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Questions and Answers
Drugs in their ______ forms will tend to distribute throughout the body more rapidly than will ionized molecules.
Drugs in their ______ forms will tend to distribute throughout the body more rapidly than will ionized molecules.
unionized
Hydrochloric salt formation occurs from an aliphatic ______.
Hydrochloric salt formation occurs from an aliphatic ______.
amine
The classification of drugs can be based on their origin and ______.
The classification of drugs can be based on their origin and ______.
medicinal use
The process of ______ involves converting chemical compounds into useful pharmaceuticals.
The process of ______ involves converting chemical compounds into useful pharmaceuticals.
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A drug is any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of ______.
A drug is any substance intended for use in the diagnosis, cure, mitigation, treatment or prevention of ______.
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Medicinal chemistry is a science that incorporates different branches of chemistry and ______ in the research for drug discovery.
Medicinal chemistry is a science that incorporates different branches of chemistry and ______ in the research for drug discovery.
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The first synthetic human ______ known as Humulin® was produced and approved by the USFDA.
The first synthetic human ______ known as Humulin® was produced and approved by the USFDA.
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Benzocaine, procaine, tetracaine, and lidocaine are structural analogs of ______.
Benzocaine, procaine, tetracaine, and lidocaine are structural analogs of ______.
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6-Mercaptopurine, marketed as ______, was developed to inhibit nucleic acid synthesis and stop tumor growth.
6-Mercaptopurine, marketed as ______, was developed to inhibit nucleic acid synthesis and stop tumor growth.
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Chlordiazepoxide, also known as ______, was one of the first benzodiazepines tested for its anxiolytic properties.
Chlordiazepoxide, also known as ______, was one of the first benzodiazepines tested for its anxiolytic properties.
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______ was isolated from a dog's pancreas by Frederick Banting and Charles Best.
______ was isolated from a dog's pancreas by Frederick Banting and Charles Best.
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Cisplatin is classified as an inorganic ______ with a simple structure aimed at targeting cancer cells.
Cisplatin is classified as an inorganic ______ with a simple structure aimed at targeting cancer cells.
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Albert Niemann is credited with the ______ of cocaine from the Erythroxylon coca plant.
Albert Niemann is credited with the ______ of cocaine from the Erythroxylon coca plant.
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Medicinal chemists study the ______, distribution, metabolism, and excretion of drugs.
Medicinal chemists study the ______, distribution, metabolism, and excretion of drugs.
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Functional groups are a group of ______ responsible for the characteristic reactions of a particular compound.
Functional groups are a group of ______ responsible for the characteristic reactions of a particular compound.
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The tetrazole ring provides the best charge ______ since resonance allows the charge to be equally shared.
The tetrazole ring provides the best charge ______ since resonance allows the charge to be equally shared.
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Basic functional groups include aliphatic and alicyclic ______, which are the most common types.
Basic functional groups include aliphatic and alicyclic ______, which are the most common types.
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Carboxylic acids can undergo acid- or enzyme-catalyzed ______ reactions.
Carboxylic acids can undergo acid- or enzyme-catalyzed ______ reactions.
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Aromatic amines, such as procainamide, are much less ______ and can be considered neutral.
Aromatic amines, such as procainamide, are much less ______ and can be considered neutral.
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Acidic functional groups are ______ and can form salts when combined with bases.
Acidic functional groups are ______ and can form salts when combined with bases.
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Aromatic, heterocyclic nitrogens vary in their basicity, but in general are much less basic than ______ and alicyclic amines.
Aromatic, heterocyclic nitrogens vary in their basicity, but in general are much less basic than ______ and alicyclic amines.
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Study Notes
Pharmaceutical and Medicinal Organic Chemistry
- Course title: Pharmaceutical and Medicinal Organic Chemistry
- Instructor: Lanzon, Kar
History of Medicinal Chemistry
- Early healers used spiritual incantations, noxious materials, and herbs/plants.
- Egyptians practiced embalming.
- The Ebers Papyrus, discovered by George Ebers, is a collection of medical knowledge. Examples include acacia, castor bean, and fennel.
- Chinese Emperor Shen Nung compiled the Pen T'Sao, a pharmacopeia. This documents include ch'ang shang (antimalarial alkaloid) and ma huang (commercial sources: Ephedra sinica, Ephedra equisetina)
- American Indians used chaulmoogra fruit (commercial sources: Hydnocarpus wightiana, Hydnocarpus kurzii).
- South American Indians used cocaine (Erythroxylum coca) and mushrooms as hallucinogens. Brazil's use of emetine (from ipecac root, Cephaelis ipecacuanha for amebiasis/amoebic dysentery).
- Greeks: Dioscorides wrote De Materia Medica (Medicinal material), which described various drugs including aloe, belladonna, colchicum, ergot, hyoscyamus, and opium.
- Middle Ages: Philippus Aureolus Theophrastus Bombastus von Hohenheim ("In all things there is a poison...the dose") stated that the impact of a substance is based on the dose given (mercury, lead, arsenic, antimony).
History: 17th to 20th Century
- Natural sources: Carl Wilhelm Scheele discovered Lactic acid, citric acid, and tartaric acid. Friedrich Sertürner isolated morphine from opium. Pierre-Joseph Pelletier isolated emetine, caffeine, quinine, and colchicine. Increased use of pure substances as therapeutic agents. William Withering studied Digitalis purpurea for edema and heart conditions. Albert Niemann isolated cocaine.
- Paul Ehrlich produced compound 606 (Salvarsan) an antisyphilitic "magic bullet", proposing selective toxicity. Penicillins replaced Salvarsan. Gerhard Domagk observed 2,4-Diaminoazobenzene-4'-sulfonamide (Prontosil) efficacy with systemic gram-positive bacterial infections. D.D. Woods and Paul Fildes observed the antagonistic action between sulfonamide-like drugs/sulfonamides and p-aminobenzoic acid.
- Alexander Fleming discovered penicillin (Penicillium notatum). Howard Florey and Ernst Chain examined and produced a pure form of penicillin.
Developments: Psychopharmacologic Agents
- Chlorpromazine (Thorazine®): Paul Charpentier - first synthesis, Simone Courvoisier - observed distinctive effects on animal behavior, Henri Laborit - noticed effects in humans. Pierre Deniker & Jean Delay published a clinical trial in psychotic patients. Marketed by Rhône-Poulenc (Largactil®).
- Anxiolytics - Benzodiazepines: Meprobamate(Miltown®) - Frank M. Berger- accidental discovery, mephenesin. Chlordiazepoxide (Librium®) - Lowell Randall - tested the crystallized compound synthesized by Leo Sternback.
Developments: Endocrine Therapy
- Insulin: Frederick Banting and Charles Best extracted insulin from a dog's pancreas. James Collip and John McLeod produced a pure form from cattle pancreases. Eli Lilly's Humulin® was the first synthetic human insulin sold and approved by the USFDA.
Developments: Local Anesthetics
- Cocaine (Erythroxylum coca): naturally occurring alkaloid - Albert Niemann - isolated cocaine from the plant. Richard Willstatter determined cocaine's structure. Carl Koller showed its value as an effective, non-irritating anesthetic for the eye.
- Benzocaine, procaine, tetracaine, and lidocaine are structural analogs of cocaine.
Developments: Anticancer Agents
- 6-Mercaptopurine (Purinethol®): George Hitchings and Gertrude Elion, discovered its ability to stop bacterial or tumor cell growth by interfering with nucleic acid synthesis.
- Cisplatin: inorganic molecule with simple structure. Second-generation compound includes carboplatin
Medicinal Chemistry
- Science combining chemistry and biology to discover, design, and develop better therapeutic chemicals into new medicines and drugs.
Roles of a Medicinal Chemist
- Make new compounds.
- Determine drug effects on biological processes.
- Alter compound structures for optimum effect and minimal side effects.
- Study uptake, distribution, metabolism, and excretion of drugs.
Review of Functional Groups
- Functional groups: a group of atoms responsible for a compound's characteristic reactions.
- Acidic Functional Groups: RCOOH, ArOH, ROH, RSH
- Basic Functional Groups: RNH2, R2NH, R3N
- Neutral Functional Groups: C=O-containing containing.
Acid & Base: Major Physicochemical Properties
- pKa and Ionization
- Lipophilicity-Hydrophilicity
- Salt formation
Estimation of the Relative Acid-Base Strength
- Ionization constant (Ka) indicates relative acid/base strength.
- An acid with a Ka of 1x10⁻³ is stronger than one with Ka of 1x10⁻⁵.
- Negative log of Ka (pKa) also indicates relative strength.
- Acid with a pKa of 5 is weaker than one with pKa of 3.
- Base with a pKa of 9 is stronger than one with pKa of 7.
Acidic-Basic: Salt Formation
- Salt is the combination of an acid and a base.
- All salts are strong electrolytes. Exceptions include mercuric and cadmium halides and lead acetate.
- Salt form of drug is more soluble than its parent molecule.
- Inorganic salts are made with inorganic acids and bases (e.g., HCl, H₂SO₄, KOH, NaOH).
- Organic salts are from combining two molecules, one acidic and one basic (e.g., citrate, acetate, maleate, gluconate, tartrate, mesylate).
Acidic-Basic: Drug Distribution and pKa
- Unionized drug forms distribute more rapidly than ionized forms.
- Drugs pass through nonpolar membranes (capillary walls, cell membranes, blood-brain barrier) while unionized.
Isomers
- Constitutional isomers have the same chemical formula but different connectivity.
- Stereoisomers have the same connectivity but different arrangement in 3D space. These include geometrical (cis/trans) and configurational (R/S, D/L).
- Enantiomers are non-superimposable mirror images. Diastereomers are stereoisomers that are not mirror images.
- Rules for determining configuration (using CIP rule; configurations/priorities if involved).
Drug Discovery and Drug Development Process (DDD Process)
- Discovery: Identify new/previously undiscovered biologically active compounds ("hits").
- Lead optimization: Convert "hits" to "leads" (prototypes) by modifying functional groups. Techniques like Lipinski's rule of five or the Pfizer rule of five are used to assess "drug-likeness" and to guide modification efforts.
- Toxicology and Clinical Development: Assessing a drug's safety. This involves rendering it as a drug candidate for clinical trials, requiring in-vitro and in-vivo testing, phase I/II/III clinical trials, data review, NDA/BLA application, FDA review, FDA approval, and Post-market monitoring.
Drug-Receptor Theories
- Drug must bind to a receptor/enzyme for effect; only one ligand per site.
- Interactions (bonds) involved: usually weak chemical bonds; hence reversible.
- Irreversible interactions (covalent bonds) are usually undesirable and often require interventions to reverse effects
Determinants of Drug Action
- Structural determinants: affect drug action based on the molecular structure.
- Physicochemical determinants: factors like pKa and lipophilicity are crucial.
Relationship of Structure to Biologic Activity
- Crum-Brown & Fraser: certain compounds exhibit muscle relaxant activity (e.g., compounds containing 3-degree amine groups; refuted by Loewi & Navrati). Specific chemical groups are responsible for particular biologic effects.
Selectivity of Drug Actions and Drug Receptors
- Paul Ehrlich; introduced concepts of receptors based on the “side chains” of cells that are complementary to drugs or dyes.
- Drugs often have selective activities;
- Ing: showed that the same functional group can have different biological effects (relaxation vs contraction), exemplified using Tubocurarine and Acetylcholine, whose actions are antagonistic.
- Woods-Fildes: examined antagonism between sulfanilamide and p-aminobenzoic acid (PABA) due to shared similar steric and electronic properties.
Biological Target for Drug Action
- Drug + biological target (receptor, enzyme, nucleic acid) = pharmacologic activity.
- The quality of fit between drug and its target often directly impacts the biologic response.
Stereo Chemistry and Drug Action
- Many drugs are racemic mixtures (equal amounts of both enantiomers); but enantiomers can have different biological activities, toxicity, or absorption.
- Easson-Stedman hypothesis: suggests that the more potent enantiomer will have a favourable three-point fit at the receptor level.
Peptide and Protein Drugs
- Made up of amino acids linked by amide or peptide bonds.
- Peptides have 15-50 amino acids. Proteins have more than 50.
- Side chain properties (MW, polarity) dictate drug action and pharmacokinetic characteristics (acidity, polarity, etc.) affecting absorption.
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Description
Test your knowledge on the fundamental concepts of medicinal chemistry, including drug classification, synthesis processes, and key pharmaceutical compounds. This quiz covers various aspects from basic definitions to specific drug types.
