Discovery and biology of novel antimalarial agents from plants

Malaria continues to be one of the world's most devastating diseases, with over 3.2 billion people at risk for contracting the disease, and an estimated 214 million malaria cases and over 400,000 deaths in 2015 [1]. The potent antimalarial drugs quinine and artemisinin are natural products, and natural products continue to make key contributions of new antimalarial agents[2, 3] and leads for medicinal chemistry [4]. Recent antimalarial work at Virginia Tech has included the discovery of the novel phloroglucinol mallotojaponin C [5], and of antimalarial 5,6-dihydro-α-pyrones from Cryptocarya rigidifolia [6].

Continuing studies have focused on the discovery of new antimalarial natural products from plants, including those from plants with an ethnomedical history of use as antimalarial medicines. In this talk some recent examples of the successful use of selective antimalarial assays coupled with bioassay-directed isolation and structure elucidation by NMR and MS will be presented, leading to the isolation and structure elucidation of three different biosynthetic classes of compound as antimalarial agents; a polyketide (1), an alkaloid (2), and a terpenoid (3).

Acknowledgements: Support from the U.S. National Center for Complementary and Integrative Health (NCCIH) under award 1 R01 AT008088 is gratefully acknowledged.

Keywords: Antimalarials, NMR, HRMS.

References:

[1] Anonymous. 10 facts on malaria. World Health Organization. 2015, http://www.who.int/features/factfiles/malaria/en/. Accessed February 18, 2016.

[2] Fotie J. Key natural products in malaria chemotherapy: From quinine to artemisinin and beyond. In: Brahmachari G editor. Bioactive Natural Products: Opportunities and Challenges in Medicinal Chemistry. Singapore: World Scientific Publishing Co. Pte. Ltd.; 2011, 223 – 272

[3] Xu Y-J, Pieters L. Recent developments in antimalarial natural products isolated from medicinal plants. Mini-Rev Med Chem 2013; 13: 1056 – 1072

[4] Fernandez-Alvaro E, Hong WD, Nixon GL, O'Neill PM, Calderon F. Antimalarial chemotherapy: Natural product inspired development of preclinical and clinical candidates with diverse mechanisms of action. J Med Chem 2016; DOI: 10.1021/acs.jmedchem.5b01485

[5] Harinantenaina L, Bowman JD, Brodie PJ, Slebodnick C, Callmander MW, Rakotobe E, Randrianaivo R, Rasamison VE, Gorka A, Roepe PD, Cassera MB, Kingston DGI. Antiproliferative and antiplasmodial dimeric phloroglucinols from Mallotus oppositifolius from the Madagascar Dry Forest. J Nat Prod 2013; 76: 388 – 393

[6] Liu Y, Rakotondraibe HL, Brodie PJ, Wiley JD, Cassera MB, Miller JS, Ratovoson F, Rakotobe E, Rasamison VE, Kingston DGI. Antimalarial 5,6-dihydro-α-pyrones from Cryptocarya rigidifolia: related bicyclic tetrahydro-α-pyrones are artifacts. J Nat Prod 2015; 78: 1330 – 1338