Introduction to Medicinal Introduction to Medicinal ChemistryChemistry

Chapter 1Chapter 1

What is medicinal What is medicinal chemistry?chemistry?

The science that deals with the The science that deals with the discovery or design of new discovery or design of new therapeutic chemicals and the therapeutic chemicals and the development of these chemicals into development of these chemicals into useful medicineuseful medicine

What is “medicine”?What is “medicine”?

Drugs, pharmaceuticsDrugs, pharmaceutics Media distinction between drugs that are Media distinction between drugs that are

used in medicine and drugs that are abused used in medicine and drugs that are abused

(addiction).(addiction).

A compound that interacts with a biological A compound that interacts with a biological

system, and produces a biological response system, and produces a biological response

(ideally desired and positive)(ideally desired and positive)

““Good” vs. “Bad” DrugsGood” vs. “Bad” Drugs

HO

O

HO

H

N

CH3

No medicine has only benefits or drawbacksNo medicine has only benefits or drawbacks

A “good” medicine would have to satisfy A “good” medicine would have to satisfy

the following criteria.: it would have to do the following criteria.: it would have to do

what it is meant to do and have no toxic or what it is meant to do and have no toxic or

unwanted side effects and be easy to take.unwanted side effects and be easy to take.

MorphineMorphine In low dose it is an Excellent analgesic, but In low dose it is an Excellent analgesic, but

have serious side effects such as:have serious side effects such as: Addiction, tolerance (the effect of the drug Addiction, tolerance (the effect of the drug

diminishes after repeated doses and so we diminishes after repeated doses and so we

need to increase the size of the dose to need to increase the size of the dose to

achieve the same results.)achieve the same results.) Respiratory depression and it may kill if Respiratory depression and it may kill if

taken in excess.taken in excess.

Barbiturates Barbiturates ( series of synthetic compounds with ( series of synthetic compounds with

sedative properties)sedative properties)

Depressants, sedatives, anestheticsDepressants, sedatives, anesthetics General anesthetics in SurgeryGeneral anesthetics in Surgery They are known to cross blood brain They are known to cross blood brain

barrier because they are fat soluble barrier because they are fat soluble Overdoses fatal (Pearl Harbor, wounded Overdoses fatal (Pearl Harbor, wounded

persons were given these drugs before persons were given these drugs before

surgery but many of them died)surgery but many of them died)

HeroinHeroin

O

O

O

H

N

CH3C

H3C

O

C

O

H3C

DiamorphineDiamorphine

One of the best painkillers (“hero”=heroic drug)One of the best painkillers (“hero”=heroic drug)

1898: on market, but 1898: on market, but

1903: withdrawn from market due to discovery 1903: withdrawn from market due to discovery

of its addictive properties.of its addictive properties.

2006: still used under strict control as the drug 2006: still used under strict control as the drug

of choice for treating patients dying of cancer. of choice for treating patients dying of cancer.

It reduces pain as well as it produces a euphoric It reduces pain as well as it produces a euphoric

effect to treat depression in patients close to effect to treat depression in patients close to

death death

Everyday drugs Everyday drugs Still produce a biological responseStill produce a biological response Caffeine (stimulant), in coffee, tea cocoa(when you take a Caffeine (stimulant), in coffee, tea cocoa(when you take a

cup of coffee you are a drug user but when you crave a cup cup of coffee you are a drug user but when you crave a cup of coffee then you are a drug addict)of coffee then you are a drug addict)

Sugar reacts with the taste buds of the tongue to produce Sugar reacts with the taste buds of the tongue to produce a sense of sweetness taste a sense of sweetness taste

Nicotine (sedation or calming effect), in cigarettesNicotine (sedation or calming effect), in cigarettes Alcohol is an unsatisfactory drug because it is difficult to Alcohol is an unsatisfactory drug because it is difficult to

judge the correct dose required to gain the happiness judge the correct dose required to gain the happiness effect without drifting into the higher dose levels that effect without drifting into the higher dose levels that produce un wanted side effects such as staggering effect. produce un wanted side effects such as staggering effect. Also, either happiness or depression may result)Also, either happiness or depression may result)

Food additives may cause allergiesFood additives may cause allergies Junk food and fizzy drinks cause hyperactivity in children Junk food and fizzy drinks cause hyperactivity in children

(contain chemicals that are converted in the body into (contain chemicals that are converted in the body into neurotransmitters leading to excess messages are neurotransmitters leading to excess messages are transmitted in the brain leading to disruptive (unsettling, transmitted in the brain leading to disruptive (unsettling, troublesome) behavior. troublesome) behavior.

VitaminsVitamins Herbs Herbs

Basil: 50 potential carcinogensBasil: 50 potential carcinogens Cultural aspectsCultural aspects

““Good” vs. “Bad” DrugsGood” vs. “Bad” Drugs

Safety of a drug depends on its :Safety of a drug depends on its : Dosage levelDosage level

Almost anything in excess will be toxic but Almost anything in excess will be toxic but in proper dose it is a good medicine in proper dose it is a good medicine

Chronic exposureChronic exposure

Measure of safety of drug = Measure of safety of drug = therapeutic index. therapeutic index.

Therapeutic indexTherapeutic index Measure of a drug’s beneficial effects at low Measure of a drug’s beneficial effects at low

dose vs. harmful effects at high dosedose vs. harmful effects at high dose Comparison of dose levels which lead to Comparison of dose levels which lead to

toxic effects to dose levels which lead to toxic effects to dose levels which lead to

maximum therapeutic effectsmaximum therapeutic effects High therapeutic index = large margin of High therapeutic index = large margin of

safetysafety Marijuana = 1000Marijuana = 1000 Alcohol = 10Alcohol = 10 Does not take chronic use into accountDoes not take chronic use into account

Medicinal ChemistryMedicinal Chemistry Under what conditions are drugs “good,” and what to they do to the Under what conditions are drugs “good,” and what to they do to the

body?body?

Curare (Tubocurarine structure)Curare (Tubocurarine structure)

It was used as a deadly poison which was used by the native It was used as a deadly poison which was used by the native

people of South America to tip their arrows such that a minor people of South America to tip their arrows such that a minor

arrow wound would be fatal.arrow wound would be fatal.

Drugs based on the tubocurarine Drugs based on the tubocurarine

structure are used in surgical structure are used in surgical

operations to relax muscles.operations to relax muscles.

Classification of drugsClassification of drugs Four main groups (overlap)Four main groups (overlap)

1.1. By biological/pharmacological effect By biological/pharmacological effect Analgesics, anti-asthmatics, antipsychotics, Analgesics, anti-asthmatics, antipsychotics,

antihypertensives, antihistaminic, antibiotics ,etc.antihypertensives, antihistaminic, antibiotics ,etc. Large and varied assortment of drugsLarge and varied assortment of drugs Many mechanisms of actionMany mechanisms of action Some drugs may have more than just one use.Some drugs may have more than just one use.

2.2. By chemical structureBy chemical structure Penicillins, opiates, barbituratesPenicillins, opiates, barbiturates Common skeletonCommon skeleton Pharmacological effects may be similar or different Pharmacological effects may be similar or different

uses in medicine uses in medicine

Classification of drugsClassification of drugs3.3. By target systemBy target system

Examples: Antihistamines Examples: Antihistamines Affect a certain target system in the body Affect a certain target system in the body Variety of structures due to large number of Variety of structures due to large number of

stages in system (synthesis, release, receptor stages in system (synthesis, release, receptor interaction and removal of histamine for interaction and removal of histamine for example)example)

Not all antihistamines are similar compoundsNot all antihistamines are similar compounds

4.4. By target site of action (more By target site of action (more specific)specific)

Anticholinesterases (inhibit Anticholinesterases (inhibit acetylcholinesterase enzyme in CNS)acetylcholinesterase enzyme in CNS)

Target enzyme or receptor with which they Target enzyme or receptor with which they interact.interact.

Usually common mechanismUsually common mechanism

History of Medicinal History of Medicinal ChemistryChemistry

Studied/practiced for thousands of yearsStudied/practiced for thousands of years Medicine men/witch doctorsMedicine men/witch doctors

Roots, plants, trees, berries, herbs (medical folklore)Roots, plants, trees, berries, herbs (medical folklore) Often placebos (useless drugs but they worked because the Often placebos (useless drugs but they worked because the

patients had a will of them to work )patients had a will of them to work )

Last 150 years: isolation and purification of active principles of Last 150 years: isolation and purification of active principles of

the remedies so Mechanism of reaction/responsethe remedies so Mechanism of reaction/response 1909: first chemotherapy means chemicals that directly 1909: first chemotherapy means chemicals that directly

interfere with the proliferation of the microorganisms at interfere with the proliferation of the microorganisms at

concentrations tolerated by the host-selective toxicity. by concentrations tolerated by the host-selective toxicity. by

Ehrlich)Ehrlich) Salvarsan (compound “606” arsenic containing compound) for Salvarsan (compound “606” arsenic containing compound) for

syphilissyphilis Later replaced with penicillin (toxic fungal metabolite,1940s)Later replaced with penicillin (toxic fungal metabolite,1940s) 2005: Structure determination2005: Structure determination

AspirinAspirin 400 BC: Hippocrates400 BC: Hippocrates

Chew bark of willow tree for pain (child birth and eye Chew bark of willow tree for pain (child birth and eye infections)infections)

Active component of willow bark = salicinActive component of willow bark = salicin Aspirin itself has an antiinflammatory actionAspirin itself has an antiinflammatory action It is a prodrug to mask the side effect (gastric bleeding) It is a prodrug to mask the side effect (gastric bleeding)

due to free phenolic group in salicylic acid, where the due to free phenolic group in salicylic acid, where the ester group is later hydrolyzed in the body into free ester group is later hydrolyzed in the body into free active drug. active drug.

OH

O

OH

O

O

OH

O

O

OH1. Hydrolysis

2. Oxidationglucose (1883: Bayer)

Ac2O

Ac

Salisylic acid - more effective - no bitter taste - gastric bleeding

Acetylsalicylic acid (aspirin) - less irritating - ester hydrolyzes to active drug

Cocaine (I)Cocaine (I) Active principle in South American coca bushActive principle in South American coca bush

Plant used as a stimulant, it is absorbed Plant used as a stimulant, it is absorbed

sublingually by chewing coca leaves sublingually by chewing coca leaves

mystical/religious reasonsmystical/religious reasons

Isolated 1880’sIsolated 1880’s It is the lead compound for Local Anesthetic in It is the lead compound for Local Anesthetic in

dentistrydentistry

Addiction (absorbed by mucous membrane of Addiction (absorbed by mucous membrane of

the nose when its powder snorted or sniffed the nose when its powder snorted or sniffed

or smoked) : Freudor smoked) : Freud Used for depression; in other drug addictionUsed for depression; in other drug addiction

Drug development based on structure (by Drug development based on structure (by

simplification of structure)simplification of structure)

Procaine II (Novocain)Procaine II (Novocain)