Hazard
Skin irritant, ingestion of pure substance
adversely affects eyes.
Chemical Properties
Quinine is odorless, but has an intense, bitter taste
Chemical Properties
white to light yellow crystal powde
Physical properties
Appearance: white granular or microcrystalline powder. No smell, slightly bitter.
Solubility: easily dissolved in ethanol, chloroform, and ethyl. Slightly soluble in
water and glycerol. Melting point: 173–175 °C. Specific optical rotation: ?172°
(ETOH, C = 1).
Occurrence
Reported present in Cinchona officinalis.
History
Quinine is a white crystalline alkaloid best known for treating malaria. Quinine is derived from the bark of several species of trees in the genus Cinchona in the Rubiaceae family. Cinchona trees grow on the eastern slopes of the Andes Mountains at elevations of several thousand feet. Because these symptoms were associated with malaria, Cinchona bark powder was recognized as a possible treatment in the 1600s by Jesuit missionaries.
After decades of
work by numerous investigators, quinine was finally isolated in 1820 by Pierre-Joseph Pelletier
(1788–1842) and Joseph-Bienaimé Caventou (1795–1877). The name quinine originates
from the native word for the Cinchona tree quina quina, which became the Spanish word
quino for cinchona. The development of organic synthesis in the middle of the 19th century
and the limited supply of quinine stimulated attempts to synthesize it. William Henry
Perkins’s (1838–1907) attempt to synthesize quinine in 1856 led to his discovery of mauve,
which was a signifi cant discovery in the dye industry (see Indigo).
Definition
A poisonous
ALKALOID found in the bark of the cinchona
tree of South America. It is used in treating
malaria.
Definition
ChEBI: A cinchona alkaloid that is cinchonidine in which the hydrogen at the 6-position of the quinoline ring is substituted by methoxy.
Definition
quinine: A white solid,C20H24N2O2·3H2O, m.p. 57°C. It is apoisonous alkaloid occurring in thebark of the South American cinchonatree, although it is now usually producedsynthetically. It forms saltsand is toxic to the malarial parasite,and so quinine and its salts are used to treat malaria; in small doses itmay be prescribed for colds and influenza.In dilute solutions it has apleasant astringent taste and is addedto some types of tonic water.
Preparation
By reaction from cinchona bark (Cinchona officinalis), where it is present at approximately 8%.
Antimicrobial activity
Quinine inhibits the erythrocytic stages of human malaria parasites
at <1 mg/L, but not the liver stages. It is active against
the gametocytes of P. vivax, P. ovale and P. malariae, but not
P. falciparum. The dextrarotatory stereoisomer, quinidine, is
more active than quinine, but epiquinine (cinchonine) and epiquinidine
(cinchonidine) have much lower antimalarial activities.
Acquired resistance
Resistance is now widespread in South East Asia, where
some strains are also resistant to chloroquine, sulfadoxine–
pyrimethamine and mefloquine. Cross-resistance with mefloquine
has been demonstrated in P. falciparum, but genetic
polymorphisms associated with chloroquine resistance are
not associated with quinine resistance.
General Description
Quinine, a cinchona alkaloid found in the bark of the cinchona tree, is known for its anti-malarial property.
Health Hazard
The toxicity of quinine is characterized bycinchonism, a term that includes tinnitus,vomiting, diarrhea, fever, and respiratorydepression. Other effects include stimulationof uterine muscle, analgesic effect,and dilation of the pupils. Severe poisoningmay produce neurosensory disorders, causingclouded vision, double vision, buzzing of theears, headache, excitability, and sometimescoma (Ferry and Vigneau 1983). Death fromquinine poisoning is unusual. Massive dosesmay be fatal, however.
LD50 value, oral (guinea pigs): 1800 mg/kg.
Flammability and Explosibility
Nonflammable
Pharmaceutical Applications
A quinolinemethanol from the bark of the Cinchona tree; the
laevorotatory stereoisomer of quinidine. Formulated as the
sulfate, bisulfate or ethylcarbonate for oral use and as the dihydrochloride
for parenteral administration. The salts are highly
soluble in water.
Biochem/physiol Actions
Potassium channel blocker
Pharmacology
In terms of its type of action, quinine is an antimalarial drug similar to chloroquine,
although it is inferior in its activity.
Like chloroquine, quinine binds with plasmodium DNA, thus interfering in the synthesis of nucleic acids and preventing its replication and transcription. Quinine also suppresses a large portion of the enzymatic system and therefore it is characterized as a
general protoplasmid toxin. This fact agrees well with the action of quinine on membranes,
its local anesthetizing and its cardiodepressive effects.
Upon oral administration, quinine effectively acts in combination with pyrimethamine,
sulfadiazine, and/or tetracycline for treating uncomplicated incidents of chloroquineresistant forms of P. falciparum. Because of the many associated side effects, its use is
extremely limited. Currently, the only indication for use is for forms of malaria that are
resistant to other synthetic drugs. Synonyms of this drug are bronchopulmin, nicopriv,
quinnam, and others.
Clinical Use
Falciparum malaria (alone or in combination with tetracycline,
doxycycline, clindamycin or pyrimethamine–sulfadoxine)
Babesiosis (in combination with clindamycin)
It is particularly used in cerebral malaria if chloroquine resistance
is suspected (Ch. 62). It is not recommended for treatment
of uncomplicated falciparum malaria.
Synthesis
Quinine, (5-vinyl-2-quinuclidinyl)-(6-methoxy-4-quinolyl)methanol (37.1.1.47), is isolated from the bark of the cinchona tree. One of the methods of making the ethyl ester of quininic acid (37.1.1.27) that should be mentioned is the method described in the following scheme. Reacting p-anisidine and acetoacetic ester in the presence of sulfuric acid gives 6-methoxylepidine (37.1.1.22). The hydroxyl group of this compound is replaced with a chlorine atom by reacting it with a mixture of phosphorus oxychloride and phosphorus pentachloride, giving 2-chloro- 4-methyl-6-methoxyquinoline (37.1.1.23). Reducing this compound with hydrogen using a palladium catalyst removes the chlorine atom at C2 and gives 4-methyl- 6-methoxyquinoline (37.1.1.24). Condensing this with benzaldehyde gives 2-(6-methoxy quinolinyl-4)-styrene (37.1.1.25), the double bond in which is oxidized using potassium permanganate to make 6-methoxyquinolinic acid—cinchonine (37.1.1.26), which is then converted into an ester (37.1.1.27) in the usual manner.
Another convenient way for preparation of quininic acid ethyl ester (37.1.1.27) is by using p-N-methylacetanisidine and diethyloxalate, which are reacted to form the p-N-methylacetaniside of oxalacetic acid (37.1.1.28). Heterocyclization of the product under acidic conditions leads to the formation of N-methyl-2-keto-4-carbethoxy-6-methoxyquinoline (37.1.1.29), which is reacted with a mixture of phosphorus oxychloride and phosphorus pentachloride to make 2-chloro-4-carboethoxy-6-methoxyquiniline (37.1.1.30). Reducing this with hydrogen using a palladium catalyst gives ethyl ester of 6-methoxyquinolinic acid (37.1.1.27).
target
Antifection | Potassium channel
Metabolism
Quinine is metabolized in the liver to the 2′-hydroxy derivative, followed by additional hydroxylation
on the quinuclidine ring, with the 2,2′-dihydroxy derivative as the major metabolite. This metabolite
has low activity and is rapidly excreted. The metabolizing enzyme of quinine is CYP3A4. With the
increased use of quinine and its use in combination with other drugs, the potential for drug
interactions based on the many known substrates for CYP3A4 is of concern.
Purification Methods
Crystallise the quinine from absolute EtOH. It has been used as a chiral catalyst (see previous entry). [Beilstein 23 H 511, 23 I 166, 23 II 416, 23 III/IV 3265, 23/13 V 395.]
References
Pelletier, Dumas., Ann. Chim. Phys., 15,291,1337 (1820)
Hesse., Annalen, 258, 133 (1890)
Fiihner., Arch. Pharm., 244, 602 (1906)
Seekles., Rev. Trav. Chim., 42, 72 (1923)
Kindler., Chem. Ztg., 56, 165 (1932)
Cohen.,J. Chem. Soc., 999 (1933)
Velter., Festschrift., 542 (Basle, 1936)
Woodward, Doering.,J. Amer. Chem. Soc., 67,860 (1945)
Pharmacology :
Acton, King., Biochem. J., 15,53 (1921)
Sterkin, Helfgat., Biochem. Zeit., 207, 8 (1929)
Wagenaar.,Pharm. Weekbl., 66, 177, 197,250,261 (1929)
Wagenaar., ibid, 71,316 (1934)
Monnet., J. Pharm. Chim., 18, 94 (1933)
Buttle, Henry, Trevan., Biochem. J., 28,426 (1934)
Seeler, Dusenbery, Malanga.,J. Pharm. Exp. Ther., 78, 159 (1943)
Marshall., ibid, 85, 299 (1945)
