med chem

Question 1

structure of dicoumarol

Answer 1

• 2 coumarin rings connected by methylene group (CH2)
• -OH substituent at 3, 4 position

Question 2

how does warfarin form sodium salt?

Answer 2

acid base reaction with NaOH

• enol acidic -> enolate salt (keto enol tautomerism)

Question 3

how does warfarin form hemiketal formation?

Answer 3

• enol interact with ketone -> hydroxyl group lone pair go to carbonyl C -> hemiketal (ring closure)
• form 2 chiral centre: di-isostereomer

Question 4

what is indane

Answer 4

fused bicyclic hydrocarbon ring

Question 5

what is phenindione

Answer 5

• orally active anticoagulant (Similar to coumarin)
• similarities with warfarin: acidic enol group, base structures (1, 3-indandione, phenyl ring)
• cross sensitivity with pt sensitive to warfarin

Question 6

types of SAR from apixaban to rivaroxaban

Answer 6

ring variation

• highly likely amide group important so keep similar form in rivaroxaban
• aromatic ring needed but H3CO- replaced with Cl -> more lipophilic

Question 7

organic chem MOA of aspirin

Answer 7

acetylation of key Ser residue on COX-1 -> irreversibly and permanently inactivate COX 1

Question 8

organic chem for MOA of clopidogrel

Answer 8

thiophene in S-clopidogrel oxidised to thiolactone -> hydrolysed into thiol and carboxylic acid -> thiol form disulfide bond with Cys in P2Y12

Question 9

inactivation of clopidogrel

Answer 9

1) Phase I: hydrolysis by esterases, oxidation by CYP3A4
2) Phase II: glucuronidation of free carboxylic acid -> form glucuronide -> glucuronide eliminated

Question 10

paracetamol MOA

Answer 10

central antipyretic mechanism: inhibition of pg in CNS (possibly COX-3)

Question 11

does paracetamol have anti inflammatory activity?

Answer 11

no but produce analgesia in arthritic and musculoskeletal disorders

Question 12

can you use paracetamol long term?

Answer 12

no cuz hepatotoxic

• minor hydroxyamide metabolite converted to NAPQI -> hepatotoxicity

Question 13

organic chemistry for paracetamol

Answer 13

1) weak acid, low water solubility

• ionisable group: phenolic OH

2) NAPQI electrophile

• resonnace = lower e- density in benzene ring
• drawn to -ve charge

3) interaction with glutathione

• SH group in glutathione e- rich -> react with electrophile

Question 14

chemical structure properties for aspirin

Answer 14

• OH group ortho to COOH essential for activity
• second phenyl ring conjugated with phenyl in salicylic acid increase anti-inflam property

Question 15

oil of wintergreen

Answer 15

• rubefacient: counter irritant
• trigger erythema when applied on skin -> sensation of heat mask pain
• used for muscle ache

Question 16

structure of aryl alkanoic acid

Answer 16

• chiral centre
• S-enantiomer active stereoisomer

Question 17

structure of indomethacin

Answer 17

1) heteroaryl acetic acid with indole ring
2) COOH required for activity

• ionise -> interact with Arg 120 in COX
• replace COOH = reduce activity
• only acetic group active

3) 2-methyl group fit into small hydrophobic pocket -> steric hindrance -> push 4-chlorobenzoyl group into cis-like position -> activate conformation
4) insertion of CH3 group in alpha carbon -> only S-stereoisomer active
5) indole

• acetylation of indole N important for activity
  ** reduce carbonyl group to methylene group = reduce activity
  ** can replace Cl with other lipophilic groups (F, CF3, SCH3)
• 5-position on indole system e- donating/withdrawing

Question 18

how is sulindac different from indomethacin?

Answer 18

bioesteric replacement

• N replaced by C -> double bond conjugated to phenyl ring -> rigidification

** need flat structure for activity

Question 19

sulindac prodrug

Answer 19

• converted to active drug during phase I
• activated by CYP/FMO into sulfide group
• inactivated metabolically by oxidation into sulfone

Question 20

diclofenac essential components

Answer 20

2 chloro group important

• steric hindrance to C3-H and COOH -> force non planar conformation between rings -> optimise binding

Question 21

why long term and frequent usage of diclofenac cause hepatotox?

Answer 21

• metabolised by CYP3A4 -> 4’-hydroxy derivative -> form hepatotoxic quinonimine
• when GSH depleted -> Cys residue in hepatocyte attack quinoamine -> irreversibly alkylation on hepatocyte -> hepatotoxicity
• quinoamine inactivated by glutathione

Question 22

advantages of nabumetone

Answer 22

non acidic prodrug = X induce direct GI mucosal damage

Question 23

nabumetone metabolism

Answer 23

extensive first pass

• metabolised into 6-MNA through beta-oxidation -> activate metabolite
• more extensive = increase efficacy

Question 24

organic chem of ibuprofen

Answer 24

• chiral centre
• racemate but S-stereoisomer active
• short duration of action cuz metabolised into many inactive metabolites
• bioequivalence: R-isomer metabolised into S-isomer

Question 25

structure of mefenamic acid that is important for binding

Answer 25

ortho NH group increase COX binding

Question 26

why 2-CH3 group important for mefenamic acid

Answer 26

promote non-coplanarity - ortho-CH3 = tendency for moleceule to be flat - planar = X fit into binding site - so need second CH3 for steric hindrance

Question 27

metabolism of mefenamic acid

Answer 27

1) Phase I: 3-CH3 oxidised to CH2OH -> COOH 2) phase II: COOH undergo glucuronidation

Question 28

how is celecoxib and eterocoxib selective

Answer 28

selective to COX-2 cuz large enough structure to be rejected by COX-2 active site = decrease affinity to COX-1 active site

Question 29

how does celecoxib and eterocoxib reduce damage effect to GI mucosa?

Answer 29

bind to allosteric site in COX-2 -> change in active form so reduce damaging effect but higher risk of platelet aggregation facilitated cardiovascular damage

Question 30

what happens in gout attack

Answer 30

- xanthine oxidase convert hypoxanthine -> xanthine -> uric acid (oxidation) - high level of uric acid = uric acid weak acid = precipitate out as crystals in joint & connective tissue = grout attack

Question 31

uses of colchicine

Answer 31

- prophylaxis and treatment - retard inflammation due to deposit of uric acid crystals

Question 32

allopurinol organic chem

Answer 32

- xanthine mimic, competitive inhibitor of xanthine oxidase - positional isomer of N atom - higher affinity for xanthine oxidase than xanthine -> Decrease level of uric acid

Question 33

febuxostat

Answer 33

- indication: chronic management of hyperuricemia in gout pt, pt X tolerate allopurinol - non commpetitive inhibitor of both oxidised and reduced form of xanthine oxidase