Medicinal chemistry is the branch of chemistry that deals with the discovery, design and development of therapeutic chemical agents for use in clinical and veterinary medicine. It deals with the relationship between chemical structure and biological activity, medicinal chemistry as a scientific discipline has introduced several new techniques over the last few years in order to speed up the drug discovery process, such as combinatorial chemistry, microwave-assisted organic synthesis, and high-throughput purification.
Synthetic organic chemistry has always been a vital part of the highly integrated and multidisciplinary process of drug development. However, the nature of its major contribution has varied over time. In recent years, efforts have been made to synthesize potential anticancer, anti microbial, anti hiv drugs. Consequently, hundreds of chemical variants of known classes of therapeutic agents have been synthesized. Recent advances in biomedical sciences and combinatorial chemistry have resulted in the design and synthesis of hundreds of new anti microbial agents with potential activity against wide range of therapeutic targets
Contents
1 Coumarin - A boon to Earth
1.1 Introduction
1.2 History
1.3 Brief view of Discoveries
1.3.1 Medicine in the antiquity
1.3.2 Medicine in the Middle Ages (400 to 1500 AC)
1.4 Discovery of Penicillin
1.5 The general stages in modern-day drug discovery and design
2 REVIEW OF LITERATURE
2.1 Anti –Microbial Agent Discovery
2.2 Chemical Synthesis Ushers in the Golden Age of Antibiotics Discovery
2.3 Early History Of Anti-Biotics Discovery and Development
2.4 The bacterial cell
2.4.1 Differences between bacterial and animal cells
2.5 Mechanism Of Anti-Bacterial Cell
2.5.1 There are four main mechanisms by which antibacterial agents act
2.5.2 Antibacterials, 1940-Present
2.5.3 Some Anti-Bacterials Agents
2.5.4 Structure-activity relationships (SAR)
2.5.5 Applications of sulfonamides
2.6 Mechanism of action
2.6.1 Biochemical Targets for Antifungal Chemotherapy
2.6.2 Inhibition of Cell Wall Formation
2.6.3 Cell Membrane Disruption
2.6.4 Inhibition of Cell Division
2.6.5 Amphotericin B
2.6.6 Mechanism of Action:
2.6.7 Adverse Effects
2.6.8 Azoles and Triazole Antifungal Agents: Ergosterol Biosynthesis Inhibitors
2.6.9 Mechanism of Action:
2.7 Azole[33,34]
2.7.1 Miconazole
2.7.2 Econazole
2.7.3 Oxiconazole
2.7.4 Sulconazole
2.7.5 Tioconazole
2.7.6 Ketoconazole
2.7.7 Itraconazole
2.7.8 Fluconazole
2.7.9 Voriconazole
2.7.10 Butoconazole
2.7.11 Terconazole
2.7.12 Posaconazole
3 PLAN OF WORK
3.1 III-A] Synthesis of Substituted 4-(1,3-benzothiazol-2-ylamino)-2 H -one
3.2 III- B Synthesis of Substituted 2-[(2-oxo-2 H -chromen-4-yl)oxy]- N '-[(Z)-phenylmethylidene]acetohydrazide
3.3 III- C Synthesis of 2-[(2-oxo-2 H -chromen-4-yl)oxy]- N -(4-oxo-2-phenyl-1,3-thiazolidin-3- yl)acetamide
3.4 III-D] Synthesis of N -[ (2 E)-4-phenyl-3,4-dihydroquinazolin- 2(1 H)- ylidene ] -1,3- benzothiazol-2-amine
4 CHEMISTRY OF COUMARIN
4.1 Occurrence
4.2 Pharmacokinetics
4.2.1 Absorption and Distribution
4.2.2 Metabolism
4.2.3 Metabolism in Man
4.3 Toxicology
4.4 Applications of Coumarin and Coumarin Derivatives
4.4.1 Clinical Uses
4.4.2 High Protein Oedema (HPO)
4.4.3 Chronic Infections
4.5 Application Of Simple Coumarins In
4.5.1 Cancer Treatment
4.5.2 Coumarin in Malignant Melanoma
4.5.3 Coumarin in Renal Cell Carcinoma
4.5.4 Coumarin in Prostate Cancer
4.6 Coumarin Derivatives and Cancer
4.6.1 Furanocoumarins
4.6.2 Warfarin
4.6.3 Isoflavones
4.6.4 Genistein in Cancer Research
4.7 Chemistry of Hydrazide
4.7.1 Chemistry of Dithiocarbamate salt
4.8 Chemistry Of Quinazolines
4.8.1 Biological importance of Quinazolinones
4.8.2 Quinazolinones as anti HIV activity
4.8.3 Quinazolinones as antifungal activity
4.8.4 Quinazolinones as antioxidant activity
4.8.5 Quinazolinones as antileishmanial activity
5 CHEMISTRY OF BENZOTHIAZOLE
5.1 Benzothiazole
5.2 Characteristics of nucleus
5.3 Synthesis of 2-amino benzothiazole (Reported methods)
5.4 Method A
5.4.1 Mechanism
5.5 Method B
6 CHEMISTRY OF SCHIFF BASE
7 CHEMISTRY OF THIAZOLIDINONE
8 REFERENCES
9 LIST OF FIGURES
1 Coumarin - A boon to Earth
1.1 Introduction
The primary objective of medicinal chemistry is the design and discovery of new compounds that are suitable for use as drugs. This process involves a team of workers from a wide range of disciplines such as chemistry, biology, biochemistry, pharmacology, mathematics, medicine and computing, amongst others.1 The discovery or design of a new drug not only requires a discovery or design process but also the synthesis of the drug, a method of administration, the development of tests and procedures to establish how it operates in the body and a safety assessment. Drug discovery may also require fundamental research into the biological and chemical nature of the diseased state. These and other aspects of drug design and discovery require input from specialists in many other fields and so medicinal chemists need to have an outline knowledge of the relevant aspects of these fields. Drugs are strictly defined as chemical substances that are used to prevent or cure diseases in humans, animals and plants. The activity of a drug is its pharmaceutical effect on the subject, for example, analgesic or β -blocker, whereas its potency is the quantitative nature of that effect. Unfortunately the term drug is also used by the media and the general public to describe the substances taken for their psychotic rather than medicinal effects. However, this does not mean that these substances cannot be used as drugs. Heroin, for example, is a very effective painkiller and is used as such in the form of diamorphine in terminal cancer cases.2
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Figure 1-1 Some Common Drugs ''Authors own work''
Drugs act by interfering with biological processes, so no drug is completely safe. All drugs, including those non-prescription drugs such as aspirin and paracetamol (Fig. 1.1)that are commonly available over the counter, act as poisons if taken in excess. For example, overdoses of paracetamol can causes coma and death. Furthermore, in addition to their beneficial effects most drugs have non-beneficial biological effects. Aspirin, which is commonly used to alleviate headaches, can also cause gastric irritation and occult bleeding in some people 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. However, side effects are not always non-beneficial; the term also includes biological effects that are beneficial to the patient. For example, the antihistamine3 promethazine is licenced for the treatment of hayfever but also induces drowsiness, which may aid sleep. Drug resistance or tolerance (tachyphylaxis) occurs when a drug is no longer effective in controlling a medical condition. It arises in people for a variety of reasons. For example, the effectiveness of barbiturates often decreases with repeated use because the body develops mixed function oxidases in the liver that metabolise the drug, which reduces its effectiveness. The development of an enzyme that metabolises the drug is a relatively common reason for drug resistance. Another general reason for drug resistance is the down regulation of receptors .Down regulation occurs when repeated stimulation of areceptor results in the receptor being broken down. This results in the drug being less effective because there are fewer receptors available for it to act on. However, down regulating has been utilised therapeutically in a number of cases. The continuous use of gonadotrophin releasing factor, for example, causes gonadotrophin receptors that control the menstrual cycle to be down regulated. This is why gonadotrophin-like drugs are used as contraceptives. Drug resistance may also be due to the appearance of a significantly high proportion of drug-resistant strains of microorganisms. These strains arise naturally and can rapidly multiply and become the currently predominant strain of that microorganism. Antimalarial drugs are proving less effective because of an increase in the proportion of drug-resistant strains of the malaria parasite. New drugs are constantly required to combat drug resistance even though it can be minimised by the correct use of medicines by patients. They are also required for improving the treatment of existing diseases, the treatment of newly identified diseases and the production of safer drugs by the reduction or removal of adverse side effects.3
1.2 History
Since ancient times the peoples of the world have had a wide range of natural products that they use for medicinal purposes. These products, obtained from animal, vegetable and mineral sources, were sometimes very effective. However, many of the products were very toxic and it is interesting to note that the Greeks used the same word pharmakon for both poisons and medicinal products. Information about these ancient remedies was not readily available to users until the invention of the printing press in the fifteenth century. This led to the widespread publication and circulation of Herbals and Pharmacopoeias, which resulted in a rapid increase in the use, and misuse, of herbal and other remedies. Misuse of tartar emetic (antimony potassium tartrate) was the reason for its use being banned by the Paris parliament in 1566, probably the first recorded ban of its type. The usage of such remedies reached its height in the seventeenth century. However, improved communications between practitioners in the eighteenth and nineteenth centuries resulted in the progressive removal of preparations that were either ineffective or too toxic from Herbals and Pharmacopoeias. It also led to a more rational development of new drugs.4
The early nineteenth century saw the extraction of pure substances from plant material. These substances were of consistent quality but only a few of the compounds isolated proved to be satisfactory as therapeutic agents. The majority were found to be too toxic although many, such as morphine and cocaine for example, were extensively prescribed by physicians. The search to find less toxic medicines than those based on natural sources resulted in the introduction of synthetic substances as drugs in the late nineteenth century and their widespread use in the twentieth century. This development was based on the structures of known pharmacologically active compounds, now referred to as leads. The approach adopted by most nineteenth century workers was to synthesise structures related to that of the lead and test these compounds for the required activity. These lead-related compounds are now referred to as analogues. The first rational development of synthetic drugs was carried out by Paul Ehrlich and Sacachiro Hata who produced arsphenamine in 1910 by combining synthesis with reliable biological screening and evaluation procedures. Ehrlich, at the beginning of the nineteenth century, had recognised that both the beneficial and toxic properties of a drug were important to its evaluation. He realised that the more effective drugs showed a greater selectivity for the target microorganism than its host.
1.3 Brief view of Discoveries
1.3.1 Medicine in the antiquity
- Chinese medicine: (3500 BC),
- chinese herbs, some of the ingredients are still in use today, e.g.Reserpin (blood high pressure; emotional and mental control),
- Ephedrine (Asthma)
- Egyptian medicine (3000 BC
- Papyrus Ebers, 877 descriptions and recipies
- Greek medicine (from 700 BC)
- illness is no punishment from God, medicine is considered a science
- diseases are due to natural causes
- Hippocratic oath
- Roman medicine (from approx. 200 BC):
- invention of hospitals
- large influence of greek medicine
- Materia Medica: pharmaceutical descriptions
1.3.2 Medicine in the Middle Ages (400 to 1500 AC)
- The church preserves greek traditional recipies
- Era of horrible epidemics (e.g. Pest, Lepra, Pox, Tuberculosis)
- Arabic medicine: Development of medical procedures for drug preparation (destillation) afterwards
- Development of scientific approaches:
- Pox: Edward Jenner discovered that people who worked with cattle and had caught the cowpox disease (a mild disease related to smallpox) were immune and never caught smallpox. He inocculated a boy with blister fluid from a woman with cowpox. He later inocculated the same boy with fluid from smallpox, and discovered that the boy was immune against the disease.
- Bill Withering introduces extracts of Digitalis for treatment of heart problems
- Louis Pasteur discovers that microorganisms are responsible for diseases and develops vaccinations against rabies. He introduces attenuated viruses for treatment of rabies. until 1900
- Digitalis (isolated from the plant digitalis, stimulation of the heart muscle)
- Chinin (alkaloid froim peruvian bark, treatment of malaria, fever lowering)
- Ipecacuanha (from the bark of ipecac, treatment of diarrhea)
- Aspirin (from the meadow bark, against fever and pain)
- Mercury (-> syphilis)
1.4 Discovery of Penicillin
- Alexander Flemming discovers in 1928 that a fungus grew on a bacterial plate containing staphylococci. Close to the fungus all bacteria were killed.
- Biotechnological production of penicillins was established during the second world war and helped saving the life of many soldiers
- Robert Koch Nobel laureate 1905 "for his discovery and treatment of tuberculosis" Since then
- Early 1900: synthetic drugs, foundation of pharmaceutical industry
- since 1930: screening of natural products, isolation of their bioactive ingredients
- late 70 es: Development of recombinant drugs (proteins, e.g. interferons). Development of biotechnology
- 2000: Deciphering of the human genome, gene therapy (?), Investigation of the molecular basis of disease history of drug development
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Figure 1-2 Chronology of Drug Innovation (Cell Biology of Infection - Molecular Biology of the Cell - NCBI Bookshelf. https://www.ncbi.nlm.nih.gov/books/NBK26833/.)
1.5 The general stages in modern-day drug discovery and design
At the beginning of the nineteenth century drug discovery and design was largely carried outby individuals and was a matter of luck rather than structured investigation. Over the last century, a large increase in our general scientific knowledge means that today drug discovery requires considerable teamwork, the members of the team being specialists in various fields, such as medicine, biochemistry, chemistry, computerised molecular modelling, pharmaceutics, pharmacology, microbiology, toxicology, physiology and pathology. The approach is now more structured but a successful outcome still depends on a certain degree of luck. The modern approach to drug discovery/design depends on the objectives of the project. These objectives can range from changing the pharmacokinetics of an existing drug to discovering a completely new compound. Once the objectives of the project have been decided the team will select an appropriate starting point and decide how they wish to proceed. For example, if the objective is to modify the pharmacokinetics of an existing drug the starting point is usually that the drug and design team has to decide what structural modifications need to be investigated in order to achieve the desired modifications. Alternatively, if the objective is to find a new drug for a specific disease the starting point may be a knowledge of the biochemistry of the disease and/or the microorganism responsible for that disease (Fig. 1.4). This may require basic research into the biochemistry of the disease causing process before initiating the drug design investigation.
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Figure 1-3 Modern Day Drug Discoveries “Authors Own Work”
The information obtained is used by the team to decide where intervention would be most likely to bring about the desired result. Once the point of intervention has been selected the team has to decide on the structure of a compound, referred to as a lead compound, that could possibly bring about the required change. A number of candidates are usually considered but the expense of producing drugs dictates that the team has to choose only one or two of these compounds to act as the lead compound. The final selection depends on the experience of the research team. The work presented in this thesis is yet another humble effort in the field of medicinal chemistry, though very minute even to be regarded as a small step in offering a practical solution to the innumerable problems to a healthier and happier human life. The work deals with some of the commonest ailments viz. bacterial and fungal infections though not considered fatal by large. But even today these irritate physicians at times, when coupled with chronic conditions and also due to the resistance offered by infecting organisms to various forms of therapy.6
2 REVIEW OF LITERATURE
The fight against bacterial infection is one of the great success stories of medicinal chemistry. Bacteria were first identified in the 1670s by van Leeuwenhoek, following his invention of the microscope. However, it was not until the nineteenth century that their link with disease was appreciated. This appreciation followed the elegant experiments carried out by the French scientist Pasteur, who demonstrated that specific bacterial strains were crucial to fermentation and that these and other microorganisms were far more widespread than was previously thought. The possibility that these microorganisms might be responsible for disease began to take hold.
2.1 Anti –Microbial Agent Discovery
The discovery and implementation of antibiotics in the early twentieth century transformed human health and wellbeing. Chemical synthesis enabled the development of the first antibacterial substances, organ arsenicals and sulfa drugs, but these were soon outshone by a host of more powerful and vastly more complex antibiotics from nature: penicillin, streptomycin, tetracycline, and erythromycin, among others. These primary defences are now significantly less effective as an unavoidable consequence of rapid evolution of resistance within pathogenic bacteria, made worse by widespread misuse of antibiotics. For decades medicinal chemists replenished the arsenal of antibiotics by semisynthetic and to a lesser degree fully synthetic routes, but economic factors have led to a subsidence of this effort, which places society on the precipice of a disaster. We believe that the strategic application of modern chemical synthesis to antibacterial drug discovery must play a critical role if a crisis of global proportions is to be averted.
The emergence of pathogenic bacteria resistant to many or all current antibiotics is a major public health concern and one of particular importance in clinical settings. The World Economic Forum recently identified antibiotic resistance as one of the greatest threats to human health in its Global Risks 2013 report.7 The Center for Disease Control and Prevention released a summary of antibiotic resistance threats in the United States in 2013, outlining the “potentially catastrophic consequences of inaction.”8 Natural selection, assisted by global misuse of existing antibiotics, and the slowing pace of discovery of new antibiotics conspire to place society at or near a crisis point. The innovation deficit is in large measure due to the fact that many major pharmaceutical companies have abandoned antibacterial research and development, a trend which has created or at the very least contributed to the steep decline in the number of new antibacterials launched in the last 30 years 9 Meanwhile, resistance rates around the world are rising,10 new resistance mechanisms are emerging,11and infections caused by multidrug-resistant Gram-negative bacteria are becoming particularly difficult to treat. The problem is exacerbated by the ease of international travel and increasing global population densities. Our current arsenal of antibiotics is steadily losing its efficacy and there is little sign that it will be adequately replenished in the near future.12 The development of bacterial resistance is an inevitable consequence of evolution, and without continued replenishment of our arsenal of antibacterial agents, humanity runs the risk of returning to a pre-antibiotic era. In this Review we examine the 100-year history of antibiotics discovery and development from its dawning with the synthesis of the first arsenical agent to those few antibiotic candidates that are currently in late-stage clinical evaluation,13 highlighting the essential and evolving role of chemical synthesis throughout. Our objectives are to recognize select key contributions of the thousands of scientists who have provided the modern antibacterial pharmacopeia and to make the point that the clearest path forward to discover future generations of life-saving medicines will involve chemical synthesis as its core activity More specifically, we suggest that the development of practical, diversifiable, fully synthetic routes to antibiotic natural product scaffolds that are not yet accessible in this way presents the greatest opportunity for rapid discovery and development of new antibiotics in the near term (5–20 years). By this analysis, many of the natural product classes that emerged during and defined the golden era of antibiotics discovery (ca. 1940–1960) represent underutilized resources. The development of practical, fully synthetic routes to antibacterial molecules is a tried-and tested strategy whose perceived constraints (molecular sizeand complexity, scalability) need to be reevaluated in light of advances in modern chemical synthesis, both strategic and methodological. We believe that ambitious, translational chemical synthesis must be a core activity of antibiotics research moving forward, as it has been since the inception of the field.
2.2 Chemical Synthesis Ushers in the Golden Age of Antibiotics Discovery
Discovery and Development of the First Antibiotics , The first effective treatment for a bacterial infection arose from a convergence of disparate advances, including an early chemical synthesis of aniline, Paul Ehrlichs “magic bullet” hypothesis, and the development of the first treatments for African sleeping sickness. In 1854 the French chemist Antoine Bechamp achieved the first economical synthesis of aniline by reduction of nitrobenzene with iron in the presence of hydrochloric acid, a discovery that catalyzed the growth of the synthetic dye industry.14 Subsequent efforts to prepare aniline derivatives led Bechamp to synthesize a compound known as atoxyl in 1859 by the reaction of aniline with arsenic acid. The chemical structure of atoxyl proposed by Bechamp was later revised.
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Figure 2-1Antibiotics Discovery (A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future – National library of Medicine, doi: 10.3389/fmicb.2010.00134
2.3 Early History Of Anti-Biotics Discovery and Development
In the latter part of the 19th century, Paul Ehrlich began his prodigious search for a “magic bullet,” a molecule that could combat disease-causing organisms. 15 Ehrlich was broadly interested in fully synthetic dyes, their apparent selective affinities for living tissues, and their therapeutic potential. He hypothesized that the affinity of specific cell types for dye molecules could be harnessed to selectively destroy microorganisms in the body without damaging human cells. An early breakthrough came in 1891 when Ehrlich and Paul Guttmann reported that two patients suffering from malaria had been successfully treated with the fully synthetic thiazine dye methylene blue,16 possibly the first example of a fully synthetic drug being used in human medicine. Ehrlich was also actively involved in the development of synthetic dye therapeutics for African sleeping sickness, which ravaged equatorial Africa around the turn of the 19th century in an epidemic that claimed between 300 000 and 500 000 lives.17 His interest was piqued by a paper by H. W. Thomas in 1905 demonstrating that Bechamps atoxyl exhibited activity against trypanosomes, including the causative organism of sleeping sickness.18
One of the key scientific breakthroughs of the 20th centuryoccurred when Alexander Fleming discovered in 1928 that a substance produced by the fungus Penicillium chrysogenum (formerly known as Penicillium notatum) exhibited antibacterial activity.19 Although this finding was made prior to the key achievements of Domagk and collaborators, the fully synthetic sulfa drugs found widespread clinical use many years before penicillin became available for the treatment of bacterial infections. Nearly a decade passed following Flemings famous discovery before Howard Florey and Ernst Chain received a grant from the Rockefeller Foundation to isolate penicillin and investigate its biological properties. In 1940, the Oxford team member Norman Heatley demonstrated that treatment with crude penicillin significantly extended the lives of mice previously injected with a lethal strain of Streptococcus.20
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Figure 2-2 Fully Synthetic approaches to penicillin V and 6-aminopenicillanic acid (Enzyme Nanoarchitectures: Enzymes Armored with Graphene-Synthesis of Essential Drugs, 2006 https://www.sciencedirect.com/topics/chemistry/
2.4 The bacterial cell
The success of antibacterial agents owes much to the fact that they can act selectively against bacterial cells rather than animal cells. This is largely due to the fact that bacterial cells and animal cells differ both in their structure and in the biosynthetic pathways which proceed inside them. Let us consider some of the differences between the bacterial cell (Fig. 2.3) and the animal cell.
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Figure 2-3 Bacterial Cell (Identification of Flagellated or Fimbriated Bacterial Cells using Digital Image Processing Techniques, Prakash Hiremath, Parashuram Bannigidad, Soumyashree S. Yelgond, DOI:10.5120/9599-4223)
2.4.1 Differences between bacterial and animal cells
- The bacterial cell has a cell wall, as well as a cell membrane, whereas the animal cell has only a cell membrane. The cell wall is crucial to the bacterial cell's survival. Bacteria have to survive a wide range of environments and osmotic pressures, whereas animal cells do not. If a bacterial cell lacking a cell wall was placed in an aqueous environment containing a low concentration of salts, water would freely enter the cell due to osmotic pressure. This would cause the cell to swell and eventually 'burst'. The cell wall does not stop water flowing into the cell directly, but it does prevent the cell from swelling and so indirectly prevents water entering the cell.
- The bacterial cell does not have a defined nucleus, whereas the animal cell does.
- Animal cells contain a variety of structures called organelles (e.g. mitochondria, etc.), whereas the bacterial cell is relatively simple
- The biochemistry of a bacterial cell differs significantly from that of an animal cell.
For example, bacteria may have to synthesize essential vitamins which animal cells can acquire intact from food. The bacterial cells must have the enzymes to catalyse these reactions. Animal cells do not, since the reactions are not required
2.5 Mechanism Of Anti-Bacterial Cell
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Figure 2-4Mechanisms of antibacterial action(Identification of Flagellated or Fimbriated Bacterial Cells using Digital Image Processing Techniques, Prakash Hiremath, Parashuram Bannigidad, Soumyashree S. Yelgond, DOI:10.5120/9599-4223)
2.5.1 There are four main mechanisms by which antibacterial agents act.
1. Inhibition of cell metabolism.: - Antibacterial agents which inhibit cell metabolism are called antimetabolites. These compounds inhibit the metabolism of a microorganism, but not the metabolism of the host. They do this by inhibiting an enzyme-catalysed reaction which is present in the bacterial cell, but not in animal cells. The best known examples of antibacterial agents acting in this way are the sulfonamides.
2. Inhibition of bacterial cell wall synthesis:- Inhibition of cell wall synthesis leads to bacterial cell lysis (bursting) and death. Agents operating in this way include penicillins and cephalosporins. Since animal cells do not have a cell wall, they are unaffected by such agents.
3. Interactions with the plasma membrane:- Some antibacterial agents interact with the plasma membrane of bacterial cells to affect membrane permeability. This has fatal results for the cell. Polymyxins and tyrothricin operate in this way.
4. Disruption of protein synthesis:- Disruption of protein synthesis means that essential enzymes required for the cell's survival can no longer be made. Agents which disrupt protein synthesis include the rifamycins, aminoglycosides, tetracyclines, and chloramphenicol.
5. Inhibition of nucleic acid transcription and replication:- Inhibition of nucleic acid function prevents cell division and/or the synthesis of essential enzymes. Agents acting in this way include nalidixic acid and proflavin .
2.5.2 Antibacterials, 1940-Present
The next antibiotic manufactured by a fully synthetic route after the sulfa drugs was chloramphenicol, a natural product first isolated in 1947 from a culture of Streptomyces venezuelae by John Ehrlich and collaborators at Parke, Davis & Co. and shown to have broad spectrum activity (Fig. 2.6.).22 Chloramphenicol is a rare case of a natural product that is more economical to produce on industrialscale by chemical synthesis rather than fermentation (another example is thienamycin, the precursor to imipenem). A practical, fully synthetic route to chloramphenicol was developed by John Controulis, Mildred Rebstock, and Harry Crooks at Parke, Davis & Co.23 and this drug was approved in 1949. Millions of patients were treated with the new antibiotic before reports of rare but fatal aplastic anemia began to emerge.24 This and other adverse effects, combined with the development of other broad-spectrum antibiotics, led to reduced use of chloramphenicol in the clinic; however, as the result of its ease of manufacture and low cost it is still produced on a massive scale and is widely employed in developing countries, and it remains a component of the WHO Model List of Essential Medicines.25 A structural analog of chloramphenicol with similar antibacterial activity—thiamphenicol—was first synthesized in 1952 (Fig. 2.5.).26 The replacement of the nitro group in chloramphenicol with a methanesulfonyl group increased potency and avoided the fatal aplastic anemia, rendering the class safer for use in humans
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Figure 2-5 Synthesis of Trimethoprim (Enzyme Nanoarchitectures: Enzymes Armored with Graphene-Synthesis of Essential Drugs, 2006 https://www.sciencedirect.com/topics/chemistry/
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Figure 2-6 Milestone on development of fully synthetic anti-bacterials 1940-1969(A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future – National library of Medicine, doi: 10.3389/fmicb.2010.00134
2.5.3 Some Anti-Bacterials Agents27
The sulfonamide story began in 1935 when it was discovered that a red dye called prontosil had antibacterial properties in vivo (i.e. when given to laboratory animals). Strangely enough, no antibacterial effect was observed in vitro. In other words, prontosil could not kill bacteria grown in the test tube. This remained a mystery until it was discovered that prontosil was not in fact the antibacterial agent. Instead, it was found that the dye was metabolized by bacteria present in the small intestine of the test animal, and broken down to give a product called sulfanilamide (Fig. 2.7). It was this compound which was the true antibacterial agent. Thus, prontosil was the first example of a prodrug. Sulfanilamide was synthesized in the laboratory and became the first synthetic antibacterial agent active against a wide range of infections. Further developments led to a range of sulfonamides which proved effective against Gram-positive organisms, especially pneumococci and meningococci. Despite their undoubted benefits, sulfa drugs have proved ineffective against infections such as Salmonella—the organism responsible for typhoid. Other problems have resulted from the way these drugs are metabolized, since toxic products are frequently obtained. This led to the sulfonamides mainly being superseded by penicillin.
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Figure 2-7 Metabolism of prontosil. “Authors own work’’
2.5.4 Structure-activity relationships (SAR)28
The synthesis of a large number of sulfonamide analogues (Fig. 2.8) led to the following conclusions.
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Figure 2-8 Sulfonamide analogues. “Authors own work’’
- The p-amino group is essential for activity and must be unsubstituted (i.e. R = H). The only exception is when R = acyl (i.e. amides). The amides themselves are inactive but can be metabolized in the body to regenerate the active compound (Fig. 2.9). Thus amides can be used as sulfonamide prodrugs (see later).
- The aromatic ring and the sulfonamide functional group are both required.
- The aromatic ring must be para-substituted only.
- The sulfonamide nitrogen must be secondary.
- R" is the only possible site that can be varied in sulfonamides.
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Figure 2-9Metabolism of acyl group to regenerate active compound. “Authors own work’’
2.5.5 Applications of sulfonamides29
Before the appearance of penicillin, the sulfa drugs were the drugs of choice in the treatment of infectious diseases. Indeed, they played a significant part in world history by saving Winston Churchill's life during the Second World War. Whilst visiting North Africa, Churchill became ill with a serious infection and was bedridden for several weeks. At one point, his condition was deemed so serious that his daughter was flown out from Britain to be at his side. Fortunately, he responded to the novel sulfonamide drugs of the day. Penicillins largely superseded sulfonamides in the fight against bacterial infections Fig 2.10 and for a long time sulfonamides were relegated backstage. However, there has been a revival of interest with the discovery of a new 'breed' of longer lasting sulfonamides. One example of this new generation is sulfamethoxine (Fig. 2.10) which is so stable in the body that it need only be taken once a week. The sulfa drugs presently have the following applications in medicine:
- treatment of urinary tract infections
- eye lotions
- treatment of infections of mucous membranes
- treatment of gut infections
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Figure 2-10 Sulfamethoxine. “Authors own work’
Sulfonamides have been particularly useful against infections of the intestine and can be targeted specifically to that site by the use of prodrugs. For example, succinyl sulfathiazole (Fig. 2.11) is a prodrug of sulfathiazole. The succinyl group converts the basic sulfathiazole into an acid which means that the prodrug is ionized in the slightly alkaline conditions of the intestine. As a result, it is not absorbed into the bloodstream and is retained in the intestine. Slow enzymatic hydrolysis of the succinyl group then releases the active sulfathiazole where it is needed.
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Figure 2-11Succinyl sulfathiazole is a prodrug of sulfathiazole. “Authors own work’’
Substitution on the aniline nitrogen with benzoyl groups (Fig. 2.12) has also given useful prodrugs which are poorly absorbed through the gut wall and can be used in the same way
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Figure 2-12 Substitution on the aniline nitrogen with benzoyl groups“Authors own work’’
2.6 Mechanism of action
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Figure 2-13 Mechanism of action ot sulfonamides. “Authors own work’’
The sulfonamides act as competitive enzyme inhibitors and block the biosynthesis of the vitamin folk acid in bacterial cells (Fig. 2.13). They do this by inhibiting the enzyme responsible for linking together the component parts of folic acid. Theconsequences of this are disastrous for the cell. Under normal conditions, folic acid is the precursor for tetrahydrofolate—a compound which is crucial to cell biochemistry since it acts as the carrier for one-carbon units, necessary for many biosynthetic pathways. If tetrahydrofolate is no longer synthesized, then any biosynthetic pathway requiring one-carbon fragments is disrupted. The biosynthesis of nucleic acids is particularly disrupted and this leads to the cessation of cell growth and division. Note that sulfonamides do not actively kill bacterial cells. They do, however, prevent the cells dividing and spreading. This gives the body's own defense systems enough time to gather their resources and wipe out the invader. Antibacterial agents which inhibit cell growth are classed as bacteriostatic, There are other antimetabolites in medical use apart from the sulfonamides. Two examples are trimethoprim and a group of compounds known as sulfones (Fig. 2.14).
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Figure 2-14 Examples of antimetabolites in medical use. “Authors own work’’ Fungal Infections
Fungal infections are caused by microscopic organisms that can invade the epithelial tissue. The fungal kingdom includes yeasts, molds, rusts and mushrooms. Fungi, like animals, are hetrotrophic, that is, they obtain nutrients from the environment, not from endogenous sources (like plants with photosynthesis). Most fungi are beneficial and are involved in biodegradation, however, a few can cause opportunistic infections if they are introduced into the skin through wounds, or into the lungs and nasal passages if inhaled. Diseases caused by fungi include superficial infections of the skin by dermatophytes in the Microsporum, Trichophyton or Epidermophyton genera. These dermophytic infections are named for the site of infection rather than the causative organism.
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Systemic infections are caused by the inhalation of spores and cause fungal pneumonia. This pneumonia cannot be transmitted from human to human. These infections can occur in otherwise healthy individuals. Many of the organisms that cause systemic fungal infections are confined to specific geographic locations due to favorable climates for their proliferation.
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Organisms that cause opportunistic infections will not gain a foothold in healthy individuals, but in the immunocompromised they can cause serious, sometimes life-threatening infections. Patients especially susceptible to these infections include individuals with leukemia and other blood diseases, cancer, HIV and other immunodeficiencies, and diabetes. These organisms can be found throughout the U.S.
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2.6.1 Biochemical Targets for Antifungal Chemotherapy31
Fungal cells are complex organisms that share many biochemical targets with other eukaryotic cells. Therefore, agents that interact with fungal targets not found in eukaryotic cells are needed. The fungal cell wall is a unique organelle that fulfills the criteria for selective toxicity. The fungal cell wall differs greatly from the bacterial cell wall and is not affected by antibacterial cell wall inhibitors such as the β-lactams or vancomycin.
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- Quote paper
- Dr Neha Mishra (Author), Dr Pritesh Sharma (Author), 2023, Coumarin as a Boon to Earth. A new Cancer Treatment?, Munich, GRIN Verlag, https://www.hausarbeiten.de/document/1321483
