RESUMO
Schistosomiasis is one of the most prevalent infectious diseases worldwide and classified as a neglected disease for which there is an urgent need for searching new drug candidates. According to TDR/WHO, existing leads with proven schistosomicidal activity, like meclonazepam, might be the objects of further exploration. Here, we decided to investigate if the benzodiazepine binding sites that we recently characterized in adult Schistosoma mansoni could represent the molecular target of meclonazepam for its effect on worm motility and morphological appearance. The EC(50) of meclonazepam for its contracturant effect is 10-20 times lower than its IC(50) for binding to the worm benzodiazepine binding sites. On the contrary, benzodiazepines like flunitrazepam and diazepam have affinities at least 50 times higher than meclonazepam for these binding sites but did not induce contraction of the worms. We also confirmed the existence of a great similarity between the appearance, kinetics, Emax and external calcium dependency of the contractile effect of praziquantel and meclonazepam. Based on computer-aided molecular modeling calculations, we verified that a certain structural similarity exists between the active enantiomers of both drugs. We further proposed the hypothesis of common pharmacophoric elements including amide and imine subunits and the asymmetric carbons of S-(+)-meclozepam and R-(-)-praziquantel. As a whole, the present data indicate that the contracturant effect of meclonazepam is not a result of its binding to the worm benzodiazepine binding sites but that it shares some basic transduction pathway with praziquantel, even if not through identical molecular targets or binding sites.
Assuntos
Benzodiazepinonas/farmacologia , Músculos/efeitos dos fármacos , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/metabolismo , Animais , Benzodiazepinas/metabolismo , Benzodiazepinonas/química , Benzodiazepinonas/metabolismo , Sítios de Ligação , Cálcio/metabolismo , Técnicas In Vitro , Isoquinolinas/metabolismo , Isoquinolinas/farmacologia , Masculino , Modelos Moleculares , Conformação Molecular , Movimento/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Músculos/metabolismo , Músculos/fisiologia , Praziquantel/química , Praziquantel/metabolismo , Praziquantel/farmacologia , Receptores de GABA-A/metabolismo , Schistosoma mansoni/fisiologia , Transdução de Sinais/efeitos dos fármacos , Coloração e RotulagemRESUMO
The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p-chloro, p-methoxy, and m-chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p-aminosalicylic acid. Several physicochemical descriptors (including Hammett's sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol-L and -B4 and molecular volume) were considered to elucidate structure-activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi-empirical method. Among the new derivatives, m-chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p-aminosalicylic acid analogs.