Application of the Quinoline Ring System, Chemistry tutorial

Introduction:

Quinoline is principally used for the preparation of nicotinic acid that prevents pellagra in humans and in the manufacture of other specialty chemicals. Around 4 tonnes are annually produced according to a report published in the year 2005. This is employed as a precursor to 8-hydroxyquinoline, that is a versatile chelating agent and precursor to pesticides. Its 2- and 4-methyl derivatives are precursors to cyanine dyes. The oxidation of quinoline affords quinoline acid (pyridine-2,3-dicarboxylic acid), a precursor of the herbicide sold under the name 'Assert'. The quinoline nucleus is contained in some groups of alkaloids (example: quinine), in a number of synthetic materials with significant physiological properties like the antimalarial plasmoquin and chloroquine, in the cyanine dyes and in the analytical reagent, oxine (8-hydroxyquinoline).

Quinine:

The Quinine is a natural white crystalline alkaloid having antipyretic (that is, fever-reducing), antimalarial, analgesic (painkilling), anti-inflammatory properties and a bitter taste. This is a stereoisomer of quinidine that, dissimilar quinine is an anti-arrhythmic. Quinine comprises two main fused-ring systems; the aromatic quinoline and the bicyclic quinuclidine. The aromatic part of the quinine molecule is a quinoline having a methoxy substituent. The amine component consists of a quinuclidine skeleton and the methylene bridge in between has a hydroxide group. The substituent at the carbon-3 position is a vinyl group. The molecule is optically active by four stereogenic (figure shown below).

1584_Structure of Quinine.jpg

Fig: Structure of Quinine

However it has been synthesized in the laboratory, the bark of the cinchona tree is the merely known natural source of quinine.  The medicinal properties of the cinchona tree were originally discovered via the Quechua Indians of Peru and Bolivia; later, the Jesuits were the first to bring the cinchona to Europe.

Quinine was the first efficient treatment for malaria caused due to Plasmodium falciparum, appearing in therapeutics in the 17th century. This remained the antimalarial drug of choice until the 1940s, whenever other drugs replaced it. As then, most of the effective anti-malarial have been introduced, however quinine is still employed to treat the disease in some critical conditions. Quinine is as well employed to treat lupus and arthritis. Quinine is very sensitive to ultraviolet light (UV) and will fluoresce in direct sunlight, because of its highly conjugated resonance structure.

Quinine is a flavor component of the tonic water and bitter lemon. Quinine is as well utilized in photochemistry as a common fluorescence standard, due to its relatively constant and well-known fluorescence quantum result.

Synthetic quinine:

Cinchona trees remain the mere economically practical source of the quinine. Though, under wartime pressure, research towards its synthetic production was undertaken. The formal chemical synthesis was accomplished in the year 1944 by American chemists R.B. Woodward and W.E. Doering. As then, some more efficient quinine total syntheses have been accomplished, however none of them can compete in economic terms by isolation of the alkaloid from natural sources. The first synthetic organic dye, mauveine was discovered via William Henry Perkin in the year 1856 while he was trying to synthesize the quinine.

Chloroquine:

Chloroquine (CQ), N'-(7-chloroquinolin-4-yl)-N,N-diethyl-pentane-1,4-diamine was discovered in the year 1934 via Hans Andersag and co-workers at the Bayer laboratories who named it 'Resochin'. This was ignored for a decade as it was considered too toxic for the use of human. All through World War II United States government-sponsored clinical trials for the anti-malarial drug development exhibited unequivocally that CQ consists of a significant therapeutic value as an anti-malarial drug. This was introduced to clinical practice in the year 1947 for the prophylactic treatment of malaria.

Uses:

a) This has long been employed in the treatment or prevention of malaria. After the malaria parasite Plasmodium falciparum began to develop widespread resistance to chloroquine new potential uses of this cheap and broadly available drug have been investigated. The Chloroquine has been extensively employed in mass drug administration's that may have contributed to the emergence and spread of the resistance.

b) Since it mildly suppresses the immune system, it is employed in a few autoimmune disorders, like rheumatoid arthritis and lupus erythematosus.

c) Chloroquine is in clinical trials as an investigational antiretroviral in the humans with HIV-1/AIDS and as a potential antiviral agent against the chikungunya fever. 

d) The radiosensitising and chemosensitising properties of the chloroquine are starting to be exploited in anticancer strategies in humans. 

e) Synthesis

f)  Chloroquine can be synthesized by using the Conrad-Limpach quinolone illustrated as shown below:

2061_Synthesis of Chloroquine.jpg

Fig: Synthesis of Chloroquine

Nicotinic Acid:

Niacin (as well termed as vitamin B3, nicotinic acid and vitamin PP) is the organic compound by the formula C6H5NO2 and, based on the definition employed one of the forty to eighty necessary human nutrients. This colourless, water-soluble solid is the derivative of pyridine, by a carboxyl group (COOH) at the 3-position. The other forms of vitamin B3 comprise the corresponding amide, nicotinamide (niacinamide), where the carboxyl group has been substituted via a carboxamide group (CONH2), and also more complex amides and a variety of esters. The words niacin, nicotinamide and vitamin B3 are often employed interchangeably to refer to any member of this family of compounds, as they encompass identical biochemical activity.

 Niacin is one of five vitamins related by a pandemic deficiency disease, niacin deficiency (pellagra), vitamin C deficiency (scurvy), thiamin deficiency (beriberi), vitamin D deficiency (rickets), vitamin A deficiency.

Niacin has been employed to raise the levels of HDL cholesterol in the blood and has been found to modestly reduce the risk of cardiovascular events in a number of controlled human trials. Though, in a recent trial AIM-HIGH, a slow-discharge form of niacin was found to have no effect on the cardiovascular event and stroke risk in a group of patients with LDL levels already well-controlled through a statin drug, and the trial was halted prematurely on proof that niacin addition actually increased stroke risk in this group. The role of niacin in treating the cardiovascular risk remains under debate.

Nicotinic acid is synthesized via the oxidation of quinoline by Chromium (vi) oxide.  Quinoline oxidizes to pyridine-2,3-dicarboxylic acid that readily loses the 2-carboxyl-substituent on being heated to form the nicotinic acid (figure shown below).

497_Synthesis of Nicotinic Acid from Quinoline.jpg

Fig: Synthesis of Nicotinic Acid from Quinoline

Other Applications of Quinoline:

The quinoline nucleus is as well contained in the plasmoquin (that is, an antimalarial agent), in cyanine dyes and in the analytical reagent, oxine (8-hydroxyquinoline).

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