Option D Medicinal Chemistry D 2 Aspirin penicillin

Option D Medicinal Chemistry D. 2 Aspirin & penicillin

Learning outcomes �Understand the mode of action of aspirin �Understand why aspirin is used �Understand that ethanol has a synergistic effect with aspirin. �Understand how aspirin is synthesised from salicylic acid �Understand how aspirin can be purified �Understand the characterisation of aspirin by melting point and infrared spectroscopy �Understand how the chemical modification of aspirin can affect its bioavailability

Analgesics �Analgesics are common pain relievers. �Many analgesics also have antipyretic properties as well. They can be used to reduce fever �Some analgesics are also anti-inflammatory drugs as well

Classification of Analgesics Strong Mild Analgesics Aspirin Analgesics Ibuprofen Acetaminophen Opium Heroin Codeine

Mild Analgesics �Mild Analgesics include over-thecounter pain relievers and fever depressants. �Examples of mild analgesics include Aspirin, acetaminophen, and ibuprofen

Aspirin �Aspirin is a derivative of salicyclic acid �Salicyclic acid was found in the bark of the willow tree and was used as a pain reliever and as a way to relieve fever symptoms of malaria Salicyclic Acid Aspirin

Aspirin � In 1899, Felix Hoffman, a chemist from the Bayer Company, developed a low-cost process to synthesize an ethanoate ester of salicyclic acid, called aspirin � In the synthesis of Aspirin, the ethanoic acid forms an ester with the alcohol group on the second carbon

Aspirin �Aspirin is believed to inhibit the enzyme, Prostaglandin synthase which is formed at the site of an injury. �This inhibits the production of prostaglandins which produce fever and swelling as well as transmitting pain signals to the brain.

Aspirin �Aspirin is able to reduce pain and fevers and dilate blood vessels �Aspirin enlarges blood vessels which helps prevent blood clots. �This vasodilation of the surface blood vessels also allows an increase of heat released which lowers the temperature of a fever �Aspirin is also taken to prevent recurring heart attacks �It may also be effective in preventing prostrate cancer

Side Effects of Aspirin �Aspirin can irritate the stomach lining which may lead to ulcers �If aspirin is used over long periods of time, it may lead to problems with blood clotting �An overdose on aspirin, such as the case with some arthritis sufferers, may lead to dizziness, ringing in the ears, gastrointestinal problems, mental confusion, and bleeding. �Some people are allergic to aspirin leading to bronchial asthma �In children under 12 Aspirin has been linked to Reye’s syndrome

The synergistic effect of ethanol �Synergism- two drugs taken together can have more effect than sum of their individual effects �Ethanol can increase the effect of other drugs, extra care must be taken while prescribing medicine to alcoholic person. �When alcohol is taken with aspirin there is an increased risk of hemorrhage (bleeding) in the stomach.

Synthesis of Aspirin The type of reaction is addition–elimination (the CH 3 CO group is added to aspirin and ethanoic acid is eliminated) and happens in the presence of a small amount of concentrated phosphoric (or sulfuric) acid catalyst.

Lab synthesis Alternate synthetic route for preparation of Aspirin involve reacting ethanoyl chloride with salicylic acid

Example page 11 �D. 1 In an experiment to synthesise aspirin, 5. 60 g of salicylic acid (Mr 138. 13) was reacted with 8. 00 cm 3 ethanoic anhydride (density 1. 08 g cm− 3) in the presence of a concentrated phosphoric acid catalyst. 5. 21 g of a white solid was obtained at the end of the reaction. Calculate: �a which reagent was in excess �b the yield of aspirin.

Purification of Aspirin �Recrystallization �The basic principles of recrystallization are that a solid is dissolved in a solvent in which it is soluble at raised temperatures but much less soluble at lower temperatures. Any impurities are present in much smaller amounts and so remain in solution at the lower temperature.

The procedure for recrystallization is: The product is dissolved in the minimum amount of hot solvent to form a close-to-saturated solution. 2. The solution is filtered while still hot to remove any insoluble impurities. Vacuum filtration is used because it is much faster – the product may start to crystallise while filtering if the solution cools too much. 3. As the solution cools, the product becomes less soluble in the solvent and comes out of solution as solid crystals – less of the solid dissolves at lower temperatures. It may be necessary to cool in ice or scratch the inside of the beaker to initiate crystallisation. 1.

4. Any solid product is separated from the solvent by vacuum filtration. 5. Any impurities also dissolve in the hot solvent, but because they are present in much smaller amounts they do not exceed their solubility, even at lower temperatures, and remain in solution. Aspirin can be recrystallised from ethyl ethanoate or ethanol 6. (usually a 95% ethanol/water mixture). Water is generally not used for recrystallisation because aspirin tends to decompose in hot water.

Purity of Aspirin can be determined by �Chromatography �Melting point – The melting point of pure Aspirin is reported between 138 - 140 0 C. If it does not melt in this range it is considered to be impure.

IR Spectra of Aspirin

The Discovery of Penicillin �Penicillin was discovered in 1929 by scientist Alexander Fleming. �He left for vacation with an agar plate covered with the bacteria Staphylococcus aureus. �When he returned he noticed that the fungus, Penicillium, had grown on the plate n The bacteria colony surrounding the fungus had become transparent because the bacterial cells had undergone lysis. 23

Development of Penicillin �Several years later Howard Florey and E. B. Chain stumbled across Fleming’s research papers and were intrigued by his findings. �They were convinced that Flemming’s discovery could save a lot of lives, prevent pain, and make it much easier to fight infectious diseases and prevent other infections. �They developed a way to mass produce penicillin making it available to soldiers wounded in world war II. �Florey and Chain were awarded the Nobel Prize in 1945 for their work on penicillin. 24

Penicillin Structure Penicillins have a special structure that allows them to interfere with the formation of the cell wall when bacteria reproduce The general structure of penicillin Video 25

How Does it Function? �Penicillin prevents the cross linking of small peptide chains in peptidoglycan, which is the main polymer in bacterial cell walls. �They do not affect bacteria which already exist, rather Penicillin’s affect the synthesis of new bacteria. �The new bacteria grow without the ability to maintain cell rigidity, making them susceptible to osmotic lysis. 26

The Action of Penicillins � The amide group in the beta lactam is more reactive due to the strained ring. � The structure of the beta lactam is similar to the structures of cysteine and valine. � The beta lactam binds to the enzyme that synthesizes the cell wall in bacteria, blocking its action. � As a result the bacteria rupture and break and cannot reproduce. Note the similarities in structure to the beta lactam. 27

Bacterial Immunity to Penicillin �Antibiotic Resistance – Mutated bacteria which are immune to antibiotics are more likely to survive when excessive antibacterials are used. �Bacteria develop enzymes known as penicillinases that destroy or render penicillin ineffective. �New antibiotics are developed by changing the R group side chain. 28

Structure of Penicillin is a group of compounds which all contain the same basic ring structure, known as beta-lactam. It is comprised of two amino-acids (valine and cyteine) through a tripeptide intermediate. The third amino acid (the R group) is replaced by another group, which gives different characteristics to differing penicillins. 29

Narrow Range and Broad Range Antibiotics �Narrow range antibiotics target specific kinds of bacteria. They are usually more potent. �Broad range antibiotics are effective against a wide range of bacteria. �When doctors diagnose patients suspected of having bacterial infections, they must first take samples of body fluids, and try to determine the precise type of infection. �A broad range antibiotic might be prescribed initially. Once a bacterial infection is properly diagnosed it may be appropriate to switch to a narrow range antibiotic. 30

Overuse of Penicillin �Leads to greater immunity of bacteria to penicillin, since the strongest and most resistant strains survive. �Greater doses of penicillin are required to be effective �Danger of developing super bacteria �Kill beneficial bacteria as well as harmful bacteria 31

Penicillin Synthesis A sterilized growth medium and an inoculum of strongly growing hyphae is added to stainless steel fermenters. The fermenters stirred continuously and glucose, nitrate and sterile air are periodically added. 32

�The first penicillin to be isolated and purified was penicillin G (benzylpenicillin) However, this penicillin has a number of disadvantages, one of which is that it is easily broken down by stomach acid and must be given by injection. Scientists have overcome this problem by making derivatives of penicillin G that have modified side-chains (R in the general penicillin structure) that can resist stomach acid and be given by the oral route.