Abstract
Human African Trypanosomiasis (HAT) also called sleeping sickness is caused by subspecies of the parasitic hemoflagellate Trypanosoma brucei that mostly occurs in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which have been developed more than 30 years ago, have undesirable toxic side effects and most of them show drug-resistance. Though development of new anti-trypanosomal drugs seems to be a priority area research in this area has lagged far behind. The given review mainly focus upon the recent synthetic and computer based approaches made by various research groups for the development of newer anti-trypanosomal analogues which may have improved efficacy and oral bioavailability than the present ones. The given paper also attempts to investigate the relationship between the various physiochemical parameters and anti-trypanosomal activity that may be helpful in development of potent anti-trypanosomal agents against sleeping sickness.
Highlights
African sleeping sickness remains one of the most neglected life threatening diseases that have been left untreated till date
This review focuses on the synthetic and computer-assisted drug design (CADD) approaches made by various research groups for the development of newer antitrypanosomal agents having improved efficacy and oral bioavailability
The results shows that N, S-blocked glutathione diesters are the most active inhibitors of T. brucei parasites and that N-acetyl-S-benzyloxycarbonylglutathione dimethyl ester and the N,S-benzyloxycarbonyl-S-2,4dinitrophenylglutathione diester derivatives (Figure 30) represent lead structures possessing minimal toxicity which potentially could be developed further to yield a therapeutically active agent for the treatment of trypanosomiasis
Summary
African sleeping sickness remains one of the most neglected life threatening diseases that have been left untreated till date. The introduction of methoxy group on the aromatic rings of compound 32 resulted into compound 41 (Figure 13b) with comparable anti-trypanosomal activity (4.2 nM) as that of furamidine These compounds of the isoxazole series that showed good in vitro antitrypanosomal activity and less cytotoxcity profile relative to furamidine, could be a candidate for further evaluation against animal models of the diseases. Those molecules that showed an excellent in vitro activity as well as high selectivity for the parasite represent new anti-trypanosomal lead compounds In light of these promising results, bis(2-aminoimidazoline) derivatives deserve more investigation as anti-trypanosomal agents and DNA minor groove binders. The synthesis and study of new derivatives and prodrugs of these lead compounds is ongoing
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