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Yerevan State Medical University After M. Heratsi YEREVAN STATE MEDICAL UNIVERSITY AFTER M. HERATSI DEPARTMENT OF PHARMACY Balasanyan M.G. Zhamharyan A.G. Afrikyan Sh. G. Khachaturyan M.S. Manjikyan A.P. MEDICINAL CHEMISTRY HANDOUT for the 3-rd-year pharmacy students (part l) YEREVAN 2013 Pharmaceutical chemistry, problems and development stages Pharmaceutical chemistry, which is also called therapeutic chemistry, medicinal chemistry, pharmacological chemistry, is that field of pharmaceutical sciences, aimed to discovery and development of new therapeutic compounds and obtained drugs chemical analysis. Thus, the primary objective of pharmaceutical chemistry is the design and discovery of new biological active compounds that are suitable for use as drugs, and quality control of those compounds. Principal problems of pharmaceutical chemistry are: New drugs discovery and development of design and synthesis methods. Study of drug molecule structure, finding relationship between structure and effect on the organism and basing on these properties conclude about its efficiency, suggest molecule possible modification ways for new generation more effective and safer drugs creation. New drugs discovery requires not only design and synthesis, but also study of drugs pharmacokinetic properties which gives possibility to change drug molecule so that it will show high efficiency. Pharmaceutical chemistry studies new discovered drugs metabolism, metabolites behavior in the organism, as drugs quantity which reaches to the action place depends on metabolism. Besides, some drugs metabolites have greater effect, than precursors. Drugs discovery requires also diseases biochemical processes fundamental researches. Basing on this knowledge, pharmacist- chemist knows how drug diffuses in the organism, penetrates through barriers and undergo metabolism. It gives pharmacist-chemist possibility to change drug molecular structure, inserting new groups, which will effect on absorption, stability, distribution, metabolism and excretion. It is known, that drugs quality and physicochemical properties have great importance for their efficiency. Pharmaceutical chemistry studies also drugs physicochemical properties, drugs quality control methods; realizes drugs qualitative and quantitative analysis and purity detection. As drugs can be changed during their keeping, it is very important to study drugs keeping conditions in order to provide drugs quality during validity. Thus, the medicinal chemist must not only be a competent organic, analytic chemist but must have a basic background in biological sciences, particularly biochemistry and pharmacology. Why do we need new drugs? In addition to their beneficial effects, most drugs have non-beneficial biological effects. Aspirin, which is commonly used as painkiller and antipyretic agent, may also cause gastric irritation, ulcer and bleeding. The non-beneficial effects of some drugs, such as cocaine and heroin, are so undesirable that the use of these drugs has to be strictly controlled by legislation. These unwanted effects are commonly referred to as side effects. 2 The great dose or over-usage of some drugs can cause resistance or tolerance. For example, antibiotics uncontrolled usage can result in the development of resistance to that drug by both the patients, microorganisms and virus, because of this, drugs become ineffective. Thus, new drugs are necessary for: Creation of more effective and safer drugs Overcoming tolerance and resistance towards drugs Treatment of new discovered diseases. Historical evolution Since ancient times, people used a wide range of natural products for medicinal purposes. These products were obtained from animals, plants and mineral sources; they were sometimes very effective. The Chinese, Hindus and people from Central America were familiar with the therapeutic use of certain plants and some minerals. In his writings on medicinal herbs, the Chinese emperor Shen Nung (about 3000 B.C.) recommended the use of the plant Chang shang for the treatment of malaria; it is known that this plant contains alkaloid artemisine, which has antimalarial activity. The Brazilian Indians used to treat dysentery and diarrhea with Ipecacuanha root; in fact it contains emetine, which is effective against these ills. The early explorers found that North American Indians also applied cocoa leaves (containing cocaine) and mushrooms (containing tryptamine) as hallucinogens. In ancient Greek “drug stores” could be found opium, preparations of belladonna, metallic compounds: iron sulfate, zinc oxide, cadmium oxide, etc. The basic studies of chemistry started from Greco-Roman and Arabian alchemists (13th-16th centuries). Paracelsus (1493-1541) used antimony and its salts in the tinctures as cure-alls (panacea) in the belief that chemicals could cure diseases. He also called attention to the fact that remedies could be useful, as well as harmful. However, many of the natural products were very toxic. For example, Digitalis and Strophanthus, which contain cardiac glycosides, were used as strong cardiac poisons, but Egyptians used it for hunting. All drugs, some more than others, have side effects, which can be the cause of death. That’s why from ancient times it was known that every drug is a potential poison. Paracelsus affirmed: “All drugs are poison: there is none, which is not a poison. The correct dose differentiates a poison from a remedy”. Over dosage, administration non adequate way or non proper usage can useful drug become dangerous poison. In fact, Greek word pharmacon itself means not only remedy, but also a poison. Information about these ancient remedies was not readily available to users until the 15th century, when the invention of publication was discovered. This invention brings to the widespread publication and circulation of literature and pharmacopeias. The first pharmacopeia was published in the 16th century. In the following century the therapeutic arsenal was enriched with new discovered drugs. Pharmacopeias were replenished with new preparations, such as digitalis, opium, ether and other drugs were introduced in the 19th century. 3 The 19th century had a great expansion in the knowledge of chemistry and chemical synthesis; herbal pharmacopeias found a wide spread. Basing on Lavoisier’s work European chemists invented and extended new methods of synthesis. The synthesis of acetic acid by Kolbe in 1845 and of methane by Berthelot in 1856 set the stage for organic chemistry. Physiological chemistry science followed the pharmacognosy. The aim of this discipline was to find new effective natural drugs and studying their structure try to separate the active ingredients, which are responsible for their pharmacological effect. The isolation of morphine by Serturner, the isolation of emetine by Pelletier, also purification of caffeine, quinine and colchicines in 1864, noted the start of “pure” substances century. At the same time William Withering applied digitalis for the treatment of cardiac failure. As a result of these discoveries and the progress made in organic chemistry, the pharmaceutical chemistry has its great development at the end of 19th century. Purposeful synthesis of drugs is one of basic parts of pharmaceutical chemistry. It has great development due to Paul Ehrlich. He produced the antiprotozoal agent Salvarsan by combined synthesis, with the help of consequent biological screening and evaluation procedures. Comparing the effectiveness of different compounds he expressed drug’s selectivity and hence its effectiveness, which was expressed by the following way: chemotherapeutic index is the ratio of minimal curative dose to the maximal tolerable dose. Now, chemotherapeutic index is transformed and called therapeutic index, which is the ratio of lethal dose to the efficient dose. In theory, the larger a drug’s therapeutic index, the greater is its margin of safety. The term structure activity relationship (SAR) is now used to describe Ehrlich’s approach to drug discovery, which consisted of synthesizing and testing a series of structurally related compounds. Salvarsan was the first antimicrobial agent which was considered as active chemotherapeutic agent among 600 synthesized compounds (Salvarsan was active towards syphilis). Attempts to quantitatively relate chemical structure to biological action were first indicated in the 19th century. But it was possible to realize due to methods discovered by Hansch and Fujita after 1960. This method was known as quantitative structure activity relationship (QSAR). The first result of these methods was synthesis of cimetidine and ranitidine. Nowadays SAR and QSAR are important and basic parts of pharmaceutical chemistry. On the other hand, during the beginning of 20th century, Emil Fischer’s lock and key theory provided a rational explanation of drugs action mechanism. In 1905 John Langley proposed that so called receptive substances in the body could accept either a stimulating compound, which would cause biological response, or a non-stimulating compound, which would prevent a biological response. Now it is clear, that there are chemical compounds (ligands), which bind with receptors, and as a result biological or pharmacological effect occurs. Furthermore, a drug is most effective, when its structure or a significant part of its structure, molecular shape and electron distribution (stereo electronic structure) are complementary with the stereo electronic structure of the receptor; due to this, drug binds with its receptor and desired biological action occurs. In the middle
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