Principles of Medicinal Chemistry

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Principles of Medicinal Chemistry Review of
Organic Functional Groups II
September 16/2002.
Zbigniew J. Witczak, Ph.D.
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Principles of Medicinal Chemistry PHA 421 Dr.
Zbigniew J. Witczak

• Learning Objectives
• After completion of theses lectures students
  should be able to
• Predict the effect on water solubility of various
  functional groups within a drug molecule.
• Should be able to describe hoe the structures of
  drug molecules influence their pharmacological
  activity.
• Should be able to explain the principle of
  bioisosterism and be able to modify drug
  molecules using this principles.
• Should be able to relate the principle of
  pharmacophore and how it is used to develop new
  drugs.

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Important Functional Groups on Drugs II
1.Phenols Metabolism
Metabolic Reactions of the Phenol Functional
Groups
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1.Ether Metabolism
Metabolic dealkylation of anisole
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Aldehydes and Ketones

• Ketones can exist as an equilibrium mixture of
  keto- and enol- froms
• Carbonyl group is permanently polar and thus can
  hydrogen bond with water to exhibit good water
  solubility

Minor oxidation of aldehydes
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Amines

• Primary and secondary amines have weaker dipole
  moments than hydroxyl groups thus poorer
  hydrogen bonding capacity
• The amines do have one pair of unshared
  electrons, which is able to provide hydrogen
  bonding with water hydrogen and thus reasonable
  solubility.
• Solubility trends primarygt secondarygt tertiary
• Amines also have basic nature due to
  availability of the two unshared electrons on
  the nitrogen
• Aromatic amines are generally less basic due to
  electron-withdrawing nature of phenyl and thus
  the unshared electrons are resonance stabilized.
• Amines can react with acids to from conjugate
  salts which would be water- soluble provided the
  conjugate is dissociable. Can from salts with
  hydrochloric, sulfuric phosphoric, succinic
  citric maleic and tartaric acids.
• Addition of base to the conjugate salts will
  liberate the free amine which can precipitate
  out of solution due to poor water solubility.
  Thus bases are chemically incompatible with
  amine salts.
• Quarternary amines cannot be converted to free
  amine by base treatment and positive charge on
  the nitrogen allows good ion-dipole interaction
  with water and thus exhibit good water
  solubility

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Carboxylic Acids

• Strong hydrogen bonds with water ensure the
  solubility of this group
• Behave as acids strength depends on stability of
  carboxylate anion which is influenced by
  electronic character of R group
  electron-donating R groups stablize the
  carbonylate anion and decrease acidity. The
  opposite is true for electron withdrawing
  groups due to resonance stablization of the
  anion.
• Carboxylic acids will r4eact with bases to from
  salts that have high water solubility.Chemical
  incompatibility of carboxylate salt conjugate
  with acids is due to formation of free carboxylic
  acid which can precipitate out of solution.

Which group on the compound is most least
acidic.
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Functional derivatives of Carboxylic Acids

• Esters
• Similar physicochemical properties to ethers is
  a combination of
• polar alcohol and polar acid to produce less
  polar ester due to lack
• of hydroxyl groups.
• Can be hydrolyzed by acid or base to an alcohol
  and acid
• Esters are incompatible with strong bases due to
  above reaction

• B. Amides
• Amides results from a polar carboxylic acid and
  weakly polar primary or
• secondary amine or ammonia have reasonable
  solubility due to
• hydrogen bonding and ion-dipole interactions.
• Amides are more stable to acid/base hydrolysis
  than esters but are
• also more neutral than basic and thus being
  unable to from acid salts.

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Structure Activity Relationships in Drug Action

• Pharmacological agents generally mimic the
  structural properties of
• endogenous substances

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Neurotransmitters
R H, Noradrenaline R Me Adrenaline
Dopamine
Serotonine
3-hydroxytryptamine
Glycine
Acetylocholine
g-aminobutiric acid (GABA)
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Structures of Clinically Useful Sulfonamides
Sulfacytine
Sulfadiazine
Sulfamethizole
R
R pKa 5.45
R pKa 6.9
Sulfamethazine
Sulfamerazine
Sulfamethoxazole
R
R
R
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Schematic Actions of Sulfonamides and Trimethoprim
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How prodrugs are made
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Chemical Delivery Systems Pharmacologically
inactive molecules that require several steps of
chemical and/or enzymatic conversion to the
active drug and enhance drug delivery to
particular organs or sites. Example
Brain-specific chemical delivery system
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New approaches
Soft Drugs Biologically active, therapeutically
useful chemical molecules (drugs) characterized
by a predictable and controllable in vivo
deactivation, after achieving the therapeutic
objective, to nontoxic, inactive compounds
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Examples
2. Improving drug delivery The pro-drug by its
improved characteristics gets closer to the
receptor site for a longer period of time, and
conversion to the parent drug takes place at the
site of action.
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