Sponsor
This work was supported by a grant from the National Institute of Allergy and Infectious Diseases of the National Institute of Health under award number R01AI141972 and internal Portland State University funds. The National Science Foundation is acknowledged for support of the BioAnalytical Mass Spectrometry Facility at Portland State University (MRI1828573).
Published In
Journal of Medicinal Chemistry
Document Type
Post-Print
Publication Date
6-10-2021
Subjects
Malaria -- Prevention -- Research
Abstract
Highly efficient and straightforward synthetic routes toward the first total synthesis of 2-(-hydroxybenzyl)-prodigiosins (-), isoheptylprodigiosin (), and geometric isomers of tambjamine MYP1 ((/)-) have been developed. The crucial steps involved in these synthetic routes are the construction of methoxy-bipyrrole-carboxaldehydes (MBCs) and a 20-membered macrocyclic core and a regioselective demethylation of MBC analogues. These new synthetic routes enabled us to generate several natural prodiginines - in larger quantity. All of the synthesized natural products exhibited potent asexual blood-stage antiplasmodial activity at low nanomolar concentrations against a panel of parasites, with a great therapeutic index. Notably, prodiginines and - provided curative in vivo efficacy against erythrocytic at 25 mg/kg × 4 days via oral route in a murine model. No overt clinical toxicity or behavioral change was observed in any mice treated with prodiginines and tambjamines.
Rights
Copyright © 2021 American Chemical Society
Locate the Document
DOI
10.1021/acs.jmedchem.1c00748
Persistent Identifier
https://archives.pdx.edu/ds/psu/35953
Citation Details
Kancharla, P., Li, Y., Yeluguri, M., Dodean, R. A., Reynolds, K. A., & Kelly, J. X. (2021). Total Synthesis and Antimalarial Activity of 2-( p -Hydroxybenzyl)-prodigiosins, Isoheptylprodigiosin, and Geometric Isomers of Tambjamine MYP1 Isolated from Marine Bacteria. Journal of Medicinal Chemistry, acs.jmedchem.1c00748. https://doi.org/10.1021/acs.jmedchem.1c00748
Supporting Information
Molecular formula strings (1).csv (3 kB)
Molecular Formula Strings
Description
This is the author’s version of a work that was accepted for publication in the Journal of Medicinal Chemistry. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Journal of Medicinal Chemistry.
Version of record: https://doi.org/10.1021/acs.jmedchem.1c00748