Abstract
Chagas, or American trypanosomiasis, remains an important public health problem in developing countries. In the last decade, trans-sialidase has become a pharmacological target for new anti-Chagas drugs. In this work, the aims were to design and find a new series of benzoic acid derivatives as trans-sialidase (TS) inhibitors and anti-trypanosomal agents. Three compounds (14, 18, and 19) sharing a para-aminobenzoic acid moiety showed more potent trypanocidal activity than the commercially available drugs nifurtimox and benznidazole in both strains: the lysis concentration of 50% of the population (LC50) was <0.15 µM on the NINOA strain, and LC50 < 0.22 µM on the INC-5 strain. Additionally, compound 18 showed a moderate inhibition (47%) on the trans-sialidase enzyme and a binding model similar to DANA (pattern A).
Highlights
Chagas disease, or American trypanosomiasis, is a chronic disease caused by the kinetoplastid protozoan parasite Trypanosoma cruzi
In order to address this major health two drugs currently used for the treatment of Chagas disease, they are not effective against issue,itsnew anti-Chagas directed to different targets are being in order chronic form [16],drugs diminish in efficacy the longer a person has designed been infected
It is noteworthy that compound 18 showed nanomolar trypanocidal activity against the NINOA strain (20 nM), whereas compounds 11 and 17 displayed similar Trypanosoma cruzi trans-sialidase (TcTS) inhibition to pyridoxal and compound 16 showed the best inhibitory activity
Summary
American trypanosomiasis, is a chronic disease caused by the kinetoplastid protozoan parasite Trypanosoma cruzi. 17 only amine-1,1-dioxide, Nfx), launched by Bayer in 1967 and Roche in 1972, respectively, are of the two drugs currently used for the treatment of Chagas disease, they are not effective yl)acetamide, Bnz) and nifurtimox (3-methyl-N-[(5-nitrofuran-2-yl)methylidene]thiomorpholinagainst its chronic form [16], diminish in efficacy the longer a person has been infected [12], and the. TcTS aids in the protection from recognition by the host’s immune system [24], and (ii) resistance to the complement recognition of and attachment to host cells through active site-mediated toalso sialic acids and/or and immediate survival of trypomastigotes released to the bloodstream binding [25]. Thetoactive of TcTS containsand several conservedsite microbial sialidase features showing a donor site related sialicsite acid interaction an acceptor associated with the β-galactose molecule. The acceptor site contains the amino acids Tyr119 and accommodating sialic acid’s N-acetyl group.
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