Chemical structure: a pharmaceutical perspective 1-5

Question 1

What is the definition of functional groups

Answer 1

Functional groups are structural units of organic compounds, defined by specific atom bonds.

Question 2

What are the 3 main memorable facts about functional groups in drugs (3)

Answer 2

1. Each drug is defined by its functional groups
2. In a given drug, some functional groups are more important than others
3. Alteration of functional groups can alter the behaviour of a drug

Question 3

What are the main types of functional groups (18)

Answer 3

1. Aromatic rings
2. Ether group - oxygen link
3. Alkyl chain (alkane) - chain of carbons and hydrogens
4. Methyl group - CH3
5. Amino group - NH
6. Alkenyl (alkene) - C=C
7. Alkyne (alkynyl) - C≡C
8. Hydroxyl - alcohol
9. Alkyl halide R-F, R-Cl, R-I, R-Br
10. Thiol - S-H
11. Aldehyde - O=C-H
12. Ketone - R’-C=O
13. Ester - O=C-O
14. Carboxylic acid - COOH
15. Amide O=C-N
16. Nitrile - C≡N
17. Nitro - O-N=O
18. Sulfide - S-R

Question 4

What effects can changing functional groups have on drug behaviour (9)

Answer 4

1. Hydrophilic/lipophilic balance - how drug dissolves in water/fat
2. Administration route - orally, iv, etc..
3. Interaction with specific biological targets -
4. Mechanism of action -
5. Route of elimination and metabolism -
6. Duration of action -
7. Suitability for a given therapeutic situation - same disease but different treatment
8. Occurrence of adverse effects
9. Give rise to drug interactions

Question 5

What effects do functional groups have on drug behaviour (3)

Answer 5

1. Electronic effects
2. Solubility effects
3. Steric (shape) effects

Question 6

What is electronic effect

Answer 6

the ability of a group to either donate electrons to or to pull electrons from adjacent functional groups

Question 7

What is electronic effect defined by (2)

Answer 7

1. resonance - occurs in the presence of conjucated lone pairs and double/triple bonds - In a conjugated system the electrons belong to the whole system not just the atoms.
2. induction - determined by intrinsic ELECTRONIC AFFINITY

Question 8

How does resonance occur in aliphatic (organic open chain) compounds in terms of lone pairs

Answer 8

lone pair atoms move in turn also moving that double bond therefore changing the negative charge position.

Question 9

How does resonance occur in aliphatic (organic open chain) compounds in terms of double bonds

Answer 9

The electronegativity of an atom pulls the double bonds towards it.

Question 10

How does resonance occur in aromatic compounds with an electron donating group (3)

Answer 10

1. The double bonds are relocating.
2. The lone pairs can be delocalised all over the ring and form a double bond.
3. The double bond and the negative charge can continue moving around the aromatic ring

Question 11

How does resonace occur in aromatic compounds with an electron withdrawing group (3)

Answer 11

1. Double bond is pulled out of the aromatic ring, introducing a positive charge within it
2. Triple bonds are broken, forming lone pairs of electrons
3. Double bonds and the positive charge can continue moving around the aromatic ring.

Question 12

What is induction (3)

Answer 12

1. intrinsic ability of an atom/group to withdraw or donate electrons depending on the electronegativity.
2. the difference in electronegativity between the two atoms participating in the bond allowing to predict the type of the bond.
3. Electronegativity is the strength of which an atom pulls electrons towards itself.

Question 13

What effect does electronegativity have in the intrinsic ability (3)

Answer 13

1. electronegativity less than 0.5 = non-polar (equally shared electrons)
2. electronegativity higher than 0.5 but less than 1.6 = polar (electrons spend more time closer to electronegative atom)
3. electronegativity higher than 2.0 = ionic (electrons are allocated to the electrogative atom and dissociate from the others).

Question 14

What are examples of electron-donating groups (5)

Answer 14

1. hydroxyl (OH) with aromatic ring
2. amino (NH₂) with aromatic ring
3. thiol (SH) with aromatic ring
4. alkyl (CH₃)with aromatic ring
5. alkoxy (OCH₃) with aromatic ring

Question 15

What happens with electron-withdrawing groups (EWG)

Answer 15

Molecules containing electron-withdrawing groups can behave as electrophiles (electron-loving)

Question 16

What happens with electron-donating groups (EDG) (4)

Answer 16

1. Resonance = EDG has electronegative atoms - attracts electrons to the neighbouring groups
2. No resonance is = EDG has non-electronegative atoms - attracts electrons away from the neighbouring groups
3. Molecules containing EDG can behave as NUCLEOPHILES (nucleus-loving)
4. The lone pairs can lead a nucleophilic attack of an electron pool centre

Question 17

Why are solubility effects fundamental for drugs (5)

Answer 17

1. The solubility of a drug in water/lipids is a fundamental parameter for a drug.
2. It mainly affects its pharmacokinetic profile.
3. drugs need to be water soluble to dissolve in the extracellular aqueous compartment.
4. A degree of solubility in lipids is also required to penetrate the phospholipid cell membrane
5. However, high solubility in lipids will prevent the drug from escaping to the intracellular aqueous compartment.

Question 18

What are the 4 main intermolecular forces (4)

Answer 18

1. Van der Waals (non-polar) → shared electrons, temporary dipole, asymmetric distribution
2. dipole-dipole interaction → permanent dipole, electron-rich dipole is attached to the electron-pool end of a neighbouring dipole
3. hydrogen bond → electropositive hydrogen is attached to the high electron density region of neighbouring molecules
4. ion-dipole interaction (polar) → positively charged ion (cation) attracts electron-rich regions of dipoles (vice versa for anions) → very water soluble

Question 19

What groups are able to interact with water to give rise to water-solubilising groups (4)

Answer 19

1. Hydrogen-bonding groups - accept or donate H bonds
2. Ionisable groups -
3. Dipoles
4. Polar molecules

Question 20

What groups are able to interact with fatty acids to form lipid-solubilising groups (4)

Answer 20

1. Alkylic chains or rings (Van der Waals interactions)
2. aromatic rings (pi stacking)
3. unsaturated chains (mix)
4. molecules without polar groups

Question 21

What is steric effect

Answer 21

Each functional group has finite size (or steric dimension) that contributes the overall shape and conformation of the drug molecule

Question 22

What does careful modification of the steric fingerprint of a drug lead to (3)

Answer 22

1. increased selectivity for the biological target e.g. methyl group in bethanechol makes it a selective agonist and lack of methyl in acetylcholine makes it non-selective agonist
2. enhanced binding interactions with the target and elimniate the binding for another target
3. favourable alteration of the rate of metabolism e.g. methoxy in cefotixin makes it more resistant to beta-lactamases

Question 23

What does the skeleton of hydrocarbons in drug molecules contribute to (3)

Answer 23

1. the electronic features of the molecule
2. the solubility and pharmacokinetics
3. the shape

Question 24

What are the different types of hydrocarbons and their hybridisation (4)

Answer 24

1. Aliphatic
   
   1. Alkanes - single bond(s) (saturated), hybridisation = sp3
   2. alkenes - double bond(s) (unsaturated), hybridisation = sp2
   3. alkynes - triple bond(s) (unsaturated), hybridisation = sp
2. Aromatic
   
   1. arenes - double bonds (unsaturated), hybridisation = sp2

Question 25

What is hybridisation (2)

Answer 25

1. An orbital is an equation describing the part of space where it is highly possible to find an electron 2. A hybrid orbital is the linear combination (sum) of the equations describing two orbitals

Question 26

How do spx orbitals come about (6)

Answer 26

1. spx orbitals result from a combination (hybridisation) of s orbitals with p orbitals 2. s orbitals = 2 electrons 3. p oribatals = 6 electrons 4. s + px, py, pz = sp3 (single bond) - tetrahedral 5. s + px, py = sp2 (double bond) - trigonal planar 6. s + px = sp (triple bond) - linear

Question 27

What are alkanes (4)

Answer 27

1. Saturated chains, consisting of C-H and C-C single bonds 2. sp3 hybridisation 3. When linked together they are availble in linear chains, branched and cyclic. 4. They have freedom of rotation as in open chains every bond rotates and structures made with single bonds are very flexible

Question 28

What are alkenes (5)

Answer 28

1. Unsaturated chains containing double bond(s) 2. sp2 hybridisation 3. sigma bonds with hydrogen and pi bonds over double bond between double bonded carbons 4. planar molecules no rotation around the double bond, to allow rotation you would have to break the double bond. 5. There is geometrical isomerisation - 2 isomers exist

Question 29

What are alkynes (4)

Answer 29

1. Unsaturated chains containing triple bond(s) 2. Rod like function - linear in shape, planar 3. sp hybridisation 4. sigma bonds between hydrogen and two pi bonds between the triple bonded carbons

Question 30

What are aromatic hydrocarbons (5)

Answer 30

1. Class of conjugated hydrocarbons - system of pi bonds are seperated by single bonds 2. The pi electrons and lone pairs can rearrange and relocate around the conjugated area behaving as a unique system 3. Benzene is a conjugated 6 membered hydrocarbon ring with 3 double bonds with sp2 hybridisation 4. The electrons in the double bonds can rearrange to give other species 5. The delocalisation (cloud of electrons above the ring) imparts electron-withdrawing behaviour to the ring creating an area of high electron density

Question 31

What is the role of hydrocarbons in drug molecules (6)

Answer 31

1. Hydrocarbons form the skeleton of virtually every drug molecule 2. High lipid solubility – help drug cross membranes and access the CNS ☆ 3. Impart conformational flexibility or stiffness to drug molecules 4. Generate zones of non-polar high electron-density 5. Relative metabolic stability (especially alkanes/cycloalkanes) ☆ 6. No other functional group could achieve the same

Question 32

What determines hydrophobicity (2)

Answer 32

1. Determined by the non-polar character of C-C and C-H bonds 2. Interactions dominated by Van der Waals forces. No dipoles, no H-bonds.

Question 33

What are Van der Waals interactions (3)

Answer 33

1. Occurs between permanent dipole and induced dipole (Debye forces) and induced dipole and induce dipole (London forces) 2. electrons in a non-polar bond are not static; instead they fluctuate rapidly, creating temporary dipoles 3. the temporary dipoles can orient themselves

Question 34

What does the nature of the hydrocarbon skeleton determine (6)

Answer 34

1. Hydrophobicity 2. The molecular shape 3. Bond length 4. Bond angles 5. Flexibility/stiffness 6. Every type of hydrocarbon has peculiarities for these parameters

Question 35

What does flexibility allow (4)

Answer 35

1. Open chain with single bonds provide flexibility to the molecule 2. Flexibility allows the molecule to adopt an active conformation in the site of action 3. This is a great property as in a structure the molecule can twist and turn to adapt to the receptor 4. double bonds, triple bonds, aromatic rings and saturated cycles provide stiffness because they prevent rotation

Question 36

How does chirality affect drug molecules (2)

Answer 36

1. when an sp3 C atom with four different substituents is present in a drug molecule, the molecule is ASYMMETRIC 2. This results in an active enantiomer which fits the active site and an inactive enantiomer which doesn’t fit the active site

Question 37

What are possible scenarios of enantiomers with different behaviour (4)

Answer 37

1. No difference in enantiomer activity 2. Enantiomers have similar activity but different potencies 3. Enantiomers have different activities 4. One enantiomer is active and the other is not active at all

Question 38

How are hydrocarbons metabolised (5)

Answer 38

1. Metabolism of hydrocarbons is oxidadtive 2. Matabolism at the end of a hydrocarbon chain can be omega or omega-1 hydroxylation 3. Omega hydroxylation is when the enzyme puts a OH group on the carbon at the end of the hydrocarbon chain, catalysed by p450 enzyme 4. Omega-1 hydroxylation is when the enzyme puts a OH group on the carbon before the carbon at the end of the hydrocarbon chain catalysed by p450 enzyme 5. When there are double bonds the P450 enzyme carries out dihydroxylation where the double bond is broken and replaced with two OH groups

Question 39

How are benzene rings metabolised (2)

Answer 39

1. Benzene rings are metabolised firstly by the insertion of an oxygen atom across the double bonds this species is toxic and a very good electrophile 2. from there it undergoes hydrogenation