Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine

Overview

Journal Org Lett

Publisher American Chemical Society

Specialties Biochemistry
Chemistry

Date 2022 May 3

PMID 35504038

Authors

Joseph R A Kincaid

Rahul D Kavthe

Juan C Caravez

Balaram S Takale

Ruchita R Thakore

Bruce H Lipshutz

Affiliations

Soon will be listed here.

Abstract

Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield. Comparisons to existing literature performed exclusively in organic solvents reveal a 5-fold decrease in environmental impact as measured by E Factors.

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References

Kremer M . Pharmaceuticals and the developing world. J Econ Perspect. 2004; 16(4):67-90. DOI: 10.1257/089533002320950984. View

Hayashi Y . Pot economy and one-pot synthesis. Chem Sci. 2017; 7(2):866-880. PMC: 5529999. DOI: 10.1039/c5sc02913a. View

Rottmann M, Jonat B, Gumpp C, Dhingra S, Giddins M, Yin X . Preclinical Antimalarial Combination Study of M5717, a Plasmodium falciparum Elongation Factor 2 Inhibitor, and Pyronaridine, a Hemozoin Formation Inhibitor. Antimicrob Agents Chemother. 2020; 64(4). PMC: 7179297. DOI: 10.1128/AAC.02181-19. View

Pradines B, Briolant S, Henry M, Oeuvray C, Baret E, Amalvict R . Absence of association between pyronaridine in vitro responses and polymorphisms in genes involved in quinoline resistance in Plasmodium falciparum. Malar J. 2010; 9:339. PMC: 3224917. DOI: 10.1186/1475-2875-9-339. View

Krishna S, Augustin Y, Wang J, Xu C, Staines H, Platteeuw H . Repurposing Antimalarials to Tackle the COVID-19 Pandemic. Trends Parasitol. 2020; 37(1):8-11. PMC: 7572038. DOI: 10.1016/j.pt.2020.10.003. View

Croft S, Duparc S, Arbe-Barnes S, Craft J, Shin C, Fleckenstein L . Review of pyronaridine anti-malarial properties and product characteristics. Malar J. 2012; 11:270. PMC: 3483207. DOI: 10.1186/1475-2875-11-270. View

Lapierre J . [Polychemoresistant Plasmodium falciparum malaria, successfully treated with a benzonaphthyridine]. Nouv Presse Med. 1982; 11(9):673. View

Mori G, Orena B, Franch C, Mitchenall L, Godbole A, Rodrigues L . The EU approved antimalarial pyronaridine shows antitubercular activity and synergy with rifampicin, targeting RNA polymerase. Tuberculosis (Edinb). 2018; 112:98-109. DOI: 10.1016/j.tube.2018.08.004. View

Li X, Thakore R, Takale B, Gallou F, Lipshutz B . High Turnover Pd/C Catalyst for Nitro Group Reductions in Water. One-Pot Sequences and Syntheses of Pharmaceutical Intermediates. Org Lett. 2021; 23(20):8114-8118. DOI: 10.1021/acs.orglett.1c03258. View

10.

Lane T, Massey C, Comer J, Anantpadma M, Freundlich J, Davey R . Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection. PLoS Negl Trop Dis. 2019; 13(11):e0007890. PMC: 6894882. DOI: 10.1371/journal.pntd.0007890. View

11.

Li J, Wang W, Yao J, Wang T, Li S, Qi W . Old drug repurposing for neglected disease: Pyronaridine as a promising candidate for the treatment of Echinococcus granulosus infections. EBioMedicine. 2020; 54:102711. PMC: 7152711. DOI: 10.1016/j.ebiom.2020.102711. View

12.

Akporji N, Singhania V, Dussart-Gautheret J, Gallou F, Lipshutz B . Nanomicelle-enhanced, asymmetric ERED-catalyzed reductions of activated olefins. Applications to 1-pot chemo- and bio-catalysis sequences in water. Chem Commun (Camb). 2021; 57(89):11847-11850. DOI: 10.1039/d1cc04774d. View

13.

Lipshutz B . When Does Organic Chemistry Follow Nature's Lead and "Make the Switch"?. J Org Chem. 2017; 82(6):2806-2816. DOI: 10.1021/acs.joc.7b00010. View

14.

Hayashi Y . Time Economy in Total Synthesis. J Org Chem. 2020; 86(1):1-23. DOI: 10.1021/acs.joc.0c01581. View

15.

Lipshutz B, Ghorai S, Abela A, Moser R, Nishikata T, Duplais C . TPGS-750-M: a second-generation amphiphile for metal-catalyzed cross-couplings in water at room temperature. J Org Chem. 2011; 76(11):4379-91. PMC: 3608414. DOI: 10.1021/jo101974u. View

16.

Fu S, Xiao S . Pyronaridine: A new antimalarial drug. Parasitol Today. 1991; 7(11):310-3. DOI: 10.1016/0169-4758(91)90267-r. View

17.

Ansari T, Sharma S, Hazra S, Jasinski J, Wilson A, Hicks F . Shielding Effect of Nanomicelles: Stable and Catalytically Active Oxidizable Pd(0) Nanoparticle Catalyst Compatible for Cross-Couplings of Water-Sensitive Acid Chlorides in Water. JACS Au. 2021; 1(9):1506-1513. PMC: 8479868. DOI: 10.1021/jacsau.1c00236. View

18.

Lipshutz B, Ghorai S, Cortes-Clerget M . The Hydrophobic Effect Applied to Organic Synthesis: Recent Synthetic Chemistry "in Water". Chemistry. 2018; 24(26):6672-6695. DOI: 10.1002/chem.201705499. View

19.

Cortes-Clerget M, Yu J, Kincaid J, Walde P, Gallou F, Lipshutz B . Water as the reaction medium in organic chemistry: from our worst enemy to our best friend. Chem Sci. 2021; 12(12):4237-4266. PMC: 8179471. DOI: 10.1039/d0sc06000c. View

20.

Bailly C . Pyronaridine: An update of its pharmacological activities and mechanisms of action. Biopolymers. 2020; 112(4):e23398. DOI: 10.1002/bip.23398. View