Medicinalchemistry unit 4.pptx

1. INTRODUCTION
TO MEDICINAL
CHEMISTRY
NAZIA TARANNUM

2. DRUG DISCOVERY AND DEFINITION
“All chemicals other than food that affect living processes.” It can be
medicine as well as poison depending on conditions of use and the person
using it. Another definition would be “medicinal agents used for diagnosis,
prevention, treatment of symptoms and cure of diseases.” Drugs were
discovered by identifying the active ingredient from traditional remedies as
with penicillin.
The idea that the effect of a drug in the human body is mediated by specific
interactions of the drug molecule with biological macromolecules led
scientists to the conclusion that individual chemicals are required for the
biological activity of the drug. This made for the beginning of the modern
era in pharmacology, as pure chemicals, instead of crude extracts of
medicinal plants, became the standard drugs.
Drug discovery is the process by which drugs are discovered.
The process of drug discovery involves the identification of
candidates, synthesis, characterization, screening and assays
for therapeutic efficacy.

3. DRUG DISCOVERY PROCESS

4. DRUG DESIGN
Drug design is the approach of finding drugs by design, based on their biological
targets. Typically a drug target is a key molecule involved in a particular
metabolic or signaling pathway that is specific to a disease condition or
pathology, or to the infectivity or survival of a microbial pathogen.
Other approaches may be to enhance the normal pathway by promoting
specific molecules in the normal pathways that promoting specific
molecules in the normal pathways that may have been affected in the
diseased state.

5. DRUG DEVELOPMENT
Drug development or preclinical development is defined in many pharmaceutical companies as
the process of taking a new chemical lead through the stages necessary to allow it to be testedin
human clinical trials.

6. BASIC RETROSYNTHESIS APPROACH
• Retrosynthetic analysis is a technique for solving problems in the planning
of organic syntheses.
• This is achieved by transforming a target molecule into simpler
precursor structures regardless of any potential reactivity/interaction
with reagents
• Retrosynthesis analysis is a technique for planning synthesis, especially of
complex organic molecules, whereby the complex target molecule (TM) is
reduced into a sequence of progressively simpler structures ( retrons) along
a pathway which ultimately leads to the identification of a simple or
commercially available starting materials(SM) from which a chemical
synthesis can be developed
• The goal of the retrosynthetic analysis is a structural simplification.
• The complete set of disconnections and functional group interconversions
for a specified target molecule is what constitutes a retrosynthesis or
retrosynthetic plan.

7. DRUG ACTION: RECEPTOR THEORY
• Drug- It is natural or chemical substance which has a physiological effect when administered into the body.
• Receptor- It is a specific binding site present on the cell surface made up of protein or nucleic acid
where a ligand can bind and initiate a characteristics response.
• The action of the drugs on the human body (or the organisms ) is called pharmacodynamics and the
body’s response to drugs is calledpharmacokinetics.
• The drug that enter an individual tend to stimulate certain receptors , ion channels, act on enzymes or transport
proteins.
• Based on drug action on receptors, there are 2 different types of drugs:
a) Agonists – they stimulate and activate the receptors. Conventional agonists increase the proportion of
activated receptors. Inverse agonists stabilize the receptor in its inactive conformation and act similarly to
competitive antagonists. Many hormones, neurotransmitters (eg, acetylcholine, histamine, norepinephrine),and
drugs (eg, morphine, phenylephrine, isoproterenol, benzodiazepines, barbiturates) act as agonists

8. ii. Antagonists – they disable the agonists from stimulating the receptors. Antagonists prevent
receptor activation. Preventing activation has many effects. Antagonists increase cellular function
if they block the action of a substance that normally decreases cellular function. Antagonists
decrease cellular function if they block the action of a substance that normally increases cellular
function.

9. INTERACTIONS INVOLVED IN THE DRUG-RECEPTOR COMPLEX
1. Ionic interactions
2. Ion-dipole and dipole-dipole interactions
3. Hydrogen bonding
4. Hydrophobic interactions
5. Vander waal’s interactions
6. Covalent bonding

10. STRUCTURE-ACTIVITY RELATIONSHIP
• SAR is the relationship between the chemical or 3D structure of a molecule and its biological
activity.
• Determination of the chemical groups
responsible for evoking a target biological effect in the organism
• Quantitative SARs ( QSAR ) as a special case of SARs ( when relationships become qualified )
Structure-Activity Relationships (SAR) can be used to predict biological activity from molecular
structure. This powerful technology is used in drug discovery to guide the acquisition or synthesis
of desirable new compounds, as well as to further characterize existing molecules.
The biological effects of a new chemical compound can often be predicted from its molecular
structure using data about other similar compounds. This is because similar compounds may have
similar physical and biological properties. There is a relationship between molecular structures and
their biological activity.

11. some important pharmacophore groups along with their physiological effects:-
• Effect of alkyl group: introduction of alkyl group in place of an active hydrogen atom –
OH or –NH2 etc., groups decrease their biological activity. E.g. replacement of an
active H atom from the amino group of aniline by the alkyl group decreases its
convulsive properties.
• Effect of Hydroxyl group:- the presence of hydroxyl groups in aliphatic compounds
decreases their biological
and physiological activity and this decrease is proportional to the number of –OH group.
on the contrary, in aromatic compounds, the hydroxyl group increases their
physiological effect. For e.g. : phenol is an antiseptic, as well as a disinfectant and, shows
strong toxicity.
• Effects of aldehydes and ketones: aldehydes are more reactive than ketones and their
physiological effect is much more intense.
• Effect on amino group: amino group is toxic in nature however alkylation and acylation
reduce their toxicity. The introduction of a second amino group in benzene ring of aniline
increases the toxicity. Aromatic amines and hydrazine possess analgesic and antipyretic
properties.

12. ANALGESIC AGENTS
• The word “analgesic” is derived from greek word “an” means “without” and “algos”
which means “pain”
• Analgesics are medicines that are used to relieve pain.
• They are also known as painkillers or pain relievers.
Many different types of medicines have pain – relieving properties, and expert tend to
group together those medicines that work in a similar way. Two of the most common
groups of pain killers are nonsteroidal anti-flammatory drugs (NSAIDs) and opiods
(narcotics), but there are many more.

13. MECHANISM OF ACTION OF ANALGESIC DRUGS
Local tissue injury releases prostaglandins. Prostaglandins have two major actions:
• Sensitize pain receptors and lower the threshold for painful stimuli
• Intensify the activation of the nerve endings by other inflammatory mediators such as
bradykinin, serotonin, and histamine
NSAIDs work by inhibiting the production of prostaglandins by inhibiting two types of
cyclooxygenase enzymes:
• COX-1
• COX-2
COX-1 is present in all cells, while COX-2 is induced in the presence of inflammation
Opioid analgesics act on the mu-opioid receptors on the nerves in the periphery, spinal cord, and
brain and reduce their excitability, in addition to preventing the transmission of pain signals.
Non-steroidal anti-inflammatory agents:- aceclofenac, aspirin, azapropazone,
dexibuprofen, diclofenac,ibuprofen, magnesium salicylate, mefenamic acid and much
more
COX-2 selective inhibitors:- celecoxib, etodolac
Opioids: diamorphine, morphine, hydrocodone, codeine, hydromorphone, oxycodone.

15. ANTIPYRETIC AGENTS
“Those drugs which reduce fever by lowering the body temperature.”
Antipyretic word has been derived from ‘anti’ means ‘against’ and ‘pyretic’ means
‘feverish’ they are a whole class of drugs that target prostaglandin-induced increase in
temperature. The main physiological effects of an induced prostaglandin are increased in
inflammation, pain, fever, and much more. The drugs cause the hypothalamus portion of the brain to
override the prostaglandin hormones in the body. This results in a reduction of pain and fever.
How does this work:- The portion of the brain called the Hypothalamus, contains millions of
small nuclei, and is connected to the nervous system via the pituitary gland. One of the main
functions of the hypothalamus is to control the temperature of the body. Antipyretic works on the
hypothalamus part to decrease the level of prostaglandin hormones.
Here is the list of some antipyretic drugs:
• Aspirin, and related salicylates such as magnesium salicylate, choline salicylate and sodium
salicylate
• Metamizole (ban in many countries)
• Nabumetone
• NSAIDs like naproxen, ibuprofen, nimesulide & ketoprofen
• Paracetamol
• Phenazone
• Docosanol etc.

17. ANTI-INFLAMMATORY AGENTS
Anti-inflammatory is the property of a substance or treatment that reduces inflammation or
swelling. Anti- inflammatory drugs, also called anti-inflammatories, make up about half of
analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which
affect the central nervous system to block pain signaling to the brain.
the NSAIDs prevent the prostaglandins from ever being synthesized, reducing or eliminating the
inflammation
and resulting pain. Some common examples of NSAIDs are aspirin, ibuprofen, and naproxen.
there are analgesics that are commonly associated with anti-inflammatory drugs but that
have no anti- inflammatory effects. An example is paracetamol
Long-term use of NSAIDs can cause gastric erosions, which can become stomach ulcers and in
extreme cases can cause severe haemorrhage, resulting in death. Other dangers of NSAIDs are
exacerbating asthma and causing kidney damage.[5] Apart from aspirin, prescription and over-
the-counter NSAIDs also increase the risk of heart attack and stroke.
Essential oils and extracts from some condiment plants have also been reported with anti-
inflammatory activities—due to the presence of bioactive compounds such as eugenol,
eucalyptol, menthone, and menthol. Applying ice, or even cool water, to a tissue injury has an
anti-inflammatory effect, and is often suggested as an injury treatment and pain management
technique for athletes.

19. ASPIRIN
• Analgesic (painkiller)
• Antipyretic (fever reducer)
• Anti -inflammatory (inhibition of the synthesis of prostaglandins
• Side effects: gastric irritation, bleeding Apparition of new analgesics
(Tylenol)

22. PARACETAMOL
• Paracetamol is an effective analgesic, especially when administered i.v., useful in a broad range of
clinical conditions.
• Its mechanism of action is yet to be fully determined and is likely to involve a number of pain pathways.
• Whilst its clinical significance may be equivocal, paracetamol may exert effects on virtually every organ
system, warranting
further research.
• There have been a number of reports of paracetamol toxicity in children after the introduction of the
i.v. formulation, prompting a recent update of the dosing guidelines by the Medicines and
Healthcare products Regulatory Agency.
• Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of
prostaglandins (PGs)
• Due to lack of an anti-inflammatory component, paracetamol has not been regarded as a member of
the NSAIDs family

23. When appropriate dosage of paracetamol is used no
serious side effects have been observed, besides possible
allergic skin reactions.
The following side effects of Paracetamol occur more
frequently than others and are generally mild:
•Nausea
•Mild stomach pain
•Diarrhea
•Headache
•Heartburn
The following side effects of Paracetamol occur very rarely
but can be life-threatening if left untreated:
•Low-grade fever with chills and/or sore throat
•Ulcers and white patches in the mouth and on the throat
•Skin rashes and hives
•Unusual bleeding or bruising
•Weakness and pain in lower back or side
•Yellowing of the eyes or skin known as jaundice
•Bloody urine or stools

24. Antibiotics are powerful drugs that are used to fight infections.
Not all infections are treated with antibiotics. While antibiotics may be effective
against infections caused by bacteria (germs), they are not effective against
viruses.
The word “antibiotics” comes from the Greek ANTI- “against” & BIOS-“life”.
Antimicrobial agents are chemical substances that can either kill or inhibit
the growth of micro- organisms that may be natural products or synthetic
chemicals.
Antibiotics are broadly classified into
• Bacterial antibiotics- they kill bacteria
• Eg: cotrimoxazole, fluoroquinolones, penicillins, cephalosporins,
aminoglycosides, vancomycin,
teicoplanin
• Bacteriostatic antibiotics- they inhibit bacterial proliferation.
• Eg: sulfonamides, tetracyclines, chloramphenicol
• Erythromycin is bacteriostatic in low doses and bactericidal in higher dosesA
substance
ANTIBIOTICS

26. CHLORAMPHENICOL
• Chloramphenicol was initially obtained from Streptomyces venezuelae in 1947. it was soon
synthesiesd chemically and the commercial product now is all synthetic.
• It is a yellowish white crystalline solid, aqueous solution is quite stable, stands boiling, but needs
protection from light. It has a nitrobenzene substitution, which is probably responsible for the
antibacterial activity and its intensely bitter taste.
• It is soluble in alcohol but poorly soluble in water. Chloramphenicol succinate, which is used for
parental administration is highly water solule. It is hydrolyzed invivo with liberation of free
chloramphenicol.

27. MECHANISM OF ACTION:-
• Chloramphenicol inhibits protein synthesis in bacteria and to a lesser extent in eukaryotic cells. The
drug readily penetrates bacterial cells probably by facilitated diffusion.
• Chloramphenicol acts primarily by binding reversibly to the 50S ribosomal subunit. Although binding
of tRNA at the codon recognition site on the 30S ribosomal subunit is thus undisturbed, the drug
appears to prevent the binding of the amino-acid-containing end of the aminoacyl tRNA to the acceptor
site on the 50S ribosomal subunit. The interaction between peptidyltransferase and its amino acid
substrate cannot occur, and peptide bond formation is inhibited

28. ANTIBACTERIAL AND ANTIFUNGAL AGENTS
(SULPHONAMIDES, SULPHANETHOXAZOL, SULPHACETAMOL)
• Antibacterial and antifungal agents are those substances that either prevent the growth/or
destroy bacteria and fungus. Sulphonamide and its derivative are widely used antibacterial and
antifungal agents.
• Sulphonamides:- this is an antimicrobial drug discovered in 1930. the mode of action of
sulphonamides is based on the competitive antagonism of certain metabolites, vital for the
growth of microorganisms and so sulphonamides are known as antimetabolites.
• When sulphonamides is administered to a patient having bacterial infection, bacteria attacks on
sulphonamides in confusion of PABA and gets destroyed. Sulphanilamide is p-amino benzene
sulponamide. Sulphanilamide is also known as sulphanilam, solfammide.

29. Synthesis of sulphanilamide:-
acetanilide
Acetyl sulphanilyl chloride
N4 Acetyl
sulphanilamide
sulphanilamide
Uses:- sulphanilamide is used for the treatment of acute and chronic gram-positive and gram-
negative bacterial infections, consisting of leprosy, malaria,trachoma, toxoplasmosis, coccidiosis and
lymphogranuloma venereum.

30. Sulphacetamide is one of the most soluble sulphanilamide drugs. It is used for urinary tact
infections without danger of kidney damage.
Synthesis of sulphacetamide:-
Sulphacetamide: N1 acetyl sulphanilamide

31. Sulphamethoxazole:- it is a sulphonamide bacteriostatic antibiotic that is commonly used in combination
with trimethoprim as the drug bacterium. Sulfamethoxazole competitively
inhibits dihydropteroate synthase preventing the formation of dihydropteroic acid, a precursor of folic
chemical formula C10H11N3O3S
sulphamethoxazole
sulphamethoxazole
acid which is required for bacterial growth.
The common side effects of sulfamethoxazole include:
Loss of appetite, Weight loss, Nausea, Mild diarrhea, Vomiting, insomnia, swollen tongue.
Synthesis

32. ANTIVIRAL AGENTS
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target
specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses.[2]
Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit its
development.
Antiviral drugs are one class of antimicrobials, a larger group that also includes antibiotic (also
termed antibacterial), antifungal and antiparasitic drugs. Most of the antiviral drugs now available
are designed to help deal with HIV, herpes viruses, the hepatitis B and C viruses, and influenza A
and B viruses.
ACYCLOVIR:- is an antiviral drug. It slows the growth and spread of the herpes virus in the body. It will not cure
herpes, but it can lessen the symptoms of the infection.
uses-Acyclovir is used to treat infections caused by herpes viruses, such as genital herpes, cold sores, shingles, and
chickenpox. It is also used for preventing cytomegalovirus infection following transplant and severe complications of
Epstein- Barr virus infection. Common side effects:- difficult breathing; swelling of your face, lips, tongue, or throat,
nausea, diarrhoea.

33. Synthesis of acyclovir-

34. CENTRALNERVOUS SYSTEM AGENTS
Central nervous system agents include sedatives and hypnotics that act as CNS depressants. Sedatives
are CNS depressants that reduce restlessness and emotional tension without producing sleep while
hypnotics are those CNS depressants that cause sleep to reduce emotional tension and restlessness.
the CNS depressants in increasing grades are referred to as causing:
General Anaesthesia > Hypnosis > Sedation These
include Barbiturates and benzodiazepine.
PHENOBARBITOL:- phenobarbital is barbiturates. Barbiturates are substituted derivatives of barbituric
acid. Phenobarbital is given orally or in form of an intravenous injection to treat and prevent the
symptoms of seizures, sedation, hypnotics, insomnia, and status epilepticus.
Its molecular formulae is C12H12N2O3

35. DIAZEPAM:- first marketed as Valium, is a medicine of the benzodiazepine family that acts as
an anxiolytic.[9] It is commonly used to treat a range of conditions,
including anxiety, seizures, alcohol withdrawal syndrome, benzodiazepine withdrawal
syndrome, muscle spasms, insomnia, and restless legs syndrome. It may also be used to
cause memory loss during certain medical procedures.[10][11] It can be taken by mouth, inserted into
the rectum, injected into muscle, injected into a vein or used as a nasal spray
Synthesis of phenobarbital:-

37. CARDIOVASCULAR DRUGS
Cardiovascular drugs are a group of drugs which have direct
action on the heart or other parts of vascular system so that they
modify the total output of the heart or the distribution of blood to
certain parts of the circulatory system. They are classified into
various groups:
• Cardiac glycosides
• Antianginal drugs
• Antihypercholesterolemic drugs
• Antiarrhythmic drugs
• Vasodiators
• Antihyperyensive drugs

38. Glyceryl trinitrate:-
• Nitroglycerin also known as glyceryl trinitrate is used as an anti-angina vasodilating agent. It is a slightly
volatile odorless oily liquid with sweet, aromatic, and pungent taste. Nitroglycerin is soluble in water, ethanol,
and methanol and miscible with ether, acetone, and chloroform.
• Glyceryl Trinitrate is used to relieve the symptoms of angina (chest pain).
• Glyceryl Trinitrate shows some common side effects like headache, blurred vision, decreased blood
pressure, dizziness, flushing (sense of warmth in the face, ears, neck, and trunk), increased heart rate, and
lightheadedness. Avoid consuming alcohol with this medicine as it can worsen the side effect.
Glyceryl trinitrate is prepared from
glycerol by its nitration with a
mixture of nitric acid and fuming
sulphuric acid.
Acid is added to glycerol
slowly.

39. HIV-AIDS RELATED DRUGS (AZT Zidovudine)
Zidovudine (ZDV), also known as azidothymidine (AZT), is an antiretroviral medication used to prevent and
treat HIV/AIDS.
It is generally recommended for use in combination with other antiretrovirals.
It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential
exposure.
It can be used by mouth or by slow injection into a vein.
Common side effects include headaches, fever, and nausea.
Serious side effects include liver problems, muscle damage, and high blood lactate levels.
It is commonly used in pregnancy and appears to be safe for the baby.
Synthesis:-

40. THANK YOU