Willian R. Rocha

N4-Phenyl-substituted 2-acetylpyridine thiosemicarbazones: Cytotoxicity against human tumor cells, structure–activity relationship studies and investigation on the mechanism of action

N(4)-Phenyl 2-acetylpyridine thiosemicarbazone (H2Ac4Ph; N-(phenyl)-2-(1-(pyridin-2-yl)ethylidene)hydrazinecarbothioamide) and its N(4)-ortho-, -meta- and -para-fluorophenyl (H2Ac4oFPh, H2Ac4mFPh, H2Ac4pFPh), N(4)-ortho-, -meta- and -para-chlorophenyl (H2Ac4oClPh, H2Ac4mClPh, H2Ac4pClPh), N(4)-ortho-, -meta- and -para-iodophenyl (H2Ac4oIPh, H2Ac4mIPh, H2Ac4pIPh) and N(4)-ortho-, -meta- and -para-nitrophenyl (H2Ac4oNO(2)Ph, H2Ac4mNO(2)Ph, H2Ac4pNO(2)Ph) derivatives were assayed for their cytotoxicity against human malignant breast (MCF-7) and glioma (T98G and U87) cells. The compounds were highly cytotoxic against the three cell lineages (IC(50): MCF-7, 52-0.16 nM; T98G, 140-1.0 nM; U87, 160-1.4 nM). All tested thiosemicarbazones were more cytotoxic than etoposide and did not present any haemolytic activity at up to 10(-5)M. The compounds were able to induce programmed cell death. H2Ac4pClPh partially inhibited tubulin assembly at high concentrations and induced cellular microtubule disorganization.

Improved quantum mechanical study of the potential energy surface for the bithiophene molecule

The potential energy surface (PES) for the 2,2′-bithiophene molecule was investigated using Hartree–Fock, correlated MP2, MP4(SDQ), CCSD, and density functional theory levels. Distinct basis sets ranging from double-zeta to triple-zeta quality, with polarization functions added on all atoms, were employed as well as the Dunning correlated consistent polarized valence double-zeta (cc-pVDZ) basis set. Single point configuration interaction CISD calculations were also performed using the cc-pVDZ basis set. Harmonic frequency calculations were performed for the unambiguous characterization of the stationary points located on the PES and also to calculate thermal Gibbs free energy corrections. Regarding the structural predictions we found that the B3LYP/6-311G** and MP2/cc-pVDZ fully optimized geometries exhibit the best agreement with the gas phase electron diffraction data. The calculated B3LYP/6-311G**, MP2/cc-pVDZ and experimental torsional angle for the syn-gauche structure are, respectively, 37.4° (B3LYP...

Pyridine-derived thiosemicarbazones and their tin(IV) complexes with antifungal activity against Candida spp.

[(n-Bu)Sn(2Ac4oClPh)Cl2] (1), [(n-Bu)Sn(2Ac4oFPh)Cl2] (2), [(n-Bu)Sn(2Ac4oNO2Ph)Cl2] (3), [(n-Bu)Sn(2Bz4oClPh)Cl2] (4), [(n-Bu)Sn(2Bz4oFPh)Cl2] (5) and [(n-Bu)Sn(2Bz4oNO2Ph)Cl2] (6) were obtained by reacting [(n-Bu)SnCl3] with 2-acetylpyridine-N4-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N4-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N4-orthonitrophenyl thiosemicarbazone (H2Ac4oNO2Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO2Ph). The antifungal activity of the studied compounds was evaluated against several Candida species. Upon coordination of H2Bz4oNO2Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO2Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.

Design, structural and spectroscopic elucidation, and the in vitro biological activities of new diorganotin dithiocarbamates.

The reaction of 2,2-dimethoxy-N-methylethyllamine or 2-methyl-1,3-dioxolane with CS(2) in alkaline media produced two novel dithiocarbamate salts. Subsequent reactions with organotin halides yielded six new complexes: [SnMe(2){S(2)CNR(R(1))(2)}(2)] (1), [Sn(n-Bu)(2){S(2)CNR(R(1))(2)}(2)] (2), [SnPh(2){S(2)CNR(R(1))(2)}(2)] (3), [SnMe(2){S(2)CNR(R(2))(2)}(2)] (4), [Sn(n-Bu)(2){S(2)CNR(R(2))(2)}(2)] (5), [SnPh(2){S(2)CNR(R(2))(2)}(2)] (6), where R = methyl, R(1) = CH(2)CH(OMe)(2), and R(2) = 2-methyl-1,3-dioxolane. All compounds were identified in terms of infrared, (1)H and (13)C NMR, and the complexes were also characterized using (119)Sn NMR, (119)Sn Mössbauer and X-ray crystallography. The biological activity of all derivatives has been screened in terms of IC(90) and IC(50) against Aspergillus flavus, Aspergillus niger, Aspergillus parasiticus, Penicillium citrinum, Curvularia senegalensis, Staphylococcus aureus, Listeria monocytogenes, Bacillus cereus, Streptococcus sanguinis, Escherichia coli, Citrobacter freundii, Salmonella typhimurium, and Pseudomonas aeruginosa and the results correlated well with a performed study of structure-activity relationship (SAR). Complexes (3), (5) and (6) displayed the best IC(90) and IC(50) in the presence of the fungi, greater than that of miconazole, used as control drug.

Ab initio conformational analysis of cyclooctane molecule

The potential energy surface (PES) for the cyclooctane molecule was comprehensively investigated at the Hartree–Fock (HF) level of theory employing the 3–21G, 6–31G, and 6–31G* basis sets. Six distinct true minimum energy structures (named B, BB, BC, CROWN, TBC, and TCC1), characterized through harmonic frequency analysis, were located on the multidimensional PES. Two transition state structures were also located on the PES for the cyclooctane molecule. Electron correlation effects were accounted for using the Møller–Plesset second‐order perturbation theory (MP2) approach. The predicted global minimum energy structure on the ab initio PES for the cyclooctane molecule is the BC conformer. A gas phase electron diffraction study at 300 K suggested a conformational mixture while an NMR study in solution at 161.5 K predicted the BC conformer as the predominant form. The equilibrium constants reported in the present study, which were evaluated from the ab initio calculated total Gibbs free energy change values, were in good agreement with both experimental investigations. The ab initio results showed that the low temperature condition significantly favored the BC conformer while above room temperature both BC and CROWN structures can coexist. © 1998 John Wiley & Sons, Inc. J Comput Chem 19: 524–534, 1998

Theoretical study of the potential energy surface for the interaction of cisplatin and their aquated species with water

In this work, a systematic study of the interaction of neutral cisplatin ([Pt(NH(3))(2)Cl(2)]) and their charged aquated species ([Pt(NH(3))(2)Cl(H(2)O)](+) and [Pt(NH(3))(2)(H(2)O)(2)](2+)) with water was carried out. The potential energy surface (PES) was analyzed by considering 35 spatial orientations for the interacting species. The calculations were performed at various levels of theory including Moller-Plesset fourth order perturbation theory and density functional theory (DFT-B3LYP) using extended basis sets. Lennard-Jones (12-6) plus Coulomb classical potential was also used to assess the repulsion-dispersion and electrostatic contributions. The effect of atomic charges on the interaction energies is discussed using Mulliken, charges from electrostatic potential grid method and natural bond orbital schemes. The outcomes show that the electrostatic term plays a primary role on the calculation of interaction energies, with the absolute values of atomic charges from different approaches significantly affecting the overall interaction. Unusual results were revealed by basis set superposition error calculations for the structures located on the platinum-water PES.

Carbonyl insertion reaction into the PtC bond in heterobimetallic Pt(SnCl3)(PH3)2(CO)(CH3) compound: Theoretical study

Quantum‐mechanical calculations were carried out at the MP4(SDQ)//MP2 level of theory to determine the energies and reaction mechanism for the carbonyl insertion reaction (second step in the olefin hydroformylation catalytic cycle), using a heterobimetallic Pt(SnCl3)(PH3)2(CO)(CH3) compound as a model catalytic species. The results show that this reaction proceeds through a three‐center transition state, with an activation energy of 26.4 kcal/mol, followed by an intramolecular rearrangement to the square‐planar cis‐Pt(SnCl3)(PH3)2(MeCO) metal–acyl product. Analysis of the nature of the bonds shows that there is a negligible participation of the tin d‐orbitals in the formation of the PtSn bond.

Quantum mechanical/effective fragment potential (QM/EFP) study of phosphate monoester aminolysis in aqueous solution.

In this work, we investigated the P-O bond cleavage of dianionic p-nitrophenyl phosphate monoester (p-NPP), with attack of aqueous methylamine on phosphorus, by using the hybrid quantum mechanical/effective fragment potential (QM/EFP) approach. We explored the structures, energetic properties, reaction mechanism, and charge distribution along the entire reaction coordinate. Our B3LYP/6-31++G(d,p)/EFP results show that the cleavage of the P-O bond of p-NPP proceeds through a concerted mechanism with an activation energy of about 26 kcal/mol and an activation free energy at 39 degrees C of 23.6 kcal/mol, in good agreement with the experimental value of 27 kcal/mol. The reaction involves a trigonal bipyramidal (TBP) transition state with less initial bonding to the nucleophile than to the leaving group. The extent of the P-O(nitrophenolate) bond dissociation at the transition state, with methylamine as the nucleophile, is less than that with OH(-). The computed charge distribution along the reaction coordinate is consistent with a progressive charge transfer from the nitrogen atom of methylamine to the phosphate unit along the reaction coordinate. A new strategy to build the initial EFP cluster, by running a classical Monte Carlo simulation and analyzing the center-of-mass radial pair distribution function, was also used.

DFT study of the full catalytic cycle for the propene hydroformylation catalyzed by a heterobimetallic HPt(SnCl3)(PH3)2 model catalyst

DFT calculations were carried out to study the full catalytic cycle for the hydroformylation of propene, catalyzed by the heterobimetallic model catalyst trans‐Pt(H)(PH3)2(SnCl3). Before the study of the full catalytic cycle, the performance of six pure GGA, one GGA with inclusion of dispersion corrections, four hybrid‐GGA, and three meta‐GGA exchange correlation functional to describe a model reaction promoted by Pt‐Sn catalyst were assessed. It is shown that the BP86 and GPW91 functionals, using extended basis set, provides reliable energetic results when compared with the CCSD(T) calculations. All intermediates and transition states along the elementary steps of the entire catalytic cycle were located and the energies involved in the catalytic cycle calculated using BP86 functional. The solvent effects along the entire catalytic cycle were evaluated using the polarizable continuum model. In contrast with the rhodium catalysts, the regioselectivity of the hydroformylation is set at the carbonylation step. The hydrogenolysis is the rate determining step of the entire cycle, with the activation energy of ∼21 kcal mol−1 in agreement with the experimental value of ∼25 kcal mol−1. The trans effect of the SnCl  3− ligand seems to be pronounced only in the first step of the catalytic cycle, facilitating the insertion of the olefin into the PtH bond trans to it. The analysis of the stationary points obtained along each elementary step of the catalytic cycle is carried out separately and discussed. The BP86/cc‐pVTZ/SBKJC results shows that the pathway leading to the linear aldehyde is preferred, being in agreement with the experimental findings.

Quantum-mechanical and molecular mechanics conformational analysis of 1,5-cyclooctadiene

The 1,5‐cyclooctadiene (COD) molecule can easily form complexes with transition metals with the molecular structure of various of these complexes being proposed with the aid of X‐ray diffraction methods. The fact that the complexes exhibit weak metal‐COD bonds makes it very important in inorganic synthesis and catalysis. In this work the potential energy surface (PES) for the COD molecule was comprehensively investigated: first with molecular mechanics (using the MM3 force field); and, in a second stage, at the ab initio Hartree‐Fock level of theory employing the 3‐21G*, 6‐31G, and 6‐31G* basis sets and also including electron correlation effects at the Moller‐Plesset second‐order perturbation theory level. This work revealed that there are three distinct conformers of the COD molecule with the predicted lowest energy conformation being in agreement with the proposed structure based on experimental electron diffraction data.