C.N Alves

A structure–activity relationship study of HEPT-analog compounds with anti-HIV activity

The molecular orbital method PM3 is employed to calculate a set of molecular descriptors (variables) for 36 deoxy analogs of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) with anti-HIV-1 activity. Pattern recognition methods, principal component analysis (PCA) and stepwise discriminant analysis (SDA) were employed in order to reduce dimensionality and investigate which subset of variables should be more effective for classifying the HEPT-analog compounds according to their degree of anti-HIV-1 activity. The PCA showed that the variables log P (partition coefficient), MR (molecular refractivity),DHf (heat of formation), QN (net atomic charge on atoms 2 and 3), and x (Mulliken’s electronegativity) are responsible for the separation between compounds with higher and lower anti-HIV-1 activity. By using the SDA we have found the following descriptors as responsible for the separation between the active and less active compounds: log P (partition coefficient), x (Mulliken’s electronegativity), m (dipole moment), Q4 (net atomic charge on atom 4), and t2 (torsional angle). From the SDA we present a prediction rule for classifying new HEPT-analog compounds with anti-HIV-1 activity. q 2000 Elsevier Science B.V. All rights reserved.

A multiple linear regression and partial least squares study of flavonoid compounds with anti-HIV activity

Abstract The molecular orbital semi-empirical method PM3 was employed to calculate a set of molecular properties (variables or descriptors) of 21 flavonoid compounds with anti-HIV activity. The correlation between biological activity and structural properties was obtained by using the multiple linear regression and partial least squares methods. The model obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with anti-HIV activity were: electronegativity (χ) and the charges on atoms C3 and C7 (Q3 and Q7, respectively). These variables led to a physical explanation of electronic molecular property contributions to HIV inhibitory potency.

A structure–activity relationship (SAR) study of synthetic neolignans and related compounds with biological activity against Escherichia coli

Abstract Structure–activity relationship techniques were employed to classify neolignan compounds and related analogues against Escherichia coli . The AM1 (Austin Model) method was used to calculate a set of molecular descriptors (properties) for 16 synthetic neolignan compounds. The descriptors were further analyzed using the principal component analysis (PCA), hierarchical cluster analysis (HCA) and K-nearest neighbor (KNN) chemometric methods. The PCA and HCA methods showed quite efficient to classify the 16 compounds in two groups (active and inactive) and three descriptors were found to be important in the classification. By using the chemometric results, 14 new neolignan molecules were analyzed through the PCA, HCA and KNN methods and 11 of them are proposed as molecules potentially active against E. coli .

Theoretical calculations on dipyridamole structure allow to explain experimental properties associated to electrochemical oxidation and protonation

PM3 calculations of charge distributions for dipyridamole (DIP) in the neutral, single- and double-ionized states allowed to estimate the first and second ionization potentials. Results are compared with electrochemical oxidation, a sequential two-step process. Single ionization produces a cation radical, the electron being removed from the nitrogen atoms in the substituent positions 2,4,6,8 with participation of the carbons in the pyrimido-pyrimidine ring. Protonation of one of the nitrogens is allowed energetically while a second protonation is forbidden due to the high energy required. Our calculations allow to explain some interesting experimental results related to electrochemical oxidation and protonation of the drug.

A theoretical study of the intramolecular hetero Diels–Alder cycloaddition reactions of azoalkenes

Abstract Ab initio Hartree–Fock and density functional theory calculations were performed to study transition geometries in intramolecular Diels–Alder cycloaddition reactions of azoalkene compounds. The Hartree–Fock (HF) calculations were formed at the RHF/3-21G level and the density functional theory (DFT) calculations were performed with the B3LYP functional and 6-31G ∗ basis set. The order of the reactivity of azoalkenes with different substituents in intramolecular hetero Diels–Alder reactions was predicted from the frontier orbital energies, and calculations of the reaction barriers were performed. The HF and DFT calculations generated transition geometries with a very small degree of asynchronicity. The DFT results are in full agreement with experimental evidence and show the capability of this level of DFT calculation to predict the reactivity of intramolecular hetero Diels–Alder cycloaddition correctly.

An AM1 theoretical study on the effect of Zn2+ Lewis acid catalysis on the mechanism of the cycloaddition between 3-phenyl-1-(2-pyridyl)-2-propen-1-one and cyclopentadiene

Abstract The mechanism of the Diels–Alder reaction between 3-phenyl-1-(2-pyridyl)-2-propen-1-one and cyclopentadiene has been investigated with the AM1 semiempirical method. Stationary points for two reactive channels, endo - cis and exo - cis , have been characterized. The role of the Lewis acid catalyst has been modeled taking into account the formation of a complex between Zn 2+ and the carbonyl oxygen atom and the pyridyl nitrogen atom of the 3-phenyl-1-(2-pyridyl)-2-propen-1-one system with and without the presence of two molecules of water around the cation. The mechanism of the uncatalyzed reaction corresponds to a concerted process, but in the presence of Lewis acid catalyst the mechanism changes and the reaction takes place through a stepwise mechanism. A first step involves the nucleophilic attack of the cyclopentadiene in the double bond of the dienophile which produces an intermediate. A second step involves the closure of the intermediate yielding the corresponding final cycloadduct. The inclusion of the Zn 2+ catalyst drastically decreases the energy barrier associated with the carbon–carbon bond formation of the first step in comparison to the concerted process.

A study on the effect of Lewis acid catalysis on the molecular mechanism of the cycloaddition between (E)-methyl cinnamate and cyclopentadiene

Abstract The molecular mechanism of the Diels–Alder reaction between (E)-methyl cinnamate and cyclopentadiene has been analyzed by means of AM1 semiempirical method and compared to the experimental results. Stationary points for two reactive channels, endo-cis and exo-cis, on potential energy surfaces have been characterized. Three Lewis acids, boron trifluoride (BF3), aluminum trichloride (AlCl3) and catechol boron bromide (CBB) have been used as catalysts taking into account the formation of a complex between the boron or aluminum atom and the carbonyl oxygen of (E)-methyl cinnamate. The molecular mechanism of the uncatalyzed reaction corresponds to a concerted process. In the presence of BF3 and AlCl3, enhancement of both the asynchronicity and charge transfer, with small decreased energy barriers, were obtained. With CBB, the molecular mechanism changes and the reaction takes place along a stepwise mechanism. The initial step corresponds to the nucleophilic attack of cyclopentadiene on the dienophile double bond to give an intermediate, followed by its closure in the second step, yielding the corresponding final cycloadduct. The inclusion of the CBB catalyst drastically decreases the energy barrier associated with the carbon–carbon bond formation of the first step, relative to the concerted process. The role of the Lewis acid catalyst emerges from the analysis of the results.

Familial Amyloid Polyneuropathy treatment with Tafamidis – evaluation of one- and two-year treatment in Porto, Portugal

Transthyretin (TTR) related Familial Amyloid Polyneuropathy presents as a severe sensory, motor and autonomic neuropathy. Tafamidis, an oral drug that stabilizes TTR preventing amyloid deposition, was recently introduced in Europe to delay neuropathy progression in ambulatory patients.

Transthyretin (ATTR) amyloidosis nephropathy: lessons from a TTR stabilizer molecule

Unidade Corino de Andrade, Porto, Portugal, Unit for Multidisciplinary Research in Biomedicine (UMIB), Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Porto University, Porto, Portugal, Department of Neurology, Centro Hospitalar do Porto, Porto, Portugal, Department of Neurophisiology, Centro Hospitalar do Porto, Porto, Portugal, Department of Nephrology, Centro Hospitalar do Porto, Porto, Portugal, and School of Economics and LIAAD-INESC Porto LA, Porto University, Porto, Portugal