INSTITUTE FOR EXCELLENCE IN HIGHER EDUCATION

A PRESENTATION BY- RUPAL AGARWAL (MSC. PREVIOUS CHEMISTRY) ROLL NO. 716058

SUBMITTED TO- DR. ANITA SHINDE

PHARMACEUTICAL CHEMISTRYTOPIC- PRODRUGS AND SOFT DRUGS, BIOACTIVE COMPOUNDS & LEAD COMPOUNDS

A drug is a single active chemical moiety which is found in medicine and used for diagnosis, prevention, treatment and cure of a disease.

What is a drug ?

Lead compound

•A lead compound is the starting point when designing a new drug.•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 ‘Cimetidine’.

Sources of lead compound

Sources

Natural Synthetic Computer Modelling

•Plants •Animals

•Micro organism

•Marine animals

•Biochemistry

•conventional methods•Combinatorial•Compound data banks/libraries•Pharmacophore & substructure searches

Natural sources

• Natural sources are very rich media of a large number of lead compounds.•They provide a highly diverse and structurally unique compound and pharmacologically active.•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

PLANTS

ANIMALS

•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.

Micro organisms Fungi, bacteriaE.g.: asperigilus (fungi) asperlicin

Marine animals Corals, sponges, fishesfishes lead compounds

Biochemistry Hormones, enzymesE.g.: histamine

Asperlicin

Synthetic sources

• 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

•Combinatorial chemistry is a new method developed by academics and researchers to reduce the time and cost of producing effective, marketable and competitive new drugs.

•Scientists use combinatorial chemistry to produce large number of molecules that can be detected easily.

Definition

• Combinatorial chemistry is a technique by which a large numbers of different but structurally similar molecules are produced rapidly and submitted for pharmacological assay.

• The technique was invented in the late 1980s and early 1990s to enable tasks to be applied to many molecules simultaneously.

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 (usually resins).

• Some means of linking the substrate to this solid phase(linkers).

• A chemical protection strategy to allow selective protection and deprotection of reactive group.

Computer modelling

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, or EDA. •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.

Prodrug concept• The concept of “prodrug” was first introduced

by Adrian Albert in 1958 to describe compounds that undergo biotransformation prior to eliciting their pharmacological effect.

• 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.

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Schematic illustration of the prodrug concept

Extracellular FluidSite of Action(cell or cell surface)

Pharmacokinetic or Physicochemical barrier

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Properties of ideal prodrug

1. •Pharmacological Inertness

2. •Rapid transformation, chemically or enzymatically, into the active form at the target site

3. •Non-toxic metabolic fragments followed by their rapid elimination

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Classification of ProdrugsProdrugs

Carrier linked prodrug

Bipartite prodrug

Tripartite prodrug

Mutual Prodrugs

Bioprecursors

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Active Drug

Inert Carrier Inert Carrier

Drug

A) Carrier linked prodrug

Chemical Prodrug Formation

Chemical/Enzymatic cleavage in vivo

Covalent Bond

Carrier linked prodrug consists of the attachment of a carrier group to the active drug to alter its physicochemical properties.

The subsequent enzymatic or non-enzymatic mechanism releases the active drug moiety.

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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

TolmetinGlycine

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2. Tripartite prodrug-

Drug Linking StructureCarrier

The carrier group is attached via linker to drug.

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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 linked.

• Benorylate is a mutual prodrug aspirin and paracetamol. • Sultamicillin, which on hydrolysis by an esterase produces

ampicillin & sulbactum.

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B) Bioprecursors• 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 .

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Applications of prodrugsPharmaceutical Applications

Masking Taste & OdorMinimizing Pain at Site of

InjectionAlteration of Drug

SolubilityEnhancement of Chemical

StabilityReduction of G.I. irritationChange of physical form of

the drug

Pharmacokinetic ApplicationsEnhancement of

bioavailability (Lipophilicity)

Prevention of Pre-systemic Metabolism

Prolongation of duration of action

Reduction of toxicitySite specific drug delivery

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Marketed Prodrugs

Fosphenytoin

Fenofibrate

Rabeprazole

CONCLUSION

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 effects.

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.

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SELECTION OR SYNTHESIS OF HARD AND SOFT DRUGS

•Drugs are divided into two types based on their Metabolic susceptibility•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 Drug• 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 safer drug.

Feature

• 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.

Advantages

• 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 soft drugs

• 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 form;

• A soft drug is pharmacologically active and uses metabolism as a means of promoting excretion.

• 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

• Bioactive compounds are extranutritional constituents that typically occur in small quantities in food.

• 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 health.

Bioactive compounds in plants

The following is a brief presentation of the main chemical groups of bioactive compounds in plants:GlycosidesThe 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 glycosides.

Tannins

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 kingdom.• Examples of plant families associated with presence of tannins are Fagaceae (beech family) and•Polygonaceae (knotweed family).

Resins Resins are complex lipid soluble mixtures usually both non-volatile and volatile compounds.Most typical are resins secreted by wood structures but they are also present in herbaceous plants.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 environment.

Bioactive compound from marine organisms

Marine sponges• Chemicals found in sponges may be used to treat yeast and fungi.• The wider biosynthetic capability of sponges could be attributed

to their biological association with other symbionts. • 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 cytotoxic activities.

• 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.

Marine fungi• 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 metabolites.

• 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.

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