Inhibitors of folate metabolism Flashcards
What is folate metabolism?
One of few central housekeeping pathways used for chemotherapy, essential for DNA and RNA synthesis and is required for C1 metabolism
Describe the bacterial pathway
They are able to make dihydropteroate and in order to do that they combine 2 molecules: para aminobenzoic acid. Glutamate is added to the resulting product to make dihydrofolate which is then reduced to make tetrahydrofolate
Describe the human pathway
we take in folate which is converted into dihydrofolate and a dihydrofolate reductase makes tetrahydrofolate
What is prontasil a prodrug for?
sulphanilamide
Describe the activity of sulphanilamide
poor activity due to low acidity of S(O)2NH2, sulfonamide group not very acidic, only 0.2% ionized at pH 7.4
Explain the SAR of substituted sulfanilamides
requires a sulfonamide group and the optimum acidic pka for antibacterial activity is 6-7, nitrogen must be secondary, aromatic ring required and must be para substituted with a para amino group, R is the only site that can be varied
What are the uses of substituted sulfanilamides?
active against gram positive bacteria including pneumococci and meningococci
What are the most active substituted sulfanilamides?
sulfapyridine, sulfadimidine, sulfadiazine & sulfamethoxazole
What do humans and bacteria make dihydrofolate from?
humans is folic acid and in bacteria its pteridine
What is trimethoprim?
an antimetabolite, A DHFR inhibitor, used for UTIs, typhoid fever chronic bronchitis, Gonorrhoea and in penicillin resistant patients
What is pyrimethamine and describe its SAR
A DHFR inhibitor, with high activity in plasmodium DHFR and is used as an antimalarial drug. Pyrimidine ring for DHFR activity and a chlorophenyl ring which makes it more hydrophobic than trimethoprim
What is methotrexate and how does its activity differ in vitro and in vivo?
A DHFR inhibitor with a pteridine ring for DHFR activity and a polar glutamate side chain for active transport by AA carrier. An anticancer drug, against rapidly proliferating tumours, also used in combo to terminate pregnancy esp ectopic In vitro it has equal activity against mammalian and bacterial DHFR and in vivo only active against mammalian DHFR.
Why is folate a dietary supplement rather that tetrahydrofolate?
folate can enter cells whereas tetrahydrofolate can’t
Why is the enzyme dihydropteroate a good antibacterial target?
because humans don’t have this enzyme
Why is diethyl glycol toxic?
because the liver oxidises the hydroxyl groups to toxic aldehydes
