Synthetic antimalarial drug

A few years ago, a problem of this general character was encountered by us in studies dealing with synthetic antimalarial drugs. Unexpected toxicity was encountered in connection with the clinical. study of a... 

In the course of 20th century, especially during World War II, a series of effective synthetic antimalarial drugs have been developed. Among them, chloroquine (2), mefloquine (3), and pyrimethamine (4), Fig. (1), became the drugs of choice in several programs and contributed to the almost complete eradication of malaria from Europe and North America. 

Curd, F.H.S., Davey, D.G. and Rose, F.L. (1945) Studies on synthetic antimalarial drugs-X. Some biguanide derivatives as new types of antimalaiial substances with both therapeutic and causal prophylactic activity. Ann. Trap. Med. 39 208-214. 

SAR of chloroquine. It may be regarded as the prototypical structure which overwhelmingly succeeded quinine and recognized as a potential synthetic antimalarial drug since the mid-1940s, as shown below ... 

Malaria is still one of the most prevalent protozoan diseases in the world. The mosquito infects the human and the parasite passes through two phases. The tissue phase causes no clinical symptoms in the human and the erythrocytic phase invades red blood cells and causes chills, fever, and sweating. In the United States the 1000 cases reported annually are almost all from international travel. Quinine was the only antimalarial drug from 1820 to the early 1940s when synthetic antimalarial drugs were developed. Chloroquine is commonly prescribed. If drug resistance develops quinine is used in combination with an antibiotic such as tetracycline. 

The next milestone in the development of organic synthesis was the preparation of the first synthetic dye, mauveine (aniline purple) by Perkin in 1856 Perkin, 1856, 1862). This is generally regarded as the first industrial organic synthesis. It is also a remarkable example of serendipity. Perkin s goal was the synthesis of the antimalarial drug quinine by oxidation of N-allyl toluidine (Fig. 2.4). 

The foundation of the synthetic dye industry is universally attributed to William Henry Perkin on account of his discovery in 1856 of a purple dye which he originally gave the name Aniline Purple, but which was later to become known as Mauveine. Perkin was a young enthusiastic British organic chemist who was carrying out research aimed not initially at synthetic dyes but rather at developing a synthetic route to quinine, the antimalarial drug. His objective in one particular set of experiments was... 

Initially approved in the 1930s as antimalarial drug, quinacrine (2) became one of the first potential substitutes to quinine. The total synthesis of quinacrine would be achieved in 1931 by German scientists at Bayer,and it would be subsequently marketed as Mepacrine or Atebrine. However, quinacrine would soon be replaced by another synthetic and more efficient antimalarial drug, chloroquine (3). 

The Cinchona tree remains the only economically practical source of quinine. Although the development of synthetic quinine is considered a milestone in organic chemistry, it has never been produced industrially as a substitute for naturally occurring quinine. Nevertheless, the implications of the total synthesis of quinine in new strategies for the development of safer and more efficient antimalarial drugs, as we will show in the course of the next paragraphs, is priceless. But, let us discuss this total synthesis first. 

Vennerstrom JL, Arbe-Bames S, Brun R, Charman SA, Chiu FCK, ChoUet J, Dong Y Dom A, Hunziker D, Matile H, McIntosh K, Padmanilayam M, Tomas JS, Scheurer C, Scomeaux B, Tang Y, Urwyler H, WittUn S, Charman WN. (2004) Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430 900-904. 

Quinidine (6) and quinine (7) are diastereomeric quinoline alkaloids obtained from Cinchona spp. Quinidine (6) is included in many pharmacopeias for its antiarrhythmic effects.Quinine was the first antimalarial drug and served as an effective remedy for this deadly infectious disease in colonial times, making European settlement in many tropical and subtropical parts of the world possible.Owing to the development of resistance to synthetic antimalarials, quinine is still reverted to some extent for this... 

Vennerstrom JL, Arbe-Barnes S, Brim R, etal.. Identification of an antimalarial synthetic trioxolane drug development candidate. Nature 430 900—904, 2004. 

J.P. Begue, D. Bonnet-Delpon, The future of antimalarials Artemisinins and synthetic endoperoxides, Drugs Fut. 30 (2005) 509-518. 

It is a new, potent antimalarial drug and is a water soluble synthetic analogue of artemisinin. 

---