Drug Discovery Processes

Drug Discovery Processes Introduction Chemistry is not merely a science of making observations in order to better understand nature. Chemistry, as the science of matter and its transformation, plays a central role in bridging between physics, material sciences and life sciences. Our science is creative and productive, generating substances and materials of very high value from almost nothing. In view of its significance, chemical synthesis demands the highest level of scientific/technological creativity and insight to explore its limitless possibilities. Chemical synthesis must pursue the goal of practical elegance; it must be logically elegant and at the same time technologically practical. We must manufacture useful compounds in an economical, energy-efficient, resource-preserving, and environmentally benign way(add ref impo-01). To maintain our current standard of living and to improve quality of life, society has come to depend on the products of chemical industry. The last century has been highly productive in this aspect as it emerges in development in pharmaceutical development, water treatment, material science, polymers, agriculture pesticides and fungicides, detergents, petroleum additives and so forth. Pharmaceutical development plays a vital role as various drugs that are developed have helped in the eradication of many infectious diseases. Although there are certain diseases that have still not found any resistance towards drugs but even though a lot of work is still being carried out on it. Research in the field of pharmaceutical has its most important task in the development of new and better drugs and their successful introduction into clinical practice. â€Å"Medicinal chemistry remains a challenging science which provides profound satisfaction to its practitioners. It intrigues those of us who like to solve problems posed by nature. It verges increasingly on biochemistry and on all the physical, genetic and chemical riddles in animal physiology which bear on medicine. Medicinal chemists have a chance to participate in the fundamentals of prevention, therapy and understanding of diseases and thereby to contribute to a healthier and happier life.† ALFRED BURGER 3   Importance of a Drug: A drug is any chemical or biological substance, synthetic or non-synthetic, that when taken into the organism’s body, will in some way after the functions of that organism’s. This broad definition can be made by including such substances as food. However more strict applications of the word prevail in everyday life. In these cases the word â€Å"drug† is usually used to refer specifically to medicine, vitamins, entheogenic sacraments, consciousness expanding or recreational drugs. Many natural substances such as beers, wine, and some mushrooms, blur the line between food and drugs, when ingested they affect the functioning of both mind and body. The word â€Å"drug† is etymologically derived from the Dutch/Low German word â€Å"droog† which means â€Å"dry†, since in the past; most drugs were dried plant parts. Drugs are usually distinguished from endogenous biochemical by being introduced from outside the organism. For example, insulin is a hormone that is synthesized in the body; it is called a hormone when it is synthesized by the pancreas inside the body, but if it is introduced into the body from outside, it is called a drug. The role played by organic chemistry in the pharmaceutical industry continues to be one of the main drivers in the drug discovery process. However, the precise nature of that role is undergoing a visible change, not only because of the new synthetic methods and technologies now available to the synthetic and medicinal chemist, but also in several key areas, particularly in drug metabolism and chemical toxicology, as chemists deal with the ever more rapid turnaround of testing data that influences their day-to-day decisions. Numerous changes are now occurring in the pharmaceutical industry, not just in the way that the industry is perceived, but also in the rapid expansion of biomedical and scientific knowledge, which affects the way science is practiced in the industry. The recent changes that have occurred in scientific advances are due to the new synthetic techniques and new technologies for rational drug design, combinatorial chemistry, automated synthesis, and compound purification and identification. In addition, with the advent of high-throughput screening (HTS), we are now faced with many targets being screened and many hits being evaluated. However, success in this arena still requires skilled medicinal chemists making the correct choices, often with insight gleaned from interactions with computational chemists and structural biologists, about which â€Å"hits† are likely to play out as true â€Å"lead† structures that will meet the plethora of hurdles that any drug candidate must surmount. It is the mission of pharmaceutical research companies to take the path from understanding a disease to bringing a safe and effective new treatment to patients. Scientists work to piece together the basic causes of disease at the level of genes, proteins and cells. Out of this understanding emerge â€Å"targets,† which potential new drugs might be able to affect. Researchers work to validate these targets, discover the right molecule (potential drug) to interact with the target chosen, test the new compound in the lab and clinic for safety and efficacy and gain approval and get the new drug into the hands of doctors and patients. The drug discovery process goes through following sequences for the development of particular drug4. Pre-discovery (Understand the disease) Before any potential new medicine can be discovered, scientists work to understand the disease to be treated as well as possible, and to unravel the underlying cause of the condition. They try to understand how the genes are altered, how that affects the proteins they encode and how those proteins interact with each other in living cells, how those affected cells change the specific tissue they are in and finally how the disease affects the entire patient. This knowledge is the basis for treating the problem. Researchers from government, academia and industry all contribute to this knowledge base. However, even with new tools and insights, this research takes many years of work and, too often, leads to frustrating dead ends. And even if the research is successful, it will take many more years of work to turn this basic understanding of what causes a disease into a new treatment. Target Identification (Choose a molecule to target with a drug) Once they have enough understanding of the underlying cause of a disease pharmaceutical researchers select a â€Å"target† for a potential new medicine. A target is generally a single molecule, such as a gene or protein, which is involved in a particular disease. Even at this early stage in drug discovery it is critical that researchers pick a target that is â€Å"drugable,† i.e., one that can potentially interact with and be affected by a drug molecule. Target Validation (Test the target and confirm its role in the disease) After choosing a potential target, scientists must show that it actually is involved in the disease and can be acted upon by a drug. Target validation is crucial to help scientists avoid research paths that look promising, but ultimately lead to dead ends. Researchers demonstrate that a particular target is relevant to the disease being studied through complicated experiments in both living cells and in animal models of disease. Drug Discovery (Find a promising molecule that could become a drug) Armed with their understanding of the disease, scientists are ready to begin looking for a drug. They search for a molecule, or â€Å"lead compound,† that may act on their target to alter the disease course. If successful over long odds and years of testing, the lead compound can ultimately become a new medicine. There are a few ways to find a lead compound: Nature: Scientists usually have turned to nature for find interesting compounds for fighting against diseases. Bacteria found in soil and mouldy plants both led to important new treatments. Nature still offers many useful substances, but now there are other ways to approach drug discovery. De novo: Thanks to advances in chemistry, scientists can also create molecules from scratch. They can use sophisticated computer modelling to predict what type of molecule may work. High-throughput Screening: This process is the most common way that leads are usually found. Advances in robotics and computational power allow researchers to test hundreds of thousands of compounds against the target to identify any that might be promising. Based on the results, several lead compounds are usually selected for further study. Biotechnology: Scientists can also genetically engineer living systems to produce disease-fighting biological molecules. Early Safety Tests(Perform initial tests on promising compounds) Lead compounds go through a series of tests to provide an early assessment of the safety of the lead compound. Scientists test Absorption, Distribution, Metabolism, Excretion and Toxicological (ADME/Tox) properties, or â€Å"pharmacokinetics,† of each lead. These studies help researchers prioritize lead compounds early in the discovery process. ADME/Tox studies are performed in living cells, in animals via computational models. Lead Optimization(Alter the structure of lead candidates to improve properties) Lead compounds that survive the initial screening are then optimized, or altered to make them more effective and safer. By changing the structure of a compound, scientists can give it different properties. For example, they can make it less likely to interact with other chemical pathways in the body, thus reducing the potential for side effects. Hundreds of different variations or â€Å"analogues† of the initial leads are made and tested. Teams of biologists and chemists work together closely: The biologists test the effects of analogues on biological systems while the chemists take this information to make additional alterations that are then retested by the biologists. The resulting compound is the candidate drug. Even at this early stage, researchers begin to think about how the drug will be made, considering formulation (the recipe for making a drug, including inactive ingredients used to hold it together and allow it to dissolve at the right time), delivery mechanism (the way the drug is taken – by mouth, injection, inhaler) and large-scale manufacturing (how you make the drug in large quantities). Preclinical Testing(Lab and animal testing to determine if the drug is safe enough for human testing) With one or more optimized compounds in hand, researchers turn their attention to testing them extensively to determine if they should move on to testing in humans. Scientists carry out in vitro and in vivo tests. In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers (â€Å"vitro† is â€Å"glass† in Latin) and in vivo studies are those in living cell cultures and animal models (â€Å"vivo† is â€Å"life† in Latin). Scientists try to understand how the drug works and what its safety profile looks like. The U.S. Food and Drug Administration (FDA) require extremely thorough testing before the candidate drug can be studied in humans. During this stage researchers also must work out how to make large enough quantities of the drug for clinical trials. Techniques for making a drug in the lab on a small scale do not translate easily to larger production. This is the first scale up. The drug will need to be scaled up eve n more if it is approved for use in the general patient population. At the end of several years of intensive work, the discovery phase concludes. After starting with approximately 5,000 to 10,000 compounds, scientists now have winnowed the group down to between one and five molecules, â€Å"candidate drugs,† which will be studied in clinical trials. The drugs that are being currently used for curing human ailments mainly comprise of several natural products having complex structures. These are derived from terrestrial micro-organisms, plants and animals. The synthetic analogues of the above or other synthetic compounds that are totally non-natural also serve as drugs. A survey of literature reveals that â€Å"HETEROCYCLES† have been increasingly important not only in the field of medicinal world but also in the agriculture. The chemistry of the heterocyclic compounds is as logical as that of aliphatic or aromatic compounds. This study is of great interest both from the theoretical as well as practical stand point. Heterocyclic compounds are the organic substrates that contain a cyclic structure bearing atoms like nitrogen, oxygen or sulfur in addition to carbon atom as the part of their ring. The cyclic part (from Greek kyklos, meaning circle) of heterocycle indicates that at least one ring structure is present in such a compound and the prefix hetero (from Greek heteros, meaning other or different) refers to non-carbon atom in the ring. The cyclic part of the heterocycle indicates that at least one ring structure is cyclic organic compound that incorporate at least one hetero atom in the rings like cyclopropane or benzene. The presence of the heteroatom gives heterocyclic compounds many significant physical and chemical properties that are usually distinct from those of all carbon-ring analogues. These structures may comprise of either simple aromatic rings or non-aromatic ring. The chemistry of heterocyclic compounds is one of the most interesting and intriguing branch of the organic chemistry which is of equal interests for its theoretical implications, for the diversity of its synthetic procedures and for the physiological and industrial significances.1-2 The variety of heterocyclic compounds is enormous, their chemistry is complex and synthesizing them requires great skill. Among large number of heterocycles found in nature nitrogen heterocycles are most abundant than those containing oxygen or sulphur owing to their wide distribution in nucleic acid instance and involvement in almost every physiological process of plants and animals. It is well known that a number of heterocyclic compounds containing nitrogen, oxygen and sulphur exhibit a wide variety of biological activities. The majority of pharmaceutical products that mimic natural products with biological activity are heterocyclic in nature3 and are of great importance to life because their structural subunits exist in many natural products such as vitamins, hormones, antibiotics and pigments.4,5 Besides the vast distribution of heterocycles in natural products, these substrates are also the major components of biological molecules such as DNA and RNA, in the form of pyrimidine and purine bases. The enzymes possess purely protein structures and the coenzymes incorporate non-amino acid moieties, most of them are aromatic nitrogen heterocycles. Porphyrins8-10 are the backbone of many major compounds and some of their derivatives are fundamental to life, such as heme11 derivatives in blood and chlorophyll is essential for photosynthesis. The heme group of the oxygen-carrying protein-hemoglobin and related compounds such as myoglobin; the chlorophyll, which are the light-gathering pigments of green plants and other photosynthetic organisms, and vitamin B12 are all formed from four pyrrole units joined in a larger ring system known as a porphyrin, such as that of chlorophyll a 1.9 and chlorophyll b 1.10. Many vitamins13 like folic acid 1.12, vitamin B5, nicotinic acid 1.13, nicotinamide 1.14, vitamin B6 pyridoxine 1.15, pyridoxal 1.16, and pyridoxamine 1.17 are well known heterocyclic compounds. Psoralen consists of coumarin fused with furan rings, is used in treatment for skin problems and it shows considerable clinical efficacy.14 Cinchona bark15 has been used for several hundred years for the treatment of malaria where quinine 1.21 is the active heterocyclic component. Caffeine (1,3,7-trimethylxanthine) 1.22 obtained commercially from methylation of xanthine with methyl chloride or dimethylsulphate and alkali, is the major stimulant in tea and coffee. Natural products containing heterocyclic compounds such as alkaloids and glycosides have been used since old age, as remedial agents. Febrifagl alkaloid from ancient Chinese drug, Chang Shan, reserpine from Indian rouwopifia, Curen alkaloid from arrow poison, codenine, j-tropine and strychnine are all examples of heterocyclic compounds. Many alkaloids37 contain a pyridine or piperidine ring structure, among them nicotine 1.55, the main alkaloid constituent of tobacco, is based on the five membered pyrrolidine and six membered pyridine structures and piperine 1.56 which is one of the sharp-tasting constituents of white and black pepper and it is obtained from the plant species piper nigrum. The benzimidazole derivatives 1.64-1.68 having antifungal, antibacterial, anti-inflammatory and analgesics properties have been successfully prepared.41 Imidazo[1,2-a]pyridines have attracted much attention since the beginning of the last century. Due to their important biological activity, they have, in recent years, been broadly investigated and utilized in the pharmaceutical industry. They are also used in bioimaging probes and molecular recognition because of their structural characters.1 In addition, the imidazo[1,2 -a]pyridine scaffolds have been found to be the core structure of many natural products and drugs such as zolpidem, alpidem, saripidem, tenatoprazole, olprinone, and DS-1.2,3 (3)Zhuan Fei, Yan-ping Zhu ⇑, Mei-cai Liu, Feng-cheng Jia, An-xin Wu Tetrahedron Letters 54 (2013) 1222–1226 (imidazo-5 in reference folder) Heterocyclic compounds are obtainable by the following methods. a. Isolation from natural sources, i.e. alkaloids, amino acids, indigo dyes etc. b. Degradation of natural products i.e. acridine, furfural, indol, pyridine, quinoline, thiophene etc. c. Synthesis: Synthesis methods for obtaining heterocyclic compounds may be divided into ring closer reactions, addition reaction and replacement reaction. Cyclisation is usually accomplished by elimination of some small molecules such as water or ammonia from chain of suitable length. Heterocyclic compounds have a great applicability as drugs because, a. They have a specific chemical reactivity. b. They resemble essential metabolism and can provide false synthons in biosynthetic process. Aims and objectives: Taking in view the applicability of heterocyclic compounds, we have undertaken the preparation of heterocycles bearing triazole and pyrimidines nucleus. The placements of a wide variety of substituents of these nuclei have been designed in order to evaluate the synthesized products for their pharmacological profile against several strains of bacteria and fungi and tuberculosis. During the course of our research work, looking to the application of heterocyclic compounds, several entities have been designed, generated and characterized using spectral studies. The details are as under. To synthesize several bioactive derivatives of benzo[d]imidazo and its Schiff’s base and dihydro pyrazolothiazoles. To generate triazolo [1,5-a]pyrimidine derivatives. To synthesize imidazo [1,2-a]pyridine by Green Synthesis and develop their Mannich base. To check purity of all synthesized compounds using thin layer chromatography. To characterize these synthesized products for structure elucidation using various spectroscopic techniques like IR, 1H and 13C NMR and mass spectral studies. To grow single crystal of the synthesized compounds and study there X-ray crystallography for establishment of the structure. To evaluate these new synthesized products for better drug potential against different strains of bacteria and fungi.