Quantitative structure-activity relationship analysis of phenolic antioxidants

In this report, the quantitative structure-activity relationship (QSAR) analyses of substituted phenols, vitamin E derivatives and flavonoids are presented. Two models have been derived using calculated parameters such as the heat of formation (H_f), the energy of the lowest unoccupied molecular orbital of radicals (E_lumo-r), the energy of the highest occupied molecular orbital of the parent compounds (E_homo) and the number of hydroxyl groups (OH). These models can be used to estimate the redox potentials or antioxidant activities of new substituted phenolic compounds or vitamin E derivatives. The Trolox equivalent antioxidant capacities (TEACs) of 42 different flavonoids are found to be mainly governed by the number and location of hydroxyl groups on the flavonoid ring system.     

Quantitative structure-activity relationships and the prediction of MHC supermotifs

The underlying assumption in quantitative structure-activity relationship (QSAR) methodology is that related chemical structures exhibit related biological activities. We review here two QSAR methods in terms of their applicability for human MHC supermotif definition. Supermotifs are motifs that characterise binding to more than one allele. Supermotif definition is the initial in silico step of epitope-based vaccine design. The first QSAR method we review here--the additive method--is based on the assumption that the binding affinity of a peptide depends on contributions from both amino acids and the interactions between them. The second method is a 3D-QSAR method: comparative molecular similarity indices analysis (CoMSIA). Both methods were applied to 771 peptides binding to 9 HLA alleles. Five of the alleles (A*0201, A*0202, A*0203, A*0206 and A*6802) belong to the HLA-A2 superfamily and the other four (A*0301, A*1101, A*3101 and A*6801) to the HLA-A3 superfamily. For each superfamily, supermotifs defined by the two QSAR methods agree closely and are supported by many experimental data.     

Synthesis and structure-activity relationships of 1,5-diazaanthraquinones as antitumour compounds

1,5-Diazaanthraquinone derivatives were synthesized employing single and double hetero Diels-Alder strategies. Their in vitro antitumour activity was assayed using three cell lines. Some of these compounds, specially those bearing methyl or ethyl groups at the C-3,7 positions or chloro at C-4 and methyl at C-7, showed IC(50) values in the 10(-8)M range for human lung carcinoma and human melanoma, which makes them attractive candidates for further development as anticancer agents.     

Quantitative structure-activity relationships of structurally similar odorless and odoriferous benzenoid musks

To reveal the difference of molecular property between structurallysimilar odorless and odoriferous musk compounds, 10 pairs ofbenzenoids (monocyclic-, dicyclic- and tricyclic-) were examined.Molecular structures of all compounds were optimized by MNDO(modified neglect of diatomic differential overlap) consideringconformation. Parameters effective in discriminating two groups,group A of 10 odorless compounds and group B of 10 musk odorcompounds, were searched from 34 candidate parameters by adaptiveleast squares. The best three parameters found were log P value(octanol/water partition coefficient), the longest side lengthof hexahedron circumscribing a molecule, and the parameter whichexpresses structural hindrance to the functional group whena molecule approaches the receptor site. The two groups of compoundswere completely discriminated using these three parameters.     

Quantitative structure-activity relationships in two-electron reduction of nitroaromatic compounds by Enterobacter cloacae NAD(P)H:nitroreductase

Enterobacter cloacae NAD(P)H:nitroreductase (NR; EC 1.6.99.7) catalyzes the reduction of a series of nitroaromatic compounds with steady-state bimolecular rate constants (kcat/Km) ranging from 10(4) to 10(7) M(-1) s(-1). In agreement with a previously proposed scheme of two-step four-electron reduction of nitroaromatics by NR (Koder, R. L., and Miller, A.-F. (1998) Biochim. Biophys. Acta 1387, 395-405), 2 mol NADH per mole mononitrocompound were oxidized. An oxidation of excess NADH by polinitrobenzenes, including explosives 2,4,6-trinitrotoluene (TNT) and 2,4,6-trinitrophenyl-N-methylnitramine (tetryl), has been observed as a slower secondary process, accompanied by O2 consumption. This type of "redox cycling" was not related to reactions of nitroaromatic anion-radicals, but was caused by the autoxidation of relatively stable reaction products. The initial reduction of tetryl and other polinitrophenyl-N-nitramines by E. cloacae NR was analogous to a two-step four-electron reduction mechanism of TNT and other nitroaromatics. The logs kcat/Km of all the compounds examined exhibited parabolic dependence on their enthalpies of single-electron or two-electron (hydride) reduction, obtained by quantum mechanical calculations. This type of quantitative structure-activity relationship shows that the reactivity of nitroaromatics towards E. cloacae nitroreductase depends mainly on their hydride accepting properties, but not on their particular structure, and does not exclude the possibility of multistep hydride transfer.     

Structure-activity relationships for inhibition of prostaglandin cyclooxygenase by phenolic compounds

Sixty-three phenolic compounds were examined for their ability to inhibit sheep vesicular gland prostaglandin cyclooxygenase. Examination of structure-activity relationships for these compounds indicated that inhibition was increased by ring substituents which were electron donating and by substituents which were hydrophobic. Inhibition was decreased by steric masking of the phenolic hydroxyl. The most potent inhibitors possessed a two aromatic ring structure connected by a short bridge. In these inhibitors, one ring was apolar, the other ring contained a phenolic hydroxyl ortho to the bridge, and the bridge contained a Lewis base such that the compounds could form bidentate metal chelates. Compounds with [I]₅₀ values of less than 10 uM included 2,4,6-trimethyl phenol, 7.2 uM; 2-(2-hydroxyphenyl)benzothiazole, 7.0 uM; 2-benzyloxyphenol, 5.2 uM; and 2-hydroxybenzophenone, 3.8 uM.Inhibition of arachidonate induced platelet aggregation was examined for three of the more potent inhibitors. 2-Benzyloxyphenol and 2,4,6-trimethylphenol were more potent than indomethacin when assayed using a 2 min preincubation of inhibitor with platelets.     

Quantitative structure-activity relationships for the pre-steady state acetylcholinesterase inhibition by carbamates

4-Nitrophenyl-N-substituted carbamates (1) are characterized as pseudosubstrate inhibitors of acetylcholinesterase. The first step is formation of the enzyme-inhibitor tetrahedral intermediate with the inhibition constant (Ki), the second step is formation of the carbamyl enzyme with the carbamylation constant (kc), and the third step is hydrolysis of the carbamyl enzyme with decarbamylation constant (kd). According to pre-steady state kinetics the Ki step is divided further into two steps: (1) formation of the enzyme-inhibitor complex with the dissociation constant (KS) and (2) formation of the enzyme-inhibitor tetrahedral intermediate from the complex with the equilibrium constant (k2/k-2). Since the inhibitors are protonated in pH 7.0 buffer solution, the virtual dissociation constant (KS') of the enzyme-protonated inhibitor complex can be calculated from the equation, -log KS'=-log KS-pKa + 14. The -logKS, -log KS', log k2, and log k-2 values are multiply linearly correlated with the Jave equation (log(k/k0)=rho*sigma* + deltaEs + psi pi). For -log KS'-sigma*-Es)pi-correlation, the rho* value of -0.4 indicates that the enzyme-protonated inhibitor complexes have more positive charges than the protonated inhibitors, the delta value of 0.44 suggests that the bulkily substituted inhibitors lessen the reaction due to the difficulty of the inhibitors to enter the narrow enzyme active site gorge, and the psi value of 0.27 implies that the inhibitors with hydrophobic substituents accelerate the inhibitors entering the active site gorge of the enzyme. For log k2/k-2,-sigma*-Es-pi-correlation, the rho* value of 1.1 indicates that the enzyme-protonated inhibitor tetrahedral intermediates have more negative charges than the enzyme-protonated inhibitor complexes, the delta value of 0.15 suggests that the bulkily substituted inhibitors are difficult to bind into a small acyl binding site of the enzyme, and the psi value of -0.3 implies that the inhibitors with hydrophobic substituents resist binding to the hydrophilic acyl binding site of the enzyme.     

Quantitative structure-activity relationships of cysteine hydrolases. Ficin hydrolysis of X-phenyl-N-methanesulfonyl glycinates

The hydrolysis of ficin of 33 X-Phenyl-N-methanesulfonyl glycinates has been studied. The resulting Km-values have been used to derive a quantitative structure-activity relationship (QSAR). The QSAR for ficin is compared with QSAR for other cysteine hydrolases. The comparisons show that although there are specific differences, overall the reaction mechanisms are very similar.     

Epibatidine structure-activity relationships

Epibatidine is a potent but nonselective nAChR agonist. Its biological effects appear to be mediated largely by alpha4beta2 nAChRs. Surprisingly, only a limited number of epibatidine analogues have been synthesized and evaluated in in vitro assays. Even fewer analogues have received in vivo pharmacological evaluation. In this paper, SAR studies directed toward epibatidine analogues will be reviewed.     

Quantitative structure-activity relationship to predict toxicological properties of benzene derivative compounds

TOPological Sub-structural MOlecular DEsign (TOPS-MODE) was used to assess acute aquatic toxicity of a series of 69 benzene derivatives. The obtained model was able to explain more than 88% of data variance, stressing the importance of molecule hydrophobicity and its dipolar moment, as well as the distance between their bonds to describe the property under study. On the other hand, this model was better than those obtained with Dragon software (Constitutional, Galvez topological charges indices and BCUT) using the same number of variables. This approach proved to be a very good method to assess acute aquatic toxicity of these king of compounds, which could be applied to other series of substances.     

Quantitative structure-activity relationships of nicotine analogues as neuronal nicotinic acetylcholine receptor ligands

Quantitative structure-activity relationships of 34 pyrrolidine-modified nicotine agonists are investigated for their binding affinity toward neuronal nicotinic acetylcholine receptor. The results indicate that a large substituent at the R₁, R₂, and R₃ position is detrimental to the binding affinity. Likewise, a large substituent at the R₂ or R₃ position as well as a hydrogen bond accepting substituent at the R_2β position are not beneficial to the binding.     

Quantitative structure-activity relationships (QSAR) in sweet aspartyl dipeptide methyl esters

In drug design the pharmacochemists frequently use physicochemicalconstants to correlate the structure with the observed potency.Curiously this approach has hardly been followed by psychophysiciststo indicate the increase of taste potency in a series of structurallyrelated compounds of the same stimulus. In the present experiments we correlated the relative sweetness(S) of 40 aspartyl dipeptide methyl esters [general formulaCH₂(COO^–). CH(NH₃⁺ ).CO.NH.CH(R).COOCH₃] with 8 physicochemicalparameters. Among the compounds we had 7 non-sweet stimuli whilethe potency of the remaining 33 peptide esters varied from 1to 27,000 (1 = sucrose). We calculated for the side chain Rthe values of the parachor parameter P, the hydrophobic fragmentalconstant f and 5 STERIMOL parameters (L, B₁ up to B₅). A multipleregression analysis programme selected by stages the most relevantparameters and tested their significance. We observed that the criterion whether a dipeptide ester issweet or not, is among others defined by the L and B₅ parametersof the side chain R. Compounds are sweet provided L is confinedto certain limits (0.50 nm<L<0.62 nm), or otherwise whenL exceeds these limits, the B₅ parameter has to be greater than0.45 nm (when L<0.50 nm) or smaller than 0.72 nm (when L>0.62nm). The sweet potency defined as log S correlated very significantlywith the parameters P and B₄ (n=33, r=0.812, s=0.60, F=29.06).When two compounds, which were shown to be situated at the borderlineof the length and volume parameters, were omitted in the analysis,the correlation improved (n=31, r=0.909, s=0.40, F=42.60). Inthe latter situation we found the following equation when theintercept was set at zero: log S=0.194f + 1.472.10^–2P—3.357B₅ A previously proposed conformation of aspartame (R=CH₂-Øat the receptor site was computed in detail. We calculated thedistances of the AH-B moieties to the third binding site (thecentre of Ø) and indicated the width of the receptoraccess for this series of sweet, structurally related, dipeptidemethyl esters.