L7 Bioisosterism SB

Question 1

A lead compound can be dramatically improved by optimising the following:

Answer 1

• Chemical Stability
• Metabolic Stability
  and an appropriate balance between hydrophobicity and hydrophilicity

Question 2

For drugs to interact in aqueous conditions with molecular targets it must be..

Answer 2

soluble

Question 3

for drugs to enter the cell and avoid rapid excretion it must be

Answer 3

hydrophobic

Question 4

describe a group that has good hydrophilic qualities and draw it. Why are hydrophilic qualities good?

Answer 4

Nitro ringed groups. they’re highly hydrophilic and with increased polarity there is reduced lipophilicity, so drugs like this have a reduced chance of crossing the Blood-brain barrier, therefore its key in reducing any CNS side effects

Question 5

Bulky groups act as… this is good for..

Answer 5

a steric shield. They protect susceptible functional groups from being hydrolysed or attacked by nucleophiles or enzymes

Question 6

Draw the structure of a carbamate and tell me what is more stable, an ester or a carbamate and why

Answer 6

carbamate is more stable because the nitrogen delocalises the electron density

Question 7

what is a metabolic blocker and give me an example of a metabolic switch

Answer 7

replacing CH3 with Cl. A metablolic blocker blocks sites on drugs where it is suseptible to metabolism. This can dramatically improve drug half life

Question 8

Bioisostere. what is it?

Answer 8

Substituents or groups with similar physical and chemical properties which produce broadly similar biological properties to another chemical compound. Without significantly changing the structure.

Question 9

What is the purpose of a bioisostere in drug discovery?

Answer 9

The purpose of bioisosteres in drug discovery is to be able to replace the one group or substituent with another, resulting in the enhancement of the desired biological or physical properties of the drug.

Question 10

What factors are important in choosing a bioisostere?

Answer 10

Group size, conformation, inductive and mesomeric effect

polarisabiliy, H bonding, pKa, hdrophobicity, reactivity and stability

Question 11

site three examples of monovalent bioisosteric replacements

Answer 11

H -> F similar size
OH -> NH2 because NH2 is harder to protonate
R-SH - > R-OH because R-SH can be oxidised into disulfide or even an acid which may be undesirable

Question 12

site one example of a benzene bioisostere

Answer 12

Benzene - > 6 membered ring but 5 carbons and one Nitrogen.

Question 13

Draw an example of an amide and its bioisostere

Answer 13

R-CF3-NH-R. The electronegativitiy of fluorines in trifluoroethylamine draw the electrons from the nitrogen away. This reduces the basicity of the amine.