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Organic Medicinal Chemistry
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Organic Medicinal Chemistry
The practice of medicinal chemistry devoted to the discovery and development of new drugs.
Metabolism
The biotransformation of drugs in the body. Important in the elimination of drugs from the body. Converts drugs to hydrophilic, inactive, and nontoxic forms.
Liver
The primary organ involved in drug metabolism. It performs metabolic functions in two phases: functionalization and conjugation.
Phase I Functionalization
The introduction of a polar functional group (e.g., OH, COOH, NH2, SH) by direct introduction or modifying/unmasking existing functionalities. It produces a handle on the molecule for Phase II reactions such as oxidation, reduction, and hydrolysis.
Oxidation
The most common phase I reaction involving the conversion of olefins, alcohols, aldehydes, and aromatic moieties (e.g., phenylbutazone) to hydrophilic and inactive metabolites (e.g., oxybutazone).
Reduction
Involves the conversion of compounds to inactive forms through reduction reactions. This includes drugs like Prednisone and other primary amino groups.
Hydrolysis
A process commonly undergone by lactams, esters, and amides, leading to the formation of hydrophilic and inactive metabolites.
Phase II Conjugation
The attachment of small ionizable endogenous compounds to the functional handles produced in Phase I. This includes reactions such as glucuronidation, sulfation, glycine/glutamine conjugation, glutathione, acetylation, and methylation.
Glucuronidation
A phase II conjugation reaction involving the transferase enzyme (TE) Glucuronyltransferase, which attaches D-glucuronic acid to functional groups. This process forms excretable inactive metabolites and terminates/attenuates drug activity.
Sulfation
A phase II conjugation reaction involving the transferase enzyme (TE) Sulfotransferase, leading to the formation of water-soluble and inactive conjugates of endogenous compounds such as steroids, heparin, catecholamines, and thyroxine.
Glycine/Glutamine Conjugation
A phase II conjugation reaction that involves the conjugation of carboxylic acids, particularly aromatic acids and arylalkyl acids, with glycine in mammals and glutamine in humans and primates.
Glutathione
A phase II conjugation reaction used for detoxifying chemically reactive electrophilic compounds. It is composed of three amino acids (cysteine, glycine, and glutamine) and is responsible for detoxification.
Acetylation
A phase II conjugation reaction used for the termination of drug activity and detoxification, particularly of primary amino groups. It involves the transferase enzyme (TE) N-acetyltransferase and is undergone by compounds like sulfonamides.
Methylation
A phase II conjugation reaction involving the transferase enzyme (TE) Methyltransferase, leading to the biosynthesis of non-polar and inactivated compounds. It is important in the biosynthesis of epinephrine, melatonin, and inactivating compounds.
First Pass Metabolism
Pre-systemic metabolism, where orally administered drugs are extensively metabolized before reaching the systemic circulation. This process is particularly relevant for drugs with extensive first-pass metabolism like propranolol, isosorbide dinitrate, and lidocaine.
Methylation
Coenzyme S-Adenosylmethionine (SAM), Methyltransferase, Minor pathway that leads to nonpolar inactivated compounds, Biosynthesis of epinephrine, melatonin, Inactivation of norepinephrine, dopamine, serotonin, histamine
First Pass Metabolism
Pre-systemic metabolism, When orally administered drugs are extensively metabolized before reaching the systemic circulation, Drugs with extensive first pass effect: Isoproterenol, Lidocaine, Morphine, Meperidine, Nitroglycerin, Pentazocine, Propoxyphene, Propranolol, Salicylamide
ENZYME INHIBITORS
6620
ENZYME INDUCERS
333560
Valencia oranges, Grapefruit
Metronidazole, Valencia oranges, Grapefruit
Anti-Infective Agents
Antisepsis: application of agent to living tissue to prevent infection, Decontamination: destruction or reduction in the number of microorganisms, Disinfection: chemical or physical treatment on inanimate surfaces, Sanitization: reduction of microbial load on inanimate surface to a level acceptable for public health purposes, Sterilization: kill or remove all types of microorganisms, Pasteurization: kills nonsporulating microorganisms by hot water (65C-100C), Germicides: anti-infective agents used locally, Cidal: kill, Static: prevent growth
ALCOHOLS RELATED COMPOUNDS
SAR: 1. DQWLEDFWHULDODFWLYLWXSWRRQO, 2. QRQSRODUZDWHUVROXELOLWDQWLEDFWHULDODFWLYLW, 3. Branching decreases antibacterial property except isopropyl alcohol - more potent, cheaper, less toxic. 60% EtOH, 40% Isopropyl Alcohol, 4. Isomeric alcohol potency decreases in the order: Primary, Secondary, Tertiary, MOA: Protein denaturation/precipitation, Alcohol USP - ethanol, grain alcohol, wine spirit, cologne spirit, spiritus vini rectificatus - most widely abused of all recreational drugs, commercial ethanol. Manufactured by: Fermentation of grains and other CHOs, Hydration of ethene. Metabolism: Ethanol to Acetaldehyde - Enzyme: alcohol dehydrogenase; Acetaldehyde to Acetic acid - Enzyme: aldehyde dehydrogenase, DRUGS THAT INTERFERE WITH ALCOHOL METABOLISM: a. Fomepizole - Inhibits alcohol dehydrogenase, Used as an antidote for methanol poisoning, b. Disulfiram - used as a deterrent for alcohol addiction, inhibits aldehyde dehydrogenase, accumulation of aldehyde, extreme hangover-like symptoms, nausea, vomiting, vasodilatory flushing, Types of Alcohols: Absolute alcohol - 95% alcohol, Dehydrated alcohol - 99% alcohol prepared by azeotropic distillation, Diluted alcohol - 49-50% alcohol, Denatured alcohol - EtOH rendered unfit for use in beverages by the addition of substances, Completely denatured alcohol contains added wood alcohol and benzene, unsuitable for internal or external use.
Absolute alcohol
Pure ethanol with no water content, often used in laboratory and industrial processes.
95 alcohol
A solution containing 95% ethanol and 5% water, commonly used as a disinfectant.
Dehydrated alcohol
Alcohol with water content removed, usually at 99% ethanol concentration, prepared by azeotropic distillation.
Diluted alcohol
An alcohol solution with a lower ethanol concentration, typically around 49-50%, often used for medicinal and household purposes.
Denatured alcohol
Ethanol rendered unfit for use in beverages by the addition of substances to make it unsuitable for consumption.
Completely denatured alcohol
Contains added wood alcohol and benzene, making it unsuitable for internal or external use.
Specially denatured alcohol
Treated with substances so that its use is permitted for specialized purposes, such as medical applications or industrial use.
2-Propanol (Isopropyl alcohol)
A substitute for ethanol, prepared by sulfuric acid-catalyzed hydration of propylene, commonly used as a disinfectant.
Untitled Deck
Study
What is the practice of medicinal chemistry devoted to?
The discovery and development of new drugs
What is metabolism in the context of organic medicinal chemistry?
The biotransformation of drugs in the body, important in the elimination of drugs from the body
What are the two phases of metabolism in the context of organic medicinal chemistry?
Functionalization and Conjugation
What is Phase I Functionalization and what are the types of reactions involved?
It introduces a polar functional group by direct introduction or modifies/unmasks existing functionalities. Reactions involved are oxidation, reduction, and hydrolysis.
What is the most common phase I reaction and what compounds undergo it?
Oxidation, undergone by olefins, alcohols, aldehydes, aromatic moieties (e.g., Phenylbutazone to oxybutazone)
What compounds commonly undergo hydrolysis in Phase I Functionalization?
Lactams, esters, and amides
What is Phase II Conjugation and what are the reactions involved?
It attaches small ionizable endogenous compounds to the functional handles. Reactions involved are glucuronidation, sulfation, glycine glutamine conjugation, glutathione, acetylation, and methylation.
What are the purposes of Phase II Conjugation?
1. Form excretable inactive metabolites 2. Terminate/Attenuate activity 3. Detoxify
What is Glucuronidation and what coenzyme and enzyme are involved?
It involves the transferase enzyme and the coenzyme Uridine diphospho D-glucuronic acid (UDPGA) and glucuronyltransferase. It is the most common conjugation reaction.
What is Sulfation and what coenzyme and enzyme are involved?
It involves the coenzyme 3-phosphoadenosine 5-phosphosulfate (PAPS) and sulfotransferase. It yields water-soluble and inactive conjugates.
What is Glycine Glutamine Conjugation and what compounds does it commonly involve?
It involves conjugating carboxylic acids, particularly aromatic acids and arylalkyl acids. Glycine is common to mammals, while glutamine is found in humans and other primates.
What is Glutathione used for in Phase II Conjugation?
It is used for detoxifying chemically reactive electrophilic compounds. Glutathione is composed of 3 amino acids: cysteine, glycine, and glutamine.
What is the purpose of Acetylation in Phase II Conjugation and what is the important route for this process?
It is for the termination of activity and detoxification. The important route is the acetylation polymorphism, with variation in acetylating activity.
What is Methylation and what coenzyme and enzyme are involved?
It is a minor pathway that leads to nonpolar inactivated compounds and involves the coenzyme S-Adenosylmethionine (SAM) and methyl transferase.
What is first pass metabolism?
It is pre-systemic metabolism where orally administered drugs are extensively metabolized before reaching the systemic circulation.
6 Methylation
Coenzyme S-Adenosylmethionine (SAM) Methyl transferase Minor pathway that leads to non-polar inactivated compounds Biosynthesis of epinephrine, melatonin Inactivation of norepinephrine, dopamine, serotonin, histamine
First Pass Metabolism
Pre-systemic metabolism When orally administered drugs are extensively metabolized before reaching the systemic circulation Drugs with extensive first pass effect: - Isoproterenol - Lidocaine - Morphine - Meperidine - Nitroglycerin - Pentazocine - Propoxyphene - Propranolol - Salicylamide
ENZYME INHIBITORS
6620 Sodium valproate Griseofulvin Isoniazid Phenobarbital Barbiturates Cimetidine Phenytoin Ketoconazole Phenylbutazone Fluconazole Rifampicin Alcohol Acute: - Sulfonylurea - Ciprofloxacin - Carbamazepine - Erythromycin Chronic: - Sulfonamide - Meprobamate - Chloramphenicol - Omeprazole
ENZYME INDUCERS
333560 Sodium valproate Griseofulvin Isoniazid Phenobarbital Barbiturates Cimetidine Phenytoin Ketoconazole Phenylbutazone Fluconazole Rifampicin Alcohol Acute: - Sulfonylurea - Ciprofloxacin - Carbamazepine - Erythromycin Chronic: - Sulfonamide - Meprobamate - Chloramphenicol - Omeprazole
6WRKQVZRUW
Metronidazole Valencia oranges Grapefruit Module 1 Organic Medicinal Chemistry Page 2 of 14 RJAV 2022
ANTI-INFECTIVE AGENTS
Antisepsis: application of agent to living tissue to prevent infection Decontamination: destruction or reduction in the number of microorganisms Disinfection: chemical or physical treatment on inanimate surfaces Sanitization: reduction of microbial load on inanimate surface to a level acceptable for public health purposes Sterilization: kill or remove all types of microorganisms Pasteurization: kills non-sporulating microorganisms by hot water (65°C-100°C) Germicides: anti-infective agents used locally Cidal: kill Static: prevent growth
ALCOHOLS & RELATED COMPOUNDS SAR
1. DQWLEDFWHULDODFWLYLWXSWRRQO 2. QRQSRODUZDWHUVROXELOLWDQWLEDFWHULDODFWLYLW 3. Branching decreases antibacterial property except isopropyl alcohol: - more potent - cheaper - less toxic (60% EtOH, 40% Isopropyl Alcohol) 4. Isomeric alcohol potency decreases in the order: Primary > Secondary > Tertiary MOA: Protein denaturation/precipitation 1. Alcohol USP (ethanol, grain alcohol, wine spirit, cologne spirit, spiritus vini rectificatus): most widely abused of all recreational drugs - Manufactured by fermentation of grains and other CHOs - Metabolism: Ethanol to Acetaldehyde (Enzyme: alcohol dehydrogenase), Acetaldehyde to Acetic acid (Enzyme: aldehyde dehydrogenase) DRUGS THAT INTERFERE WITH ALCOHOL METABOLISM: - Fomepizole: inhibits alcohol dehydrogenase, used as an antidote for methanol poisoning - Disulfiram: used as a deterrent for alcohol addiction, inhibits aldehyde dehydrogenase, accumulation of aldehyde, extreme hangover-like symptoms, nausea, vomiting, vasodilatory flushing Types of Alcohols: - Absolute alcohol (95% alcohol) - Dehydrated alcohol (99% alcohol, prepared by azeotropic distillation) - Diluted alcohol (49-50% alcohol) - Denatured alcohol: EtOH rendered unfit for use in beverages by the addition of substances, completely denatured alcohol contains added wood alcohol and benzene, unsuitable for internal or external use
Types of Alcohols: Diluted alcohol
Chemical name: 49 50 alcohol
Types of Alcohols: Denatured alcohol
EtOH rendered unfit for use in beverages by the addition of subs. Completely denatured alcohol contains added wood alcohol and benzene, unsuitable for internal or external use.
Types of Alcohols: Specially denatured alcohol
Treated with subs so that its use is permitted for a specialized purpose. E.g. Iodine in alcohol, 2 Isopropyl alcohol (2-propanol) substitute for ethanol, Made by sulphuric acid catalyzed hydration of propylene.
Types of Alcohols: 3-Ethylene alcohol
C2H4O, MOA - alkylation of bacterial protein by nucleophilic opening of oxide ring, used to sterilize gas, sterilant temperature sensitive, SKDUPDFHXWLFDOVDQGHTXLSPHQWWKDWFDQWEHDXWRFODYHG, Carboxide 10 ethylene oxide, 90 CO2.
Types of Alcohols: Formaldehyde
Chemical name: Methanal, MOA - direct and nonspecific alkylation of nucleophilic functional groups of proteins, contains not less than 37% of formaldehyde, Uses: embalming fluid, disinfectant.
Types of Alcohols: Glutaraldehyde
Also known as Glutarol, sterilizing solution for equipment and phcals that cannot be autoclaved, used in medical missions in remote areas. Cidex B.
Phenol and Its Derivatives: Phenol USP
Also known as Carbolic acid, discovered by Joseph Lister, SAR - Substitution at para position increases bacterial activity, Activity: straight chain alkyl branched, Germicidal standard: Phenol coefficient, Dilution of a disinfectant, Dilution of phenol that is required to kill a strain of Salmonella typhi.
Phenol and Its Derivatives: Liquefied phenol
Phenol with 10% water.
