med chem Flashcards
structure of dicoumarol
- 2 coumarin rings connected by methylene group (CH2)
- -OH substituent at 3, 4 position
how does warfarin form sodium salt?
acid base reaction with NaOH
- enol acidic -> enolate salt (keto enol tautomerism)
how does warfarin form hemiketal formation?
- enol interact with ketone -> hydroxyl group lone pair go to carbonyl C -> hemiketal (ring closure)
- form 2 chiral centre: di-isostereomer
what is indane
fused bicyclic hydrocarbon ring
what is phenindione
- 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
types of SAR from apixaban to rivaroxaban
ring variation
- highly likely amide group important so keep similar form in rivaroxaban
- aromatic ring needed but H3CO- replaced with Cl -> more lipophilic
organic chem MOA of aspirin
acetylation of key Ser residue on COX-1 -> irreversibly and permanently inactivate COX 1
organic chem for MOA of clopidogrel
thiophene in S-clopidogrel oxidised to thiolactone -> hydrolysed into thiol and carboxylic acid -> thiol form disulfide bond with Cys in P2Y12
inactivation of clopidogrel
1) Phase I: hydrolysis by esterases, oxidation by CYP3A4
2) Phase II: glucuronidation of free carboxylic acid -> form glucuronide -> glucuronide eliminated
paracetamol MOA
central antipyretic mechanism: inhibition of pg in CNS (possibly COX-3)
does paracetamol have anti inflammatory activity?
no but produce analgesia in arthritic and musculoskeletal disorders
can you use paracetamol long term?
no cuz hepatotoxic
- minor hydroxyamide metabolite converted to NAPQI -> hepatotoxicity
organic chemistry for paracetamol
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
chemical structure properties for aspirin
- OH group ortho to COOH essential for activity
- second phenyl ring conjugated with phenyl in salicylic acid increase anti-inflam property
oil of wintergreen
- rubefacient: counter irritant
- trigger erythema when applied on skin -> sensation of heat mask pain
- used for muscle ache
structure of aryl alkanoic acid
- chiral centre
- S-enantiomer active stereoisomer
structure of indomethacin
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
how is sulindac different from indomethacin?
bioesteric replacement
- N replaced by C -> double bond conjugated to phenyl ring -> rigidification
** need flat structure for activity
sulindac prodrug
- converted to active drug during phase I
- activated by CYP/FMO into sulfide group
- inactivated metabolically by oxidation into sulfone
diclofenac essential components
2 chloro group important
- steric hindrance to C3-H and COOH -> force non planar conformation between rings -> optimise binding
why long term and frequent usage of diclofenac cause hepatotox?
- 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
advantages of nabumetone
non acidic prodrug = X induce direct GI mucosal damage
nabumetone metabolism
extensive first pass
- metabolised into 6-MNA through beta-oxidation -> activate metabolite
- more extensive = increase efficacy
organic chem of ibuprofen
- chiral centre
- racemate but S-stereoisomer active
- short duration of action cuz metabolised into many inactive metabolites
- bioequivalence: R-isomer metabolised into S-isomer
structure of mefenamic acid that is important for binding
ortho NH group increase COX binding
why 2-CH3 group important for mefenamic acid
promote non-coplanarity
- ortho-CH3 = tendency for moleceule to be flat
- planar = X fit into binding site
- so need second CH3 for steric hindrance
metabolism of mefenamic acid
1) Phase I: 3-CH3 oxidised to CH2OH -> COOH
2) phase II: COOH undergo glucuronidation
how is celecoxib and eterocoxib selective
selective to COX-2 cuz large enough structure to be rejected by COX-2 active site = decrease affinity to COX-1 active site
how does celecoxib and eterocoxib reduce damage effect to GI mucosa?
bind to allosteric site in COX-2 -> change in active form so reduce damaging effect but higher risk of platelet aggregation facilitated cardiovascular damage
what happens in gout attack
- 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
uses of colchicine
- prophylaxis and treatment
- retard inflammation due to deposit of uric acid crystals
allopurinol organic chem
- xanthine mimic, competitive inhibitor of xanthine oxidase
- positional isomer of N atom
- higher affinity for xanthine oxidase than xanthine -> Decrease level of uric acid
febuxostat
- indication: chronic management of hyperuricemia in gout pt, pt X tolerate allopurinol
- non commpetitive inhibitor of both oxidised and reduced form of xanthine oxidase
