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the carrier linked prodrugs have a major drawback that they are linked through covalent linkage with specialized nontoxic protective groups or carriers or promoieties in a transient manner to alter or eliminate undesirable properties in the parent molecule.
INSTITUTE FOR EXCELLENCE IN HIGHER EDUCATION
A PRESENTATION BY- RUPAL AGARWAL
(MSC. PREVIOUS CHEMISTRY)
ROLL NO. 716058
SUBMITTED TO- DR. ANITA SHINDE
TOPIC- PRODRUGS AND SOFT DRUGS, BIOACTIVE COMPOUNDS & LEAD
A drug is a single active chemical moiety
which is found in medicine and used for
diagnosis, prevention, treatment and cure of a
What is a drug ?
•A lead compound is the starting point when designing a
•It must possess biological activity likely to be
therapeutically useful but may still require some
modification to fit better to the target.
•There are various sources from which lead compounds
can be identified.
•The most common example of lead compound is
Histamine which was used to develop an anti-ulcer drug
Sources of lead compound
• Natural sources are very rich media of a large number of lead compounds.
•They provide a highly diverse and structurally unique compound and
•Some lead compound from natural sources are:
Natural Sources Drugs
Bark of cinchona tree Quinine
Leaves of osmium tree Quinine
Poppies plant Morphine
Yew tree Taxol
Chinese plants Artemisinin
African willow tree Combretastatin
•Another extraction of lead compounds from
natural sources includes animals.
•There are various animals and insects which
possess therapeutic importance
•Examples include snakes, spider, etc.
Synthesis of captopril
A chemical synthesis of captopril by treatment of L-
proline with (2s)-3acetylthio-2-methylpropanoyl
chloride under basic conditions(NaoH), followed by
aminolysis of the protective acetyl group to unmask
the drug’s free thiol is depicted in the figure.
• There are several synthetic compounds which have
therapeutic, clinical and biological activity and have
proved to be useful lead compounds.
• The most common example of this class is Prontosil.
• It was synthesised as a dye, but was the lead
compound for development of sulfonamides and acts
as an anti-bacterial drug.
• The methods of isolation synthetically are
combinatorial, conventional, compound libraries.
•Combinatorial chemistry is a new method
developed by academics and researchers to
reduce the time and cost of producing
effective, marketable and competitive new
•Scientists use combinatorial chemistry to
produce large number of molecules that can
be detected easily.
• Combinatorial chemistry is a technique by which a
large numbers of different but structurally similar
molecules are produced rapidly and submitted for
• The technique was invented in the late 1980s and
early 1990s to enable tasks to be applied to many
Solid phase technique
• Merrifield first developed solid phase synthesis and
got Nobel prize in 1963.
• The use of solid support for organic synthesis needs
three interconnected requirements:
• A cross linked, inert and insoluble polymeric material
• Some means of linking the substrate to this solid
• A chemical protection strategy to allow selective
protection and deprotection of reactive group.
Computer-aided design (CAD) is the use of computer
systems to aid in the creation, modification, analysis,
or optimization of a design.
• CAD software is used to increase the productivity of
the designer, improve the quality of design, improve
communications through documentation, and to
create a database for manufacturing.CAD output is
often in the form of electronic files for print,
machining, or other manufacturing operations.
• The term CADD (for Computer Aided Design and
Drafting) is also used.
•Its use in designing electronic systems is
known as electronic design automation,
•In mechanical design it is known
as mechanical design automation (MDA)
or computer-aided drafting (CAD), which
includes the process of creating
a technical drawing with the use
of computer software.
• The concept of “prodrug” was first introduced by Adrian
Albert in 1958 to describe compounds that undergo
biotransformation prior to eliciting their pharmacological
• A prodrug is defined as a biologically inactive derivative
of a parent drug molecule that usually requires a
chemical or enzymatic transformation within the body to
release the active drug, and possess improved delivery
properties over the parent molecule.
• The development of prodrugs is now well established as
a strategy to improve the physicochemical,
biopharmaceutical or pharmacokinetic properties of
pharmacologically potent compounds, and thereby
increase usefulness of a potential drug.
Schematic illustration of the prodrug
Site of Action
(cell or cell surface)
Properties of ideal prodrug
• Pharmacological Inertness
• Rapid transformation, chemically or enzymatically,
into the active form at the target site
• Non-toxic metabolic fragments followed by their
A) Carrier linked prodrug
Chemical Prodrug Formation
Chemical/Enzymatic cleavage in
Carrier linked prodrug consists of the attachment of a
carrier group to the active drug to alter its physicochemical
The subsequent enzymatic or non-enzymatic mechanism
releases the active drug moiety.
1. Bipartite prodrug
• It is composed of one carrier (group) attached to the drugs.
• Such prodrugs have greatly modified lipophilicity due to the
attached carrier. The active drug is released by hydrolytic
cleavage either chemically or enzymatically.
• E.g. Tolmetin-glycine prodrug.
It can be further subdivided into
2. Tripartite prodrug-
The carrier group is attached via linker to drug.
3. Mutual Prodrugs
• A mutual prodrug consists of two pharmacologically active
agents coupled together so that each acts as a promoiety for
the other agent and vice versa.
• A mutual prodrug is a bipartite or tripartite prodrug in which
the carrier is a synergistic drug with the drug to which it is
• Benorylate is a mutual prodrug aspirin and paracetamol.
• Sultamicillin, which on hydrolysis by an esterase produces
ampicillin & sulbactum.
• Bio- precursor prodrugs produce their effects after in vivo chemical
modification of their inactive form.
• Bioprecursor prodrugs rely on oxidative or reductive activation
reactions unlike the hydrolytic activation of carrier-linked prodrugs.
• They metabolized into a new compound that may itself be active or
further metabolized to an active metabolite .
Applications of prodrugs
Masking Taste & Odor
Minimizing Pain at Site of Injection
Alteration of Drug Solubility
Enhancement of Chemical Stability
Reduction of G.I. irritation
Change of physical form of the drug
Enhancement of bioavailability (Lipophilicity)
Prevention of Pre-systemic Metabolism
Prolongation of duration of action
Reduction of toxicity
Site specific drug delivery
Prodrug design is a part of the general drug discovery process,
in which a unique combination of therapeutically active
substances is observed to have desirable pharmacological
In human therapy prodrug designing has given successful
results in overcoming undesirable properties like absorption,
non specificity, and poor bioavailability and GI toxicity.
Thus, prodrug approach offers a wide range of options in
drug design and delivery for improving the clinical and
therapeutic effectiveness of drug.
SELECTION OR SYNTHESIS OF HARD
AND SOFT DRUGS
•Drugs are divided into two types based on their
•1)Hard drugs: these can be defined as drugs that are
biologically active and non metabolizable in vivo e.g.:
enalaprilat, lisinopril, cromolyn, and bisphophonates
•2)Soft drugs: these can be defined as drugs that
Are produce predictable and controllable in vivo
metabolism to form nontoxic product after they have
shown their therapeutic role.
• eg: cetyl pyridinium chlorides, soft cloramine
• Soft drugs are biologically active drugs designed to
have a predictable and controllable metabolism to
nontoxic and inactive products after they have
achieved their desired pharmacological effect.
• The molecule could be deactivated and detoxified
shortly after it has exerted its biological effect, the
therapeutic index could be increased, providing a
• It has a close structural similarity to the lead;
• It has a metabolically sensitive moiety built
into the lead structure;
• The incorporated metabolically sensitive spot
does not affect the overall physicochemical or
steric properties of the lead compound.
• Elimination of toxic metabolites, thereby increasing
the therapeutic index of the drug;
• Avoidance of pharmacologically active metabolites
that can lead to long-term effects;
• Elimination of drug interactions resulting from
metabolite inhibition of enzymes;
• Simplification of pharmacokinetic problems caused
by multiple active species.
The difference between prodrugs and
• The concepts of prodrugs and soft drugs are
opposite, as follow:
• A prodrugs is an inactive compound that
requires a metabolic conversion to the active
• A soft drug is pharmacologically active and
uses metabolism as a means of promoting
• However, it is possible to design a pro-soft
drug, a modified soft drug that requires
metabolic activation for conversion to the
active soft drug.
• It is not possible to prepare soft-pro drug.
• Bioactive compounds are extranutritional
constituents that typically occur in small quantities in
• They vary widely in chemical structure and function
and are grouped accordingly.
• Bioactive compounds can be defined as secondary
metabolites eliciting pharmacological or toxicological
effects in man and animals.
Difference from nutrients
In the field of nutrition bioactive compounds are
distinguished from essential nutrients. While
nutrients are essential to the sustainability of a
body, the bioactive compounds are not essential
since the body can function properly without them,
or because nutrients fulfill the same function.
Bioactive compounds can have an influence on
Bioactive compounds in plants
The following is a brief presentation of the main
chemical groups of bioactive compounds in plants:
The glycosides consist of various categories of
secondary metabolites bound to a mono- or
oligosaccharide or to uronic acid. The saccharide or
uronic acid part is called glycone, and the other part
the aglycone. The main groups of glycosides are
cardiac glycosides, cyanogenic glycosides,
glucosinolates, saponins and anthraquinone
There are two distinct types of tannins. Condensed
tannins which are large polymers of flavanoids and
hydrolysable tannins which are polymers composed
of a monosaccharide core (most often glucose) with
several catechin derivatives attached. The two types
of tannins have most properties in common, but
hydrolysable tannins are less stable and have greater
potential to cause toxicity.
•The water solubility is restricted and decrease in
general with the size of the tannin molecule.
•Tannins indiscriminately bind to proteins and larger
tannins are used as astringents in cases of diarrhoea,
skin bleedings and transudates.
•Tannins are very widely distributed in the plant
• Examples of plant families associated with presence
of tannins are Fagaceae (beech family) and
•Polygonaceae (knotweed family).
Resins are complex lipid soluble mixtures
usually both non-volatile and volatile
Most typical are resins secreted by wood
structures but they are also present in
They are all sticky and the fluidity depends on
their content of volatile compound.
When exposed to air they harden.
• Marine bioactive compounds are organic compounds
produced by microbes, sponges, gorgonians, soft and
hard corals seaweeds, and other marine organisms.
• These products are the current interest of industry for
new drugs and chemicals.
• Marine microorganisms form highly specific and
symbiotic relationships with filter-feeding organisms like
sponges, alcyonarians, ascidians and marine plants.
• The host organism synthesizes these compounds as
non-primary or secondary metabolites to protect
themselves and to maintain homeostasis in their
Bioactive compound from marine organisms
• Chemicals found in sponges may be used to treat yeast and
• The wider biosynthetic capability of sponges could be
attributed to their biological association with other
• About 38% of the sponge body comprises of microorganisms.
• A wide variety of secondary metabolites were isolated from
sponges and these have been associated with antibacterial,
antimicrobial, antiviral, antifouling, HIV-protease inhibitory,
HIV reverse transcriptase inhibitory, immunosuppressant and
• In addition to potential anticancer applications, the bioactive
compounds of sponges have a myriad of activities ranging
from antibiotic activity including anticoagulant, antithrombin,
anti-inflammatory, as well as immuno modulatory activities.
• Although terrestrial fungi have represented a major
biomedicinal resource (e.g., penicillin from
Penicillium), studies to develop the biomedicinal
potential of marine fungi were less.
• The isolation of a small lactone, leptosphaerin from
Leptosphaeria oraemaris demonstrated that marine
fungi may form important resource for unique
• Later, the useful chemical, Gliovictin was isolated from
marine fungus, Asteromyces cruciatus.
• Since then more than twenty useful bioactive
compounds have been derived from marine fungi.