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Non‐natural Acetogenin Analogues as Potent Trypanosoma brucei Inhibitors
Author(s) -
Florence Gordon J.,
Fraser Andrew L.,
Gould Eoin R.,
King Elizabeth F. B.,
Menzies Stefanie K.,
Morris Joanne C.,
Tulloch Lindsay B.,
Smith Terry K.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402272
Subject(s) - trypanosoma brucei , trypanocidal agent , acetogenin , natural product , african trypanosomiasis , stereochemistry , biology , neglected tropical diseases , polyketide , chemistry , structure–activity relationship , combinatorial chemistry , annonaceae , computational biology , biochemistry , trypanosomiasis , biosynthesis , in vitro , enzyme , virology , botany , gene , medicine , disease , pathology
Abstract Neglected tropical diseases remain a serious global health concern. Here, a series of novel bis‐tetrahydropyran 1,4‐triazole analogues based on the framework of chamuvarinin, a polyketide natural product isolated from the annonaceae plant species are detailed. The analogues synthesized display low micromolar trypanocidal activities towards both bloodstream and insect forms of Trypanosoma brucei , the causative agent of African sleeping sickness, also known as Human African Trypanosomiasis (HAT). A divergent synthetic strategy was adopted for the synthesis of the key tetrahydropyran intermediates to enable rapid access to diastereochemical variation either side of the 1,4‐triazole core. The resulting diastereomeric analogues displayed varying degrees of trypanocidal activity and selectivity in structure–activity relationship studies. Together, the biological potency and calculated lipophilicity values indicate that while there is room for improvement, these derivatives may represent a promising novel class of anti‐HAT agents.