Alkoxy Side Research Articles

Activation of benzoate model prodrugs by mycobacteria. Comparison with mammalian plasma and liver hydrolysis

Due to difficulties in drug penetration in M. tuberculosis, a prodrug approach based on mycobacterial activation appears as a promising strategy to increase the delivery of antitubercular drugs to the target microorganisms. Esters have been successful used by us and others to deliver drugs to mycobacteria, however because very little is known about the metabolic hydrolysis of esters by mycobacteria in connection with prodrug activation, we decided to study the process further. For that we selected a series of 13 benzoates with different chain lengths and ramifications in the alkoxy side as model prodrugs and examined their hydrolysis by a mycobacterial homogenate, comparing the results with those obtained parallelly in human plasma and in total rat liver homogenate. In all biological media, the benzoates with a linear alkyl group showed a parabolic dependence between log(k) and logP (or the number of carbons of the linear alkyl chain) that reached a maximal value for the n-butyl chain. Considering linear correlations for the total number of compounds between log(k) and chosen descriptors, for mycobacterial esterases, pKa of the leaving alcohol (pKaLG) seem to be the most important descriptor. Plasma esterases seem to be quite sensitive to the Taft polarity parameter σ* and also to pKaLG and less sensitive to steric effects. Liver esterases seem to be more sensitive to the Taft steric descriptor ESc. Lipophilicity correlates weakly with log(k) in all the 3 media, however, is more important when one looks for mycobacterial activation selectivity in relation to plasma metabolism or in relation to liver homogenate metabolism. The importance of lipophilicity increases further when biparametric expressions are considered. We showed that it is easy to activate a wide variety of benzoate esters using a mycobacterial homogenate. The data also suggest that with careful design is possible to obtain tuberculostatic prodrug esters sensitive to mycobacterial hydrolases while reasonably resistant to plasma and liver hydrolysis. One important observation is that mycobacterial hydrolysis is less affected by bulky substituents than liver homogenate or plasma hydrolysis. tert-Butyl is probably the substituent in the alkoxy side that seems more adequate to resist simultaneously plasma and liver metabolism, while allowing activation by mycobacterial esterases. Hexyl is also a good option for the medicinal chemist if a linear alkoxy chain is needed.

Photoinduced charge separation in poly(1,4-phenylenevinylene) derivatives studied by electron paramagnetic resonance

We report a study of photoinduced charge separation in poly(1,4-phenylenevinylene) (PPV) derivatives with enhanced exciton dissociation using light-induced electron paramagnetic resonance (EPR). Four polymers were studied; all contained alkoxy and fluorenyl side chain units, and two of them also contained a nitro group on the 7-positon of the fluorenyl moieties. Pulsed EPR detected a light induced polaron for all the polymers with the intensity significantly higher for those with nitro groups. A second center was observed for these materials and spectra could be fitted assuming a radical anion was localized on the nitro groups. The fraction of radical anion and polaron centers was comparable, consistent with intramolecular exciton dissociation for the PPV derivatives containing the nitro groups.

ChemInform Abstract: A Series of Mono and Diesters of Itaconic Acid: Synthesis and Structural Determination.

A series of mono and diesters of itaconic acid containing alkoxy and sulfide side chains of variable lengths has been synthesized. Their structures have been established on the basis of their spectral data.

Neutron scattering by liquid crystals. A new analysis

Abstract This paper presents a new analysis of all (old and new) quasi-elastic neutron scattering results obtained for seven members of the PAA series (n = 1,…, 7). The analysis is based upon a discussion of the parameter p, which is the deviation of the intensity of the elastic component from the intensity demanded by a reorientational model. If the value of this parameter is negative, it may be interpreted as an indication of an additional motion which has not been taken into account in the model. The first model analysed in this way for all seven substances in the nematic phase was that of the rotational diffusion of the whole molecule in its stretched (trans) conformation, around the long axis. A very large negative values of p (p ≊ -60 per cent) was obtained, clearly showing that some motions have been neglected. The second model was that of the rotational diffusion of moieties consisting of benzene rings plus alkoxy side-chains. The diffusion occurs around the benzene para-axes, and the alkoxy side-...