1 Hz, a consequence of the nonlinear arrangement of N, H, O, and P atoms. For complexes with these structures, 3hJN-P may not be experimentally measurable. In contrast, complexes in which the N, H, O, and P atoms are collinear or nearly collinear have larger values of 3hJN-P, even though the N−P distances are longer than N−P distances in cyclic and open structures. In linear complexes, 3hJN-P is dominated by the Fermi-contact term, which is distance dependent. Therefore, N−P (and hydrogen-bonding N−O) distances in these complexes can be determined from experimentally measured 15N−31P coupling constants.

J. Chem. Soc., Perkin Trans. 2, 894 - 898 (2002)

DOI: 10.1039/B200915N 

Interaction of adenine with synthetic receptors: a theoretical study

The interaction of adenine with synthetic macrocyclic receptors has been modelled using, as simplified molecular systems, the monoamide derivatives of pyridine and 1,8-naphthyridine. DFT methods (B3LYP/6-31+G**) have been used to characterise the complexes stabilised by multiple hydrogen bonds. The theoretical results indicate that while the synthetic receptors with pyridines can interact simultaneously forming pseudo-Watson–Crick and pseudo-Hoogsten complexes with adenine, in the case of the 1,8-naphthyridines only one of the complexes is possible. The energetic results that favour the pyridine receptors are in agreement with the experimental binding constants.

J. Am. Chem. Soc., 123, 7898-7906 (2001).

DOI: 10.1021/ja002688l

A Solid-State NMR, X-ray Diffraction, and ab Initio Computational Study of Hydrogen-Bond Structure and Dynamics of Pyrazole-4-Carboxylic Acid Chains

Using high-resolution solid-state 15N CMAS NMR, X-ray crystallography, and ab initio calculations, we have studied the structure of solid pyrazole-4-carboxylic acid (1). The crystal structure was determined at 295 and 150 K. Molecules of 1 are located on a two-fold axis, implying proton disorder of the NH and OH groups; no phase transition was observed between these two temperatures. The compound forms quasi-linear ribbons in which the molecules are linked by cyclic hydrogen bonds between pyrazole and carboxylic acid groups with disordered hydrogen-bonded protons. Crystallography is unable to decide whether the disorder is dynamic or static. NMR shows that this disorder is dynamic, that is, consisting of very fast degenerate double proton transfers between two rapidly interconverting O−H···N and O···H−N hydrogen bridges. However, at low temperature, NMR shows a proton disorder−order transition where the protons are preferentially localized on given nitrogen and oxygen atoms. An amorphous phase exhibiting proton order is observed when the compound is precipitated rapidly. In this case, the defects are annealed by moderate heating. Ab initio calculations performed on oligomers of 1 show that the O−H···N hydrogen bridge is about 0.064 Å shorter and less bent (∼171°) than the O···H−N hydrogen bridge (∼150°). For an isolated ribbon, this result leads to structures with localized protons, either to a cycle with about 200 molecules, or to a quasi-linear ribbon involving an undulated structure, or to a combination of both motifs. Only the undulated structure is compatible with the linear ribbon observed by X-ray crystallography, where the fast proton transfer in the high-temperature phase is assisted by the motions of the undulated chain. A disordered structure is assigned to the amorphous phase, which exhibits the combination of the curved and the undulated motifs.

Angew. Chem. Int. Ed. 39,717-721 (2000)


Also: Angew. Chem., 112, 733-737 (2000)

Water Clusters: Towards an Understanding Based on First Principles of Their Static and Dynamic Properties

At the molecular – supramolecular border lie water clusters. Such molecular water clusters, Wi, fori=2 to i=10, have been used to discuss some fundamental problems, such as the covalent nature of hydrogen bonds, the properties of bulk water, and their conformations. The picture represents some examples of W8.

J. Chem. Soc. Perkin II, 2671-2675 (1998)

DOI: 10.1039/A804677H

A computational approach to intermolecular proton transfer in the solid state: assistance by proton acceptor molecules

Ab initio (B3LYP/6-311++G**) calculations have been carried out on the proton transfer of 2H-tetrazole and 5-phenyl-2H-tetrazole with and without the assistance of different nitrogen bases (hydrogen cyanide, ammonia and imidazole). In the absence of base, the proton transfer barrier amounts to 210 kJ mol–1 while in the presence of ammonia it is lowered to 119 kJ mol–1. Moreover, the inclusion of a solvent cavity of the Onsager type, which increases the first barrier, decreases the second one to 67 kJ mol–1 (for ε = 5) which is consistent with experimental data for irbesartan (a 5-aryl-2H-tetrazole derivative).

New. J. Chem., 20,1081-1086 (1996)

DOI:No available

Hexadeca(pyrazol-1-yl)phthalocyanine: A Soluble Phthalocanine Absorbing at 780 nm.

Hexadeca(pyrazol-1-yl)phthalocyanine, a phthalocya-nine bearing in its periphery 16 pyrazole residues has been prepared in two steps from 3,4,5,6-tetrafluoro-1,2-dicyanobenzene in 90% yield. The crystal and molecular structure of 3,4,5,6-tetra(pyrazol-1-yl)-1,2-dicyanobenzene intermediate has been determined: triclinic P-1, a = 11.6632(5), b = 11.2553(7), c = 8.7338(4) , a = 110.893(4), b = 104.709(4), g = 60.608(4), V = 928.86(9) 3, Z = 2, R(F) = 0.037 and Rw(F) = 0.045. The new phthalocyanine is soluble in organic solvents and has an absorption band at 780 nm in ethanol 95. Semiempirical AM1 calculations have been carried on 3,4,5,6-tetrafluoro-1,2-dicyanobenzene and several (pyrrol-1-yl and pyrazol-1-yl)phthalocyanines.

Rev. Acad. Ciencias, 84, 183-188 (1990)

DOI: Not available

Modelizacion Molecular: Ejemplos de aplicación.

In recent years, the use of computer aided molecular modelling has expanded considerably. Althoigh its greatest impact has probably been in the field of drug design, this technique can be applied to many areas of chemistry. The basis equipment consisting of a relatively powerful computer, a graphics terminal and standard modelling software enables the chemist to build 3-D models of chemical structures, calculate a wide range of molecular properties and to study molecular interactions. In order to illustrate the versatility of this research tool, two different aplication of the molecular modelling program Chem X are described. One refers to the study of the conformation-activity relationship in hexapeptides related to substance P showing similar biological activities, and the other deals with energy calculations and computer modelling of chromatographic separations on microcrystalline cellulose triacetate.