8-Aminoquinolines: future role as antiprotozoal drugs

This review focuses on recent developments on evaluation of 8-aminoquinoline analogs with broader efficacy and reduced toxicity, which would provide better drugs for treatment of protozoal infections.

The earlier efforts towards development of 8-aminoquinoline analogs have been directed to extensive derivatization programs. This has led to discovery of tafenoquine for prophylaxis against malaria infections and sitamaquine with utility for treatment of visceral leishmaniasis. Bulaquine, a primaquine pro-drug, has shown reduced methemoglobin toxicity and better malaria-transmission-blocking activity than primaquine. Stereoselective pharmacologic and toxicologic characteristics of chiral 8-aminoquinolines provided the lead for enantiomeric separation of an 8-aminoquinoline analog NPC1161B, with greatly reduced toxicity and potent antimalarial action against blood as well as tissue stages of the parasite. NPC1161B has also shown promising use as an antileishmanial agent. Better understanding of the mechanisms of toxicity and efficacy may help in development of 8-aminoquinoline analogs with superior therapeutic actions, reduced toxicity and broader utility.

Extensive derivatization approaches followed by better understanding of structure-activity relationships and biotransformation mechanisms of toxicity have provided 8-aminoquinoline analogs with better pharmacologic and reduced toxicologic profiles. The novel 8-aminoquinoline analogs may have broader utility in public health as future antiprotozoals.