Chemical Derivatization and Characterization of Novel Antitrypanosomals for African Trypanosomiasis
Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
molecules
Abstract
The search for novel antitrypanosomals and the investigation into their mode of action
remain crucial due to the toxicity and resistance of commercially available antitrypanosomal drugs. In
this study, two novel antitrypanosomals, tortodofuordioxamide (compound 2) and tortodofuorpyramide
(compound 3), were chemically derived from the natural N-alkylamide tortozanthoxylamide
(compound 1) through structural modification. The chemical structures of these compounds were
confirmed through spectrometric and spectroscopic analysis, and their in vitro efficacy and possible
mechanisms of action were, subsequently, investigated in Trypanosoma brucei (T. brucei), one of the
causative species of African trypanosomiasis (AT). The novel compounds 2 and 3 displayed significant
antitrypanosomal potencies in terms of half-maximal effective concentrations (EC50) and
selectivity indices (SI) (compound 1, EC50 = 7.3 M, SI = 29.5; compound 2, EC50 = 3.2 M, SI = 91.3;
compound 3, EC50 = 4.5 M, SI = 69.9). Microscopic analysis indicated that at the EC50 values, the
compounds resulted in the coiling and clumping of parasite subpopulations without significantly
affecting the normal ratio of nuclei to kinetoplasts. In contrast to the animal antitrypanosomal drug
diminazene, compounds 1, 2 and 3 exhibited antioxidant absorbance properties comparable to the
standard antioxidant Trolox (Trolox, 0.11 A; diminazene, 0.50 A; compound 1, 0.10 A; compound 2,
0.09 A; compound 3, 0.11 A). The analysis of growth kinetics suggested that the compounds exhibited
a relatively gradual but consistent growth inhibition of T. brucei at different concentrations. The
results suggest that further pharmacological optimization of compounds 2 and 3 may facilitate their
development into novel AT chemotherapy
Description
Research Article
Keywords
Trypanosoma brucei, tortodo fuordioxamide, tortodofuorpyramide, ortozanthoxylamide, zanthoxyloides, antitrypanosomal
Citation
https://doi.org/10.3390/ molecules26154488