Microbiological Evaluation of 4-substituted-imidazolidine Derivatives
In the present studies, two series of 4-substituted-imidazolidines (IIIa-i and IIIj,k) were synthesized by reacting different tetrahydro-di-Schiff bases (IIa-i and IIj,k) with p-diethylaminobenzaldehyde/ dimethylaminobenzaldehyde. The title compounds were evaluated for their antibacterial and antifungal actions against some selected microbes. The results of microbiological evaluation revealed that two compounds, 4-(1,3-bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin-2-yl)-N,N-diethyl aniline (IIIj), 4-(1,3-bis(benzo[d][1,3]dioxol-5-ylmethyl)-4-methylimidazolidin-2-yl)-N,N-dimethyl aniline (IIIk) were good in their antibacterial as well as antifungal actions. Minimum inhibitory concentration values (MIC) of the compounds are reported.
Biological and immunological activity of new imidazolidines against adult worms of Schistosoma mansoni
The only drug available for treating schistosomiasis is praziquantel, however there are already reports of resistance to its use in treatment, making it necessary to search and develop new compounds to combat schistosomiasis. We tested, in vitro, two new products, Laboratório de Planejamento de Síntese de Fármacos (LPSF)/5-(4-chloro-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-2) and LPSF/5-(4-fluoride-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one (RZS-5) imidazolidines, against adult worms of Schistosoma mansoni. Efficacy and safety of these compounds were analyzed through IC50 cytotoxicity, immune response and cell viability tests. At different concentrations ranging from 40–640 µM, the imidazolidines produced motor abnormalities, inhibition of pairing and oviposition and mortality within 24 h at the higher concentrations. Although not triggering changes in IFN-γ and IL-10, LPSF/RZS-2 and LPSF/RZS-5 induced production of nitric oxide and showed similar behavior to praziquantel in the cell death test.
Histone deacetylase inhibitors induce apoptosis, histone hyperacetylation and up-regulation of gene transcription in Schistosoma mansoni.
In order to explore the conservation/divergence of transcriptional regulation in the platyhelminth parasite Schistosoma mansoni, we are studying the structures and functions of transcriptional mediators and in particular histone-modifying enzymes. Reversible histone acetylation changes chromatin structure and modulates gene transcription. The removal of acetyl residues from histones and other proteins is catalyzed by histone deacetylases (HDACs) that are under increasing study as therapeutic targets, both in cancer and parasitic diseases. In order to determine the extent and importance of histone acetylation in S. mansoni, we tested the effects of three histone deacetylase inhibitors (HDACi) on both larval and adult worms in culture. Trichostatin A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) inhibited global HDAC activity at all life-cycle stages. TSA and VPA, but not SAHA, caused mortality of schistosomula and adults, with TSA showing the most rapid effect. Moreover, TSA caused an increase in apoptosis in schistosomula shown by the TUNEL assay and an increase in caspase 3/7 activity. Both TSA and VPA were shown to cause an increase in general levels of protein acetylation in schistosomes; more particularly of histone 4 whereas histone 3 acetylation was less affected. In the case of TSA treatment this histone hyperacetylation was correlated with the increased expression of caspases 3 and 7 transcripts. Finally, quantitative chromatin immunoprecipitation showed that the proximal promoter region of the S. mansoni caspase 7 gene was hyperacetylated on histone H4 after TSA treatment.