Antimalarial agents

Historical Introduction
The antibiotic revolution can be dated to the early 1940's when Howard Florey and his colleagues in Oxford turned Alexander Fleming's penicillin into a major drug and Selman Waksman in the USA began his systematic search of antibiotics from soil micro-organisms. However the quest for substances active against pathogenic microbes began much earlier.

By the end of nineteenth century Paul Ehrlich, the father of chemotherapy, gave the kick off to the quest for antibiotics. Before that, the earliest therapeutic successes against infecting organisms came in the form of natural products such as honey that could be applied topically to infected lesions, or infusions that expelled worms. Herbal remedies against worms were known since antiquity and include extract of male fern (Dryopteris filix-mas), which is an effective vermifuge for tapeworms, and two compounds that eliminate roundworms from the intestine, namely santonin (obtained from the seed-heads of Artemisia), and chenopodium oil (Chenopodium ambrosioides).

Dryopteris filix-mas           Chenopodium ambrosioides          Wild Quinine                Quinine

Other ancient remedies include quinine, obtained from the bark of the cinchona tree, and emetine, an alkaloid obtained from ipecacuanha root. These compounds, active against protozoa (the parasites of malaria and amoebic dysentery respectively),were introduced into Europe from South America in the seventeenth century and  are still in use.


Emetine: 6′,7′,10,11-tetramethoxyemetan; an alkaloid from Cephaelis ipecacuanha that is a gastrointestinal irritant and potent emetic and used as an expectorant and antiamoebic agent. It inhibits protein synthesis by preventing translocation of peptidyl-tRNA from the A- to the P-site on the ribosome.

                                                                              Mercury                       Chaulmoogra                   hexamine


 When Ehrlich began his work, the number of antibacterial remedies was limited to a few options. Syphilis had been treated with Mercury  since the sixteenth century (giving rise to the aphorism "one night with Venus a lifetime with Mercury"), and chaulmoogra oil from the seeds of Hydnocarpus species had been used since ancient times in India for the treatment of leprosy. Otherwise the only useful antibacterial compounds were topical antiseptics that were far too toxic for systemic use. At the end of the nineteenth century hexamine, a compound that spontaneously decomposes in acid conditions to release formaldehyde, was described as being useful in urinary tract infection.

Twentieth century chemotherapy started with the work of Paul Ehrlich searching for antiprotozoal agents, in particular looking for new substances active against the newly discovered parasites of malaria and African sleeping sickness (trypanosomiasis). He was convinced that, since these parasites could be differentiated from the tissues of infected patients by various dyes in the laboratory, these substances might selectively bind to the parasites cells exhibiting therefore selective cytotoxicity.Actually certain aniline dyes were found to have some useful effects in trypanosomiasis of animals. However, after some work, Ehrlich directed his interests to another class of compounds: the arsenicals.

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