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.
A versatile synthesis of 2‐(substituted phenyl)‐6,7‐dihydro‐1H‐indol‐4(5H)‐ones from adducts of the Morita–Baylis–Hillman reaction between 2‐oxo‐2‐(substituted phenyl)acetaldehydes and cyclohex‐2‐enone under mild conditions is described.
An unprecedented synthesis of aromatic ring annulated pyridines from suitably substituted primary allylamines via intramolecular electrophilic aromatic cyclization mediated by molecular iodine under mild conditions is described.
A palladium-catalyzed pyrazole-directed regioselective oxidative C(sp2)-H functionalization of the N-phenyl ring in N-phenylpyrazoles to afford either a biaryl bis-pyrazole (via dehydrogenative homocoupling) or N-(o-hydroxyphenyl)pyrazole (via C-H oxygenation) or their mixture is described. The substitutions on the N-phenyl ring and the pyrazole ring and the dilution of the reaction medium with respect to the TFA/TFAA mixture (substrate concentration) have a remarkable influence on the outcome of the reaction. It was discovered that if the reactions were performed under highly dilute conditions (ca. 10 times) then N-(o-hydroxyphenyl)pyrazoles were the major or the sole products.
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