Chapter 1 GENERAL INTRODUCTION - shodhganga.inflibnet.ac.inshodhganga.inflibnet.ac.in/bitstream/10603/44285/9/09_chapter 1.pdf · STUDIES ON NEW HETEROCYCLIC COMP... 14 unless the

STUDIES ON NEW HETEROCYCLIC COMP...

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Chapter 1

GENERAL INTRODUCTION


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1.1 MEDICINAL CHEMISTRY

The role played by organic chemistry in

pharmaceutical industry continues to be one of

the main drivers in the drug discovery process.

However, the precise nature of the role is

undergoing a visible change, not only because

of the new synthetic methods and technologies

now available to the synthetic, medicinal chemists, 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 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 in the way that synthetic chemistry is practiced in this

environment center around new scientific advances in synthetic techniques and new

technologies for rational drug design, combinational 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 “hits” (1) are likely to play out as true “lead” (1) structures that will

meet the plethora of hurdles that any drug candidate must surmount.


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NEW DRUGS FOR NEGLECTED DISEASES: FROM PIPELINE TO PATIENTS:

In wealthy countries, state-funded research has yielded breakthroughs in

molecular biology, chemistry, and engineering. These advances have been taken up

by the pharmaceutical industry and applied to drug development for a growing

range of illnesses and conditions. As a result, patients have access to new drugs that

are better tolerated, more specific, and more effective than old ones. In poor

countries, however, millions of people have yet to experience the benefits wrought

by science.

[Fig. 3: New drugs for neglected diseases]

EMERGENCE AS A FORMALIZED DISCIPLINE

Medicinal chemistry’s roots can be found in the fertile mix of ancient folk

medicine and early natural product chemistry, and hence its name. As appreciation


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for the links between chemical structure and observed biological activity grew,

medicinal chemistry began to emerge about 150 years ago as a distinct discipline

intending to explore these relationships via chemical modification and structural

mimicry of nature’s materials, particularly with an eye toward enhancing the

efficacy of substances thought to be of therapeutic value(1). Understanding

structure–activity relationships (SARs) at the level of inherent physical organic

properties (i.e., lipophilic, electronic, and steric parameters) coupled with

consideration of molecular conformation soon became the hallmark of medicinal

chemistry research. Furthermore, it follows that because these fundamental

principles could be useful during designing of new drugs, applications toward drug

design became the principal domain for a still young, basic science discipline.

Perhaps somewhat prematurely, medicinal chemistry’s drug design role became

especially important within the private sector where its practice quickly took root

and grew rampantly across the rich fields being staked out within the acres of

patents and intellectual property that were of particular interest to the industry.

EARLY DEVELOPMENTS

As a more comprehensive appreciation for the links between observed

activity and pharmacological mechanisms began to develop about 50 years ago and

then also proceeded to grow rapidly in biochemical sophistication, medicinal

chemistry, in turn, entered into what can now be considered to be an adolescent

phase. Confidently instilled with a new understanding about what was happening

at the biomolecular level, the ensuing period was characterized by the high hope of

being able to independently design new drugs in a rational (i.e., ab initio) manner

rather than by relying solely upon Mother Nature’s templates and guidance for

such. While this adolescent “heyday of rational drug design”(2) should certainly be

credited with having spurred significant advances in the methods that can be

deployed for considering molecular conformation, the rate of actually delivering

clinically useful therapeutic entities having new chemical structures within the

private sector was not significantly improved for most pharmacological targets


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unless the latter’s relevant biomolecules also happened to lend themselves to

rigorous analysis (e.g., obtainment of an X-ray diffraction pattern for a crystallized

enzyme’s active site with or without a bound ligand). One of the major reasons

rational drug design fell short of its promise was because without experimental data

like that afforded by X-ray views of a drug’s target site, medicinal chemistry’s

hypothetical SAR models often reflected speculative notions that were typically far

easier to conceive than were the actual synthesis of the molecular probes needed to

assess a given model’s associated hypotheses. Thus, with only a small number of

clinical success stories to relay, medicinal chemistry’s “preconceived notions about

what a new drug ought to look like” began to take on negative rather than positive

connotations, particularly when being “hand-waved” within the context of a private

sector drug discovery program.

Furthermore, from a practical point of view, the pharmaceutical industry, by

and large, soon concluded that it was more advantageous to employ synthetic

organic chemists and have them learn some pharmacology, than to employ formally

trained medicinal chemists and have them rectify any shortcomings in synthetic

chemistry that they might have due to their exposure to a broader range of

nonchemical subject matter during graduate school. Indeed, given the propensity

for like-to-hire-like, the vast majority of today’s investigators who practice

medicinal chemistry within big pharma, and probably most within the smaller

company segment of the pharmaceutical industry as well, have academic

backgrounds from organic chemistry rather than from formalized programs of

medicinal chemistry.

Arriving at the next historical segment, however, one finds that medicinal

chemistry’s inability to accelerate the discovery of new chemical entities (NCEs) by

using rational drug design became greatly exacerbated when the biotechnology

rainfall began to hover over the field of drug discovery just somewhat less than

about 25 years ago(3). With this development, not only did the number of interesting

biological targets begin to rise rapidly, but also the ability to assay many of these

targets in a highthroughput manner suddenly prompted the screening of huge


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numbers of compounds in very quick timeframes. Ultimately, the need to satisfy

high-throughput screening’s (HTS’s)(4,5) immense appetite for compounds was

addressed not by either of natural product or synthetic medicinal chemistry but by

further developments within what had quickly become a flood-level(6)continuing

downpour of biotechnology-related breakthroughs.

PRESENT STATUS

Interestingly, the marriage of HTS with combinatorial chemistry has led to a

situation where identifying initial lead compounds is no longer considered to be a

bottleneck for the overall process of drug discovery and development. Indeed, many

of the programs within pharmaceutical companies are presently considered to be

suffering from “compound overload” with far too many initial leads to effectively

follow up.

ADMET assessments are now regarded as the new bottleneck, along with the

traditionally sluggish clinical and regulatory steps. This situation, in turn, has

prompted an emphasis to move ADMET-related parameters into more of an HTS

format undertaken at earlier decision points. Thus, even though efficacy-related

HTS and combinatorial chemistry reflect very significant incorporations of new

methodologies, from a strategic point of view the most striking feature of the new

drug discovery and development paradigm shown in Figure 1, actually becomes the

trend to place ADMET-related assays closer to the beginning of the overall process

by also deploying HTS methods. Clearly, with the plethora of biologically based

therapeutic concepts continuing to rise even further and the identification of lead

compounds now being much quicker because of the HTS-combinatorial chemistry

approach, a more efficient handling of ADMET-related concerns represents one of

the most significant challenges now facing drug discovery and development.

Because of its importance, this challenge is likely to be resolved within just the near

term of the new millennium.


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Figure 1

1.2 DRUGS

Drugs are the chemicals that are normally of low molecular weight and

which interact with macromolecular targets to produce a biological response. That

response may be therapeutically useful in the case of medicines, or harmful in the

case of poisons. Most of drugs used as medicine are potential poisons if taken in the

doses higher than those recommended. Drugs seeking are analogous, it is essential

to have a good idea of what kind of molecules are likely to become successful drugs

before beginning. The normally preferred means of administration of medicaments

is oral. Whereas there are no guarantees and many exceptions, the majority of

effective oral drugs obey the Lipinski rule of five. The data upon which this rule

rests is drawn from 2500 entries extracted from the US Adopted Names, the World

Drug lists, and the internal Pfizer compounds collection. There are four criteria’s:


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1. Substance should have a molecular weight of 500 or less.

2. It should have less than five hydrogen-bond donating functions.

3. It should have less than ten hydrogen-bond accepting functions.

4. The substance should have calculated log P (c Log) between approximately -

1 to 5.

In short, the compound should have a comparatively low molecular weight,

be relatively non-polar and partition between an aqueous and a particular lipid

phase in favor of the lipid phase, but at the same time, possess perceptible water

solubility.

DEFINITION AND DISCOVERY OF DRUGS

Specialists in biological sciences and medicinal chemistry work in close

collaboration throughout the entire process of drug discovery. In addition to

specialists in biology and therapeutic chemistry, the discovery of a new drug

involves the collaboration of pharmaceutical R&D specialists and clinical research

teams, composed of doctors, nurses and other health specialists. For the

pharmaceutical industry, the discovery of a new drug presents an enormous

scientific challenge and consists essentially in the identification of new molecules or

compounds. Ideally, the latter will become drugs that act in new ways upon

biological targets specific to the diseases requiring new therapeutic approaches.

CLASSIFICATION OF DRUGS

There are several ways in which drugs can be classified

1. According to their pharmacological effect – for example, analgesics drugs

which have a pain-killing effect.

2. Depending on whether they act on a particular biochemical process – for

example, antihistamines act by inhibiting the action of the inflammatory

agent histamine in the body.


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3. According to their chemical structure – drugs classified in this way share a

common structural feature and often share a similar pharmacological

activity – for example, penicillin contains β-lactum ring and kills

bacteria by the same mechanism.

4. According to their molecular target-this is the most useful classification as far

as medicinal chemist is concerned, since it allows rational comparison of

the structures involved. For example, anticholinesterases are

compounds that inhibit an enzyme called acetyl cholinesterase.

Many drugs are either organic acids or organic bases that are used as salts.

These bring about: (a) modifications of physiochemical properties, such as

solubility, stability, photosensitivity and organoleptic characteristics. (b)

Improvement of bioavailability through modification of absorption, increase of

potency and extension of effect and (c) reduction of toxicity.

APPLICATIONS OF DRUGS

(A) For providing elements lacking in the organism: for example, vitamins,

mineral salts, protein hydrolysates and hormones.

(B) For prevention of a disease or an infection: for example, sera and vaccines.

(C) To fight against an infection: for example, chemotherapeutics, including

antibiotics.

(D) Temporary blocking of a normal function: for example, general and local

anaesthetics and oral contraceptives.

(E) Correction of a deranged function: (i) disfunction: for example, cardiotonics

for treatment of congestive heart failure: (ii) hypofunction: for example,

hydrocortisone for treatment of suprarenal insufficiency: (iii)

hyperfunction: for example, methyldopa in arterial hypertension.

(F) Detoxification of the body: for example, antidotes.


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Most of the drugs currently undergoing pre-clinical and clinical development

are artemisinin combination drugs (LapDap/Artesunate,

Pyronaridine/Artesunate, Piperaquine/DHA etc.) and improvement on

existing compounds such as antifolates and quinolines (LapDap and

Isoquine). Although these classes are expected to deliver new drugs in the

short term, one can argue that they have limited innovation and will require

more investments in drug discovery research to identify new classes of

compounds.

Once a compound has shown satisfactory efficacy in animal model, it is

subjected to pre-clinical assessment which evaluates initial parameters such as drug

metabolism, pharmacokinetics and toxicity in animals. After successfully passing

through the preclinical stage, the New Chemical Entities can progress to clinical

development. In US an Investigational New Drug approval (IND) need to be

obtained from FDA before progressing to clinical trials. In Europe, the equivalent of

an IND does not exist, however discussions are underway to introduce it. The IND

will then enter Phase I (safety and tolerability in healthy volunteers); Phase II

(efficacy in a small number of patients); and Phase III (efficacy in large population

of patients) should the drug pass all three clinical phases, it is submitted to

regulatory authorities for approval as new drug.


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Modern drug discovery often involves screening small molecules for their

ability to bind to a preselected protein target. Target-oriented syntheses of these

small molecules, individually or as collections (focused libraries), can be planned

effectively with retrosynthesis analysis. Drug discovery can also involve screening

small molecules for their ability to modulate a biological pathway in cells or

organisms, without regard for any particular protein target. This process is likely to

benefit in future from an evolving forward analysis of synthesis pathways, used in

diversity-oriented synthesis that leads to structurally complex and diverse small

molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a

collection of small molecules capable of perturbing any disease-related biological

pathway, leading eventually to the identification of therapeutic protein targets

capable of being modulated by small molecules.

Modern methods for the organic synthesis have increased the efficiency with

which small molecules can be prepared. These compounds include new drugs and

drug candidates and reagents used to explore biological processes. However, it is a

nearly four decades old method for purifying reaction products that is currently

having greatest impact on organic synthesis, Solid phase organic synthesis, adapted

from the original solid phase peptide synthesis, promises to increase dramatically

the diversity and number of small molecules available for medical and biological

applications.


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The evolution of stereoselective organic synthesis from the solution to the

solid phase has created strategic challenges for organic chemists because it has

provided the means to synthesize not only single target compounds or collections

of related targets but also collections of structurally diverse compounds. Target-

oriented syntheses are used in drug discovery efforts involving preselected protein

syntheses in efforts to identify simultaneously therapeutic protein targets and their

small-molecule regulators. Target-oriented synthesis has benefited from a powerful

planning algorithm named retrosynthesis; a comparable algorithm for diversity-

oriented synthesis is only now beginning to be developed. Planning diversity-

oriented syntheses will become increasingly important for organic chemists as

methods to screen large collections of small molecules become more effective.

Target-oriented synthesis has a long history in organic chemistry. In

universities, the targets are often natural products and drugs, whereas in

pharmaceutical companies, the targets are drugs and libraries of drug candidates.

Beginning in the mid-1960’s, a systematic method to plan syntheses of target

molecules, names retrosynthesis analysis was devised. This problem-solving

technique involves the recognition of key structural elements in reaction products,

rather than reaction substrates, that code for synthetic transformations. Repetitive

application of this process allows a synthetic chemist to start with a structurally

simple compound that can be used to start a synthesis.

Organic synthesis, especially diversity-oriented synthesis, will likely play a

vital role in drug discovery in the future. Retrosynthetic analysis can be used to plan

target-oriented syntheses effectively, but we have, at this stage, an incomplete set of

guiding principles for planning diversity-oriented syntheses. In this review, author

has outlined a few concepts for planning synthetic pathways that yield structurally

complex and diverse small molecules. The identification of pairs of complexity-

generating reactions that have a unique product-substrate relation, the use of

conformational analysis and the use of branching reaction pathways that allow

many different building blocks to be appended to many different skeletal arrays of

atoms are likely to be useful planning elements. However, our ability to plan


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currently lacks guidance from our growing knowledge of small molecule binding

sites on biological macromolecules. This knowledge could in principle be used to

constrain the structures of synthetic compounds to those optimally fitted for

binding. Input from structural, biophysical and theoretical studies may therefore

provide additional guiding principles. An understanding of the evolutionary

principles underlying the selection of biosynthetic pathways and their small

molecule products may also be helpful. There are many new challenges, both

intellectual and technical, for synthetic organic chemists engaged in diversity-

oriented synthesis. It is a fertile ground for chemists, one that is beginning to

facilitate the discovery of new drugs today and that promises to make man new

connections to biology and medicine in future.

RAMIFICATION IN THE DEVELOPMENT OF DRUG ANALOGUES:

Drug analogues are used as lead and modified molecules in an appropriate

manner to produce medicinally important bioactive molecules, which may further

be used as drug analogues.

The practice of medicinal chemistry is devoted to the discovery and

development of new chemical entities used as medicinally important leads. The

typical development of lead compounds used to follow a relatively simple path of

discovery and modification, need to follow the synthesis of a series of analogues

keeping in view the functional group and activity parameter of medicinal

importance. After that, it follows extensive tests for active its on microorganism and

laboratory animals to determine the therapeutic effect, side effect and toxicity. The

mission of drug research is to discover new drugs, which are used as tools to cure

or prevent or disease. The rapid screening techniques for synthetic drugs for various

pharmacological activities have provided impetus and tools for the discovery of

trend setting leads. Greater understanding of the physiological mechanism has

made it possible for a mechanistic approach to research and starts from a rationally

argued hypothesis to design a drug.


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Once a new drug entity has been discovered, extensive and costly efforts

usually are made to prepare a series of analogues in the hope that even better

activity will be found. In an effort to improve the efficiency of analogue

development, a variety of methods have been introduced to study the relationships

between functional group changes and biological activity called as Structure

Activity Relationship. (SAR)

1.3 ANTI-MICROBIAL AGENTS:

The past few decades have witnessed a significant increase in microbial

diseases. The infections caused by bacteria, fungi, viruses etc. has affected human

as well as animals. Hence, this class of drugs is the greatest contribution of the 20th

century to medicinal chemistry. Substantial attention has been focused on

developing a more potent and effective anti-microbial agents. Most of this attention

has been devoted to the study of antibacterial and antifungal agents in the

development of antimicrobial agents.

Bacterial cells grow and divide, replicating repeatedly to form large

numbers present during an infection or on the surfaces of the body. To grow and

divide, organisms must synthesize or take up many types of biomolecules. An

antimicrobial agent interferes with specific processes that are essential for growth

and / or division. Antibacterials can be separated into groups based on the mode of

action as inhibitors of bacterial and fungal cell walls, inhibitors of cytoplasmic

membranes, inhibitors of nucleic acid synthesis and inhibitors of ribosome function.

Antimicrobial agents may be either bactericidal, killing the target bacterium or

fungus, or bacteriostatic, inhibiting its growth. Antibiotics destroy bacteria in

various ways. Foreign picture shows antibiotics interfere with cell walls and the

production of essential proteins.

Bactericidal agents are more effective, but bacteriostatic agents can be

extremely beneficial since they permit the normal defenses of the host to destroy

microorganisms. It can also be useful to combine various antimicrobial agents for


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broadening the activity spectrums and to minimize the possibility of the

development of bacterial resistance. Some antibiotic combinations are more

effective together than the combine effectiveness of the single agent. This is termed

as Synergism. Combination therapy has proved its value as latest therapy for

antimicrobials. Some bacteriostatic agents on novel combination give bactericidal

activity. Sulphamethoxazole is bacteriostatic and Trimethoprime is also

bacteriostatic but combination of both the drugs is now widely used as a bactericidal

combination. Two such bactericidal drugs are also used in combination therapy.

Refampin + Dapsone are used in leprosy, Refampin + Isoniazide in Tuberculosis.

NON-CLINICAL DEVELOPMENT

Non-clinical testing is the animal and cell based studies that are needed to

support the clinical trials. The testing is conducted both prior to and at the same

time as the clinical trials. In non-clinical studies the compound is tested for safety

and efficacy in animal studies. Non-clinical development includes: Mutagenicity,

single and repeat dose toxicity, safety pharmacology, pharmacokinetics, toxico-

kinetics and analysis of formulation and kinetic samples. The initial non-clinical

tests, i.e. preclinical tests are used to select dose levels and/or formulation for phase

I and the later tests to assess if the development programme should continue.

CLINICAL DEVELOPMENT

Clinical development is split into four phases; phase I to Phase IV. Phase I to

Phase III represents clinical trials producing necessary documentation for the

registration of a new product. Phase IV includes trials with registered products.

Generally, products are to be tested on healthy volunteer in phase I and be further

tested on patients in phase II. Deviation from this principle is made in cases where

drugs or devices target life-threatening diseases, e.g cancer.


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Phase I

Trials on healthy volunteers are performed. The mission is primarily to examine the

pharmacokinetic properties and to test for safety and tolerance. However, proof of

principle studies can be 50-150 healthy volunteers.

Phase II

Documentation of effect in patients, during phase IIa the drug is tested on a limited

number of patients. The aim is to obtain proof of principle and to test for tolerance

and safety. The number of patients can be 100-200.

Phase II

Verification of effect and determination of the therapeutic dose. In this phase the

optimum dose will be determined as a compromise between efficacy, tolerance and

safety. The number of patients can be 100-300+.

Phase III

The identified optimum dose is tested in relation to the existing optimum

therapeutics/drugs. The number of patients can be 500-5,000. The lowest number of

patients is usually found in orphan drug development.

1.4 CHEMOTHERAPY

Paul Ehrlich discovered the famous organo arsenical compound Salvarsan

which was active against the causative organisms of syphilis. The term

chemotherapy was introduced by him to indicate the treatment of microbial disease

by the administration of a drug which had a lethal or inhibitory effect on the microbe

responsible. This was described as a “magic bullet” which when introduced into the

body, would destroy only the bacteria at which it was aimed.

A chemotherapeutic agent is defined in terms of its function rather than its

origin. These substances are prepared in the chemical laboratory or obtained from

microorganisms and some plants and animals. The science of chemotherapy rests

on many disciplines which includes organic chemistry, natural product research,


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biology of the invader and host, pharmacology, toxicity and therapeutics. Prontosil

(2,4-diamino azobenzene-4’-sulfon-amide) introduced by Domagk in 1932 was the

first chemotherapeutic agent active against bacteria. In spite of its therapeutic effect,

it had no in vitro antibacterial activity.

During the 20th century, a number of compounds have been isolated,

synthesized and subjected to detailed investigation for their structure and

pharmacological action. Some of the compounds have been found to possess

definite physiological activity and later on it was observed that the physiological

activity is associated with a particular structure unit and hence structural similarity

in other compounds. The part of the drug, which is responsible for the actual

physiological activity, is known as pharmacophore group. This has been somewhat

modified by the common and simple unit processes to give more active compounds

with low toxicity.

The chances of designing a clinically useful medicinal chemical are indeed

very slim now, since several restrictive conditions are imposed. Even on the best

laboratory findings, high potency should be maintained in man. There should be

minimum side effect and acute toxicity, and there should be no chronic toxicity.Four

principal approach for drug discovery are: (i) the expansion of known drug classes

to cover organisms resistant to earlier members of the class, (ii) the reevaluation of

unexplored molecules, (iii) the classical screening of synthetic compounds and

natural compounds (iv) the identification of novel agents active against previously

not-exploited or even unknown (novel) targets within the pathogen.

MECHANISM OF ACTION OF CHEMOTHERAPEUTIC AGENTS:

It is important of know the exact mechanism of action of specific

chemotherapeutic agents because such knowledge helps to explain the nature

and degree of selective toxicity of individual drugs and sometimes aids in the

design of new chemotherapeutic agents.


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The cell is structural and functional unit for unicellular microorganisms.

Various types of metabolic activities proceed in a young active multiplying cell. The

anti-biotics as a main chemotherapeutic agent can attack the structural organization

of the microbial cell or prevents the biosynthesis of cell macromolecules. Thus

antibiotics and other chemotherapeutic agents attack on cell wall synthesis or cell

membrane structure and cause cell lysis. Certain broad-spectrum antibiotics prevent

the synthesis of protein and nucleic acids in the target microbial cell, which leads

to death. Some synthetic chemotherapeutic agents act by interfering with enzyme

activity of microbial cell that prevents biochemical reactions that leads to death of

cell or cessation of growth.

IDEAL CHARACTERISTICS OF CHEMOTHERAPEUTIC AGENTS

For chemical compounds to be ideal chemotherapeutic agents used for

treating microbial infections, it should have the following qualities:

1. Selective toxicity: The drug should demonstrate selective toxicity. This

means that, at the optimum concentration, the drug should be toxic for

microorganism, but not for the host.

2. Antimicrobial spectrum: The drug should be able to destroy or inhibit many

kinds of pathogenic microorganisms. The larger the number of different

microbial pathogenic species affected the better. For instance, the most

widely used antibiotics are broad-spectrum antibiotics. A narrow-spectrum

drug is active against one or only a few species, either the Gram-positive or

Gram-negative groups. (e.g., Penicillin).

3. No side effects: The drug should not produce undesirable side effects, such

as allergic reactions, nerve damage, irritation of the kidney or damaging

blood cells etc.

4. No killing effect on normal flora: The drug should not eliminate the normal

microbial flora that inhibits the intestinal tract or other areas of the body. The


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normal flora also plays an important role in preventing pathogens from

growing.

5. No inactivation: If the drug is given orally, it should not be inactivated by

stomach acids and it should be absorbed into the body from the intestinal

tract. If it is administered by injection, it should not be inactivated by binding

to blood proteins.

6. Solubility in body fluids: The drug must have solubility in the body fluids

because it must be in a solution to be active and can rapidly penetrate body

tissue.

7. Sufficient concentration of the drug in target tissues: The drug must be able

to reach sufficiently high concentration in the tissues or blood of the patient

to kill or inhibit the pathogen.

8. Low break-down rate of drug: The rates at which the drug is broken down

and excreted from the body must be low enough so that the drug remains in

the infected body tissues long enough to exert its effects.

9. No development of drug-resistance: The drug should inhibit

microorganisms in such a way as to prevent the development of drug-

resistance forms of pathogens.

10. Stable viability: The drug should have long viable activity even if stored at

room temperature.

11. Easily availabilityat affordable cost/price: Clinicians must make

comparison amongst the available chemotherapeutic agents to select the one

best suited for the treatment of a specific infection. However, developers of a

drug attempt to obtain the best possible combination of properties for

effective human use.


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1.5 REFERENCES:

1. Burger A; Medicinal Chemistry Part 1, 3rd ed., Wiley-Interscience, New York,

1970 (first published in 1951).

2. Erhardt P W; “Drug Metabolism data: past, present and future

considerations”, in Drug Metabolism-Databases and High-Throughput Testing

During Drug Design and Development, P W Erhardt (Ed.), 2,

IIUPAC/Blackwell, Boston, 1999.

3. Venuti M C; Ann. Rep. Med. Chem.,25, 289, 1990.

4. Oldenburg K R; Ann. Rep. Med. Chem.,33, 301, 1998.

5. Ausman D J; Modern Drug Discov.,Jan., 18, 2001.

6. Felton M J; Modern Drug Discov.,Jan., 24, 2001.

Documents

Chapter 1 GENERAL INTRODUCTION - shodhganga.inflibnet.ac.inshodhganga.inflibnet.ac.in/bitstream/10603/44285/9/09_chapter 1.pdf · STUDIES ON NEW HETEROCYCLIC COMP... 14 unless the