María Virginia Mirífico

A comparative QSAR on 1,2,5-thiadiazolidin-3-one 1,1-dioxide compounds as selective inhibitors of human serine proteinases.

Selective inhibitors of target serine proteinases have a potential therapeutic role for the treatment of various inflammatory and related diseases. We develop a comparative quantitative structure-activity relationships based analysis on compounds embodying the 1,2,5-thiadiazolidin-3-one 1,1-dioxide scaffold. By means of classical Molecular Dynamics we obtain the conformation of each lowest-energy molecular structure from which we derive more than a thousand of structural descriptors necessary for building predictive QSAR models. We resort to two different modeling approaches with the purpose of testing the consistency of our results: (a) multivariable linear regressions based on the replacement method and forward stepwise regression, and (b) the calculation of flexible descriptors with the CORAL program. All the models are properly validated by means of standard procedures. The resulting QSAR models are supposed to be of great utility for the rational search and design (including synthesis and/or in vitro biochemical studies) of new effective non-peptidyl inhibitors of serine proteinases.

Electrochemistry of 3,4-diphenyl-1,2,5-thiadiazole 1,1-dioxide (I) and its derivatives in ethanol—acetonitrile solutions and interactions of the dianion of I with metal cations

The equilibrium between I and the product resulting from the addition of ethanol to one of its CN double bonds: 3-ethoxy- 3,4- diphenyl- 1,2,5-thiadiazoline 1,1-dioxide (II), is studied by electrochemical methods in ethanol (EtOH)—acetonitrile (ACN) solvent mixtures. The equilibrium constant is measured and a complete mechanism for the electroreduction of I and II in ACN solutions containing EtOH is proposed. The voltammetric properties of the newly synthesized compound 3-ethoxy- 2- methyl- 3,4- diphenyl- 1,2,5-thiadiazoline 1,1-dioxide (IV) are also reported. A stabilization of the dianion of I by alkali-metal cations, such as K+, Na+ and Li+, and divalent cations (Sr2+ and Mg2+) is voltammetrically measured. Equilibrium constants are estimated and compared for the interaction of I2− and the alkali-metal cations in ACN solutions of I.

Crystallographic study and molecular orbital calculations of 1,2,5-thiadiazole 1,1-dioxide derivatives

Single-crystal x-ray diffraction studies are reported for 3,4-dimethyl (I), 3-methyl-4-phenyl (II) and 3,4-diphenyl (III) derivatives of 1,2,5-thiadiazole 1,1-dioxide. Ab initio MO calculations on the electronic structure, conformation and reactivity of I, II and III are also reported and compared with the x-ray results. The structural data are related to previous kinetic and electrochemical experimental results on these compounds.

Unexpected production of 2,4,6-triphenyl-1,3,5-triazine in the electroreduction of 3,4-diphenyl-1,2,5-thiadiazole 1-oxide. Theoretical estimation of reactive sites for 1-oxide and 1,1-dioxide 1,2,5-thiadiazoles

Abstract 3,4-Diphenyl-1,2,5-thiadiazole 1-oxide ( 1a ) in acetonitrile solution is electroreduced to 2,4,6-triphenyl-1,3,5-triazine and 3,4-diphenyl-1,2,5-thiadiazole. This behavior is very different from that of similar compounds with other oxidation states of the heterocyclic sulfur atom, such as the 1,1-dioxide derivative ( 2 ) and the aromatic 3,4-diphenyl thiadiazole parent ring. The Fukui functions were calculated for 1a and 2 to estimate their reactivity, compare their reactive site, and rationalize the divergent electrochemical properties of 1a .

ELECTROREDUCTION OF 3,4-DIPHENYL-1,2,5-THIADIAZOLE-1,1-DIOXIDE IN ACETONITRILE SOLUTION AND REACTIONS WITH PROTON DONORS

Abstract The electroreduction of 3,4-diphenyl-1,2,5-thiadiazole-1,1-dioxide ( T ) has been investigated in acetonitrile solutions containing LiClO 4 as the supporting electrolyte by cyclic voltammetry and bulk electrolysis techniques. T is reduced successively to T .− and to T 2− at ca −0.8 V vs Ag/Ag + . The potential difference between the two charge transfers reactions is −0.062 V. The presence of Li + ion stabilizes the T 2− dianion. The addition of trifluoroacetic or benzoic acid in sufficient concentration allows observation of the electroreduction of TH + . The basic equilibrium constant of T to form TH + , estimated from peak potential displacement, is 8 × 10 13 . The product of voltammetric T electroreduction in the presence of proton donors is the corresponding thiadiazoline ( TH 2 ).

Crystallographic study and molecular orbital calculations of thiadiazole derivatives. 1. Phenanthro[9,10-c]-1,2,5-thiadiazole 1,1-dioxide and acenaphtho[1,2-c]-1,2,5-thiadiazole 1,1-dioxide

Abstract Single-crystal X-ray diffraction studies are reported for phenanthro[9,10-c]-1,2,5-thiadiazole 1,1-dioxide (I) and acenaphtho[1,2-c]-1,2,5-thiadiazole 1,1-dioxide (II). Ab initio molecular orbital (MO) calculations on the electronic structure, conformation and reactivity of I and II are also reported and compared with the X-ray results. A charge sensitivity analysis of the studied molecules has been performed by resorting to density functional theory (DFT), obtaining several sensitivity coefficients such as the molecular energy, net atomic charges, global and local hardness, global and local softness and Fukui functions. With these results and the analysis of the dipole moments and the total electron density maps, several conclusions have been inferred about the preferred sites of chemical reaction of the studied compounds.

Assessment of cytotoxic and cytogenetic effects of a 1,2,5-thiadiazole derivative on CHO-K1 cells. Its application as corrosion inhibitor.

This work focuses on the possible use of phenanthro[9,10-c]-1,2,5-thiadiazole 1,1-dioxide (TDZ) as a harmless corrosion inhibitor. TDZ range-dose providing minimum adverse effects to the environment and human health, with satisfactory corrosion-inhibiting properties was evaluated. Cytotoxicity and genotoxicity of TDZ at 0.57-12.50 microM concentration range were tested by neutral red, chromosomal aberrations, mitotic index, and colony formation assays. Results showed a significant increase of chromatid-type aberrations for the highest concentration of TDZ assayed (12.50 microM). Additionally, a reduction in the proliferative rate for lower concentrations was detected by the MI assay. We concluded that TDZ should be used at concentrations lower than 1.16 microM. Corrosion assays performed showed good inhibition effect (ca. 50%) at low (0.65 microM) TDZ concentration. Consequently, our results indicated that TDZ induced a time- and dose-dependent genotoxic and cytotoxic response on CHO-K1 cells. Short assays should be complemented with long exposure tests to simulate chronic contact with TDZ since lower threshold levels may be found for shorter exposures and a wrong safety range could be determined.

Crystallographic study and molecular orbital calculations of thiadiazole derivatives. 2. 3,4-diphenyl-1,2,5-thiadiazole 1-monoxide

Single-crystal X-ray diffraction studies are reported for 3,4-diphenyl-1,2,5-thiadiazole 1-monoxide (I). Ab initio MO calculations on the electronic structure, conformation and reactivity for this compound are also reported and compared with the X-ray results. A charge sensitivity analysis is performed on the results applying concepts derived from density functional theory (DFT), obtaining several sensitivity coefficients such as the molecular energy, net atomic charges, global and local hardness, global and local softness and Fukui functions. With these results and the analysis of the dipole moment and the total electron density and electrostatic potential maps, several conclusions have been inferred about the preferred sites of chemical reaction of the compound.

Crystallographic study and molecular orbital calculations of thiadiazole derivatives. Part 3: 3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide, 3,4-diphenyl-1,2,5-thiadiazolidine 1,1-dioxide and 4-ethoxy-5-methyl-3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide

Abstract Single-crystal X-ray diffraction studies are reported for 3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide (I), 3,4-diphenyl-1,2,5-thiadiazolidine 1,1-dioxide(II) and 4-ethoxy-5-methyl-3,4-diphenyl-1,2,5-thiadiazoline 1,1-dioxide (III). Ab initio MO calculations on the electronic structure, conformation and reactivity of these compounds are also reported and compared with the X-ray results. A charge sensitivity analysis is performed on the results applying concepts derived from density functional theory, obtaining several sensitivity coefficients such as the molecular energy, net atomic charges, global and local hardness, global and local softness and Fukui functions. With these results and the analysis of the dipole moment and the total electron density and electrostatic potential maps, several conclusions have been inferred about the preferred sites of chemical reaction of the studied compounds.

Synergistic cytotoxic effects of ions released by zinc–aluminum bronze and the metallic salts on osteoblastic cells†

The use of copper-based alloys for fixed dental crowns and bridges is increasingly widespread in several countries. The aim of this work is to study the dissolution of a zinc-aluminum-bronze and the cytotoxic effects of the ions released on UMR-106 osteoblastic cell line. Two sources of ions were used: (1) ions released by the metal alloy immersed in the cell culture and (2) salts of the metal ions. Conventional electrochemical techniques, atomic absorption spectroscopy [to obtain the average concentration of ions (AC) in solution], and energy dispersive X-ray (EDX) spectroscopy analysis were used to study the corrosion process. Corrosion tests revealed a strong influence of the composition of the electrolyte medium and the immersion time on the electrochemical response. The cytotoxicity was evaluated with (a) individual ions, (b) combinations of two ions, and (c) the mixture of all the ions released by a metal disc of the alloy. Importantly, synergistic cytotoxic effects were found when Al-Zn ion combinations were used at concentration levels lower than the cytotoxic threshold values of the individual ions. Cytotoxic effects in cells in the vicinity of the metal disc were also found. These results were interpreted considering synergistic effects and a diffusion controlled mechanism that yields to concentration levels, in the metal surroundings, several times higher than the measured AC value.