10.1021/acsinfecdis.9b00380.s001
Nicholas G. Paciaroni
Nicholas G.
Paciaroni
David L. Perry
David L.
Perry
Verrill M. Norwood
Verrill M.
Norwood
Claribel Murillo-Solano
Claribel
Murillo-Solano
Jennifer Collins
Jennifer
Collins
Srinivasarao Tenneti
Srinivasarao
Tenneti
Debopam Chakrabarti
Debopam
Chakrabarti
Robert W. Huigens
Robert W.
Huigens
Re-Engineering of Yohimbine’s Biological Activity
through Ring Distortion: Identification and Structure–Activity
Relationships of a New Class of Antiplasmodial Agents
American Chemical Society
2020
ring distortion
compound
chloroquine-resistant Plasmodium falciparum Dd 2 cells
ring cleavage synthesis pathways
40 μ M
Y 7j
Antiplasmodial Agents Select
EC 50
HepG 2 cells
indole alkaloid yohimbine
ring distortion approach
0.33 μ M
2020-01-16 19:07:04
Journal contribution
https://acs.figshare.com/articles/journal_contribution/Re-Engineering_of_Yohimbine_s_Biological_Activity_through_Ring_Distortion_Identification_and_Structure_Activity_Relationships_of_a_New_Class_of_Antiplasmodial_Agents/11631999
Select natural products are ideal
starting points for ring distortion, or the dramatic altering of inherently
complex molecules through short synthetic pathways, to generate an
array of novel compounds with diverse skeletal architectures. A major
goal of our ring distortion approach is to re-engineer the biological
activity of indole alkaloids to identify new compounds with diverse
biological activities in areas of significance to human health and
medicine. In this study, we re-engineered the biological activity
of the indole alkaloid yohimbine through ring rearrangement and ring
cleavage synthesis pathways to discover new series of antiplasmodial
agents. One new compound, <b>Y7j</b>, was found to demonstrate
good potency against chloroquine-resistant <i>Plasmodium falciparum</i> Dd2 cells (EC<sub>50</sub> = 0.33 μM) without eliciting cytotoxicity
against HepG2 cells (EC<sub>50</sub> > 40 μM). <b>Y7j</b> demonstrated stage-specific action against parasites at the late
ring/trophozoite stage. A series of analogues was synthesized to gain
structure–activity relationship insights, and we learned that
both benzyl groups of <b>Y7j</b> are required for activity and
fine-tuning of antiplasmodial activities could be accomplished by
changing substitution patterns on the benzyl moieties. This study
demonstrates the potential for ring distortion to drive new discoveries
and change paradigms in chemical biology and drug discovery.