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Re-Engineering of Yohimbine’s Biological Activity through Ring Distortion: Identification and Structure–Activity Relationships of a New Class of Antiplasmodial Agents
ACS Infectious Diseases ( IF 4.911 ) Pub Date : 2020-01-16 , DOI: 10.1021/acsinfecdis.9b00380
Nicholas G. Paciaroni; David L. Perry, II; Verrill M. Norwood, IV; Claribel Murillo-Solano; Jennifer Collins; Srinivasarao Tenneti; Debopam Chakrabarti; Robert W. Huigens, III

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, 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.
更新日期:2020-01-17

 

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