7 research outputs found
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work
Escaping from flatland: antimalarial activity of sp<sup>3</sup>-rich bridged pyrrolidine derivatives
We utilized synthetic photochemistry to generate novel sp3-rich scaffolds and report the design, synthesis, and biological testing of a diverse series of amides based on the 1-(amino-methyl)-2-benzyl-2-aza-bicyclo[2.1.1]hexane scaffold. Preliminary antimalarial screening of the library provided promising compounds with activity in the 1-5 μM range with an enhanced hit rate. Further evaluation (solubility, drug metabolism and pharmacokinetics (DMPK), and toxicity) of a selected compound (9) suggested that this series represents an excellent opportunity for further optimization with the framework offering multiple opportunities for the addition of uniquely vectorally positioned extra functionality
Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei
There is an urgent need for new,
brain penetrant small molecules
that target the central nervous system second stage of human African
trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides
have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe
the optimization and characterization of this series. Potent antiproliferative
activity was observed. The series demonstrated excellent pharmacokinetic
properties, full cures in a stage 1 mouse model of HAT, and a partial
cure in a stage 2 mouse model of HAT. Lack of tolerability prevented
delivery of a fully curative regimen in the stage 2 mouse model and
thus further progress of this series
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.
The development of new antimalarial compounds remains a pivotal part of the strategy for malaria elimination. Recent large-scale phenotypic screens have provided a wealth of potential starting points for hit-to-lead campaigns. One such public set is explored, employing an open source research mechanism in which all data and ideas were shared in real time, anyone was able to participate, and patents were not sought. One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change. A second subseries displayed high potency, including activity within gametocyte and liver stage assays, but at the cost of low solubility. As an open source research project, unexplored avenues are clearly identified and may be explored further by the community; new findings may be cumulatively added to the present work