The Methylation Effect in Medicinal Chemistry

The importance of the simple methyl group as a very useful structural modification in the rational design of bioactive compounds and drugs is examined. The methyl effect alters both biological phases of a drug, represented by its pharmacodynamic and pharmacokinetc profile, due to the modifications introduced in the stereoeletronic properties. Cimetidine contains an imidazolyl nucleus and a methyl group at C-5, thus favoring the tautomeric form necessary for H 2 receptor selectivity. The thioether in the side chain of cimetidine ensured adequate hydrophobic properties and led to increased selective antagonist activity. The activation mechanism of proton pump inhibitors (PPI) is directly related to the nitrogen nucleophilicity of the pyridine moiety, which depends on the electronic effect of substituents on the pKa of the pyridine ring. When electron-donating substituent, such as methyl groups are attached to the pyridine ring then its pKa increases, thus increasing its protonation rate at any given pH.