Studies toward the total synthesis of quinine
T1 - Synthesis, antimalarial properties and 2D-QSAR studies of novel triazole-quinine conjugates
studies toward the total synthesis of quinine | …
A recent use for quinine drugs has been for the treatment of muscle spasms and leg cramps. A 1998 study documented the beneficial effects of quinine for leg cramps, with tinnitus being the only documented side effect. In 2002, a double-blind placebo study was undertaken in which 98 people with nocturnal leg cramps were given 400 mg of quinine daily for 2 weeks. The results stated that quinine administered at this dose effectively reduced the frequency, intensity, and pain of leg cramps without relevant side-effects. This use has fueled the natural product market and more people are looking for natural quinine bark as an alternative to the synthesized prescription drugs for this purpose.
A recent use for quinine drugs has been for the treatment of muscle spasms and leg cramps. A 1998 study documented the beneficial effects of quinine for leg cramps, with tinnitus being the only documented side effect. In 2002, a double-blind placebo study was undertaken in which 98 people with nocturnal leg cramps were given 400 mg of quinine daily for 2 weeks. The results stated that quinine administered at this dose effectively reduced the frequency, intensity, and pain of leg cramps without relevant side-effects. This use has fueled the natural product market and more people are looking for natural quinine bark as an alternative to the synthesized prescription drugs for this purpose.CURRENT PRACTICAL USES Quinine bark is harvested today much as it has been for hundreds of years. The tree trunks are beaten and the peeling bark is removed. The bark partially regenerates on the tree and, after a few years and several cycles of bark removal, the trees are uprooted and new ones are planted. The commercial quinine market today is difficult to calculate. It is thought that 300-500 metric tons of quinine alkaloids are extracted annually from 5,000-10,000 metric tons of harvested bark. Nearly half of the harvest is directed to the food industry for the production of quinine water, tonic water, and as an FDA-approved bitter food additive. The remainder is utilized in the manufacture of the quinidine prescription drug. Quinine is very bitter tasting and commercially sold tonic waters often use quinine as it's bitter ingredient/component. Commercially-produced tonic water usually contains around 100 to 300 parts per million quinine and up to a maximum allowable concentration of 70 milligrams of quinine per liter. The longstanding natural remedy for quinine bark usually calls for a cup of boiling water to be poured over approximately 1-2 g of ground or chopped natural bark and allowed to steep for ten minutes. A cupful of this infusion is drunk half an hour before meals to stimulate the appetite, or after meals to treat digestive disorders. The use of pure quinine at large dosages can be toxic. The reported therapeutic oral dose for quinine alkaloids in adults is between 167-333 mg three times per day. Reportedly, a single dose of 2-8 grams of pure quinine alkaloids taken orally may be fatal to an adult. Natural bark teas prepared in the traditional manner, however, have a long history of use without toxic effects. A cup of traditional quinine bark tea would provide approximately 100 mg of total alkaloids, including quinine (based upon an average of 5% total alkaloid content in the raw bark).The history of the cinchona tree provides a perfect example of how a natural product can go from folklore and indigenous use into world trade-and then into the drug market. It's also a perfect example of how indigenous peoples and countries with important natural resources are too often pirated and left out of the profit loop by industrialized nations and rich, multinational, profit-driven organizations. Despite the fact that quinine and quinidine drugs were patented and sold, Peru and Bolivia - from whence the discovery was made and the resources extracted - did not share in the patents or resulting profits. Their natural resources were smuggled out and profitable world markets were created from them. They were poor, developing nations without multinational backing or investment capital - and ended up at the bottom of the heap while competing in a global market for resources indigenous to their countries.While governments are making inroads and new laws concerning biodiversity and intellectual property rights to correct this situation, business still has a long way to go to "do the right thing." Ideally, if natural quinine bark makes a comeback in the growing natural products industry or new drugs are developed for these drug-resistant strains of malaria, these new laws will protect the natural resources of these developing nations.
Traditional Preparation: One-half cup bark decoction 1-3 times daily or 1-2 ml of a 4:1 tincture is taken twice daily. One to 2 grams daily of powdered bark in tablets or capsules can be substituted if desired. See page if necessary for definitions. Contraindications: Quinine bark contains naturally-occurring quinine alkaloids. These quinine alkaloids are sold as prescription drugs with numerous side effects and warnings documented in the literature. Do not exceed the quinine bark natural remedy amounts shown above unless you are under the care and advice of a qualified health care practitioner who is familiar with the warnings, side effects, and contraindications of higher therapeutic levels of quinine alkaloids. Drug Interactions: May potentiate blood thinning medications such as Warfarin.®
Tropical Plant Database entry for: Quinine Bark (Cinchona)
We were struck by the initial low yield of quinine obtained from the aluminum powder reduction and the trace material which we were able to isolate mandated the use of silica gel chromatography, a purification technique not yet discovered at the time of the Rabe-Kindler work nor available in 1944 to Woodward and Doering. It is of course impossible now to determine where Rabe and Kindler had obtained their aluminum powder, or the level of purity of the reagent that they had employed in their work. We thus set out to examine other reduction methods of the quinidinone/quininone mixture into quinine, to establish the robustness of this general transformation before returning to the issue of the quality of the aluminum powder. This was achieved through a relay synthesis of quinidinone (formed through oxidation of quinine)[,] to provide adequate quantities of pure material to study the reduction step.
Interestingly enough, natural quinine extracted from quinine bark and the use of natural bark tea and/or bark extracts are making a comeback in the management and treatment of malaria. Malaria strains have evolved which have developed a resistance to the synthesized quinine drugs. It was shown in early studies that an effective dose of natural quinine bark extract elicited the same antimalarial activity as an effective dose of the synthesized quinine drug. Scientists are now finding that these new strains of drug-resistant malaria can be treated effectively with natural quinine and/or quinine bark extracts. As evolving pathogens develop widespread resistance to our standard antibiotics, antivirals, and antimalarial drugs, it is of little wonder that the use of the natural medicine in quinine bark is being revisited, even by such giants as the World Health Organization.
Quinine - New World Encyclopedia
Lactone synthesis - Organic chemistry
Artesunate (AS) is a medication used to treat malaria
The intravenous form is preferred to quinidine for severe malaria
Artesunate - Wikipedia
Oto = ear; toxicity = poisoning
Cinchona - Wikipedia
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