Base pairs with 5-chloroorotic acid and comparison with the natural nucleobase. Structural and spectroscopic study, and three suggested antiviral modified nucleosides.

A structural and spectroscopic study of 5-chloroorotic acid (5-ClOA) biomolecule was carried out by IR and FT-Raman and the results obtained were compared to those achieved in 5-fluoroorotic acid and 5-aminoorotic acid compounds. The structures of all possible tautomeric forms were determined using DFT and MP2 methods. To know the tautomer form present in the solid state, the crystal unit cell was optimized through dimer and tetramer forms in several tautomeric forms. The keto form was confirmed through an accurate assignment of all the bands. For this purpose, an additional improvement in the theoretical spectra was carried out using linear scaling equations (LSE) and polynomic equations (PSE) deduced from uracil molecule. Base pairs with uracil, thymine and cytosine nucleobases were optimized and compared to the natural Watson-Crick (WC) pairs. The counterpoise (CP) corrected interaction energies of the base pairs were also calculated. Three nucleosides were optimized based on 5-ClOA as nucleobase, and their corresponding WC pairs with adenosine. These modified nucleosides were inserted in DNA:DNA and RNA:RNA microhelices, which were optimized. The position of the -COOH group in the uracil ring of these microhelices interrupts the DNA/RNA helix formation. Because of the special characteristic of these molecules they can be used as antiviral drugs.Communicated by Ramaswamy H. Sarma.

Base pairs with 4-amino-3-nitrobenzonitrile: comparison with the natural WC pairs. Dimer and tetramer forms, Infrared and Raman spectra, and several proposed antiviral modified nucleosides.

Base pairs of 4-amino-3-nitrobenzonitrile (4A-3NBN) molecule with uracil, thymine and cytosine nucleobases were optimized and compared to natural Watson-Crick (WC) pairs. The slightly greater flexibility of the -NO2 group of 4A-3NBN than the N3-H group of the natural nucleobases together with a noticeable higher dipole moment of its pairs can facilitate disruption of the DNA/RNA helix formation. Several new mutagenic modified nucleosides with 4A-3NBN and 3-amino-2-nitrobenzonitrile (3A-2NBN) were proposed as antiviral prodrugs and their base pairs optimized. The special characteristics of these prodrugs appear appropriated for their clinical use. The counterpoise (CP) corrected interaction energies of the base pairs were calculated and compared to the natural ones. The M06-2X DFT method was used for this purpose. The molecular structure of 4A-3NBN was analyzed in detail and the crystal unit cell was simulated by a tetramer form and eight dimer forms. The performance of the B3LYP, X3LYP and M06-2X methods was tested on the vibrational wavenumbers in the monomer, dimer and tetramer forms of 4A-3NBN. The observed IR and Raman bands were assigned according to the optimum dimer II form determined by B3LYP and by the tetramer form calculated by M06-2X, which is the expected unit cell that forms the crystal net. The two best scaling procedures were used.Communicated by Ramaswamy H. Sarma.

Effect of bromine atom on the different tautomeric forms of microhydrated 5-bromouracil, in the DNA:RNA microhelix and in the interaction with human proteins.

This study focuses on the effects of the bromine atom on the molecular structure parameters in the main tautomeric forms of 5-bromouracil (5BrU), and as well, its effect on hydration and on the Watson-Crick (WC) pairs as compared to uracil molecule. The influence of the bromine atom was studied in several environments. The hydration effect on the molecular structure and energies of the main tautomeric forms of 5BrU was analyzed by considering a variable number of water molecules in explicit form up to 30 to simulate the first and second hydration shells. The 'mutagenic' 2-hydroxy-4-oxo (U2) enol tautomer of 5BrU, but not of uracil, was absolutely favored over the keto form in clusters with more than 20 water molecules. For all calculations, B3LYP and M06-2X Methods were used. The effect of the bromine atom when it was inserted into the natural and reverse WC pairs uridine-adenosine was also determined, and counterpoise (CP) corrected interaction energies were calculated. The effect of the bromine atom was analyzed in several DNA:RNA hybrid microhelices. Different backbone and helical parameters were calculated and compared. The bromine atom destabilizes its base pair, with a remarkable increase in the rise parameter (Dz) corresponding to the microhelix, and to a slight increase in the diameter (d). Molecular docking calculations were also carried out with 5BrU for targeted proteins associated with diabetes, hepatocellular carcinoma and breast and lung cancers. The molecular docking analysis confirms that the 5BrU molecule may play an important role as a promising inhibitor against breast cancer.Communicated by Ramaswamy H. Sarma.

Biomolecules of 2-Thiouracil, 4-Thiouracil and 2,4-Dithiouracil: A DFT Study of the Hydration, Molecular Docking and Effect in DNA:RNAMicrohelixes.

The molecular structure of 2-thiouracil, 4-thiouracil and 2,4-dithiouracil was analyzed under the effect of the first and second hydration shell by using the B3LYP density functional (DFT) method, and the results were compared to those obtained for the uracil molecule. A slight difference in the water distribution appears in these molecules. On the hydration of these molecules several trends in bond lengths and atomic charges were established. The ring in uracil molecule appears easier to be deformed and adapted to different environments as compared to that when it is thio-substituted. Molecular docking calculations of 2-thiouracil against three different pathogens: Bacillus subtilis, Escherichia coli and Candida albicans were carried out. Docking calculations of 2,4-dithiouracil ligand with various targeted proteins were also performed. Different DNA: RNA hybrid microhelixes with uridine, 2-thiouridine, 4-thiouridine and 2,4-dithiouridine nucleosides were optimized in a simple model with three nucleotide base pairs. Two main types of microhelixes were analyzed in detail depending on the intramolecular H-bond of the 2'-OH group. The weaker Watson-Crick (WC) base pair formed with thio-substituted uracil than with unsubstituted ones slightly deforms the helical and backbone parameters, especially with 2,4-dithiouridine. However, the thio-substitution significantly increases the dipole moment of the A-type microhelixes, as well as the rise and propeller twist parameters.

FT-IR and FT-Raman spectra of 5-chlorocytosine: Solid state simulation and tautomerism. Effect of the chlorine substitution in the Watson-Crick base pair 5-chlorodeoxycytidine-deoxyguanosine.

The laser Raman and IR spectra of 5-chlorocytosine have been recorded and accurately assigned in the solid state using Density functional calculations (DFT) together with the linear scaling equation procedure (LSE) and the solid state simulation of the crystal unit cell through a tetramer form. These results remarkably improve those reported previously by other authors. Several new scaling equations were proposed to be used in related molecules. The six main tautomers of the biomolecule 5-chlorocytosine were determined and optimized at the MP2 and CCSD levels, using different basis sets. The relative stabilities were compared with those obtained in cytosine and their 5-halo derivatives. Several relationships between energies, geometric parameters and NBO atomic charges were established. The effect of the chlorine substitution in the fifth position was evaluated through the stability of the Watson-Crick (WC) base pair of 5-chlorodeoxycytidine with deoxyguanosine, and through their vibrational spectra.

Effect of the sulphur atom on geometry and spectra of the biomolecule 2-thiouracil and in the WC base pair 2-thiouridine-adenosine. Influence of water in the first hydration shell.

The effect of the sulphur atom on 2-thiouracil (2TU) and 2-thiouridine molecules, as compared with uracil and uridine molecules, respectively, was carried out in several environments. The predicted IR spectrum of 2TU in the isolated state was compared with that obtained for uracil molecule and with those reported experimentally in matrix isolation. Its crystal unit cell in the solid state was simulated through a tetramer form using DFT methods for the first time. The calculated Raman spectrum was compared to the experimental ones in the solid state. A linear scaling procedure was used for this task. The first hydration shell was simulated by explicit number of water molecules surrounding 2TU up to 30 and was compared with that obtained in uracil molecule. Water molecules 'distributed' around 2TU was preferred over that 'clustering', because it can better reproduce the hydration and their effects on different parameters of the molecular structure of 2TU and uracil. The total atomic charges and several calculated thermodynamic parameters were discussed. The effect of the sulphur atom on the Watson-Crick (WC) and reverse WC base pair uridine-adenosine was estimated, and the CP corrected interaction energies were calculated. 2-thiouridine has a weaker WC pair than that with uridine, although its slight higher dipole moment (µ) facilitates the interaction with the water molecules. Several helical parameters were determined.

FT-IR and FT-Raman spectra, MEP and HOMO-LUMO of 2,5-dichlorobenzonitrile: DFT study.

The experimental FT-IR and FT-Raman spectra of 2,5-dichlorobenzonitrile molecule were recorded at room temperature, and the results compared with quantum chemical theoretical values using MP2 and DFT methods. Molecular geometry, vibrational wavenumbers and thermodynamic parameters were calculated. With the help of specific scaling procedures for the computed wavenumbers, the experimentally observed FTIR and FT-Raman bands were analyzed and assigned to different normal modes of the molecule. Most of the modes have wavenumbers in the expected range and the error obtained was in general very low. Several general conclusions were deduced. The NBO analysis has been done and Molecular Electrostatic Potential (MEP) has been plotted.

Conformational analysis of the anti-HIV Nikavir prodrug: comparisons with AZT and Thymidine, and establishment of structure-activity relationships/tendencies in other 6'-derivatives.

A comprehensive theoretical conformational analysis of the anti-HIV Nikavir prodrug was carried out; this prodrug has noticeable advantage over the approved drug AZT. The whole conformational parameters (χ, α, ß, γ, δ, ϕ, P and νmax) were analysed as well as the NBO natural atomic charges. The calculations were carried out by means of DFT/B3LYP and ab initio MP2 methods with full relaxation of all geometrical parameters. The search located at least 67 stable structures, 4 of which were within a 1 kcal/mol electronic energy range of the global minimum. By MP2 it corresponds to the calculated values of the exocyclic torsional angles χ=-108.0°, ß=14.5°, γ=76.7° and ε=71.5°. The results obtained are in accordance to those found in related anti-HIV nucleoside analogues. Comparisons of the conformers with those determined in the common anti-HIV drug AZT were carried out. A detailed analysis of the lowest vibrations (<200 cm(-1)) in the best conformer of Nikavir was carried out. The most stable hydrated cluster of this conformer with 20 explicit water molecules was determined. Calculations in five of its 6'-derivatives were performed to identify structural trends that might correlate with the anti-HIV activity of these compounds. Ten structure-activity relationships/tendencies were established that can help for the design of new drugs. Several recommendations for this design were expressed.

Structure and conformational analysis of the anti-HIV reverse transcriptase inhibitor AZT using MP2 and DFT methods. Differences with the natural nucleoside thymidine. Simulation of the 1st phosphorylation step with ATP.

A comprehensive quantum-chemical investigation of the conformational landscape of the HIV-1 reverse transcriptase inhibitor AZT (3'-azido-3'-deoxythymidine) nucleoside analogue was carried out. The whole conformational parameters (χ, γ, ß, δ, ϕ, P, νmax) were analysed as well as the NBO charges. The search located at least 55 stable structures, 9 of which were by MP2 within a 1 kcal mol(-1) electronic energy range of the global minimum. Most conformers were anti or high-anti around the glycoside bond and with North sugar ring puckering angles. The distribution of all the conformers according to the ranges of stability of the characteristic torsional angles was established. The results obtained were in accordance with those found in related anti-HIV nucleoside analogues. The best conformer in the anti form corresponded to the calculated values by MP2 of χ = -126.9°, ß = 176.4° and γ = 49.1°. An analysis of the lowest vibrations in conformer C1 was carried out. The first hydration shell was simulated and the structural differences with the natural nucleoside deoxythymidine (dT) were determined. The first phosphorylation step was simulated by interacting ATP with the best hydrated clusters of AZT and dT. The Na cations act as a bridge between the phosphate moieties of ATP making it easy for -P3O3 to receive the H5' proton from AZT or dT. A proton-transfer mechanism is proposed through the water molecules. When the number of the water molecules surrounding AZT is lower than 8, the first phosphorylation step of AZT can be carried out. However, the appropriate orientation of the O5'-H in dT avoids this limitation and it can be performed with large numbers of water molecules.

FT-IR and FT-Raman spectra of 5-fluoroorotic acid with solid state simulation by DFT methods.

FT-Raman and FT-IR studies of the biomolecule 5-fluoroorotic acid in the solid state were carried out. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify wavenumber assignments of the experimental observed bands in the spectra. Correlations with the molecule of uracil were made, and specific scale equations were employed to scale the wavenumbers of 5-fluoroorotic acid. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of the bands. This fact confirms our simplified solid state model. The molecular structure was fully optimized using DFT and MP2 methods. The relative stability of both the syn and anti conformations was investigated, and the anti-form was found to be slightly more stable, by 7.49 kJ/mol at the MP2 level. The structures of all possible tautomeric forms were determined. The keto-form appeared as the most stable one. The NBO atomic charges and several thermodynamic parameters were also calculated.

FT-IR and FT-Raman spectra of 6-chlorouracil: molecular structure, tautomerism and solid state simulation. A comparison between 5-chlorouracil and 6-chlorouracil.

A Raman and IR study of the biomolecule 6-chlorouracil was carried out in the solid state. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. Specific scale factors and scaling equations deduced from uracil molecule were employed in the predicted wavenumbers of 6-chlorouracil. The scaled wavenumbers were used in the reassignment of the IR and Raman experimental bands. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. A comparison between the molecular structure and charge distribution of 6-chlorouracil and 5-chlorouracil molecules was presented. The effect of the hydration with the PCM model in the molecular structure and charges was discussed. The optimum tautomers of 6-chlorouracil were optimized and analyzed. Six of them were related to those of uracil molecule. The effect of the halogen substitution in the sixth position of the pyrimidine ring in the stability of the different tautomers was evaluated. HOMO and LUMO orbital energy analysis were carried out.

FT-IR, FT-Raman spectra and other molecular properties of 2,4- dichlorobenzonitrile: a interpretation by a DFT study.

FT-IR and FT-Raman spectra of 2,4-dichlorobenzonitrile at room temperature have been recorded in the regions 200-3500cm(-)(1) and 0-3400cm(-)(1), respectively. The observed vibrational bands were analyzed and assigned to different normal modes of the molecule according to the Wilson's notation. Density functional calculations were performed to support our frequency assignments. Specific scale equations deduced from the benzene molecule were employed to improve the calculated values. For the majority of the normal modes, the deviations between the corresponding experimental and scaled theoretical wavenumbers are located in the expected range. A correct characterization of each normal mode is of vital importance in the assignment of the observed bands, and the same has been successfully done by the aid of Potential Energy Distributions (PEDs) calculated separately for each normal mode of 2,4-dichlorobenzonitrile. The molecular structure was optimized and several thermodynamic parameters were determined. HOMO and LUMO orbital energy analysis were carried out.

Molecular structure differences between the antiviral Nucleoside Analogue 5-iodo-2'-deoxyuridine and the natural nucleoside 2'-deoxythymidine using MP2 and DFT methods: conformational analysis, crystal simulations, DNA pairs and possible behaviour.

5-iodo-2'-deoxyuridine Nucleoside Analogue (IUdR) was the first selective antiviral nucleoside against herpes simplex virus type 1 and 2, and it was also a meaningful anticancer drug. Within a full study of this drug and its possible behaviour, previously, a comprehensive theoretical conformational analysis by MP2 and B3LYP was carried out, and all the possible stable structures were determined with full relaxation of all geometrical parameters. The search located 45 stable structures, and in all them, the whole conformational parameters ([Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], P, [Formula: see text]max) were analyzed as well as the NBO natural atomic charges. Comparisons of the conformers with those of the natural Nucleoside 2'-deoxythymidine (dT) were carried out, and the main differences between IUdR and dT were analyzed. The accuracy of the methods used was probed with the simulation of the X-ray crystal data by a tetramer form. Watson-Crick (WC) IUdR/dT···2'-deoxyadenosine pairs were analyzed for the first time using quantum chemical calculations, as well as the mispairing IUdR/dT···2'-deoxyguanosine. As result, it is observed that IUdR give rises to a slightly stronger WC pair and weaker mispairing than those with dT, therefore deforming slightly the DNA axis and difficulting the growth of the DNA virus and consequently, killing it.

FT-IR, FT-Raman spectra and other molecular properties of 3,5-dichlorobenzonitrile: a DFT study.

The IR and Raman spectra of 3,5-dichlorobenzonitrile (3,5-DCBN) molecule were recorded at room temperature and then the assignment of the observed fundamental bands were achieved by the aid of the theoretical vibrational spectral data obtained from a quantum chemical study carried out for the free molecule case. In the calculations performed to determine the molecular geometry, vibrational spectral data and thermodynamic parameters, Møller-Plesset second order perturbation theory (MP2) and hybrid Density Functional Theory (DFT) types of electronic structure methods, B3LYP and B3PW91, were used. The overestimations of the calculated harmonic wavenumbers were efficiently corrected by the aid of a specific scaling procedure. This empirical scaling process significantly increased the reliability of our assignments and analyses on the observed bands due to different vibrational normal modes of the molecule. For the majority of the normal modes, the deviations between the corresponding experimental and scaled theoretical wavenumbers have located in the expected range. A correct characterization of the normal modes is of vital importance in the assignment of the observed bands, and this was successfully done by the aid of the Potential Energy Distributions (PEDs) separately calculated for each normal mode of 3,5-DCBN.

Vibrational spectral investigations and density functional theory study of 4-Formylbenzoic acid.

An accurate assignment of the vibrational spectra of 4-Formylbenzoic acid in solid state was carried out. For this purpose density functional calculations (DFT) were performed to clarify wavenumber assignments of the experimentally observed bands for the first time. A scaling of the wavenumbers was carried out to improve the calculated values. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. The NBO analysis was carried out, and it reveals hyper conjugative interaction, ICT and stabilization of molecules.

The biomolecule of 5-bromocytosine: FT-IR and FT-Raman spectra and DFT calculations. Identification of the tautomers in the isolated state and simulation the spectra in the solid state.

An accurate assignment of the IR spectrum in Ar matrix of 5-bromocytosine and of the IR and Raman spectra in the solid state was carried out. For this purpose Density functional calculations (DFTs) were performed to clarify wavenumber assignments of the experimental observed bands. The calculated values were scaled using scaling equations and they were compared with IR and Raman experimental data. Good reproduction of the experimental wavenumbers is obtained and the% error is very small in the majority of cases. In the isolated state all the tautomer forms of 5-bromocytosine were determined and optimized. The wavenumbers corresponding to C1 and C2b tautomers were identified and assigned in the IR experimental spectrum reported in Ar matrix. Our study confirms the existence of at least two tautomers, the amino-oxo and the amino-hydroxy in the isolated state. In the solid state the FT-IR and FT-Raman spectra of 5-bromocytosine in the powder form were recorded in the region 400-4000 cm(-1) and 50-3500 cm(-1), respectively. The unit cell found in the crystal was simulated as a tetramer form in three tautomers. Thus, it has been possible to assign all the 33 normal modes of vibration. The study indicates that the features, that are the characteristic of the vibrational spectra of cytosine, are retained by the spectra of 5-bromocytosine and it exists in the solid phase in the amino-oxo form.

Simulation of a tetramer form of 5-chlorouracil: the vibrational spectra and molecular structure in the isolated and in the solid state by using DFT calculations.

A Raman and FT-IR study of the biomolecule 5-chlorouracil in the solid state was carried out. The unit cell found in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify the assignments of the experimentally observed bands in the spectra. Calculations in the monomer form and comparisons with the experimental data in Ar matrix were also carried out. The error in the calculated frequencies was analyzed and reduced by using scaling equations and scaling factors deduced from the uracil molecule. The calculations with the B3LYP method and with the 6-31G(d,p) and 6-311+G(2d,p) basis set, appear in general to be useful, when combining with a scaling equation procedure or with the specific scale factors, for interpretation of the general features of the IR and Raman spectra. The scaled values were used in the reassignment of the IR and Raman experimental bands. Comparison of the results with those determined in uracil and 5-halogenated derivatives were performed. The substitution at 5-position of the uracil ring by a chlorine atom has a little effect on the geometric parameters.

2-Amino-3,5-dichlorobenzonitrile: DFT calculations in the monomer and dimer forms, FT-IR and FT-Raman spectra, molecular geometry, atomic charges and thermodynamical parameters.

The experimental IR and Raman spectra of 2-amino-3,5-dichlorobenzonitrile molecule were recorded, and the results compared with theoretical values. Molecular geometry, vibrational wavenumbers and thermodynamic parameters were calculated using MP2 and DFT quantum chemical methods. With the help of specific scaling procedures for the computed wavenumbers, the experimentally observed FTIR and FT-Raman bands were analyzed and assigned to different normal modes of vibrations of the molecule. Simulations in the dimer form were carried out to improve the assignment of the bands in the solid state experimental spectra. The error obtained was in general very low. Using PED's were determined the contributions of the different modes to each wavenumber. Several general conclusions were also deduced.

Solid state simulation of tetramer form of 5-aminoorotic acid: the vibrational spectra and molecular structure study by using MP2 and DFT calculations.

The Raman and IR spectra of the biomolecule 5-aminoorotic acid in the solid state were simulated by a dimer and tetramer forms, with the special interest in the interactions that involve the NH and NH(2) groups. The unit cell expected in the crystal was simulated as a tetramer form by density functional calculations. They were performed to clarify wavenumber assignments of the experimentally observed bands in the spectra. Correlations with the molecule of uracil were made, and accurate scaling procedures deduced by us were employed in the calculated wavenumbers of 5-aminoorotic acid. Good reproduction of the experimental wavenumbers is obtained and the % error is very small in the majority of cases. This fact confirms our simplified solid state model. The scaling leads to a reassignment of the IR and Raman experimental bands. The NBO atomic charges and several thermodynamic parameters were also calculated.

Vibrational spectra, tautomerism and thermodynamics of anticarcinogenic drug: 5-fluorouracil.

The FT-IR and FT-Raman spectra of 5-Fluorouracil were recorded in the solid phase in the regions 400-4000 cm(-1) and 50-4000 cm(-1), respectively. The vibrational spectra were analysed and the observed fundamentals were assigned to different normal modes of vibration. The experimental wavenumbers were compared with the scaled vibrational values using DFT methods: the Ar matrix data were related to gas phase calculations, while the values of the solid state spectra were compared to those with dimer simulations. The study indicates that some features that are characteristic of vibrational spectra of uracil and its derivatives are retained in the spectrum of 5-fluorouracil and it exists in ketonic form in the solid phase. The tautomerism was also studied and the spectra of the two most stable forms were simulated. The calculated wavenumbers have been employed to yield thermodynamic properties.