Showing papers by "Rosa M. Claramunt published in 2019"

Multinuclear NMR spectra and GIAO/DFT calculations of N-benzylazoles and N-benzylbenzazoles

Abstract: The 1H, 13C, and 15N chemical shifts of almost the whole series of N-benzyl azoles and benzazoles, with the exception of the unknown 1-benzyl-1H-pentazole (10) and the very unstable 2-benzyl-2H-isoindole (12), have been measured. In addition, the X-ray crystal structure of 1-benzyl-1H-indazole (14) was solved (monoclinic, space group P21/n), its geometry being very close to that used for the calculations. The absolute chemical shieldings were calculated at the gauge-independent atomic orbital (GIAO)/Becke, 3-parameter, Lee-Yang-Parr (B3LYP)/6-311++G(d,p) level and then transformed with very robust empirical equations into chemical shifts of the three nuclei showing an excellent agreement with the 313 experimental values.

A theoretical NMR study of polymorphism in crystal structures of azoles and benzazoles

Abstract: The NMR chemical shifts of two azoles and one benzazole whose crystal structures present polymorphism have been computed using the GIPAW approach. 15 N and 13 C nuclei have been studied. Statistical analysis of the computed 13 C and 15 N chemical shifts indicates that the GIPAW chemical shifts reproduce with a high degree of accuracy those experimentally reported. This methodology can be used to identify other polymorphic crystal structures.

An Example of Polynomial Expansion: The Reaction of 3(5)-Methyl-1H-Pyrazole with Chloroform and Characterization of the Four Isomers.

Abstract: The reaction in phase-transfer catalyzed conditions of 3(5)-methyl-1H-pyrazole with chloroform affords four isomers 333, 335, 355 and 555 in proportions corresponding to the polynomial expansion (a + b)3, with a = 0.6 and b = 0.4, a and b being 3-methyl and 5-methyl proportions. The up (u) and down (d) conformation of the pyrazolyl rings with regard to the Csp3–H atom was established by X-ray crystallography and by 1H-, 13C- and 15N-NMR in solution combined with gauge-including atomic orbitals (GIAO)/B3LYP/6-311++G(d,p) calculations. A comparison with other X-ray structures of tris-pyrazolylmethanes was carried out.

New N,C-Diaryl-1,2,4-triazol-3-ones: Synthesis and Evaluation as Anticancer Agents.

Abstract: Background A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps and evaluated as regards their activity in some relevant biological targets related to cancer. Objective This study is focused on the synthesis and the biological evaluation of 2,5-diaryl-1,2,4- triazol-3-ones. In this sense, the effect of the synthetic triazolones on the proliferation of HT-29 and A549 cancer cells and on HEK non-cancer cells has been measured. In addition, the effects of triazolones on the expression of hTERT, c-Myc and PD-L1 genes and on the production of c-Myc and PD-L1 proteins have also been evaluated. Method A set of 2,5-diaryl-1,2,4-triazol-3-ones was synthesized in two steps. Firstly, N- (aminocarbonyl)-3-methoxybenzamide was prepared by coupling 3-methoxybenzoic acid and cyanamide followed by aqueous HCl hydrolysis. Then, the 2,5-diaryl-1,2,4-triazol-3-ones were obtained upon reaction of N-(aminocarbonyl)-3-methoxybenzamide with arylhydrazines in decaline at 170oC. The ability of the triazolones to inhibit cell proliferation was measured against two human carcinoma cell lines (colorectal HT-29 and lung A549), and one non-tumor cell line (HEK- 293) by MTT assay. The downregulation of the synthetic triazolones on the expression of the hTERT, c-Myc and PD-L1 genes was measured by an RT-qPCR analysis. Their ability to regulate the expression of the c-Myc and PD-L1 proteins, as well as their direct interaction with c-Myc protein, was determined by the ELISA method. Finally, the direct interaction of triazolones with PD-L1 protein was assessed by the thermal shift assay. Results Ten 2,5-diaryl-1,2,4-triazol-3-ones were synthesized and characterized by spectroscopic methods. A thorough study by 1H, 13C, 15N and 19F NMR spectroscopy showed that all the synthetic compounds exist as 4H-triazolones and not as hydroxytriazoles or 1H-triazolones. Some triazolones showed relatively high activities together with very poor toxicity in non-tumor cell line HEK-293. 2-(2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (4) was particularly active in downregulating c-Myc and PD-L1 gene expression although 2-(4- chloro-2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8) is the one that combines the best downregulatory activities in the three genes studied. Considering protein expression, the most active compounds are 2-(4-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro- 3H-1,2,4-triazol-3-one (5) and 2-(2,4,6-trifluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H- 1,2,4-triazol-3-one (10) (c-Myc expression) and 2-(2,3,5,6-tetrafluorophenyl)-5-(3-methoxyphenyl)- 2,4-dihydro-3H-1,2,4-triazol-3-one (11) and (8) (PD-L1 expression). Conclusion Some of the triazolones studied have shown relevant activities in the inhibition of the hTERT, c-Myc and PD-L1 genes, and in the inhibition of c-Myc and PD-L1 protein secretion, the 2-(4-chloro-2-fluorophenyl)-5-(3-methoxyphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (8) was found to be a particularly promising lead compound.

The synergy of different solid-state techniques to elucidate the supramolecular assembly of two 1H-benzotriazole polymorphs

Abstract: 1H-Benzotriazole crystallizes as two different polymorphs, namely 4aα and 4aβ. One polymorph is chiral and it resolves spontaneously as conglomerates. The other polymorph crystallizes in a centrosymmetric space group and it is therefore achiral. In both polymorphs supramolecular structures are formed starting from achiral monomers. An analysis of these two polymorphs of 1H-benzotriazole has been carried out by a complete strategy involving different solid-state experimental techniques and quantum chemical calculations (DFT, Density Functional Theory). In particular, X-ray crystallography, NMR spectroscopy and vibrational spectroscopy techniques (FarIR, IR and Raman) that are not sensitive to chirality have been used to characterize the two polymorphs structurally. Vibrational spectroscopy (VCD, Vibrational Circular Dichroism) that is sensitive to chirality was employed to determine the absolute configuration (M or P helices) of the chiral supramolecular structure of 4aα.

The structure of the anti-aging agent J147 used for treating Alzheimer's disease

Abstract: The mol­ecular structure of the anti-aging agent J147 [systematic name: (E)-N-(2,4-di­methyl­phen­yl)-2,2,2-tri­fluoro-N′-(3-meth­oxy­benzyl­idene)acetohydra­zide], C18H17F3N2O2, has been determined at 150 K. The crystal structure corresponds to the minimum-energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111. NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111, 1112, 1121 and 1222); in addition, the calculated barriers connecting these minima are low enough to permit their inter­conversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloro­form solution.