Re-Engineering of Yohimbine’s Biological Activity through Ring Distortion: Identification and Structure–Activity Relationships of a New Class of Antiplasmodial Agents

• DOI: 10.1021/acsinfecdis.9b00380
• Publication Date: 2020-01-08T17:38:21Z
• Authors: Nicholas G. Pacia...; David L. Perry; Verrill M. Norwood; Claribel Murillo-...; Jennifer Collins; Srinivasarao Tenneti; Debopam Chakrabarti; Robert W. Huigens
• Keywords: Indole alkaloid

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 novel compounds with diverse skeletal architectures. A major goal our distortion approach is re-engineer biological activity indole alkaloids identify new activities in areas significance human health and medicine. In this study, we re-engineered alkaloid yohimbine rearrangement cleavage synthesis pathways discover series antiplasmodial agents. One compound, Y7j, was found demonstrate good potency against chloroquine-resistant Plasmodium falciparum Dd2 cells (EC50 = 0.33 μM) without eliciting cytotoxicity HepG2 > 40 μM). Y7j demonstrated stage-specific action parasites at late ring/trophozoite stage. analogues synthesized gain structure–activity relationship insights, learned that both benzyl groups required fine-tuning could be accomplished by changing substitution patterns on moieties. This study demonstrates potential drive discoveries change paradigms chemical biology drug discovery.