The cinchona alkaloids and the aminoquinolines

The bark of the cinchona tree was first employed to treat malaria in Europe during the 15th century. Its active ingredients are natural products that are collectively known as the cinchona alkaloids and include quinine. In the 17th century, quinine became the first mass produced pharmaceutical agent and is still in use today for the treatment of malaria. However, synthetic alternatives to quinine have long been sought and inspired one of the first coordinated drug discovery programs. This program, which took place between 1920 and 1945, led to the discovery of pamaquine and chloroquine. Chloroquine is a synthetic 4-aminoquinoline antimalarial that was first employed clinically in 1947 and rapidly replaced quinine as the mainstay treatment for malaria. However, the first cases of resistance to this drug were reported less than a decade after its introduction and soon became an urgent problem, spurring a new search for replacements that continues to this day. In this chapter, a brief historical overview of the discovery and development of these drugs is followed by a more detailed discussion of the medicinal chemistry of three classes of quinoline antimalarials: the 4-aminoquinolines, the 8-aminoquinolines, and the quinoline methanols—a class that includes quinine and the cinchona alkaloids.