id9b00380_si_001.pdf (5.27 MB)
Re-Engineering of Yohimbine’s Biological Activity through Ring Distortion: Identification and Structure–Activity Relationships of a New Class of Antiplasmodial Agents
journal contribution
posted on 2020-01-16, 19:07 authored by Nicholas G. Paciaroni, David L. Perry, Verrill M. Norwood, Claribel Murillo-Solano, Jennifer Collins, Srinivasarao Tenneti, Debopam Chakrabarti, Robert W. HuigensSelect 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, Y7j, was found to demonstrate
good potency against chloroquine-resistant Plasmodium falciparum Dd2 cells (EC50 = 0.33 μM) without eliciting cytotoxicity
against HepG2 cells (EC50 > 40 μM). Y7j 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 Y7j 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.