Synthesis of 2-amine/2-hydrazinethiazoles as potential schistosomicidals

Abstract

Schistosomiasis is a parasitic disease caused by species of the genus Schistosoma, which reaches approximately 218 million people worldwide, according to the World Health Organization. Considered a neglected disease for not arousing the interest of the large pharmaceutical industries, its treatment is currently based on a single drug, praziquantel, which despite being safe and effective in the treatment of schistosomiasis, has no activity against the immature forms of the parasite and, in addition, as it is commonly used as a prophylactic, it has an imminent risk of suffering resistance from the genus Schistosoma. This way, this project proposes the synthesis of 8 compounds derived from 2-aminothiazoles and 2-hydrazinothiazoles, which may be potential schistosomicidal agents. The molecules proposed have a thiazolic scaffold, which has been explored by the Chemical-Pharmaceutical Research Group of UNIFESP (GPQFfesp), in recent years in search of new schistosomicides and has promising results. The choice of these derivatives was based on the the similarity with compounds explored in the literature - such as thiosemicarbazides and thiazois - that act on cathepsin B1 from S. mansoni, which significantly influences the nutrition, development and production of new individuals of the worm. The compounds to be synthesized will also allow the exploration of sulfonamide and nicotinic derivatives in addition to the thiazole scaffold, since they are privileged structures from the chemical-medicinal point of view. To perform the synthetic steps, it is proposed to apply the classic Hantzsch reaction to obtain 2-aminothiazois intermediates and to use alpha-bromoacetophenone synthesis to obtain 2-hydrazinothiazois intermediates, followed by reaction with specific acyl chlorides to couple the sulfonamide or nicotinic groups to the central skeleton of the structures. After syntheses, the compounds are expected to be active against both mature and immature forms of S. mansoni.