Design, synthesis and cruzain docking of 3-(4-substituted-aryl)-1,2,4-oxadiazole-N-acylhydrazones as anti-Trypanosoma cruzi agents

Abstract

Research in recent years has demonstrated that the Trypanosoma cruzi cysteine protease cruzain (TCC) is a valid chemotherapeutic target, since inhibitors of this protease affect the pathology appropriately. By exploring the N-acylhydrazones (NAH) as privileged structures usually present in antiparasitic agents, we investigated a library of 16 NAH bearing the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold (NAH 3a-h, 4a-h). The in vitro bioactivity against epimastigote and trypomastigote forms of T. cruzi was evaluated, and some NAH under study exhibited antitrypanosomal activity at concentrations that are not toxic to mammalian cells. The series of compounds based on the 3-(4-substituted-aryl)-1,2,4-oxadiazole scaffold revealed the remarkable importance of each substituent at the phenyl's 4-position for the inhibitory activity. Non-nitrated compounds 3a and 4e were found to be as potent as the reference drug, Benznidazole. In addition, the molecular origin of the antitrypanosomal properties for these series was investigated using docking studies of the TCC structure.

Optimization of peptidyl allyl sulfones as clan CA cysteine protease inhibitors

“…To date, a number of cysteine protease inhibitors have been developed using a variety of reactive functional groups 31 , also referred to as "warheads, " including aldehydes 20 , fluoromethyl ketones 21 , nitriles 32 , α-ketoesters, amides, and acids 33 , tetrafluorophenoxymethyl ketones 34 , epoxysuccinates 35 , thiosemicarbazones 36 , hydrazone derivatives 37,38 , vinyl sulfones 39 and allyl sulfones 40 . These warheads are attached to either a peptidyl or peptidomimetic scaffold 16,41 .…”

Biological Potential of Synthetic Hydrazones in the Last Decade: A Systematic Review

“…9,21,22,24, [28][29][30] As investigações biológicas feitas na última década revelam a versatilidade dessa classe de compostos que, a depender das modificações estruturais, apresentam um amplo espectro de atividades.…”

Novel Therapeutic Strategies for Chagas` Disease

“…Knowledge of the Cz crystal structure has promoted the design of a variety of cysteine peptidase inhibitors including peptidyl and non-peptidyl inhibitors. Among peptidyl inhibitors, the irreversible inhibitor, N-acylhydrazone has been studied (Ifa, 2000;dos Santos Filho, 2009), as well as the halomethyl ketone based (Ashall, 1990;Harth, 1993), diazomethane ketones (Shaw, 1994;Lalmanach, 1996), vinyl sulfones (Roush, 2001;Engel, 1998;Barr, 2005;Jacobsen, 2000), and reversible inhibitors such as oxadiazoles (Ferreira,2009), and aryl ureas (Du, 2000). In the non-peptidyl group thiosemicarbazones (Du, 2002), triazole, triazine nitriles (Brak, 2010;Mott, 2010) and non-peptidic vinylsulfones ) can be found some of which are presented in Table 4.…”