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

Abstract

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 Objective: Herein, we report the synthesis of seven analogues, three of them unpublished, their biological investigation against Schistosoma mansoni and Target Fishing studies.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.

Antiparasitic Properties of Cardiovascular Agents against Human Intravascular Parasite Schistosoma mansoni

“…Thus, our data suggest that amiodarone should have antischistosomal properties under its current antiarrhythmic drug regimen. Although the amiodarone is commonly used in clinical practice, the risk of adverse effects acts as a limiting factor to its utilization [34][35][36][37][38][39][40][41][42][43][44][45][46][47]. As community-wide treatment would be expected at least in most endemic areas for schistosomiasis, this would be a problem.…”

“…As community-wide treatment would be expected at least in most endemic areas for schistosomiasis, this would be a problem. However, many of the safety issues reported in clinical studies with amiodarone are especially in the long term [ 47 ]. If effective against schistosomes, the use of amiodarone orally in a single dose or daily for 3–5 days may be advantageous.…”

“…All data from the in vitro anthelmintic experiments are presented as the mean ± standard deviation (SD) of at least three independent assays. EC 50 and EC 90 values were calculated using sigmoid dose–response curves and 95% confidence intervals [ 46 , 47 ]. The overall survival of the adult schistosomes was determined by comparison using Kaplan–Meier survival curves and the log rank (Mantel–Cox) test [ 12 ].…”

Evaluation of Gibbilimbol B, Isolated from Piper malacophyllum (Piperaceae), as an Antischistosomal Agent

“…Values were expressed as percentage of the control and the results were used to calculate the CC 50 values. The selectivity index (SI) was determined by the CC 50 /EC 50 ratio [44] …”

Recent Advances in Medicinal Chemistry to Treat Filariasis and Helminthiasis

“…Target fishing studies pointed out some probable targets, such as the serine-threonine kinases, dihydroorotate dehydrogenases and carbonic anhydrase II. The GPQF-407 can be easily synthesized on large scale from commercially available materials [4].…”