Schiff bases of 4-Phenyl-2-Aminothiazoles as hits to new antischistosomals: Synthesis, in vitro, in vivo and in silico studies.

The treatment of schistosomiasis is based on a single drug, the praziquantel (PZQ), an oral bioavailable and efficient agent which causes minimal side effects. The main concern about this approach, however, is that relying on only one drug to treat a helminthic disease is a dangerous strategy since history shows that pathogens easily evolve to resistant forms. Actually, reports about experimental strains exhibiting low sensibility to PZQ can be found in literature. The search for new antischistosomals, consequently, is urgent. Here we report the synthesis of seventeen Schiff bases of 4-(4-Substituted phenyl)-N-(4-substituted benzylidene)thiazole-2-amines which were tested in vitro and in vivo against Schistosoma mansoni adult worms. Moreover, in silico studies to propose potential macromolecular targets and to predict the oral bioavailability were also performed. The analog GPQF-108 exhibited the best in vitro performance (IC50: 29.4 µM, SI:6.1) associated with promising in vivo activity, with a significant decrease in the adult life forms and oviposition. Oral bioavailability could be impaired by the predicted low water solubility of GPQF-108, although it also exhibited good membrane permeability. The water solubility, however, could be improved by decreasing the particles size. Serine/Threonine- and Tyrosine Kinases, Carbonic Anhydrase, Tyrosine Phosphatase and Arginase were predicted as potential macromolecular targets through which the GPQF-108 could be acting against the helminth. This class of compounds exhibited an interesting initial therapeutic profile with the advantage of being chemically diverse from the PZQ and be easily synthesized from commercial reagents which could lead to low-cost drugs. These aspects make this class of compounds interesting hits to be explored against schistosomiasis.

Vanillin-Related N-Acylhydrazones: Synthesis, Antischistosomal Properties and Target Fishing Studies.

BACKGROUND: Schistosomiasis is a neglected disease, which affects millions of people in developing countries. Its treatment relies on a single therapeutic alternative, the praziquantel. This situation may lead to drug resistance which, in turn, made urgent the need for new antischistosomal agents. Nacylhydrazones are usually explored as good antimicrobial agents, but the vanillin-related N-acylhydrazones have never been tested by their antiparasitic potential. OBJECTIVE: Herein, we report the synthesis of seven analogues, three of them unpublished, their biological investigation against Schistosoma mansoni and Target Fishing studies. METHODS: The compounds were synthesized following classical synthetical approaches. The anthelmintic potential was assessed as well as their cytotoxicity profile. Confocal laser scanning microscopy and target fishing study were performed to better understand the observed antischistosomal activity. RESULTS: Compound GPQF-407 exhibited good antischistosomal activity (47.91 µM) with suitable selectivity index (4.14). Confocal laser scanning microscopy revealed that it triggered severe tegumental destruction and tubercle disintegration. Target fishing studies pointed out some probable targets, such as the serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II. CONCLUSION: The GPQF-407 was revealed to be a promising antischistosomal agent which, besides presenting the N-acylhydrazone privileged scaffold, also could be easily synthesized on large scales from commercially available materials.