Human African trypanosomiasis (HAT; sleeping sickness) is a highly neglected disease in sub-Saharan Africa caused by two subspecies of the protozoan parasite Trypanosoma brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense [1]. The parasites are introduced into the mammalian host by the bite of an infected tsetse fly. The disease progresses from a haemolymphatic first stage, during which the parasites are found in the bloodstream, to a meningoencephalitic second stage, on which the parasites enter the central nervous system (CNS), giving rise to the classic symptoms of HAT such as dementia, epileptic attacks, coma, and, if left untreated, death. At the moment, there are five treatments available, although none of them are satisfactory, due to toxicity, treatment failures, and the requirement for parenteral administration that is inappropriate in a rural African setting [2]. Among the five licensed drugs, two are used against stage 1 disease, pentamidine and suramin, whereas against stage 2 disease melarsoprol, eflornithine and a combination of nifurtimox/eflornithine (NECT) can be used. Beyond these issues the lack of a single agent that is effective against both species and both stages leads to the requirement that speciation and staging remain critical aspects of diagnosis, and the therapy must be performed under the difficulty of rural community hospitals. This scenario requires the development of new small molecules aiming at both prevention and control of these parasite infections, since T. brucei has a number of novel metabolic pathways and unusual biological features that are under study for their potential in drug discovery programs. The chemistry of hydrazone-containing compounds is particularly intriguing because of its capability to easily furnish valuable chemotherapeutics such as anticancer, antibacterial, antifungal, and antiprotozoal agents as well as enzyme inhibitors. In continuation of our search for bioactive small molecules, we investigated if the 4-acyl-5-pyrazolone-based hydrazone scaffold would generate novel templates which are likely to exhibit anti-T. brucei activity. The results of this study will be discussed. 1. Cavalli, A.; Bolognesi, M. A. Neglected Tropical Diseases: Multi-Targeted-Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania. J. Med. Chem., 2009, 52, 7339-7359. 2. Jacobs, R. T.; Nare, B.; Phillips, M. A. State of the Art in African Trypanosome Drug Discovery. Curr. Top. Med. Chem. 2011, 11, 1255−1274.

4-acyl-5-pyrazolone-based hydrazones as novel anti-Trypanosoma brucei agents: structural design, synthesis and biological evaluation

PETRELLI, Riccardo;TORQUATI, ILARIA;SCORTICHINI, MIRKO;DI GIOACCHINO, Valentina;PALUMBO, FRANCESCA;BARTELUCCI, LUCA;PETTINARI, Riccardo;CONDELLO, FRANCESCA;PETTINARI, Claudio;MARCHETTI, Fabio;CAPPELLACCI, Loredana
2015

Abstract

Human African trypanosomiasis (HAT; sleeping sickness) is a highly neglected disease in sub-Saharan Africa caused by two subspecies of the protozoan parasite Trypanosoma brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense [1]. The parasites are introduced into the mammalian host by the bite of an infected tsetse fly. The disease progresses from a haemolymphatic first stage, during which the parasites are found in the bloodstream, to a meningoencephalitic second stage, on which the parasites enter the central nervous system (CNS), giving rise to the classic symptoms of HAT such as dementia, epileptic attacks, coma, and, if left untreated, death. At the moment, there are five treatments available, although none of them are satisfactory, due to toxicity, treatment failures, and the requirement for parenteral administration that is inappropriate in a rural African setting [2]. Among the five licensed drugs, two are used against stage 1 disease, pentamidine and suramin, whereas against stage 2 disease melarsoprol, eflornithine and a combination of nifurtimox/eflornithine (NECT) can be used. Beyond these issues the lack of a single agent that is effective against both species and both stages leads to the requirement that speciation and staging remain critical aspects of diagnosis, and the therapy must be performed under the difficulty of rural community hospitals. This scenario requires the development of new small molecules aiming at both prevention and control of these parasite infections, since T. brucei has a number of novel metabolic pathways and unusual biological features that are under study for their potential in drug discovery programs. The chemistry of hydrazone-containing compounds is particularly intriguing because of its capability to easily furnish valuable chemotherapeutics such as anticancer, antibacterial, antifungal, and antiprotozoal agents as well as enzyme inhibitors. In continuation of our search for bioactive small molecules, we investigated if the 4-acyl-5-pyrazolone-based hydrazone scaffold would generate novel templates which are likely to exhibit anti-T. brucei activity. The results of this study will be discussed. 1. Cavalli, A.; Bolognesi, M. A. Neglected Tropical Diseases: Multi-Targeted-Directed Ligands in the Search for Novel Lead Candidates against Trypanosoma and Leishmania. J. Med. Chem., 2009, 52, 7339-7359. 2. Jacobs, R. T.; Nare, B.; Phillips, M. A. State of the Art in African Trypanosome Drug Discovery. Curr. Top. Med. Chem. 2011, 11, 1255−1274.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/391590
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