cycloguanil

Cycloguanil is a dihydrofolate reductase inhibitor that acts as the active metabolite of the antimalarial proguanil. It was developed as part of antifolate strategies to disrupt parasite nucleotide synthesis and DNA replication.

Mechanism of action involves inhibition of the parasite enzyme dihydrofolate reductase (DHFR), which is essential for converting dihydrofolate to tetrahydrofolate. By limiting tetrahydrofolate availability, cycloguanil disrupts thymidylate and purine synthesis, impairing parasite replication and survival. Its activity is most relevant against Plasmodium species, especially during stages where folate metabolism is critical.

Pharmacokinetics and metabolism: cycloguanil is produced in the liver from proguanil through hepatic biotransformation. As the active metabolite, its antimalarial effect reflects the pharmacokinetics of both the parent drug and the metabolite. Its efficacy can be influenced by parasite DHFR variants that reduce drug binding, contributing to resistance patterns observed with DHFR inhibitors.

Medical use: Cycloguanil’s clinical role is primarily as the active metabolite contributing to the activity of proguanil. In modern regimens, proguanil is often used in combination with atovaquone (for example, in the atovaquone–proguanil combination), where proguanil’s conversion to cycloguanil supports the antimalarial effect. Cross-resistance with other DHFR inhibitors can limit effectiveness against resistant Plasmodium strains.

Safety and adverse effects: As with other antimalarials, adverse effects may include gastrointestinal upset, headaches, rash, or hypersensitivity in some individuals. Serious adverse events are uncommon but can occur, and use should consider regional resistance patterns and guidelines.

See also: proguanil, dihydrofolate reductase inhibitors, atovaquone, pyrimethamine, malaria therapy.