Issue 42, 2024

Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents

Abstract

Natural product ring distortion strategies have enabled rapid access to unique libraries of stereochemically complex compounds to explore new chemical space and increase our understanding of biological processes related to human disease. Herein is described the development of a ring-cleavage strategy using the indole alkaloids yohimbine, apovincamine, vinburnine, and reserpine that were reacted with a diversity of chloroformates paired with various alcohol/thiol nucleophiles to enable the rapid synthesis of 47 novel small molecules. Ring cleavage reactions of yohimbine and reserpine produced two diastereomeric products in moderate to excellent yields, whereas apovincamine and vinburnine produced a single diastereomeric product in significantly lower yields. Free energy calculations indicated that diastereoselectivity regarding select ring cleavage reactions from yohimbine and apovincamine is dictated by the geometry and three-dimensional structure of reactive cationic intermediates. These compounds were screened for antiplasmodial activity due to the need for novel antimalarial agents. Reserpine derivative 41 was found to exhibit interesting antiplasmodial activities against Plasmodium falciparum parasites (EC50 = 0.50 μM against Dd2 cultures), while its diastereomer 40 was found to be three-fold less active (EC50 = 1.78 μM). Overall, these studies demonstrate that the ring distortion of available indole alkaloids can lead to unique compound collections with re-engineered biological activities for exploring and potentially treating human disease.

Graphical abstract: Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents

Supplementary files

Article information

Article type
Paper
Submitted
22 May 2024
Accepted
26 Jun 2024
First published
27 Jun 2024

Org. Biomol. Chem., 2024,22, 8423-8436

Author version available

Chloroformate-mediated ring cleavage of indole alkaloids leads to re-engineered antiplasmodial agents

D. C. Schultz, A. Chávez-Riveros, M. G. Goertzen, B. R. Brummel, R. A. Paes, N. M. Santos, S. Tenneti, K. A. Abboud, J. R. Rocca, G. Seabra, C. Li, D. Chakrabarti and R. W. Huigens, Org. Biomol. Chem., 2024, 22, 8423 DOI: 10.1039/D4OB00853G

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