José Alberto Caram

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.

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. 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.

A study of the anodic voltammetric properties of triphenylphosphine

Abstract Although several bulk electrolysis studies of the electro-oxidation of triphenylphosphine (Ph 3 P) have been published, and its products, triphenilphosphonium salts and triphenylphosphine oxide are well characterized, only scant and qualitative information on its anodic voltammetric properties is available. The voltammetric behavior of Ph 3 P in acetonitrile solutions, using vitreous carbon anodes, is studied in detail. Results using dimethylformamide solvent with vitreous carbon and platinum anodes are also reported and compared. In ACN solution, with vitreous carbon anodes, the radical cation formed in the first electron transfer step reacts with residual water. A one-electron, diffusional, EC errev voltammetric peak is observed for the anodic electro-oxidation of Ph 3 P at sweep rates higher than 0.020 Vs −1 . The effect of a second charge transfer is experimentally observed at lower sweep rates. Implicit finite difference-simulated voltammograms are calculated to reproduce the results. The protonation reaction of Ph 3 P is demonstrated to be slow in the time scale of cyclic voltammetry, but it is catalyzed by the Pt anode, where Ph 3 P adsorption is also observed. Ph 3 P is voltammetrically electro-oxidated in DMF in a two-electron E 1 C 1 E 2 process with E 2 ⩽ E 1 . Diffusion coefficents for Ph 3 P, based on these anodic voltammetric measurements, which agree with the known polarographic values, are given for the first time.