history of medicinal chem and driving up life expectancy

Louis Pasteur

first to understand immunisation and to deliberately synthesise a weakened strain to inject into a patient

Paul Ehrlich

made Salvarsan to treat syphilis

salvarsan

arsenic ‘azo dye’

contains arsenic and a coating to reduce toxicity

replaced using Hg salts

magic bullet

therapeutic index

LD50/ED50

lethal dose / effective dose for 50% of sample

killed / treated

large is better

salvarsan mode of action

prodrug

syphilis has far more thiol-containing enzymes than humans, this is what it targets

sulfa drugs

1935, treat many bacterial infections

using azo dyes to kill bacteria, as have similar structure to salvarsan

tested in vitro and in vivo

prontosil red was first active agent from in vivo studies

pharmacophore

essential part of a drugs’ structure required for activity

inhibiting folate synthesis

humans eat folate, bacteria must make it with enzymes. the active form of prontosil red sits in the binding site of this enzyme and inhibits synthesis so bacteria die

cons of sulfonamide drugs

poor solubility

tend to crystallise in kidneys

relatively low activity

structure of penicillin

B-lactam ring

the amide in the ring makes the resonance form v unstable and v susceptible to nucleophilic attack

penicillin mode of action

bacterial cell walls stabilised by crosslinking of glycoproteins

cross linking occurs between D-Ala-D-Ala

penicillin mimics D-Ala-D-Ala so it binds to crosslinking transpeptidase instead of the actual cell wall

it reacts with a Nu- on transpeptidase which releases ring strain and forms a covalent bond with the enzyme

irreversible inhibition