Introduction to Medicinal Chemistry Flashcards
Describe the basis of ancient medicines and the most influencetial civilisations and medicines from this era.
Medicines in the ancient era were all from plants, herbs and animals, normally without much alteration from the natural form.
Egypt - senna for constipation. The Egyptions have the oldest recorded perscriptions and treatment guides.
China - ephedrine, morphine and castor oil. Many herbal and animal cures are used.
South America - quinine and cocaine.
Aboriginal - tea tree oil.
Briefly describe the key figures and stages of the development of western medicine.
The Greeks used the work of the Egyptions and built upon it. Hippocrates developed the modern medicial principles.
In the middle ages, Paracelsus founded modern medicinal chemistry. He advocated for evidence based, simple perscriptions.
In the 18th century, the placebo effect meant that many bizarre treatments were thought to work. Now we always compare to a placebo.
Describe how morphine transitioned from a herbal remedy to a modern medicine.
The seeds of the opium poppy were long known as a narcotic painkiller. In the early 19th century the morphine was extracted and later distribution began. By 1827 it was commercially avaliable. When the hyperdermic needle was introduced, popularity spiked and was highly addicting.
Describe the history and adaptation of asprin.
How was this approach used in other medicines?
Willow bark was know as a painkiller and anti-inflammatory but had unwanted side effects such as gastric bleeding.
Chemists modified salicylic acid to an ester (robust 19th century reaction) which reduced the acidity. This was commercialised by Bayer.
Building from their success, Bayer modified morphine to have ester groups and created Heroin which was marketed as a cough medicine.
Describe the discoveries and work of Louis Pasteur.
In 1877 he demostrated that microorganisms spoilt milk and beer, leading to the introduction of pasturisation. He was also the first to deliberately synthesise a weakened strain of diseases as a vaccination.
What role did Paul Ehrlich play in the development in anti-biotics?
He synthesised the first chemical drug to treat an infectious disease - syphilis, an STI which can kill without treatment. The drug, Salvarsan, was two poisoness arsenic atoms with a ‘coating’ of aromatic rings bonded to it. It selectively attacted the bacterial cells more than human cells.
Define the theraputic index of a drug.
LD50/ED50
Where LD50 is the dose where 50% of subjects die, and ED50 is the dose where 50% of subjects recieve and effective treatment.
What were the main causes of the incresase in life expectancy in the 20th century?
The biggest was antibiotics - the first effective way of treating infections. Additionally better health, hygiene and safety.
Describe and draw the action of Salvarsan. Why is this effective against syphilis?
Salvarsan is a pro-drug meaning it is converted to the active form in vivo. The As=As double bond is oxidised, then binds to thiol groups, deactivating the connected enzymes.
The syphilis bacteria has much more cysteine than human cells making it like a magic bullet.
Briefly describe the early development of sulfa drugs by Bayer.
Bayer tested their azo dyes on bacteria in vitro and in vivo. They found that Prontosil Red was active in vivo only. However the azo dye wasn’t the active part of the drug, it was acting as a pro-drug for one of the reactants.
Define a Pharmacophore and describe how Prontosil Red works as an anti-biotic.
What issues do sulfonamide drugs have in treatment?
Pharmacophore - Essential part of a drug, required for activity.
Humans consume folic acid but bacteria must make it. Therefore bacteria have enzymes to make folate which sulfonamides bind to.
Sulfonamides have poor solubility and tend to crystallise in the kidneys. They also have a low activity so have to be taken in large doses.
Describe the discovery of penicillin and how it was developed into use. What was its main use?
When a dirty petri dish grew mould it killed bacteria on the dish. In 1938, crude penicillin could be isolated and was found to work in mice. It was then produced by large-scale fermentation in america. In the war it was used to treat wounds but was actually more used to treat STIs.
How was the structure of penicillin deduced and what is the main active feature? Why is it notable?
The structure was found by Dorothy Hodgkin by x-ray crystallography to have a beta-lactam ring - a four membered ring with an amide. The amide is highly reactive since it cannot resonate like a typical amide due to the ring strain this would produce. This makes it highly suspectable to nucleophilic attack.
Describe, in depth, the mode of action of penicillin.
Bacteria must have strong cell walls to be able to survive outside the body. They have glycopeptide cell walls which end in a D-Lys-D-Ala-D-Ala chain. The wall is strengthaned by cross-linking the Lys to the middle Ala between chains.
Penicillin interupts the cross-linking by mimicing a D-Ala-D-Ala chain, then reacting with a nucleophile from the enzyme, transpeptidase. This permanently blocks the active site by ireversible (covalent) inhibition.
Describe the 4 limitations of penicillin.
Low acid stability - required injection
Only works on gram positive bacteria (gram test for glycopeptide cell wall)
Allergic in significant number of patients - can be fatal
Resistance can form by evolution of a beta-lactamase enzyme (meaning it hydrolyses the beta-lactam)
Describe the breakthroughs of semi-synthetic penicillin and how they are formed.
In 1947, PhOCH2CO2H was added to the fermentation vat to change the R group on the amine. This was acid resistant and became the first orally active penicillin.
The most common synthetic applications require sythesis using the fermented product and have aromatic groups which give better cell wall penetration (amoxycillin, ampicillin, methicillin).
Methicillin is the most active form as its two methoxy groups hinder beta-lactamase but still inhibit transpeptidase. When resistance is develop it is know as MRSA.
How can co-drugs be used to fight antibiotic resistance? Describe their mode of action.
Sacrifical compounds can be added to penicillin to inhibit the beta-lactamase.
Clavulanic acid has a 4 membered ring which breaks down to form an imine which binds the beta-lactamase by acting as an electrophile. It can form an imine since it has an oxygen which is more electron withdrawing than the sulphur on penicillin.
Describe the action, binding strength and resistance of Vancomycin.
For a long time vancomycin was the drug of last resort when all other antibiotics fail. It binds to the Lys-D-Ala-D-Ala cell wall via 5 H-Bonds. This prevents cross-linking and kills bacteria by inhibiting the transpeptidase.
The binding strength is reversible and very strong. It can be resisted by replacing the final Ala on the chain with a Lac (not an amino acid) which removes the NH with an O that cannot hydrogen bond and causes repulsion. This makes the drug 2-3x weaker at binding the cell wall.
The Vancomycin can be modified to account for this resistance but this requires a 36 step sythesis.
Describe the basic structure of viruses, how they are typically treated and why some can be especially hard to treat.
Viruses are simple ‘organisms’ which consist of genetic material (DNA/RNA) with a protective protein/enzyme coat with glycopeptide ‘spikes’. They have to hijack a human host cell to graft their genetic material to the cell and to produce new copies of the virus.
The most reliable treatment is vaccination which lets the immune system recognise the virus.
Viruses like HIV and influenza rapidally change their external coat to get round the immune systems recognition systems.
Describe how Acyclovir works as an anti-viral agent to combat herpes.
It mimics guanosine as a DNA base but is missing the next OH which the DNA chain is continued through. The virus builds Acyclovir into the structure 3000x faster than human cells and terminates the DNA chain.
This only slows the replication of the herpes virus however - it is a life long virus once you have it.
Describe the history of the treatment of HIV/AIDS and the drug thats currently perscribed.
When AIDS first came about it was treated like a death sentance - left untreated it killed in 10 years. Acyclovir only slowed the onset of AIDS in 20% of patients.
AZT - azido-thymidine was found to be active against AIDs. AZT was found to be active only 4 years after HIV/AIDS was first recognised and one year after it was confirmed that HIV caused AIDS. It is a thymidine base with an azido group instead of the normal OH required for chain growth.
Within another 5 years AZT was approved for use first in AIDS patients, then HIV+ patients. This was one of the fastest route to clinic of any drug after it was shown to quarter the death rate in trials.
Describe the structures of Relenza and Tamiflu highlighting their similarities and differences.
Both have negative charged tops, positive charged lefts and hydrophobic bottoms.
Relenza (GSK) has a hydrophilic right to gain H-bonds. This means it is too hydrophilic to cross cell membranes in the intestine so it has to be inhaled by a powder. This can cause lung irritation.
Tamiflu (Roche) has a smaller hydrophobic right to allow the drug to cross cell membranes in the intestine making the drug orally active.
Describe the delivery methods of drugs and the ways the drug is excreted including all the stages in between.
Oral delivery goes into the gastrointestinal (GI) tract and is absorbed into the liver where it has the 1st pass liver metabolism. The molecules can then pass into the blood and travel round the body. All non-absorbed material is excreted in faeces.
Intravenous injections go into the blood and intramuscular injections go into the muscle depot, then the blood over time. From the blood the drugs can diffuse to the extracellular fluid, then to the site of action or filtered by the kidney and excreted as urine.
Describe in depth, the phase 1 metabolism reactions, the relevent modes of action and the problems/challenges that occur.
Oxidation occurs in the liver by P450 enzymes, these are a family of enzymes which are different patient to patient. The most common reactions are introducing OH groups to aryl or akyl chains. They can also oxidise alkenes to epoxides and amines to n-oxides.
The P450 enzyme contains a porphyrin ring which contains a Fe(IV) complex with a carbonyl. The reaction with aromatic rings is a homolytic reaction which forms an expoxide (reduced to an alcohol) and forms stable a stable Fe(II) complex. P450 can also remove H2.
P450 is affected by food such as grapefruit juice which can lead to lower P450 activity.
Reductions can occur but are rarer and mainly occur for carbonyls. Hydrolysis reactions can occur readily or with -ase enzymes on groups such as esters, amides, carbamates and carbonates.
Describe the phase 2 conjugation reactions that occur by the metabolism. What are the modes of action?
Glucoronidation transform nucleophilic groups by attaching them to glucuronic acid - a sugar structure which has an UDP (Uracil Diphosphate) leaving group allowing the nucleophilic group to be attached.
Sulfate conjugation can occur with alcohols to convert them into sulfates which will be ionised.
Glutathione conjugation is where the amino acid chain glutathione attacks electrophiles through a thiol making a thioether.
Other reactions include methylation and acetylation which lead to more polar groups forming.
Describe the considerations for drug dosing and how they are managed.
The half-life of a drug is the time taken for the concentration of the active drug to fall by half from the peak plasma level. Typically this is 3-8 hours.
The drug is administered in intervals and once the steady state is reached (where the highest and lowest values of the drugs concentration are constant) it is known as the theraputic window.
Describe the toxicity issues associated with paracetamol and how they arise.
Paracetamol has an OH group which is converted by phase 2 metabolism to either a sulfate group or a glucuronide group. This increases its solubility and allows urinary excretion.
It can also be oxidised by loss of H2 by phase 1 metabolism. This allows a 1,4 attack by nucleophiles, which can be glutathione in a phase 2 conjugation which allows it to be excreted in urine. If there is a lack of glutathione then liver proteins with cystine groups act as nucleophiles causing toxic stress and liver faliure. As such any thiol can be a rescue drug.
Briefly describe how ampicillin is administered.
Ampicillin is only about 40% absorbed when taken orally so functional groups are added to increase the lipophilic nature of the drug. Acetals and carbonates are added which are hydrolysed in vivo to form the active drug.
Describe the history of asthma, the initial treatments and the key discovery for selective treatment.
It was one of the most serious respiratory diseases and was frequently fatal. Adrenaline was known to simulate the lungs but also stimulated the heart, leading to oxygen deficiency in a different way. A study found that there is different receptors in adrenaline in the body, named alpha and beta, and the natural hormones with similar structures to adrenaline activated the receptors to varying degrees. Increasing steric bulk on adrenalines amine group showed increased activity for beta receptors.
Synthetic hormones with bulky amine groups were developed whilst the heart and lungs were shown to have slightly different beta receptors which became a target for drug discovery. This is known as the structure-activity relationship.
What challenges arose from the development of adrenaline as an asthma treatment and what was the solution?
The phase 2 metabolism formed a methoxy group from one of the alcohol groups on the aromatic ring. The solution was to place the alcohol group on a carbon coming off the aromatic ring. This didn’t affect the reactivity but protected from the metabolism. Salbutamol transformed the lives of asthma patients.
One problem with the drug is that it only had a four hour mode of action so an alternative with a long lipophilic side chain was developed to adhere to the membranes and fatty tissues and lengthen the half-life to 12 hours to work for patients overnight.
