Synthesis and biological evaluation of novel imidazolidine derivatives as candidates to schistosomicidal agents

ABSTRACT Introduction: Schistosomiasis is an infectious parasitic disease caused by trematodes of the genus Schistosoma, which threatens at least 258 million people worldwide and its control is dependent on a single drug, praziquantel. The aim of this study was to evaluate the anti-Schistosoma mansoni activity in vitro of novel imidazolidine derivatives. Material and methods: We synthesized two novel imidazolidine derivatives: (LPSF/PTS10) (Z)-1-(2-chloro-6-fluorobenzyl)-4-(4-dimethylaminobenzylidene)-5-thioxoimidazolidin-2-one and (LPSF/PTS23) (Z)-1-(2-chloro-6-fluoro-benzyl)-5-thioxo-4-(2,4,6-trimethoxy-benzylidene)-imidazolidin-2-one. The structures of two compounds were determined by spectroscopic methods. During the biological assays, parameters such as motility, oviposition, mortality and analysis by Scanning Electron Microscopy were performed. Results: LPSF/PTS10 and LPSF/PTS23 were considered to be active in the separation of coupled pairs, mortality and to decrease the motor activity. In addition, LPSF/PTS23 induced ultrastructural alterations in worms, after 24 h of contact, causing extensive erosion over the entire body of the worms. Conclusion: The imidazolidine derivatives containing the trimetoxy and benzylidene halogens showed promising in vitro schistosomicidal activity.

New imidazolidinic bioisosters: potential candidates for antischistosomal drugs

The emergence of strains of Schistosoma resistant to praziquantel has drawn attention to the search for new schistosomacide drugs. Imidazolidinic derivatives have performed outstandingly against adult S. mansoni worms when evaluated in vitro. The molecular modification of imidazolidine by way of bioisosteric replacement gives rise to variations in its biological response. This study verifies the potential of substituent groups in the derivatives (Z)3-benzyl-5-(2-fluoro-benzylidene)-imidazolidine-2,4-dione NE4, 3-benzyl-5-(4-chloro-arylazo)-4-thioxo-imidazolidin -2-ona PT5, 3-benzyl-5-(3-fluoro-benzylidene)-1-methyl-2-thioxo-imidazolidin-4-one JT53; 3-benzyl-1-methyl-5-(4-methyl-benzylidene)-2-thioxo-imidazolidin-4-one JT63; 3-benzyl-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo -imidazolidin-4-one JT68; 3-(4-chloro-benzyl)-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo-imidazolidin-4-one JT69; 3-(4-phenyl-benzyl)-1-methyl-5-(4-methoxi-benzylidene)-2-thioxo-imidazolidin-4-one JT72 by determining the viability in vitro of adult S. mansoni worms in the presence of these derivatives. The susceptibility of the worms obtained from mice and kept in culture in the presence of different concentrations was determined by way of schistosomacide kinetic, observed every 24 h over a period of eight days. The results show that the worms were more sensitive to the PT5 derivative at a concentration of 58 æM which killed 100 percent of the worms after 24 h of contact, also giving rise to alterations in the tegument surface of the worms with the formation of bubbles and peeling. These observations suggest a strong electronic contribution of the arylazo grouping in the biological response.

Synthesis and antischistosomal activity of some new thiazolidinones and 1,3,4-thiadiazoline

In this study, new series of thiazolidinones 3a-e was synthesized by the cyclocondensation of the Schiff bases 2a-e with mercaptoacetic acid. The thiadiazole 5 was obtained by refluxing 4 with carbondisulfide. The antischistosomal activity was determined for the new representative compounds

Reactions with maleimides, IX+: Synthesis and antischistosomal activity of several new pyrrolidino [3,4-b] benzthiazolo [3',2'-a'] -pyridinedione derivatives

Several new pyrrolidino [3,4-b] benzothiazolo [3',2'-a'] pyridinedione derivatives were synthesized via the dipolar cycloaddition reaction of several 2-benzothiazolylacrylonitriles with several N-arylmaleimides. The antischistosomal activity of a variety of these derivatives is tested. Structures are based on elemental and spectral data

Niridazole prodrugs: Synthesis, characterization and hydrolysis kinetics of some N-acyloxymethyl niridazoles

A series of 3-acyloxymethylniridazole have been prepared by acylation of 3-hydroxymethylniridazole. The structure of the prepared compounds was confirmed by IR, 1 H-NMR and elemental analysis. They were also evaluated with regard to water solubility, partition coefficient, hydrolysis kinetics and enzymatic cleavage. The water solubility of some of these prodrugs was markedly improved over that of niridazole. Meanwhile, their lipid solubility was comparable with that of the parent drug. In vitro chemical stability of all the synthesized prodrugs was studied at different pH-values, as well as in 80% human plasma for one of themas representative example to assess its cleavage enzymatically to the parent drug, in both cases a strict first- order hydrolysis kinetics was observed. The t 1/2 values varied with variation of the acyl-moiety. The obtained results show as significant improvement in physicochemical properties of the products relative to the parent drug

Preparación y caracterización de pro-fármacos del Praziquantel potencialmente esquistosomicidas / Preparation and characterization of pro-drugs of the Praziquantel potentially schistosomicidal

Se reporta la preparación y acción esquistosomicida de nuevos profármacos obtenidos mediante la reacción de Mannich. Se emplearon en la formación de las bases de Mannich cantidades equimoleculares de praziquantel y distintos compuestos amínicos como benznidazol, morfolina, oxamniquina y piperazina con solución de formaldehido. Los productos obtenidos fueron analizados por microanálisis, espectroscopía al infrarrojo (IR) y resonancia magnética nuclear 1-HRMN. Los pro-fáremacos mostraron mayor liposolubilidad que el fármaco de origen. La actividad esquistosomicida en cepa de Schistosoma mansoni fue determinada experimentalmente en ratones. In vivo fue comprobada la mayor actividad schistosomicida de tres de los profármacos sintetizados en comparación con el sustrato no modificado