1. Introduction to Medicinal Chemistry Chapter 1

2. What is medicinal chemistry? The science that deals with the discovery or design of new therapeutic chemicals and the development of these chemicals into useful medicine The science that deals with the discovery or design of new therapeutic chemicals and the development of these chemicals into useful medicine

3. What is “medicine”? Drugs, pharmaceutics Drugs, pharmaceutics Media distinction between drugs that are used in medicine and drugs that are abused (addiction). Media distinction between drugs that are used in medicine and drugs that are abused (addiction). A compound that interacts with a biological system, and produces a biological response (ideally desired and positive) A compound that interacts with a biological system, and produces a biological response (ideally desired and positive)

4. “Good” vs. “Bad” Drugs No medicine has only benefits or drawbacks No medicine has only benefits or drawbacks A “good” medicine would have to satisfy the following criteria.: it would have to do what it is meant to do and have no toxic or unwanted side effects and be easy to take. A “good” medicine would have to satisfy the following criteria.: it would have to do what it is meant to do and have no toxic or unwanted side effects and be easy to take. Morphine Morphine In low dose it is an Excellent analgesic, but have serious side effects such as: Addiction, tolerance (the effect of the drug diminishes after repeated doses and so we need to increase the size of the dose to achieve the same results.) Respiratory depression and it may kill if taken in excess.

5. Barbiturates ( series of synthetic compounds with sedative properties) Depressants, sedatives, anesthetics Depressants, sedatives, anesthetics General anesthetics in Surgery General anesthetics in Surgery They are known to cross blood brain barrier because they are fat soluble They are known to cross blood brain barrier because they are fat soluble Overdoses fatal (Pearl Harbor, wounded persons were given these drugs before surgery but many of them died) Overdoses fatal (Pearl Harbor, wounded persons were given these drugs before surgery but many of them died)

6. Heroin Diamorphine Diamorphine 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(“hero”=heroic drug) One of the best painkillers (“hero”=heroic drug) 1898: on market, but 1898: on market, but 1903: withdrawn from market due to discovery of its addictive properties. 1903: withdrawn from market due to discovery of its addictive properties. 2006: still used under strict control as the drug of choice for treating patients dying of cancer. It reduces pain as well as it produces a euphoric effect to treat depression in patients close to death 2006: still used under strict control as the drug of choice for treating patients dying of cancer. It reduces pain as well as it produces a euphoric effect to treat depression in patients close to death

7. Everyday drugs Still produce a biological response Still produce a biological response Caffeine (stimulant), in coffee, tea cocoa(when you take a cup of coffee you are a drug user but when you crave a cup of coffee then you are a drug addict) Caffeine (stimulant), in coffee, tea cocoa(when you take a cup of coffee you are a drug user but when you crave a cup of coffee then you are a drug addict) Sugar reacts with the taste buds of the tongue to produce a sense of sweetness taste Sugar reacts with the taste buds of the tongue to produce a sense of sweetness taste Nicotine (sedation or calming effect), in cigarettes Nicotine (sedation or calming effect), in cigarettes Alcohol is an unsatisfactory drug because it is difficult to judge the correct dose required to gain the happiness effect without drifting into the higher dose levels that produce un wanted side effects such as staggering effect. Also, either happiness or depression may result) Alcohol is an unsatisfactory drug because it is difficult to judge the correct dose required to gain the happiness effect without drifting into the higher dose levels that produce un wanted side effects such as staggering effect. Also, either happiness or depression may result) Food additives may cause allergies Food additives may cause allergies Junk food and fizzy drinks cause hyperactivity in children (contain chemicals that are converted in the body into neurotransmitters leading to excess messages are transmitted in the brain leading to disruptive (unsettling, troublesome) behavior. Junk food and fizzy drinks cause hyperactivity in children (contain chemicals that are converted in the body into neurotransmitters leading to excess messages are transmitted in the brain leading to disruptive (unsettling, troublesome) behavior. Vitamins Vitamins Herbs Herbs Basil: 50 potential carcinogens Basil: 50 potential carcinogens Cultural aspects Cultural aspects

8. “Good” vs. “Bad” Drugs Safety of a drug depends on its : Safety of a drug depends on its : Dosage level Dosage level Almost anything in excess will be toxic but in proper dose it is a good medicine Almost anything in excess will be toxic but in proper dose it is a good medicine Chronic exposure Chronic exposure Measure of safety of drug = therapeutic index. Measure of safety of drug = therapeutic index.

9. Therapeutic index Measure of a drug’s beneficial effects at low dose vs. harmful effects at high dose Measure of a drug’s beneficial effects at low dose vs. harmful effects at high dose Comparison of dose levels which lead to toxic effects to dose levels which lead to maximum therapeutic effects Comparison of dose levels which lead to toxic effects to dose levels which lead to maximum therapeutic effects High therapeutic index = large margin of safety High therapeutic index = large margin of safety Marijuana = 1000 Marijuana = 1000 Alcohol = 10 Alcohol = 10 Does not take chronic use into account Does not take chronic use into account

10. Medicinal Chemistry Under what conditions are drugs “good,” and what to they do to the body? Under what conditions are drugs “good,” and what to they do to the body? Curare (Tubocurarine structure) Curare (Tubocurarine structure) 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 arrow wound would be fatal. Drugs based on the tubocurarine structure are used in surgical operations to relax muscles.

11. Classification of drugs Four main groups (overlap) Four main groups (overlap) 1. By biological/pharmacological effect Analgesics, anti-asthmatics, antipsychotics, antihypertensives, antihistaminic, antibiotics,etc. Analgesics, anti-asthmatics, antipsychotics, antihypertensives, antihistaminic, antibiotics,etc. Large and varied assortment of drugs Large and varied assortment of drugs Many mechanisms of action Many mechanisms of action Some drugs may have more than just one use. Some drugs may have more than just one use. 2.By chemical structure Penicillins, opiates, barbiturates Penicillins, opiates, barbiturates Common skeleton Common skeleton Pharmacological effects may be similar or different uses in medicine Pharmacological effects may be similar or different uses in medicine

12. Classification of drugs 3. By 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 stages in system (synthesis, release, receptor interaction and removal of histamine for example) Variety of structures due to large number of stages in system (synthesis, release, receptor interaction and removal of histamine for example) Not all antihistamines are similar compounds Not all antihistamines are similar compounds 4. By target site of action (more specific) Anticholinesterases (inhibit acetylcholinesterase enzyme in CNS) Anticholinesterases (inhibit acetylcholinesterase enzyme in CNS) Target enzyme or receptor with which they interact. Target enzyme or receptor with which they interact. Usually common mechanism Usually common mechanism

13. History of Medicinal Chemistry Studied/practiced for thousands of years Studied/practiced for thousands of years Medicine men/witch doctors Medicine 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 patients had a will of them to work ) Often placebos (useless drugs but they worked because the patients had a will of them to work ) Last 150 years: isolation and purification of active principles of the remedies so Mechanism of reaction/response Last 150 years: isolation and purification of active principles of the remedies so Mechanism of reaction/response 1909: first chemotherapy means chemicals that directly interfere with the proliferation of the microorganisms at concentrations tolerated by the host-selective toxicity. by Ehrlich) 1909: first chemotherapy means chemicals that directly interfere with the proliferation of the microorganisms at concentrations tolerated by the host-selective toxicity. by Ehrlich) Salvarsan (compound “606” arsenic containing compound) for syphilis Salvarsan (compound “606” arsenic containing compound) for syphilis Later replaced with penicillin (toxic fungal metabolite,1940s) Later replaced with penicillin (toxic fungal metabolite,1940s) 2005: Structure determination 2005: Structure determination

14. Aspirin 400 BC: Hippocrates 400 BC: Hippocrates Chew bark of willow tree for pain (child birth and eye infections) Chew bark of willow tree for pain (child birth and eye infections) Active component of willow bark = salicin Active component of willow bark = salicin Aspirin itself has an antiinflammatory action Aspirin itself has an antiinflammatory action It is a prodrug to mask the side effect (gastric bleeding) due to free phenolic group in salicylic acid, where the ester group is later hydrolyzed in the body into free active drug. It is a prodrug to mask the side effect (gastric bleeding) due to free phenolic group in salicylic acid, where the ester group is later hydrolyzed in the body into free active drug.

15. Cocaine (I) Active principle in South American coca bush Active principle in South American coca bush Plant used as a stimulant, it is absorbed sublingually by chewing coca leaves mystical/religious reasons Isolated 1880’s Isolated 1880’s It is the lead compound for Local Anesthetic in dentistry Addiction (absorbed by mucous membrane of the nose when its powder snorted or sniffed or smoked) : Freud Addiction (absorbed by mucous membrane of the nose when its powder snorted or sniffed or smoked) : Freud Used for depression; in other drug addiction Drug development based on structure (by simplification of structure) Drug development based on structure (by simplification of structure) Procaine II (Novocain)