Screening and optimization of specific chemical series against HAT

HAT – sleeping sickness | 2006-2010

 

Partners

SCYNEXIS Inc. as part of the DNDi HAT Lead Optimization Consortium

 

Context

The majority of compounds released by DNDi in this dataset of 4926 compounds were identified by screening chemical compound libraries of two structural classes prepared by SCYNEXIS, Inc. against Trypanosoma brucei parasites in vitro. Hit-to-Lead and Lead Optimization programmes were conducted on compounds found to be active in these two series (2-aryl-5-aminomethyloxazoles and N-substituted pyridylamidoximes) leading to the structure-based design of additional compounds, which were in turn tested in vitro against T.brucei parasites, and their physicochemical and pharmacological properties evaluated.

Work in both series was suspended when it was found that the structural requirements for good in vitro anti-parasitic activity were inconsistent with those with a good potential for in vivo activity. More specifically, in both series, compounds with good in vitro anti-parasitic activity tended to be lipophilic, metabolically unstable and with limited solubility in water.

In addition to these two series, a number of small sets of compounds based on reported in vitro parasitic activity are included, such as the pyrazolopyrimidines series. These compounds were found to be poorly selective for in vitro anti-parasitic activity relative to cytotoxicity in mammalian cells, and were therefore not pursued further.

 

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