Primaquine revisited six decades after its discovery

Area of Science:

• Medicinal Chemistry
• Pharmacology
• Infectious Diseases

Background:

• Primaquine, an 8-aminoquinoline antimalarial, has been crucial for over 60 years.
• It is the only clinically available drug that blocks malaria transmission by targeting gametocytes.
• Primaquine is also effective against exoerythrocytic parasite stages and used for *Plasmodium vivax* and *ovale* malaria.

Purpose of the Study:

• To review the properties and historical significance of primaquine.
• To provide an overview of efforts to develop safer and more effective primaquine analogues.
• To highlight the progress in developing new antimalarial drugs based on primaquine.

Main Methods:

• Literature review of primaquine's synthesis, properties, and clinical use.
• Analysis of toxicological data and adverse effects associated with primaquine.
• Examination of medicinal chemistry strategies to improve primaquine's safety and bioavailability.

Main Results:

• Primaquine exhibits broad-spectrum activity against malaria parasites, including resistant strains.
• Toxic metabolites and poor oral bioavailability contribute to primaquine's adverse effects, especially in G6PD-deficient individuals.
• New analogues, aablaquine and tafenoquine, show promise in late-stage clinical trials.

Conclusions:

• Despite its toxicity, primaquine remains essential for malaria control and transmission blocking.
• Ongoing research focuses on developing primaquine analogues with improved safety profiles and efficacy.
• Aablaquine and tafenoquine represent significant advancements, offering new hope for treating malaria and other primaquine-sensitive diseases.