Dolores Santa María

Theoretical calculations of a model of NOS indazole inhibitors: interaction of aromatic compounds with Zn-porphyrins.

We report a theoretical approach, at the M05-2x/6-311+G(d) level, to explain the affinity of indazoles for nitric oxide synthases using a simplified model of porphyrin. The theoretical E(rel)=E(i) stacking-E(i) apical values correlate with the experimental inhibition percents allowing to predict that 3,7-dinitro-1H-indazole should be a good NOS inhibitor.

Structural Studies of Two Tinuvin ® P Analogs: 2-(2,4-Dimethylphenyl)-2H-benzotriazole and 2-Phenyl-2H-benzotriazole

2-(2,4-Dimethylphenyl)-2H-benzotriazole (1) has been synthesized in a three step procedure starting from 2,4-dimethyl-N-(2-nitrophenyl)benzamide via a 5-(2,4- dimethylphenyl)-1-(2-nitrophenyl)-1H-tetrazole intermediate. Its structure and those of Tinuvin P and 2-phenyl-2H-benzotriazole (5) have been studied by multinuclear NMR (1H-, 13C- and 15N-) in solution and in the solid state. X-ray diffraction analysis of 1 and 5 allowed to us establish the molecular conformation around the single bond connecting the two aromatic systems, in agreement with the conclusions drawn from the NMR study. In the case of 1 ab initio geometry optimization was achieved at the Hartree-Fock HF/6- 31G** and DFT B3LYP/6-31G** levels.

15N-15N spin-spin coupling constants through intermolecular hydrogen bonds in the solid state

A 2hJNN intermolecular spin-spin coupling constant (SSCC) of 10.2±0.4 Hz has been measured for the powdered tetrachlorogallate salt of pyridinium solvated by pyridine (pyridine-H+⋯pyridine cation 3). Density Functional Theory (DFT) calculations at the B3LYP/6-311++G(d,p) level reproduced this value and two others reported in the literature for 2hJ intermolecular SSCCs, which were measured for complexes in solution.

Synthetic hosts for molecular recognition of ureas

Four hosts (7-10) containing 2,6-bisamidopyridine- and 2,5-bisamidopyrrole-bearing pyridyl or 1,8-naphthyridyl groups have been prepared and their structures studied by a combination of multinuclear NMR spectroscopy and X-ray crystallography. Their behavior in molecular recognition of urea derivatives, including (+)-biotin methyl ester, has been approached by molecular modeling (Monte Carlo conformational search, AMBER force field). The minimum energy values for the complexes are correlated with the experimental binding energies determined by means of (1)H NMR titrations.

The behavior of Gliclazide in solution and in the solid state: a case of organic compound presenting a solid‐solution structure

The structure of the hypoglycemic agent Gliclazide has been studied by 1H, 13C, and 15N NMR in solution (CDCl3 and DMSO‐d6) and in the solid state. In the solid state, the compound crystallizes as an EZ isomer without dynamic properties. In CDCl3 solution, the structure is still EZ but with a slow nitrogen inversion about the pyrrolidine nitrogen: two invertomers have been observed and characterized. In DMSO‐d6, the rate is faster and only averaged signals were observed. GIAO calculated absolute shieldings were used to confirm the nature of the observed species. In the solid state, Gliclazide presents the phenomenon of solid‐solution with two disordered conformations present in the crystal at a 90:10 ratio. Copyright

Molecular Recognition Studies on Naphthyridine Derivatives

The association constants Kb of three hosts I–III designed to have both enhanced hydrogen bonding donor strength and conformational preorganization with biotin analogues 1–5 are reported. 1H-NMR titrations under two different concentration conditions have been employed to determine the association constants Kb. A statistical analysis using a presence absence matrix has been applied to calculate the different contributions. Hydrogen bond interactions make naphthyridine derivatives II and III potent binders and effective receptors for (+)-biotin methyl ester (1), due to the complex stabilization by additional hydrogen bonds.

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 (CQ22Ag2+2+) 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.

The structures of two aldazines: [1,1'-(1E,1'E)-hydrazine-1,2-diylidenebis(methan-1-yl-1-ylidene)dinaphthalen-2-ol] (Lumogen) and 2,2'-(1E,1'E)-hydrazine-1,2-diylidenebis(methan-1-yl-1-ylidene)diphenol (salicylaldazine) in the solid state and in solution.

A combination of NMR spectroscopy and theoretical methods Density functional theory including dispersion corrections (DFT‐D) was used to study the structures of Lumogen and salicylaldazine. In the solid state, Lumogen exists as the dihydroxy tautomer 1a (an azine, CN–NC) as was already known from an X‐ray determination. In a deuterated dimethyl sulfoxide solution, another tautomer is observed besides 1a; its structure corresponds to the hydroxy‐oxo tautomer 1b (a hydrazone, CN–NH–Csp2). In what concerns salicylaldazine, we have observed only the dihydroxy tautomer 2a. Copyright

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

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.

New macrocyclic compounds with naphthyridine units for molecular recognition studies of biotin and urea derivatives

Two macrocyclic hosts containing benzenedicarboxamide or pyridinedicarboxamide moieties and two 1,8-naphthyridine units linked by a crown ether like chain, have been synthesized and fully characterized by multinuclear NMR spectroscopy. X-ray diffraction analysis is provided for one of the macrocycles including a DMSO guest molecule. Binding constant determination of both hosts with four ureido derivatives, amongst them (+)-biotin methyl ester, was achieved by means of 1H NMR titrations.