MedChem Exams > 143M_P_03W

PHR 143M - Dr. Patrick Davis, Course CoordinatorPHR [email protected]

PHR 143P - Dr. Sean Kerwin, Course CoordinatorPHR [email protected]

TA’s:Asha Nadipuram [email protected] PHR 4.212; 471-7546

Bodin Tuesuwan [email protected] PHR 3.204A; 471-5859

Liping Feng [email protected] PHR 3.204A; 471-5859

Scott Miller [email protected] PHR 4.116; 471-8860

Troy Purvis [email protected] PHR 1.116A; 471-3027

Megan Cornwell [email protected] ARC 1.240; 232-2785

Hector Serrano [email protected] PHR 4.116; 471-8860

mailto:[email protected]







Class Times:

PHR 143M F 1-2pm PHR 3.106PHR 143P F 2-3pm PHR 3.106 (Pre-Lab)

PHR 143P Labs:MWF 3-6pm PHR 2.116Tu/Th 2-5pm PHR 2.116Texts:

Lemke “Review of Organic Functional Groups” 3rd Ed (required)Foye “Principles of Medicinal Chemistry” 5th Ed” (required)

Overview of the Drug Discovery and Development Process

Discovery

Development

Market

>10,000 Compounds

~ 5 Compounds

Phase 1

Phase 2

Phase 32003

2010

20112012

2017 2018 1 Compound

Phase 4

Drug Discovery Overview

Target identification: The selection of a specificreceptor and/or properties that are expectedto lead to a new drug.

Lead identification: The selection of a specific compound that has some of the desired activities for a new drug.

Lead optimization: The process of designing andsynthesizing new analogs of the lead compound in order to find a suitable drug candidate.

Promotion to Development: Selection of one compound for eventual clinical trials (filing of IND).Requires Scale-up synthesis, formulation, stability,and toxicity testing prior to first human dose.

See Foye p 12-23 for more detail

“Lead Compound”

Observation

Screening

RationalDesign

LeadOptimization

Where do the 10,000+ CompoundsCome From?

Where do “Lead Compounds” Come From?

• Natural Products- Random screening and ethanopharmacology

• Screening Chemical Libraries• Rational Design• Existing Drugs

- Side effects: antihistamine promethazine (sedative)chlopromazine - antipsychotic

- Metabolism Studies: azodye prontosil -> sulfonamides

What is Medicinal Chemistry and Where DoesIt Fit in this Process?

Medicinal Chemistry is broadly defined as the study of the chemistryRelated to drug discovery and drug action.

It has many components:– Natural products chemistry– Synthesis– Computational Chemistry– Enzymology/Biochemistry/Molecular Biology

It is essential during the Drug Discovery Process, in theSelection of Leads, and Lead Optimization.

It is also essential for understanding the following properties of drugs:- Chemical compatibility, stability,

ADME, potency, and selectivity

Much of Medicinal Chemistry is concerned with defining the relationship between the structure of a chemical compound and its biological activity.

Elucidating Structure-Activity Relationships (SAR) is a key function of medicinal chemistry

In order to study SAR, one must first understandhow structure affects physicochemical properties of compounds.

What is Medicinal Chemistry and Where DoesIt Fit in this Process?

Acid/base properties, solubility, partition coefficient, ionization state, Resonance and inductive effects, ionization potential, 3D shape, stereochemisty, conformation

Physicochemical Properties

Biological ActivityOral

Administration

Gastrointestinal Tract

DRUG

OtherParenteral

Administration

Tissue depots

IntravenousInjection

DRUG DRUG DRUG-DRUGMETABOLITES

Receptor(s)for Desired

Effect(s)

DRUG Serum Albumin

DRUG DRUG-DRUG METABOLITESDRUG-DRUGMETABOLITES

DRUG-DRUGMETABOLITES

Liver Intestinal Tract Receptor(s)for UndesiredEffect(s)

Kidney

Excretion

Medicinal Chemist use their knowledge of theserelationships and of organic synthesis to design and make new molecules with desired activities (drugs).

1.1 Intro to Medicinal Chemistry – Organic Functional Groups

Important REQUIRED text: Lemke“Review of Organic Functional Groups - Intro. to Organic Medicinal Chemistry”

Today Chapters 1-5 (p 1-22) and Appendix B (p 132-141)

Sept. 9: Chapters 6-10, 14 (p 23-46, 79-80)

Sept. 12 Chapters 11-13 (p 47-78)

Also read Foye Chapter 2, p 37–49

Why a Functional Group Approach?

Organic Medicinal

Functional Group Interconversions

Functional GroupMetabolism/ Degradation

Functional Group Reactions

Functional Group Interactions

N

HO O OH

CH3

N

NCH3

NH3C

O

H

O

OH

N+

HO O OH

CH3H3C

N

N+

CH3H3C

N+H3C

O

H

O

OH

CH3

Morphine - analgesic N-Methylmorphine

N-MethylnicotineNicotine - stimulant

Atropine - mydriatic N-Methylatropine

muscle relaxants

Historical Perspective: "One functional group - One biological activity"

Current understanding of SAR focuses on the chemicalNature of drugs in total (e.g, the overall electronic structure); however, functional group analysis is still a useful approach due to its relative simplicity and the uniformity of the electronic structure of functional groups in molecules.

AlkanesAlkenesAlkynesAromatic HydrocarbonsAromatic Heterocycles (Heteroaromatics)

The Drug Skeletons (Frameworks):

Halogens AlcoholsEthersPhenolsThiolsThioethersSulfoxidesSulfones Amines Amine oxidesQuaternary Ammonium ionsAnilinesAmidinesGuanidines

AldehydesKetonesImines Carboxyic AcidsEstersAmidesSulfonic AcidsSulfonamides

Functional Groups

Drug Molecule Evaluation

Analysis of Individual Functional Groups:NameShapeHydrophobic/Hydrophilic CharacterPolar vs. Non-polar CharacterAcid/Base CharacterBinding InteractionsChemical/Enzymatic Stability

Analysis of the Whole MoleculeFunctional Group InteractionsFunctional Group Balance: Physicochemical Prop.Ionization StateDrug Combinations: Chemical Interactions

Hydrocarbons - Alkanes

Alkanes - CnH2n+2

methane - CH4

ethane - C2H6

propane - C3H8

H

HHH

HH

H H

H

H

CH3

H H

H

H

H

bp =

- 161 °C

- 89°C

- 42 °C

Dispersion Interaction - van der Waals attraction “instantaneous” dipoles

–– ++ ––

+ ––

+ ––

Averaged over time, the electron densityon the surface of an alkane is uniform

But at any one moment, the distribution isuneven. Some areas are electron-rich (dark)While others are electron poor (light).

Electron poor areas of one moleculecan induce a complementary electron-rich area in an adjacent molecule.

The result is an attraction between the two.

Understanding the Physical Properties of Alkanes

The larger the molecule (the greater the # of electrons) - The stronger the attraction

Dispersion Interaction - van der Waals attraction “instantaneous” dipoles

This attractive force is rather weak and highly dependentOn the distance between the two molecules - it isOnly important when the molecules are very close Together.

Alkanes

Effect of Branching:

n-Butane

CH3CH2CH2CH3

iso-Butane

(CH3)3CH

bp =

- 0.5 °C

- 12 °C

Alkanes

Effect of Branching:

n-Butane

iso-Butane

bp =

- 0.5 °C

- 12 °C

effective dispersion interaction between mols.

Less dispersion interaction between mols.

Hydrocarbons

Van der Waals interactions determine the physical properties of hydrocarbons.All organic drugs are hydrocarbon based - The physical properties of drugs are determined by the hydrocarbon-like skeleton of these drugsmodified by functional groups.

Example - the branching effect that tends to decreasebp in simple alkanes is the same effect that causes drugs with branched alkyl side chains to bemore water soluble than those with linear alkyl sidechains (of the same # of atoms).

Remember:

Water solubility - How well does water interactwith molecules Vs. molecules interact witheach other (crystal packing).

O

H H

O

H H

O

H H

O

H H

O

H

H

O

H

H

O

H

H

For two solid drugs of similar structure (e.g., functional groups), the one with the lower mp will have __________ water solubility.HIGHER

OH OH

OHHO

HO HOHO

HOHO

HOHO

HO

H O HO

HOHO

Octanol/Water

OH H

OH HO

H H

OH

H OH

H

drug OH OH

OHHO

HO HOHO

HOHO

HOHO

HO

H O HO

HOHO

Octanol/Water

OH H

OH HO

H H

OH

H OH

H

Partition Coefficient (LogP)

LogP = LogConc. In Octanol Layer

Conc. In Water Layer

For two drugs of similar structure, the drug with More potential for intermolecular van der WaalsInteractions will have the ____________ log P.HIGHER

Lipophilicity: Preferring to interact with a lipid phase.e.g, high log P

Hydrophilicity: Preferring to interact with water.e.g., low log P

Butabarbital Butethal

Water insol.Sl. Sol in water

logP = 1.65 logP = 1.73

NH

NH

O

O O

NH

NH

O

O O

Example: Barbiturates

Ethylene CH2=CH2

Hydrocarbons - Alkenes:

H H

H H bond: Sharedelectrons that are not in the sameplane as the atoms.

Properties associated with alkenes ( bonds):• Attack by electrophiles:

O"electrophilicoxygen"

Electrophiles: electron-deficient chemical species that “want” more electrons (attack nucleophiles).

Nucleophiles: electron-rich chemical species (attack electrophiles).

Alkenes Reactivity:Oxidation

O2

R R'

H

Alkene

R R'

O

OH

Hydroperoxide

Decomposition

Alkenes:

Properties associated with alkenes ( bonds):

• Isomerization - (E)/(Z) isomers

2-buteneH3C

H

CH3

H(Z)

H3C

H

H

CH3(E)

O

OH

9-THC

O

OH

8-THC

Restricted bond rotation about C=C

- Double bond migration

Alkenes:

Properties associated with alkenes ( bonds):

• Conjugation with other functional groups

- can alter alkene’s properties

EWG EWG

EDG EDG

Conjugation - electronic coupling of functionalgroups of portions of molecules through electrons.

OH

H

CH3

Hydrocarbons - Alkynes:

H H

acetylene

Linear, electron rich, can be reactiveOnly a few drugs are alkynes

HH

N

MeMe

Me

Me

Terbinafine (antifungal)

H

H

H H

H

H

Aromatic Hydrocarbons

H

H

H

H

H

HBenzene

delocalized: aromatics are not as reactiveas alkenes

pi-cloud: resonance forms

H

H

H

H

H

H

H

H

H

H

H

H

Aromatic: 4n+2 pi-electrons delocalized in a ring= Hückel’s Rule

Benzene: 3 double bonds =6 pi-electron= (4*1)+2

Aromatic Hydrocarbons

Naphthalene10 electrons= (4*2)+2

Anthracene14 electrons= (4*3)+2

Phenanthrene14 electrons= (4*3)+2

Hückel Series:2, 6, 10, 14, 18, …

Aromatic Heterocycles

NH

N

pyridine

pyrrole

:

N lone pair is not in the system-> we don't count it 6 electrons -> aromatic

N

N H

N lone pair is in the system-> it counts6 electrons -> aromatic

:

X:

Lone pairnot in system

General Rule:

X:

Lone pairis in system

Aromatic Heterocycles

NH O S

N N

N

pyridine pyrimidine

pyrrole furan thiophene

All are 6 electron aromatic systems

Other Common Aromatic Heterocycles

N

HN

O

HN

S

HN

O

HN

N N

HN

N N

S

imidazole oxazole isoxazole Thiazole

s-triazole 1,3,4-thiadiazole

Other Common Aromatic Heterocycles

NH

O NH

N

NN

N

N N

N

IsoquinolineQuinoline

IndoleBenzofuran Benzimidazole

Pteridine

N

N NH

N

Purine

N

Acridine

Other Common Heterocycles (Not Aromatic)

NH

S

phenothiazine

N

HN

1H-1,4-benzodiazepine

NH

NH

O

NH

HN

piperidine

morpholine piperazine

Properties of Aromatics

Physical properties are similar to structurally relatedalkenes

Charge-transfer and cation- interactions:

Electron-Rich aromatic

Electron-poor aromatic

O

O

O

O

+

Charge-TransferComplex

cation-Complex

Electron-Rich aromatic

cation

R

+

N

N

R



Functional Groups

Halogens

methylbromide

Br

HHH

iodoform CHI3

Halothane CF3CHBrCl

Halogens

Can be reactive (alkylators) except when halogen is attached to aromatic ring)

Br

RH

H

Nu:

Nu

RH

H

Br-

Increased sterics (size) relative to Hydrogen

Halogens

Are lipophillic (Remember vdW attraction increases with # of electrons)

Cl

Log P = 2.13 Log P = 2.84

(log P) = +0.71

So each chlorine added to a drug increases Log P by ~0.7

Log Pdrug = skeleton + funct. Group 1 + funct. Group 2 + ..

We can derive a simple equation for predicting the log P ofA drug:

Log Pdrug = fragments

or

Halogens

C (aliphatic) = +0.5Ph = +2.0F = +0.14Cl = +0.5Br = +0.86

Halothane CF3CHBrCl

2 C (aliphatic) = 2 x 0.5 = 13 Fluorine = 3 x 0.14 = 0.421 Chlorine = 0.51 Bromine = 0.82Predicted LogP = 2.74

There are more accurate ways to predict LogP, but the values still provide a good estimate for the effectof individual functional groups on the lipophilic/hydrophilicBalance of a drug.

Dipoles

-q +qr

dipole moment = q x r (coulomb meters)

1 debye (D) = 3.336 x 10-30 coulomb meters

Where do dipoles come from? Bond Dipoles:

In molecular hydrogen (H2) there is no permanent dipole H H =

Halogens

Dipoles

In hydrogen chloride, there is a dipole:

H Cl

-q+q

The chlorine atom “wants” electrons much more than the hydrogen atom. The chlorine atom has a partialnegative charge (-q) and the hydrogen is left with a partial positive (+q). A permanent dipole results. The dipole can be denoted with an arrow:

H Cl

Halogens

H(2.21)Li

(0.98)C

(2.55)N

(3.04)O

(3.44)F

(3.98)Na

(0.93)P

(2.19)S

(2.58)Cl

(3.16)K

(0.82)Br

(2.96)I

(2.66)

Average Electronegativities of Selected Elements.

C H

For an average C–H bond, the dipole is:

Halogens

H

CH

H

H

H

H

NH

:

Cl

CH

H

H

H ClHydrogen Chloride

Methane

Ammonia

Water

Chloromethane

Bond Dipole ResultantMoment (D) Dipole Moment (D)

H-Cl, 1.05 1.05

H -C, 0.2 0

H-N, 1.5 1.5

H-O, 1.6 1.8

C-Cl, 1.7 2.0

H

OH

:

:

Halogens

Halogens in Drugs:

Polarity: relative measure of a compounds ability tointeract with a polar phase by favorable H-bond and molecular dipoles or ionic interactions.

Halogenated hydrocarbons can be more polar thanSimple hydrocarbons due to the molecular dipoles thatcan result from halogen-carbon bond dipoles. In all but theSimplest halogenated hydrocarbons, this effect is typicallySmall due to the size of the halogens (prevents effectiveDipole-dipole interactions) and the number of other bond dipoles involved.

Halogens in Drugs:

Cl

Halogens attached to aromatic rings withdraw electronDensity from the aromatic ring, making it less easilyAttacked by electrophiles (metabolized).

Halogens in Drugs:

A few drugs contain halogens, particular F, Cl, and Br. (Due to the relative instability of the carbon-iodine bond, There are fewer iodine-containing drugs)

In some cases (e.g., nitrogen mustards) the halogen and its reactivity is required for drug action.

Most halogen substituents are on aromatic rings, where they have the effect of blocking/decreasing metabolism while increasing lipophilicity.

Analysis of Halogen Functional Groups:Shape: Spherical, large: F < Cl < Br < IHydrophobic: F < Cl < Br < ISlightly Polar due to bond dipoles Neutral Binding Interactions: Increased size and potential for

vdW interactionsCan be chemically unstable (aliphatic), decrease

metabolism (aromatic)

Halogens in DrugsSummary:



Functional Groups

Alcohols

methanol CH3OH

:

OMe

H

1-butanol CH3CH2CH2CH2OHa primary alcohol

2-butanol CH3CH2CH(OH)CH3

a secondary alcohol

tert-butanol (CH3)3COH

a tertiary alcohol1-pentanol CH3CH2CH2CH2CH2OH

Solubilitybp (g/100mL H2O)

66 °C ∞

117 °C 7.9

100 °C 12.5

137 °C 2.3

82 °C ∞

Alcohols

Hydrogen bonding:

H

OR

R

OH

Compare the bp of ethane (-89 °C) to methanol (66 °C).What does this tell us about the strength ofHydrogen bonds versus van der Waals interactions?

Each Hydroxyl groupCan donate one andAccept two H-bonds= 3 potential H-bonds

vdW interaction (C - C) ~ 0.5 kcal/moleH-bond ~ 2-5 kcal/mole

Alcohols

Hydrogen bonding:

H

OR

R

OH

Alcohols and hydroxyl-containing drugs are polar due toThe ability to H-bond.

Alcohols

Water Solubility: in simple alcohols, each Hydroxyl group can "solubilize" 5–6 carbons.

In polyfunctional drugs, each hydroxyl group cansolubilize 3–4 carbons.

Lipophilicity: aliphatic OH = -1.0

Homologation: Alcohols

CNSDepressantActivity

CH3(CH2)nOH

n = 7 (n-octanol)

n

1 4 7 10

Biological ActivityOral

Administration

Gastrointestinal Tract

DRUG

OtherParenteral

Administration

Tissue depots

IntravenousInjection

DRUG DRUG DRUG-DRUGMETABOLITES

Receptor(s)for Desired

Effect(s)

DRUG Serum Albumin

DRUG DRUG-DRUG METABOLITESDRUG-DRUGMETABOLITES

DRUG-DRUGMETABOLITES

Liver Intestinal Tract Receptor(s)for UndesiredEffect(s)

Kidney

Excretion

O

O

O

O

OP

O

O

O–

R

n

n

=

OH

H2O

~

Octanol and Biological Membranes

Alcohols - Metabolism

Oxidation:

R

R'

OHR

R'

OOxidation

Reduction

R' = H AldehydeR ≠ H Ketone

Alcohol

R

OH

O

R' = H

Oxidation

Reduction

Acid

Alcohols - Metabolism

Conjugation:

HO

R

R'OHO

HOOH

HO2C

O

R

R'

enzyme

Hydroxyl Groups in Drugs:

A number of drugs contain the hydroxyl group. In some cases, the hydroxyl group is essential for receptor interaction (H-bonding).

The hydroxyl group can increase water solubility and decrease logP.

The hydroxyl group can be prone to metabolictransformations.

Analysis of Hydroxyl Functional Group:Shape: Similar in size to a methyl group.HydrophilicPolar due to H-bond potential (3)Neutral Binding Interactions: H-bondingCan be metabolically unstable

Hydroxyl Groups in DrugsSummary:

Ethers

ODiethyl ether

O

Tetrahydrofuran

1,4-dioxaneO

O

Ooxirane (epoxide)

Immiscible w/ water

Miscible w/ water

(Soluble in waterin all proportions)

Ethers - Properties

Water Solubility: in simple ethers, the ether group can "solubilize" 4–5 carbons.

In polyfunctional drugs, each ether group cansolubilize ~2 carbons.

Lipophilicity: ether = -1.0 (excludes the added carbon(s))

Ethers are not as polar as alcohols

N

O

OH

Me

OH

morphine

N

O

O

Me

OH

Me

codeine

logP = 0.89 logP = 1.19

Ethers

Chemistry

O

peroxide formation (low MW ethers)

air

explosive!!O

O OH

Hydrolysis (strained ethers = epoxides)

OHO

OH

H2O:

Ethers

Metabolism

Enzymatic De-alkylation

:

RO

CH3

enzymeR

OH

enzyme

S-adenosyl-methionine(SAM)

Ethers in Drugs

Ether functional group is present in many drugs.It provides increased polarity for interaction withReceptor functional groups and is more metabolicallyStable than the corresponding alcohol functionalGroup.

Analysis of Ether Functional Group:Shape: Ether oxygen similar is size to CH2 group.Hydrophilic Slightly Polar due to H-bond potential (2)Neutral Binding Interactions: H-bonding, dipole, vdWMetabolically stable, except for possible dealkylation

Ether Groups in DrugsSummary:



Functional Groups

Phenols - Hydroxylated Aromatic Compounds

phenol

OH

OH

OH

OH

OH

OH

HO

catecholresorcinol hydroquinone

Solubility = 9.3g/100mL

Compare: 3.6 g/mLOH

Phenols - Hydroxylated Aromatic Compounds

phenol phenolate

OHO

-

+ H+

The ability of phenols to give up a proton to waterDistinguishes them from aliphatic alcohols:Phenols are (weakly) acidic.

This accounts for the increased water solubility of phenolsRelative to alcohols - the phenolate species, being chargedIs much more water soluble.

Understanding Acid-Base Properties

What makes one acid “more acidic” than another?

BH <=> B – + H+

Or, where does this equilibrium lie for two “BH” acids?Or, what is the G associated with this reaction?

To understand from the medicinal chemistry viewWe must be able to relate the answers to theseQuestions to the STRUCTURE of BH.

(BH)sol <=> (B –)

sol + (H+) sol

Ka =

[(B –) sol] [(H+) sol]

[(BH) sol]pKa = - log (Ka) pH = - log [(H+) sol]

Acidity in Solution (Water)

B1H <=> B1 – + H+

Understanding Functional Group Acidity and Structural Effects

Look at the energetics of this equilibrium and focus on the forces which tend to stabilize or destabilizethe charged species:

B – + H+ Common to all BHFocus on this!

If B2- is more stable than B1

-, the pKa of B2H will

be ________ than the pKa of B1H.

B2H <=> B2 – + H+

Look at relative acidity - Compare two BH acids:

LOWER

OHO

-

+ H+

OHO

-

+ H+

phenol

cyclohexanol

O– O

–O

–

O

The resonance stabilization of the phenolate anion makes phenolsA million times more acidic than alcohols.

pKa ~ 16

pKa ~ 10

Phenols

OHO

-

+ H+

phenol

pKa ~ 10

Phenols

To what extent is phenol ionized at pH 7?

[BH]10 = 7 + log

[B-]

Henderson-Hassalbach Equation:

pKa = pH + log _____[BH]

[B-]

[BH]

[B-]= 1,000

Phenol is~0.1% ionizedat pH 7.Phenol is aVery weak acid.

Phenols

Substituent Effects

OH

O–

+ H+

R R

If R = electron donating group, pKa goes ______ relative to R = H.

If R is electron withdrawing group, pKa goes _______ relative to R = H.

UP

DOWN

Phenols

Properties

Water Solubility: in simple phenols, each phenolic hydroxyl group can "solubilize" 6–7 carbons.

In polyfunctional drugs, each phenolic hydroxyl group can solubilize 3–4 carbons.

Lipophilicity: phenol OH = -1.0

NOTE: phenyl = +2.0

Phenols

Chemical Instability

Oxidation (NOTE: different from alcohols)

OH

O

O

O

OAir

p-quinone o-quinone

Phenols - MetabolismConjugation (Similar to alcohols)

OHO

S

O O

O-Enzyme

MethylationOH

OCH3

Enzyme

OHOH

OxidationOH

OHEnzyme

OH

Phenols in Drugs

A number of drugs have phenol functional groups. In some cases, these functional groups are essential for receptor interaction.

Phenol functional groups can increase water solubility but do not prevent passive diffusion through membranes.

Phenol functional groups are prone to metabolictransformations and chemical instability.

Analysis of Phenol Functional Group:Shape: Phenol OH is similar in size to CH3 group.Hydrophilic Polar due to H-bond potential (3) and ionizationVery weak acidBinding Interactions: H-bonding, dipole, ionicChemically and Metabolically unstable.

Phenol Groups in DrugsSummary:



Functional Groups

Thiols (Sulfhydryls)

Ethanthiol (Ethyl mercaptan)

CH3C2SH

bp = 37°CSolubility 1.5g/100mL H2O

Compare ethanol: bp =78°C, miscible with water

Sulfur in thiols is large, lipophilicThiols do not form strong H-bonds

Thiols are weak acids

CH3CH2OH <=> CH3CH2O – + H+ pKa ~ 16

CH3CH2SH <=> CH3CH2S – + H+ pKa ~ 10

Thiols form good ligands for metal ions, especially zinc

thiol SH

O

N

HO2C

captopril

Thiols - Chemical Reactivity

R

S H

R

S SR or R'

disulfidethiol

Thiols are prone to oxidative disulfide formation. Mixed disulfides can form when thiols react withDisulfides.

air

Thiols - Chemical Reactivity

R

S H

R

S SR or R'

disulfidethiol

Thiols are prone to disulfide formation. They are Also associated with a variety of side effects.Very few drugs contain the thiol functional group.

Thiols in Drugs

Very few drugs have thiol functional groups.

Thiol functional groups are weakly acidic, and serve asligands for metal ions.

Thiol functional groups are chemically unstable(disulfide) and associated with side effects.

Analysis of Thiol Functional Group:Shape: SH is similar in size to ethyl group.Hydrophobic&hydrophilic (thiol = 0)weakly polarVery weak acidBinding Interactions: metal ion coordinationChemically unstable.

Thiol Groups in DrugsSummary:

Thioethers

RS

R'

MeS

Me

90°

Large, lipophilic, decreased bond angle relativeTo ethers (112°)

Thioethers

Unlike ethers, thioethers are prone to (metabolic)oxidation to sulfoxides (tetrahedral!) and lessoften, sulfones

RS

R'

Ooxidation

RS

R'

OOoxidation

sulfoxide sulfonethioether

RS

R'

Thioethers

How readily is thiophene oxidized to the corresponding sulfoxide?

S S

O

S S

O

:

Lone pair involved in resonance, Less available for oxidation

Thioethers in drugs

A number drugs contain thioether groups, especiallyas part of an aromatic ring (e.g., thiophene,phenothiazine).

The increase in lipophilicity can offset the metabolicinstability

Analysis of Thioether Functional Group:Shape: S is similar in size to ethyl group, 90° bond

angles.hydrophilic (thiol = 0)non-polarneutralBinding Interactions: vdWmetabolically unstable.

Thioether Groups in DrugsSummary:



Functional Groups

Amines

:

HN

MeH

methylamine

NH

NH2HOSerotonin (5-hydroxytrypamine - 5-HT)

NHMe

OH

Me

Ephedrine

(a primary amine)

(a secondary amine)

Amines - Properties

triethylamine

(a tertiary amine)N Solubility = 14g/100mL

Water Solubility: in simple amines, each amino group can "solubilize" 6–7 carbons.

In polyfunctional drugs, each amino group can solubilize 3–4 carbons.NOTE: Salt formation can increase the solubilitysignificantly.

Lipophilicity: amine = -1.0

Amines can donate (1° and 2°) and accept H-bonds.

Acidity / Basicity

Simple amines

NH3 + H3O+ NH4+ + H2O

Base Conjugate Acid

:

Typically, we talk about the Deprotonation of the Conjugate acid:

NH4+ + H2O NH3 + H3O+

pKa

:

Amines - Properties

Amine Conjugate pKa (BH)Acid

NH3 N+H4 9.2CH3NH2 CH3N+H3 10.6(CH3)2NH (CH3)2N+H2 10.7(CH3)3N (CH3)3N+H 9.8

Little change in basicity of amines with alkylsubstitution.

Amines - Properties

Amines - Metabolism: Oxidation:

Methylation / N-dealkylation

N

O

OH

O

Atropine

N

O

OH

O

O

Atropine N-oxide

N-methylnicotineNicotine

enzyme

enzyme

N

NCH3

N

N+

H3CCH3

Amine oxide

QuateraryAmmoniumion

enzyme

Amines as Drugs

The amino functional group is the most common functional group in drugs:

• Many biogenic amines are natural receptor ligands.• Amines can exist in the unprotonated (lipophilic) form,

which enables passive diffusion through membranes,as well as in the protonated, ionized form, whichallows for interaction with receptors (and improved water solubility).

• The relative insensitivity of pKa to substitutent effectsallows for a wide variety of structural variation in amine-containing drugs while maintaining desiredpKa and lipophilic/hydrophilic balance.

Analysis of Amine Functional Group:Shape: N is similar in size to CH2 group, tetrahedralhydrophilic (amine = -1)very polarbasicBinding Interactions: ionic, H-Bond, Can be metabolically unstable.

Amine Groups in DrugsSummary:



Functional Groups

Anilines: Properties

N,N-Dimethylaniline

N(CH3)

:

2

Solubility = 1.4g/100mL H2O

Solubilization, Hydrophilicity similar to amines

pKa ~ 4ConjugateAcid

Anilines: Properties

N+(CH2CH3)

N,N-Diethylaniline

N(CH2CH3)

:

H

<=>

+ H+

2

2

Compare to simple amines with pKa of 9-10!

N,N-Diethylaniline

Anilines: Resonance Effects

N(CH2CH3):

N(CH2CH3)+

– 2

N(CH2CH3)+

–2

N(CH2CH3)+

–

2

2

Anilines - Metabolism

Conjugation:

H2N

OHCO2H

HN

OHCO2H

HO

O

HOOH

HO2Cenzyme

Anilines as Drugs

The aniline functional group occurs in a number of drugs.

Although the analine group is similar to the amino groupIn hydrophilicity and solubilzation, it is only very weakly basic

The aniline group can be metabolically unstable.

Analysis of Aniline Functional Group:Shape: N is similar in size to CH2 group, planarhydrophilic (aniline = -1)polarweakly basicBinding Interactions: H-Bond, dipolar, ionicCan be metabolically unstable.

Aniline Groups in DrugsSummary:

Review of Functional Group pKa(In units of Fives)

Functional Approx. pKa

GroupAlcohols ROH ~15 NeutralPhenols PhOH ~10 Weak AcidsAmines RNH3

+ ~10 BasesAnilines PhNH3

+ ~5 Weak Bases

Other Basic Functional Groups

N

Pyridine

pKa = 5

Is the nitrogen lp involvedIn (aromatic) resonance?

:

Is this nitrogen lp involvedin (aromatic) resonance?

NH

N

Imidazole:

:

pKa = 7

Why is this “amine” so differentFrom trimethyl amine?

Why is imidazole so differentFrom pyridine?


N

N+

H

H

N+

N

H

H

Resonance stabilization of the protonated formIncreases the pKa relative to pyridine


R

NH

NH2 NH

NH

NH2

R

AmidinepKa ~ 12 Guanidine

pKa ~ 12

R

N+

NH

HH

HR

N

N+

HH

H

H

Resonance stabilizationOf the protonated formIncreases the pKaRelative to simple amines

What is the pKa of N-methylnicotine?

N

N+

H3CCH3

Identify the basic functional group(s).

Pyridines have pKa’s ~ 5–6



Functional Groups

Carbonyl Compounds

OR

'R

R’R

O

R’R

O–

+

Aldehydes and Ketones - Properties

H H

O

Me H

O

H

O

Formaldehyde Acetaldehyde

Benzaldehyde bp 179 °C, 0.3g/100 mL H2O

Compare benzyl alcohol

H

OH

H

bp 205 °C, 4g/100 mL H2O

In simple carbonyl compoundAldehyde and ketone groupsSolubilize 4-6 carbons.In polyfunctional drugs, each aldehyde or ketone group can solubilize 2 carbons.

Aldehydes and Ketones - Chemistry:Hydration

+ H2OO

Cl3C H

chloral

OH

Cl3C H

OH

chloral hydrate

O–

Cl3C H+

:


O

R R’+ H2O

R’

OH

R

OH

If R is electron withdrawing, the unfavorable dipole-dipoleInteraction with the carbonyl group destabilizes theCarbonyl form and facilitates formation of the hydrate

carbonyl Carbonyl hydrate

Aldehydes and Ketones - Chemistry:Acetal/Ketal Formation

R H

O+ R'OH

H+

R H

R'O OH

+ R'OH

H+

R H

R'O OR'

aldehyde hemiacetal acetalalcohol

Intramolecular:

OHH

HHO

OHH

OHH

CH2OH

OH

H+

OHO

HO

OHOH

H

OH

Other Nucleophiles too (e.g., protein thiol, hydroxyl groups)


HO

NH2

OHOH2N

NH2OR

HO

HO HO

NH2

OHOH2N

NH2OR

HO

OP

O–O

–O

BacterialEnzyme

AminoglycosideAntibiotic INACTIVE

HO

NH2

OOH

H2N

NH2OR

HO

O

HOP

O

–O

–O

HO

NH2

OOH

H2N

NH2OR

HO

HO

HO

H2OOHO

NH2

OHOH2N

NH2OR

HO

BacterialEnzyme

– HPO42-

Spontaneous

Aldehydes - Chemistry:Reactivity

O

R H

O

R OH

Air

O

O

O

R

RR

Acid

Aldehydes /Ketones - Chemistry:Tautomers

RR'

OH

Enol

RR'

O

KetoHH

RR'

O–

HH

+

:

Tautomers: Differ only in the attachment of one proton

RR'

O+

–

H

Aldehydes /Ketones - Chemistry:Enolization

RR'

O

KetoHH

RR'

O

–

RR'

O

Enolate

–

+ H+

pKa ~ 20

BUT: if R’ is alsoC=O, pKa ~ 10.

Aldehydes /Ketones - Chemistry:Imine formation

R' R

O "RNH2

R' R

N

R"

Ketone orAldehyde (R = H)

Imine (Shiff’s Base)

Aldehydes /Ketones - Metabolism:Oxidation/Reduction

R

R'

OHR

R'

OOxidation

Reduction

R' = H AldehydeR ≠ H Ketone

Alcohol

R

OH

O

R' = H

Oxidation

Reduction

Acid

Aldehydes / Ketones in Drugs

Very few drugs possess the aldehyde functional group dueTo its chemical and metabolic instability.

A number of drugs contain the ketone functional group,which is generally part of a ring or, if acyclic, is often Flanked by at least one aromatic group (reduces reactivity).

O

O

OH

Nabilone

O

OH

9-THC

Analysis of Ketone and Aldehyde Functional Groups:Shape: C=O is similar is size to C=CH2 group,

planarhydrophilicpolarneutral or weakly acidicBinding Interactions: dipolar, H-Bond, covalentCan be chemically and metabolically unstable.

Ketone/Aldehyde Groups in DrugsSummary:



Functional Groups

Carboxylic Acids

H3C OH

OAcetic acid

Benzoic acidO

OH

bp = 250 °C, 0.34g/100 mL H2O

In simple carboxylic acids the carboxylic acid groupCan solubilize 5-6 carbons.In polyfunctional drugs, each carboxylic acid group can solubilize 3 carbons.

Carboxylic Acids

O

OHNaOH

0.34g/100 mL H2O

O

O–Na+

55 g/100 mL H2O

Carboxylic acid salts are much more soluble thanCarboxylic acids.

H3C OH

O

O

OH

pKa = 4.76

H OH

O

pKa = 3.75

pKa = 4.21

O

OH

O2N

pKa = 3.50

Review of Inductive Effect

Carbocation Stability:

Primary

Secondary

Tertiary

Least Stable

Most Stable

H3C CH3

H3C CH3

CH3

H

H H

H

+

+

+

Ion–Dipole Interactions

An ionic center interacts favorably with a properly aligned dipole.

+q’ -q +q

+q -q-q’

PEIon-Dipole q / r2

C H

For an average C–H bond, the dipole is:

+H H

H

+ =H3C CH3

CH3

+ = +

Inductive effect is an Ion–bond dipole effect

+H3C CH3

CH3

+ =

CH bond Inductive Effect Stabilizes Positive charges

Good

H3C CH3

CH3

– –Bad

CH bond Inductive Effect Destabilizes Negative charges

=

Review of the Inductive Effect:

H

HH

C O–F

FF

O

C O–

Which is more inductively Stabilized?

or

What are the bond dipoles involved?

O

Review of the Inductive Effect:

Which is more inductively Stabilized?(Least inductively de-stabilized)

or

What are the bond dipoles involved?

H

HH

O–

What is the magnitude of this effect?

q / r2PEIon-dipole C–H bond = 0.2 D1 debye (D) = 3.336 x 10-30 coulomb meters

SMALL

O

HO–

O

R

O

OH

HO

O

R

Carboxylic Acids - Properties

Hydrogen bonding (2-3)

Polar

carboxyl = -0.7

Carboxylic Acids - Metabolism

R

O

OH R

O

NH

CO2Henzyme

Conjugation:

-oxidation:

And other conjugation reactions

O

OH R

O

OHR

enzyme

Carboxylic Acids in Drugs

A large number of drugs contain the carboxylic acid functionality.

The chemistry of the carboxylic acid functionality is dominated by its acidity.

Carboxylic acids can be metabolically unstable.

Analysis of Carboxyl Functional Group:Shape: Similar in size to -CH(Me)2 group , planarhydrophilic (carboxyl = -0.7)polarweakly acidicBinding Interactions: ionic (metal ion coordination),

H-Bond, Can be metabolically unstable.

Carboxylic Acid Groups in DrugsSummary:

Esters - PropertiesO

OCH3Methyl benzoate bp = 199 °C

0.016g/100 mLH2O

In simple esters the ester functional groupCan solubilize 5-6 carbons.

In polyfunctional drugs, each ester group can solubilize 3 carbons. Each ester functional group can accept up to 2

Hydrogen bondsPolar, but neutral

ester = -0.7

N

O

O

Me

O

O

CH3

O

CH3

Heroin

N

O

O

Me

OH

Me

codeine

N

O

O

H

Me

OH

morphinelogP = 0.89 logP = 1.19

logP = 1.58

O'R

O

R

Esters - Properties

O'R

O

R

Tetrahedral O–R OxygenRelatively free rotation about the C–O bond

Esters - Chemistry/Metabolism:Hydrolysis

–OH

R'

OR

–O OH

Tetrahedral Intermediate

R' OR

OAcid, baseor enzyme

R'

HORO

OHH2O

Amides - Properties

O

NH2

Benzamidebp = 288 °C 1.35 g/100 mL H2O

In simple amides the amide functional groupCan solubilize 6 carbons.

In polyfunctional drugs, each amide group can solubilize 2-3 carbons. Each amide functional group can accept up to 2

Hydrogen bonds and donate 0-2 H-bonds (depending on the number of N-substituents)

Polar, but neutral

amide = -0.7

O'R

O

R

O'R

R

NH

Amides vs. Esters

O'R

O

R

N is planarRestricted rotation about C–N bond

'R NR

O

H

'R N+R

O–

H

Resonance - NOT tautomerization

N OH NH

O

Tautomerization

Amides - Chemistry/Metabolism:Hydrolysis

'R NH

R

OStrong Acidor enzyme

H2O 'R

H2NRO

OH

H2O

R'

NH

RHO OH

Tetrahedral Intermediate

H +

H

+

Esters and Amides - Chemistry:Hydrolysis

Ester hydrolysis occurs more readily than amide hydrolysis, both chemically and in vivo (esterases).

Esters and Amides in Drugs:

Acyclic esters are most often used as pro-drugs of thecorresponding carboxylic acids.

Cyclic esters are more stable to hydrolysis, and can be found in a variety of drugs.

Both acyclic and cyclic amide functional groupsare found in a number of drugs.

Pro-Drug: a compound that is inactive, but whichundergoes metabolic transformation to anactive form.

Analysis of Ester (CO2R) Functional Group:Shape: Similar in size to -CH(Me)2 group , C=O planar,

-OR oxygen tetrahedral, relatively free C–O bondrotation

hydrophilic (ester = -0.7)polarneutralBinding Interactions: H-Bond, dipolarIs chemically, metabolically unstable.

Easter and Amide Groups in DrugsSummary:

Analysis of Amide Functional Group:Shape: Similar in size to -CH(Me)2 group , planar,

restricted C–N bond rotationhydrophilic (ester = -0.7)polarneutralBinding Interactions: H-Bond, dipolarCan be metabolically unstable.

Easter and Amide Groups in DrugsSummary:

QUIZO

N

Me

Amide

O

O OH

Ether

Alcohol / Hydroxyl group

Insoluble (simple amide-> 6 carbons)

Insoluble (OH -> 3-4 C’s, two ethers -> 2* 2 C’s)

logPpred. = (2*2)+0.5+(-0.7) = 3.8

logPpred. = (2*2)+(4*0.5)+(2*-1) = 4.0

CO2H

O

Me

Me

Me

Ketone - Carbonyl group

Alkene

Carboxylic Acid - Carboxylgroup

Insoluble (simple ketone -> 5-6 C’s)

Insoluble (simple carboxylic acid -> 6-7 C’s)

logPpred. = (13*0.5)+(-0.7) = 5.8

logPpred. =2+ (6*0.5)+(-0.7) = 4.3

O

O Me

MeO2C

Ester - Carbomethoxy group

Borderline Soluble (two esters-> 2*3 C’s)

logPpred. = (2*2)+(2*0.5)+(2*-0.7) = 3.6



Functional Groups

Read Lemke p 77-78

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MedChem Exams > 143M_P_03W