STUDIES IN OXYGEN AND NITROGEN HETEROCYCLIC COMPOUNDS OF PHARMACOLOGICAL INTEREST

Abstract

By the isolation or synthesis of therapeutic agents, organic chemists have made possible some of the noblest achievements of human history. The organic chemist, employing the art of synthesis, has been responsible for the vast majority of drugs used in modern medical practice. In the last twentyfive years or so, untold suffering and deaths have been alleviated or prevented by the use of these drugs. Organic chemistry and medicinal chemistry share a venerable common history. Many of the founders of organic chemistry were interested not only in natural products but also in the effects of synthetic compounds on living systems. With the development of a series of efficacious synthetic medicinal agents, an understanding of structure-activity relationship gained firm footing. Medicinal chemistry is thus a discipline which applies the principles of chemistry and biology to the creation of knowledge leading to the introduction of new therapeutic agents. The operational manipulations are still those of organic chemistry and only the emphasis of the work changes from the classical organic chemistry. The beginning of effective therapy by chemicals is lost in antiquity. Early successes in the quest for chemicals effective against disease were predominantly natural products. Opium, hashish, cocaine and caffeine all derivedfrom these 2 ancient sources. Though, there was an early success, the area remained unexplored until the development of more sophisticated synthetic methods made the preparation of more complex molecules feasible. Another source for biologically active material came out of the biochemical investigation on hormonal substances. This resulted in isolation of substances such as thyroxin, epinephrine, the steroids, and most recently the prostaglandins. £, The use of these chemical messengers produced by endocrine glands that stimulate or inhibit metabolic activity in other tissues or organs constitutes an important area of therapy. The natural hormones in crude or pure form have been found to mimic or antagonize the action of hormones. Synthetic work that took the structure of epinephrine as the starting point resulted in the development of large number of chemical agents useful as central nervous stimulants, antiappetite agents, and blood pressure-lowering agents. t Pituitary - the master gland of the body secrets X adrenocorticotropic hormone (ACTH) besides other hormones. ACTH stimulates the adrenal gland to produce a number of steroidal compounds. The adrenal hormones govern a wide variety of metabolic processes and are necessary for life. The best known member cortisone and its chemical modification prednisone are useful as antiinflammatory agents. Sex hormones and their derivatives, analogues and antagonists may be divided in three main classes - 3 (a) Androgens and anabolic steroids, (b) Estrogens and progestagens, (c) Oral contraceptives. The original indication for the preparation of steroidal drugs seemed to be for use in replacement therapy for cases of insufficiency. A combination of clever synthetic work and biological evaluation led to a drug which has revolutionized the sexual ethic in modern society - the •Pill'. More recently it has been observed that manipulation of unstable prosta glandin results in a molecule which has significant use in medical practice as an abortifacient agent. To date, the most important source of new structures for drugs, comes from the synthetic efforts of the medicinal chemist, combined with biological evaluation by a pharmaco logist. Prompted either by some pet structural theory or some dimly perceived structural features present in biologically active compounds already described in literature, medicinal chemists have synthesized structurally novel compounds. In most of the cases the results of testing these J merely added to the world's enormous mass of negative data. But sometimes, however, these compounds turned out to have promising activity, although not necessarily that which was intended. Such a finding then starts the exhaustive search for structural features that optimize activity at the expense of side effects. If all went well, the compound reaches the market as a drug. This endeavour has often met with unexpected success and it is because of this reason costly research programmes have been sustained in this area.