Biguanides and dihydrotriazines are antimalarial drugs characterized by the presence of a biguanide functional group or a dihydrotriazine ring in their chemical structure, respectively.
They primarily act by inhibiting the enzyme dihydrofolate reductase, which is essential for the synthesis of nucleic acids in the Plasmodium parasite.
Some SAR observations for these compounds include:
For biguanides, the presence of the biguanide functional group is crucial for activity. The guanidine moieties provide basic centres that interact with the active site of dihydrofolate reductase.
Proguanil, a biguanide, is a prodrug that is converted into its active metabolite cycloguanil, a dihydrotriazine. The conversion involves a cyclization reaction that forms the dihydrotriazine ring, which is crucial for inhibiting dihydrofolate reductase.
The lipophilicity of biguanides and dihydrotriazines can influence their cellular uptake and potency. For example, the introduction of a lipophilic side chain can improve the cell permeability and antimalarial activity of the compounds.
The basic amine groups in these compounds may also be protonated, which can influence their membrane permeability and intracellular distribution.
