Synthesis and mechanism of Primaquine

1. Primaquine
ADVANCED PHARMACEUTICAL CHEMISTRY

2. Introduction
• Primaquine is an 8-aminoquinoline
• Primaquine is used alone or with another medication to treat malaria (a serious infection that is spread
by mosquitoes in certain parts of the world and can cause death) and to prevent the disease from
coming back in people that are infected with malaria.
• Primaquine is in a class of medications called antimalarials.
• It works by killing the organisms that cause malaria.

3. Synthesis of Primaquine
Primaquine, 8-[(4-amino-1-methylbutyryl)amino]-6-
methoxyquinoline (37.1.2.4), is made from 6-methoxy-
8-nitroquinoline (37.1.2.1), which is synthesized in a
Skraup reaction from 4-methoxy-2-nitroaniline and
glycerol in the presence of sulfuric acid. The nitro group
in this compound is reduced to make 6-methoxy-8-
aminoquinoline (37.1.2.2). Alkylating the amino group
with 4-bromo-1-phthalimidopentane gives 8-[(4-
phthalimido-1-methylbutyryl)amino]-6-
methoxyquinoline (37.1.2.3), the hydrazinolysis of which
removes the phthalimide protection, giving primaquine

4. Stereochemical aspects of Primaquine
• Primaquine is a synthetic aromatic compound
with one chiral center.

5. Mechanism of Action
• Primaquine is an antimalarial drug. In the blood, the malaria parasite breaks down a part of red blood
cells known as hemoglobin.
• When this happens, the hemoglobin splits into two parts. heme and globin. Heme is toxic to malaria
pathogens. To keep it safe, the malarial parasite produces chemicals that convert the toxic heme into
non-toxic products.
• Primaquine works by interfering with some of the parasites (mitochondrial) responsible for its energy
supply. Without energy, the parasite dies. This prevents the infection from continuing and allows the
patient to recover.
• Primaquine kills the intrahepatic forms of Plasmodium vivax and Plasmodium ovale and prevents the
development of erythroid forms that cause relapse (it also kills gametocytes).

6. Metabolism Of Primaquine
•
Primaquine is rapidly metabolized to carboxyprimaquine by oxidative deamination. Phenolic metabolites
of primaquine have long been suggested as potential hematotoxic species. Oxidation products have
been identified as primaquine metabolites in body fluids of primaquine-treated experimental animals.
• The three oxidative metabolites identified are... 8-(3-carboxyl-1-methylpropylamino)-6-
methoxyquinoline, 5-hydroxy-primaquine, and 5 -Hydroxy-6-desmethylprimaquine. Carboxylic acid
derivatives are major metabolites in human plasma. A single dose reaches plasma concentrations 10
times greater than primaquine.
• This non-toxic metabolite is excreted more slowly and accumulates over multiple doses... three
metabolites... appear to have significantly less antimalarial activity than primaquine. Except, their
hemolytic activity, determined by the formation of methemoglobin in vitro, is greater than that of the
parent compounds.

7. Route of Administration of Primaquine
• Primaquine is a drug used to treat and prevent malaria. It is typically administered orally in tablet,
capsule, or solution form. Primaquine inhibits the growth of malaria parasites in red blood cells,
preventing their growth and systemic spread. Primaquine is usually taken once daily for up to 3 weeks,
depending on the type of malaria being treated.
• Primaquine is not recommended for use in children under the age of 8, pregnant women, and people
with certain medical conditions such as G6PD deficiency, severe anemia, or porphyria

8. Commercial aspects of Primaquine
• The Primaquine Market division has grown into an important and complex business
• Global Primaquine market size is projected to reach millions by 2028 compared to 2021,
• The worldwide Primaquine Market is categorized into Component, Deployment, Application,
and Region.

9. Side Effects of Primaquine
1. Nausea
2. Headache
3. Vertigo
4. Rash
5. Abdominal pain
6. Anaemia
7. Haemolytic anaemia
8. Allergic reactions

10. References
1. Brocks, Dion R, and Reza Mehvar. “Stereoselectivity in the Pharmacodynamics and Pharmacokinetics of the Chiral
Antimalarial Drugs.” Clinical Pharmacokinetics, vol. 42, no. 15, 2003, pp. 1359–1382, 10.2165/00003088-200342150-
00004. Accessed 29 Dec. 2019.
2. Zanders, Edward D. “Commercial Aspects of Drug Development.” The Science and Business of Drug Discovery, vol., no.,
2011, pp. 305–328, 10.1007/978-1-4419-9902-3_16. Accessed 24 Dec. 2022.
3. Taylor, Walter R J, et al. “Short-Course Primaquine for the Radical Cure of Plasmodium Vivax Malaria: A Multicentre,
Randomised, Placebo-Controlled Non-Inferiority Trial.” Lancet (London, England), vol. 394, no. 10202, 14 Sept. 2019, pp.
929–938, www.ncbi.nlm.nih.gov/pmc/articles/PMC6753019/, 10.1016/S0140-6736(19)31285-1. Accessed 26 Mar. 2021.
4. Avula, Bharathi, et al. “Metabolism of Primaquine in Normal Human Volunteers: Investigation of Phase I and Phase II
Metabolites from Plasma and Urine Using Ultra-High Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass
Spectrometry.” Malaria Journal, vol. 17, no. 1, 13 Aug. 2018, 10.1186/s12936-018-2433-z. Accessed 21 Feb. 2021.
5. Elderfield, Robert C., et al. “Synthesis of Primaquine and Certain of Its Analogs1.” Journal of the American Chemical Society,
vol. 77, no. 18, Sept. 1955, pp. 4816–4819, 10.1021/ja01623a038. Accessed 24 Dec. 2022.