Structure-activity relationships and mechanism of action of tetragomycin derivatives as inhibitors of Staphylococcus aureus staphyloxanthin biosynthesis.

Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S. aureus virulence. Herein, we report the inhibitory profile of 27 tetrangomycin derivatives over staphyloxanthin production. The experimental result showed that naphthoquinone dehydro-α-lapachone (25 - EC50 = 57.29 ± 1.15 µM) and 2-Isopropylnaphtho[2,3-b]furan-4,9-dione (26 EC50 = 82.10 ± 1.09 µM) are the most potent compounds and suggest that hydrogen acceptor groups and lipophilic moieties decorating the naphthoquinone ring are crucial for STXBI. In addition, we present an in situ analysis, through RAMAN spectroscopy, that is inexpensive and might be employed to probe the mechanism of action of staphyloxanthin biosynthesis inhibitors. Therefore, our molecular simplification strategies afforded promising lead compounds for the development of drugs that modulate S. aureus staphyloxanthin biosynthesis.

Molecular dynamics of dibenz[a,h]anthracene and its metabolite interacting with lung surfactant phospholipid bilayers.

The interaction of dibenz[a,h]anthracene and its ultimate carcinogenic 3,4-diol-1,2-epoxide with lung surfactant phospholipid bilayers was successfully performed using molecular dynamics. The DPPC/DPPG/cholesterol bilayer (64 : 64 : 2) was used as the lung surfactant phospholipid bilayer model and compared with the DPPC bilayer as a reference. Dibenz[a,h]anthracene and its 3,4-diol-1,2-epoxide were inserted in water and lipid phases in order to investigate their interactions with the lung surfactant phospholipid bilayers. The radial distribution function between two P atoms in polar heads shows that the 3,4-diol-1,2-epoxide affects the order between the P atoms in the DPPC/DPPG/cholesterol model more than dibenz[a,h]anthracene, which is a consequence of its preference for the polar heads and dibenz[a,h]anthracene prefers to be located in the hydrocarbon chain of the phospholipid bilayers. Dibenz[a,h]anthracene and its 3,4-diol-1,2-epoxide may form aggregates in water and lipid phases, and in the water-lipid interface. The implications for the possible effect of dibenz[a,h]anthracene and its 3,4-diol-1,2-epoxide in the lung surfactant phospholipid bilayers are discussed.

Synthesis and antiplasmodial activity of some 1-azabenzanthrone derivatives.

Some synthetic 1-azabenzanthrones (7H-dibenzo[de,h]quinolin-7-ones) are weakly to moderately cytotoxic, suggesting that they might also show antiparasitic activity. We have now tested a small collection of these compounds in vitro against a chloroquine-resistant Plasmodium falciparum strain, comparing their cytotoxicity against normal human fibroblasts. Our results indicate that 5-methoxy-1-azabenzanthrone and its 2,3-dihydro analogue have low micromolar antiplasmodial activities and showed more than 10-fold selectivity against the parasite, indicating that the dihydro compound, in particular, might serve as a lead compound for further development.

Chemometrics-assisted excitation-emission fluorescence spectroscopy on nylon membranes. Simultaneous determination of benzo[a]pyrene and dibenz[a,h]anthracene at parts-per-trillion levels in the presence of the remaining EPA PAH priority pollutants as interferences.

This work presents a novel approach for the simultaneous ultratrace determination of benzo[ a]pyrene and dibenzo[ a,h]anthracene, the two most carcinogenic polycyclic aromatic hydrocarbons (PAHs), in a very interfering environment, combining the recently discovered ability of the nylon membrane to strongly retain and concentrate PAHs on its surface, the sensitivity of molecular fluorescence, and the selectivity of second-order chemometric algorithms. The fluorescence excitation-emission matrices, directly measured on a nylon-membrane surface, are processed by applying parallel factor analysis (PARAFAC) and unfolded partial least-squares coupled to residual bilinearization (U-PLS/RBL). The superiority of U-PLS/RBL to quantify BaP and DBA at concentrations below 10 ng L (-1) in the presence of the remaining 14 US EPA (United States Environmental Protection Agency) PAHs at total concentrations ranging from 1400 and 14,000 ng L (-1) is demonstrated. The present method successfully faces this complex challenge without using organic solvents, which are to known produce environmental contamination. Finally, the high sensitivity of the present method avoids preconcentration and elution steps, considerably decreasing the analysis time and the experimental errors. Because the instrumental involved in the determination is nonsophisticated, the experiments could be carried out in routine laboratories.

Carbocations from oxidized metabolites of benzo[a]anthracene: a computational study of their methylated and fluorinated derivatives and guanine adducts.

Structure-reactivity relationships and substituent effects on carbocation stability in benzo[a]anthracene (BA) derivatives have been studied computationally at the B3LYP/6-31G and MP2/6-31G levels. Bay-region carbocations are formed by O-protonation of the 1,2-epoxides in barrierless processes. This process is energetically more favored as compared to carbocation generation via zwitterion formation/O-protonation, via single electron oxidation to generate a radical cation, or via benzylic hydroxylation. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). Charge delocalization mode in the BA carbocation framework was deduced from NPA-derived changes in charges, and substitution by methyl or fluorine was studied at different positions selected on basis of the carbocation charge density. A bay-region methyl group produces structural distortion with consequent deviation from planarity of the aromatic system, which destabilizes the epoxide, favoring ring opening. Whereas fluorine substitution at sites bearing significant positive charge leads to carbocation stabilization by fluorine p-pi back-bonding, a fluorine atom at a ring position which presented negative charge density leads to inductive destabilization. Methylated derivatives are less sensitive to substituent effects as compared to the fluorinated analogues. Although the solvent decreases the exothermicity of the epoxide ring-opening reactions due to greater stabilization of the reactants, it provokes no changes in relative reactivities. Relative energies in the resulting bay-region carbocations are examined taking into account the available biological activity data on these compounds. In selected cases, quenching of bay-region carbocations was investigated by analyzing relative energies (in the gas phase and in water) and geometries of their guanine adducts formed via covalent bond formation with the exocyclic amino group and with the N-7.

Structure-activity relationships of several anisidine and dibenzanthracene isomers in the w/w+ somatic assay of Drosophila melanogaster.

Several structurally related anisidine and dibenzanthracene isomers were evaluated for genotoxic effects in the somatic w/w+ assay of Drosophila melanogaster employing insecticide-susceptible (IS) and insecticide-resistant (IR) tester strains. In addition, and in order to find whether or not at the genetic level a regulatory effect is found, crosses between ISxIR strains and IRxIS strains were done. Chemicals tested were the aromatic amines (AAs) ortho-anisidine (o-AN), meta-anisidine (m-AN), and para-anisidine (p-AN) and the polycyclic aromatic hydrocarbons (PAHs) 1,2;3,4-dibenzanthracene (1,2;3,4-DBA) and 1,2;5,6-dibenzanthracene (1,2;5,6-DBA). As positive control N-nitrosodimethylamine (DMN) was used. Our results show that the genotoxic activity of DMN was higher in the IR than in the IS strain. There seems to be a tendency for slightly lower values as measured by clone induction in crosses between ISxIR and IRxIS. o-AN was positive in the IS strain and in crosses between ISxIR and IRxIS but negative in the IR strain. m-AN, p-AN and 1,2;3,4-DBA proved to be not recombinogenic in all strains and crosses while 1,2;5,6-DBA was positive at the highest concentration tested in all the crosses assayed. These findings show that the recombinogenic activity of the anisidine isomers depends on the position of the chemical group relative to one another and that the position of the benzene ring seems to be structurally relevant for genotoxicity of DBA isomers. With respect to IR and IS strains it remains to be determined to what extent the spectrum of metabolizing capacity really differs between the strains of the test assay. Thus more information is needed about the regulation and expression of the cytochrome-P450 genes and action at the molecular level taking place in the eye imaginal disc as well as between insecticide susceptible and resistant strains after exposure to genotoxic chemicals.