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).
Journal of Medicinal Chemistry
Malaria -- Prevention -- Research
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.
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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