Artemisinin: An Evolving Antimalarial-Part One

Abstract

This review was conceived with the aim of presenting a compact, yet engaging account of the evolution of artemisinin from its humble and ancient origins as an herbal remedy to a modern chemotherapeutic agent, highlighting its unique pharmacological and toxicological profile and the central position it occupies at present in the battle against malaria. Artemisinin is a sesquiterpene lactone end operoxide with a long and enchanting history. The Chinese had been using concoctions of Artemisia for the treatment of various febrile ailments for close to two millennia. The impetus for its extraction in 1972 from Artemisia annua came from the battlefields of the Vietnamese war of 1965 to 1973 and the political milieu of the Cultural Revolution that encouraged an inward-looking disposition. Owing to solubility problems with the parent compound, artemisinin other semi-synthetic derivatives are now available and include artesunate, artemether, dihydroartemisinin and arteether. Parasiticidal action resides in the endoperoxide moiety which is also primarily responsible for the toxicity of the artemisinin compounds. As a class, they are the most rapidly acting antimalarial chemotherapeutic agents ever in use, reducing initial parasite burden by a factor of 10 4 per cycle of schizogony. Despite this, high rate of recrudescence occur with monotherapies which necessitates their use in combination with longer acting agents-ACTs. The basis of this high recrudescence is not unrelated to short plasma half-lives, dormancy phenomenon and autoinduction of the metabolizing enzymes. Though safe in humans at recommended dosages, animal studies have continually revealed disturbing side effects most notably, neurotoxicity and, reproductive toxicity manifesting in the twin phenomenon of embryolethality and fetal dysmorphogenesis. In the light of the cautionary tale of thalidomide tragedy, it may not be wise to totally ignore these findings in experimental animals.

An overview on the antimalarial activity of 1,2,4‐trioxanes, 1,2,4‐trioxolanes and 1,2,4,5‐tetraoxanes

“…Several models of ART action have been presented, each having experimental data to back it up. The research findings on this topic are extensive, diverse, and usually superficially conflicting, to the point were tying up the end and generating a coherent and representative image becomes a challenging endeavor at times 64 …”

“…ART has a wide range of pharmacological characteristics, a broad medicinal spectrum, and no clinically significant sensitivity. As a result of this, more than 40 years after its extraction and identification, the search for its exact mode of action continues to attract huge volumes of research publications 60–64 . This is not an uncommon case, as some therapeutic compounds discovered by traditional drug discovery and development (rather than rational drug design) had their mechanisms of action identified after decades of clinical use.…”

“…As a result of this, more than 40 years after its extraction and identification, the search for its exact mode of action continues to attract huge volumes of research publications. [60][61][62][63][64] This is not an uncommon case, as some therapeutic compounds discovered by traditional drug discovery and development (rather than rational drug design) had their mechanisms of action identified after decades of clinical use. Numerous 1,2,4trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane derivatives, including ART (Figure 2), have recently been devised, produced, and tested for their ability to combat malaria.…”

“…The research findings on this topic are extensive, diverse, and usually superficially conflicting, to the point were tying up the end and generating a coherent and representative image becomes a challenging endeavor at times. 64 It has been demonstrated that in the blood the ring stages of Plasmodium and mature trophozoites are sensitive to the activity of ART, its first-generation derivatives, and related endoperoxides. Certain gametocyte stages have also shown sensitivity to the AM activity of its derivatives.…”

A simplified and scalable synthesis of artesunate

“…The sesquiterpene endoperoxide artemisinin ( 1 ) [1, 2], is the lead component of the so-called artemisinin combination therapies (ACTs), which is currently the most valuable weapon in the fight against this disease. Several easily accessible artemisinin derivatives, including dihydroartemisinin (DHA, 2 ) and artesunate ( 3 ), exhibit potent antimalarial activity against drug-resistant malaria strains [3–5].…”