Pharmaceutical Treatment of Malaria: Quinine

Diane Lokou

Dr. Caroline Sheppard

Fall 2014

Overview of malaria

Malaria is caused by Plasmodium falciparum.

It is transmitted by female Anopheles mosquito from one person to the other.

Others routes of transmission:

- blood transfusion

- organ transplant

- shared use of needles or syringes contaminated with blood

- a mother to her unborn infant before or during delivery ("congenital" malaria).

Overview of malaria

Common signs and symptoms:

- High fever

- Chills

- Headache

- Nausea

- Vomiting

- Body aches

- Anemia

Prevention includes:

- Insecticide bed nets

- Insects repellents

- Long sleeves shirts

- Drugs such as Chloroquine, Atovaquone, and Proguanil.

Overview of malaria

Treatments differ from countries and regions.

Antimalarial medications such as:

- Artemisinin

- Artesunate

- Artemether

- Quinine

Quinine

Molecular Formula: C20H24N2O2

Average mass: 324.417 Da

Monoisotopic mass: 324.183777 Da

Systematic Name: (8α,9R)-6'- Methoxycinchonan-9-ol

Structure includes quinoline and quinuclidine rings

Four asymmetric centers N

OH

H

N

H

H

H3CO

CH2:CH2

9R

8S

34

http://pubs.acs.org/cen/img/83/i25/8325quinine.gif

http://www.malariajournal.com/content/figures/1475-2875-2-26-1.jpg

Quinine: background

• Discovered in 17th century by Jesuits

• Part of plant used

• Properties

• Others uses

• History of its Synthesis

Bark of the cinchona tree

http://www.chemistryviews.org/SpringboardWebApp/userfiles/chem/image/2013/2013_05/Bild2.jpg

Synthesis

• 1817: First isolation of quinine from cinchona tree bark by Pierre Joseph Pelletier and Joseph Caventou.

• 1853: Quinotoxine (or quinicine in older literature) obtained  by acid catalyzed  isomerization of quinine by Louis Pasteur.

http://en.wikipedia.org/wiki/File:QuininePasteur.png

Synthesis

• 1856: synthesis of quinine by William Henry Perkin

http://en.wikipedia.org/wiki/File:QuininePerkinsAttempt.png

Published in: Karina Ap. F. D. Souza; Paulo A. Porto; J. Chem. Educ.  2012, 89, 58-63.DOI: 10.1021/ed1003542Copyright © 2011 The American Chemical Society and Division of Chemical Education, Inc.

Scheme 4. Smith and Williams’ (2008) Procedure for Conversion of D-Quinotoxine to Quinine

Entry Reducing conditions Temp.(°C)

Isolated yield ofquinine/quinidine

yield ofquinine

1 DIBAL-H benzene 20 72% 33%2 NaBH4, EtOH 0 11% 4%

3 Al powder (new) NaOEt, EtOH

reflux trace trace

4 Al powder (new) NaOEt, EtOH

reflux 30% (1.1:1) 16%

5 Al powder + Al2O3 NaOEt, EtOH

reflux 26% (1.1:1) 14%

6 Al powder (aerated) NaOEt, EtOH

reflux 24% (1.1:1) 13%

7 Al powder MeOH, NaOMe

reflux 8% (1.2:1) 4%

8 Al powder (sonication) NaOEt, EtOH

reflux 22% (1.1:1) 12%

9 Al powder, Na(OiPr), i-PrOH

reflux 32% (1:1.2) 15%

10 Al(Oi-Pr)3, iPrOH reflux 28% 16%

11 LiAlH4, ether −78 45% trace

12 LiAlH4, ether 0 59% trace

13 LiAlH4, ether 20 56% trace

14 LiAlH4, ether  0 40% (1:1.5) 16%

Conditions for reducing quinidinone/quininone to quinine.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085927/table/T1/

How does quinine work ?

• Mechanism of action

- Interaction with the organism

- Interaction in body

- Side effects such as nausea, decreased hearing, dizziness, blurred vision, hypoglycemia, death by pulmonary edema, constipation, erectile dysfunction, or diarrhea.

Writing Assignment

My writing assignment will consist of a brochure to educate people on not only malaria and the treatments that are available, but also to raise an awareness of its devastation effects in the places where it exists today.

Conclusion

Works Cited

• Ron Dagani, Chem. Eng. News Archive, 2005, 83 (25), p 106 Publication Date (Print): June 20, 2005

• Karina Ap. F. D. Souza and Paulo A. Porto, “History and Epistemology of Science in the Classroom: The Synthesis of Quinine as a Proposal”, J. Chem. Educ., 2012, 89 (1), pp 58–63

• Bohórquez E, Chua M, Meshnick S. Quinine localizes to a non-acidic compartment within the food vacuole of the malaria parasite Plasmodium falciparum. Malaria Journal [serial online]. October 22, 2012;11:350. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed November 16, 2014.

• Sanchez C, Stein W, Lanzer M. Dissecting the components of quinine accumulation in Plasmodium falciparum. Molecular Microbiology [serial online]. March 2008;67(5):1081-1093. Available from: MEDLINE with Full Text, Ipswich, MA. Accessed November 17, 2014.

• www.malariajournal.com/content/2/1/26 • http://www.chemspider.com/Chemical-Structure.84989.html (accessed 02:49, Oct 28, 2014)

• www.webmd.com/drugs/2/drug-869/quinine-sulfate.../details

• www.ncbi.nlm.nih.gov/... National Center for Biotechnology Information