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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.