Medchem Exams > 143m_p_03w

PHR 143M ­ Dr. Patrick Davis, Course Coordinator PHR 5.112 475­9751 [email protected] PHR 143P ­ Dr. Sean Kerwin, Course Coordinator PHR 4.220E 471­5074 [email protected] TA’s: Asha Nadipuram  [email protected] PHR 4.212; 471­7546 Bodin Tuesuwan  [email protected] PHR 3.204A; 471­5859 Liping Feng  [email protected]  PHR 3.204A; 471­5859 Scott Miller [email protected] PHR 4.116;  471­8860 Troy Purvis  [email protected]  PHR 1.116A;  471­3027 Megan Cornwell  [email protected] ARC 1.240;  232­2785 Hector Serrano  [email protected]  PHR 4.116;  471­8860

Class Times: PHR 143M PHR 143P

F 1­2pm F 2­3pm

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

 

PHR 3.106 PHR 3.106 (Pre­Lab)

PHR 2.116 PHR 2.116

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 2017

2018

2012 2011

~ 5 Compounds

1 Compound

Market Phase 4

2010

2003

>10,000 Compounds

Phase 3 Phase 2 Phase 1 Development

Discovery

Drug Discovery Overview Target identification: The selection of a specific receptor and/or properties that are expected to 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 and synthesizing 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

Where do the 10,000+ Compounds Come From? Observation Screening Rational Design

Lead Optimization

“Lead Compound”

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 Does It Fit in this Process? Medicinal Chemistry is broadly defined as the study of the chemistry Related 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 the Selection of Leads, and Lead Optimization. It is also essential for understanding the following properties of drugs: ­  Chemical compatibility, stability, ADME, potency, and selectivity

What is Medicinal Chemistry and Where Does It Fit in this Process? Much of Medicinal Chemistry is concerned with defining the  relationship between the structure of a chemical compound and  its biological activity. Elucidating Structure­Activity Relationships  (SAR) is a key function of medicinal chemistry

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

Physicochemical Properties

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

Oral Administration Gastrointestinal Tract

DRUG

Biological Activity

Other Parenteral Administration

Intravenous Injection

Tissue depots

DRUG

DRUG DRUG

Receptor(s) for Desired Effect(s)

Serum Albumin

DRUG

DRUG-DRUG METABOLITES

Liver

Intestinal Tract

DRUG-DRUG METABOLITES

Kidney Excretion

DRUG-DRUG METABOLITES DRUG-DRUG METABOLITES

Receptor(s) for Undesired Effect(s)

Medicinal Chemist use their knowledge of these relationships 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 Functional Group Interconversions Functional Group Reactions

Medicinal Functional Group Metabolism/ Degradation Functional Group Interactions

Historical Perspective: "One functional group - One biological activity" H3C

N CH3

O

HO

OH

Morphine - analgesic N CH3

N

O

HO

OH

N-Methylmorphine

N

Nicotine - stimulant

N+ CH3

N+ H3C CH3

N-Methylnicotine H3C N+ CH3

H3C N H O

H

OH O

O

Atropine - mydriatic

OH

O

N-Methylatropine

m u s c l e r e l a x a n t s

Current understanding of SAR focuses on the chemical Nature 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.

The Drug Skeletons (Frameworks): Alkanes Alkenes Alkynes Aromatic Hydrocarbons Aromatic Heterocycles (Heteroaromatics)

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Drug Molecule Evaluation Analysis of Individual Functional Groups: Name Shape Hydrophobic/Hydrophilic Character Polar vs. Non-polar Character Acid/Base Character Binding Interactions Chemical/Enzymatic Stability Analysis of the Whole Molecule Functional Group Interactions Functional Group Balance: Physicochemical Prop. Ionization State Drug Combinations: Chemical Interactions

Hydrocarbons - Alkanes Alkanes - CnH2n+2

bp = H

methane - CH4

H H

- 161 °C

H

H

ethane - C2H6

H

H

- 89°C

H

H

propane - C3H8

H H

H CH3

H

H H

- 42 °C

Understanding the Physical Properties of Alkanes Dispersion Interaction - van der Waals attraction “instantaneous” dipoles Averaged over time, the electron density on the surface of an alkane is uniform

–

+

+–

+

+–

–

But at any one moment, the distribution is uneven. Some areas are electron-rich (dark) While others are electron poor (light). Electron poor areas of one molecule can induce a complementary electronrich area in an adjacent molecule. The result is an attraction between the two.

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 dependent On the distance between the two molecules - it is Only important when the molecules are very close Together.

Alkanes Effect of Branching: n-Butane

bp = - 0.5 °C

CH3CH2CH2CH3

iso-Butane (CH3)3CH

- 12 °C

Alkanes Effect of Branching: n-Butane

bp = - 0.5 °C

effective dispersion interaction between mols.

iso-Butane

- 12 °C

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 drugs modified by functional groups. Example - the branching effect that tends to decrease bp in simple alkanes is the same effect that causes drugs with branched alkyl side chains to be more water soluble than those with linear alkyl side chains (of the same # of atoms).

Remember: Water solubility - How well does water interact with molecules Vs. molecules interact with each other (crystal packing). H

H

O

H

H H

H H

O H

H H H

H

H

O

O

O

H

O

O

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

Partition Coefficient (LogP)

Octanol/Water

HO

OH

HO HO

HO

HO HO

H H

O H H

O

HO

HO

HO HO

HO

H

drug

OH

HO

O

H

HO

HO

H

O

H

LogP = Log

OH

HO HO HO

OH

O H H

HO

HO

HO

H

O

H

O H H

HO

OH

HO HO

HO HO

HO

H

OH

O H H

Octanol/Water

O

H

H

Conc. In Octanol Layer Conc. In Water Layer

O

H

For two drugs of similar structure, the drug with More potential for intermolecular van der Waals Interactions 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

Example: Barbiturates

Butabarbital O

NH

O

Butethal O

NH NH

NH O

Sl. Sol in water logP = 1.65

O

O

Water insol. logP = 1.73

Hydrocarbons - Alkenes: π bond: Shared electrons that Ethylene CH2=CH2 H H are not in the same plane as the atoms. Properties associated with alkenes (π bonds): • Attack by electrophiles: H

H

"electrophilic oxygen"

O

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

Alkenes Reactivity: Oxidation

O2

H R

R'

Alkene

OH O R

R'

Hydroperoxide

Decomposition

Alkenes: Properties associated with alkenes (π bonds): • Isomerization - (E)/(Z) isomers 2-butene

H3 C H

CH3

(Z)

H3 C H

H

H

(E)

CH3

Restricted bond rotation about C=C - Double bond migration OH

O

∆9­THC

OH

O

∆8­THC

Alkenes: Properties associated with alkenes (π bonds): • Conjugation with other functional groups

EDG

EDG

- can alter alkene’s properties

EWG

EWG

Conjugation - electronic coupling of functional groups of portions of molecules through π electrons.

H H

O CH3

Hydrocarbons - Alkynes: H

H

acetylene H

H

Linear, electron rich, can be reactive Only a few drugs are alkynes Me N

Terbinafine

Me

Me Me

(antifungal)

Aromatic Hydrocarbons H H

Benzene

H

H

H H

H H

H H

H H

H

H H

H

H H

pi-cloud: resonance forms delocalized: aromatics are not as reactive as alkenes Aromatic: 4n+2 pi-electrons delocalized in a ring = Hückel’s Rule Benzene: 3 double bonds =6 pi-electron = (4*1)+2

Aromatic Hydrocarbons

Naphthalene 10 π electrons = (4*2)+2

Anthracene 14 π electrons = (4*3)+2

Hückel Series: 2, 6, 10, 14, 18, …

Phenanthrene 14 π electrons = (4*3)+2

Aromatic Heterocycles General Rule:

:

N

N

:

pyridine

N H

pyrrole

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

N lone pair is in the π system -> it counts 6 π electrons -> aromatic

X:

Lone pair not in π system

X:

Lone pair is in π system

Aromatic Heterocycles

N N

N

pyridine

N H

pyrrole

pyrimidine

O

furan

S

thiophene

All are 6 π electron aromatic systems

Other Common Aromatic Heterocycles H N

H N

N

O

imidazole

H N

oxazole

H N N N

s-triazole

H N

O

S

isoxazole

Thiazole

S N N

1,3,4-thiadiazole

Other Common Aromatic Heterocycles N N H

Indole

O

Benzofuran

N

N N

N H

Benzimidazole

N

N

Quinoline

N H

Isoquinoline N

N N

N

Pteridine

N

Acridine

Other Common Heterocycles (Not Aromatic) H N

N H

N

piperidine

1H-1,4-benzodiazepine O S N H

phenothiazine

N H

morpholine

H N N H

piperazine

Properties of Aromatics Physical properties are similar to structurally related alkenes Charge-transfer and cation-π interactions: ElectronRich aromatic + Electronpoor aromatic

ChargeTransfer Complex

O

O

O

O

ElectronRich aromatic

R

+ cation

R N

N

cationπ Complex

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Halogens Br

methylbromide

H H

H

iodoform CHI3

Halothane CF3CHBrCl

Halogens Increased sterics (size) relative to Hydrogen Can be reactive (alkylators) except when halogen is attached to aromatic ring) Br Br R

Nu:

H

H

H

H Nu

­

R

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

Log P = 2.13

∆(log P) = +0.71

Log P = 2.84

So each chlorine added to a drug increases Log P by ~0.7 We can derive a simple equation for predicting the log P of A drug: Log Pdrug = πskeleton + πfunct. Group 1 + πfunct. Group 2 + .. or Log Pdrug = Σ πfragments

Halogens πC (aliphatic) = +0.5 πPh = +2.0 πF = +0.14 πCl = +0.5 πBr = +0.86

Halothane CF3CHBrCl 2 C (aliphatic) = 2 x 0.5 = 3 Fluorine = 3 x 0.14 = 1 Chlorine = 1 Bromine = Predicted LogP =

1 0.42 0.5 0.82 2.74

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

Halogens Dipoles -q

r

+q

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: +q

­q

H

Cl

H

Cl

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

Halogens Average Electronegativities of Selected Elements. H (2.21) Li (0.98) Na (0.93) K (0.82)

C (2.55)

N (3.04) P (2.19)

O (3.44) S (2.58)

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

H

F (3.98) Cl (3.16) Br (2.96) I (2.66)

Halogens Bond Dipole Moment (D) H

Hydrogen Chloride

Cl

Resultant 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

Methane

C H H H H

Ammonia

H

:

N H H

Water

H

:

O

: Cl

Chloromethane

H

C H H

Halogens in Drugs: Halogenated hydrocarbons can be more polar than Simple hydrocarbons due to the molecular dipoles that can result from halogen-carbon bond dipoles. In all but the Simplest halogenated hydrocarbons, this effect is typically Small due to the size of the halogens (prevents effective Dipole-dipole interactions) and the number of other bond dipoles involved.

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

Halogens in Drugs:

Cl

Halogens attached to aromatic rings withdraw electron Density from the aromatic ring, making it less easily Attacked 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.

Halogens in Drugs Summary: Analysis of Halogen Functional Groups: Shape: Spherical, large: F < Cl < Br < I Hydrophobic: F < Cl < Br < I Slightly Polar due to bond dipoles Neutral Binding Interactions: Increased size and potential for vdW interactions Can be chemically unstable (aliphatic), decrease metabolism (aromatic)

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Alcohols Solubility bp    (g/100mL H2O) methanol CH3OH : Me H

66 °C

∞

117  °C

7.9

100 °C   82 °C  

12.5  ∞ 

137 °C

2.3

O

1-butanol CH3CH2CH2CH2OH a primary alcohol

2-butanol CH3CH2CH(OH)CH3 a secondary alcohol

tert-butanol (CH3)3COH a tertiary alcohol

1-pentanol CH3CH2CH2CH2CH2OH

Alcohols Hydrogen bonding:

R

H O

H

R O

Each Hydroxyl group Can donate one and Accept two H-bonds = 3 potential H-bonds

Compare the bp of ethane (-89 °C) to methanol (66 °C). What does this tell us about the strength of Hydrogen bonds versus van der Waals interactions? vdW interaction (C - C) ~ 0.5 kcal/mole H-bond ~ 2-5 kcal/mole

Alcohols Hydrogen bonding:

R

H O

H

R O

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

Alcohols Water Solubility: in simple alcohols, each Hydroxyl group can "solubilize" 5–6 carbons. In polyfunctional drugs, each hydroxyl group can solubilize 3–4 carbons. Lipophilicity: πaliphatic OH = -1.0

Homologation: Alcohols

n = 7 (n-octanol)

CNS Depressant Activity 1

4

7

n

CH3(CH2)nOH

10

Oral Administration Gastrointestinal Tract

DRUG

Biological Activity

Other Parenteral Administration

Intravenous Injection

Tissue depots

DRUG

DRUG DRUG

Receptor(s) for Desired Effect(s)

Serum Albumin

DRUG

DRUG-DRUG METABOLITES

Liver

Intestinal Tract

DRUG-DRUG METABOLITES

Kidney Excretion

DRUG-DRUG METABOLITES DRUG-DRUG METABOLITES

Receptor(s) for Undesired Effect(s)

Octanol and Biological Membranes O

n

O

O O

n

O

= O– P

O

OH

H2O

O R

~

Alcohols - Metabolism Oxidation: R

OH R'

Alcohol

Oxidation

Reduction

R' = H

R

O R'

Oxidation Reduction

R' = H  Aldehyde R ≠ H  Ketone

R

O OH Acid

Alcohols - Metabolism Conjugation: R'

HO R

enzyme

HO2C HO HO

O OH

R'

O R

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 metabolic transformations.

Hydroxyl Groups in Drugs Summary: Analysis of Hydroxyl Functional Group: Shape: Similar in size to a methyl group. Hydrophilic Polar due to H-bond potential (3) Neutral Binding Interactions: H-bonding Can be metabolically unstable

Ethers

Diethyl ether

O

Immiscible w/ water O

Tetrahydrofuran O

Miscible w/ water

1,4-dioxane O

oxirane (epoxide)

O

(Soluble in water in all proportions)

Ethers - Properties Ethers are not as polar as alcohols Water Solubility: in simple ethers, the ether group can "solubilize" 4–5 carbons. In polyfunctional drugs, each ether group can solubilize ~2 carbons. Lipophilicity: πether = -1.0 (excludes the added carbon(s))

Me

OH

N O

OH

morphine logP = 0.89

Me

OH

N O

O

codeine logP = 1.19

Me

Ethers Chemistry peroxide formation (low MW ethers) O

air

O

OH O

explosive!! Hydrolysis (strained ethers = epoxides) H2O: O

HO OH

Ethers Metabolism

R

Enzymatic De-alkylation enzyme O

CH3

enzyme S­adenosyl­ methionine (SAM)

:

R

OH

Ethers in Drugs Ether functional group is present in many drugs. It provides increased polarity for interaction with Receptor functional groups and is more metabolically Stable than the corresponding alcohol functional Group.

Ether Groups in Drugs Summary: 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, vdW Metabolically stable, except for possible dealkylation

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Phenols - Hydroxylated Aromatic Compounds OH

Solubility = 9.3g/100mL Compare:

OH

3.6 g/mL

phenol

OH

OH OH catechol

OH resorcinol

OH HO hydroquinone

Phenols - Hydroxylated Aromatic Compounds OH

­

O

+      H phenol

+

phenolate

The ability of phenols to give up a proton to water Distinguishes them from aliphatic alcohols: Phenols are (weakly) acidic. This accounts for the increased water solubility of phenols Relative to alcohols - the phenolate species, being charged Is 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 view We must be able to relate the answers to these Questions to the STRUCTURE of BH.

Acidity in Solution (Water) (BH)sol <=> (B –) sol + (H+) sol [(B –) sol] [(H+) sol]

Ka = [(BH) sol] pKa = - log (Ka)

pH = - log [(H+) sol]

Understanding Functional Group Acidity and Structural Effects Look at relative acidity - Compare two BH acids:

B1H <=> B1 – + H+ B2H <=> B2 – + H+

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

B – + H+

Common to all BH

If B2- is more stable than B1-, the pKa of B2H will LOWER be ________ than the pKa of B1H.

Phenols ­

OH

O

+

pKa ~ 16

+      H cyclohexanol

­

OH

O

+

+      H

pKa ~ 10

phenol

O

–

O

O

–

O

–

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

Phenols ­

OH

O

+

+      H

pKa ~ 10

phenol

To what extent is phenol ionized at pH 7? Henderson-Hassalbach Equation: pKa

=

pH

+ log

[BH] _____ [B-]

[BH] 10 = 7 +

[BH]

log [B ] -

[B-]

= 1,000

Phenol is ~0.1% ionized at pH 7. Phenol is a Very weak acid.

Phenols Substituent Effects O

R

O–

H

+

H+

R

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

DOWN goes _______

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: πphenol OH = -1.0 NOTE: πphenyl = +2.0

Phenols Chemical Instability Oxidation (NOTE: different from alcohols) O O

H

O O

Air

O

p-quinone

o-quinone

Phenols - Metabolism Conjugation (Similar to alcohols) OH

Enzyme

O

Enzyme

O

­

O

S O O

Methylation OH OH

Oxidation

OH

CH3

OH

Enzyme

OH 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 metabolic transformations and chemical instability.

Phenol Groups in Drugs Summary: Analysis of Phenol Functional Group: Shape: Phenol OH is similar in size to CH3 group. Hydrophilic Polar due to H-bond potential (3) and ionization Very weak acid Binding Interactions: H-bonding, dipole, ionic Chemically and Metabolically unstable.

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Thiols (Sulfhydryls)

CH3C2SH Ethanthiol (Ethyl mercaptan) bp = 37°C Solubility 1.5g/100mL H2O Compare ethanol: bp =78°C, miscible with water

Sulfur in thiols is large, lipophilic Thiols 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

H

O S

N HO2C

captopril

Thiols - Chemical Reactivity S R

thiol

H

air

S

S

R or R'

R

disulfide

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

Thiols - Chemical Reactivity

S R

thiol

H

S

S

R or R'

R

disulfide

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 as ligands for metal ions. Thiol functional groups are chemically unstable (disulfide) and associated with side effects.

Thiol Groups in Drugs Summary: Analysis of Thiol Functional Group: Shape: SH is similar in size to ethyl group. Hydrophobic&hydrophilic (πthiol = 0) weakly polar Very weak acid Binding Interactions: metal ion coordination Chemically unstable.

Thioethers R

Me

S

S

R'

Me

90°

Large, lipophilic, decreased bond angle relative To ethers (112°)

Thioethers

R

S

oxidation R'

thioether

O R

S

oxidation O

R'

sulfoxide

R

O S

sulfone

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

R'

Thioethers

:

S

Lone pair involved in resonance, Less available for oxidation

S O

O S

S

How readily is thiophene oxidized to the corresponding sulfoxide?

Thioethers in drugs A number drugs contain thioether groups, especially as part of an aromatic ring (e.g., thiophene, phenothiazine). The increase in lipophilicity can offset the metabolic instability

Thioether Groups in Drugs Summary: Analysis of Thioether Functional Group: Shape: S is similar in size to ethyl group, 90° bond angles. hydrophilic (πthiol = 0) non-polar neutral Binding Interactions: vdW metabolically unstable.

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Amines :

methylamine

Me H

N

H

(a primary amine)

Serotonin (5-hydroxytrypamine - 5-HT)

NH2

HO

N H

OH NHMe

Ephedrine (a secondary amine)

Me

Amines - Properties triethylamine

N

Solubility = 14g/100mL

(a tertiary amine)

Amines can donate (1° and 2°) and accept H-bonds. 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 solubility significantly. Lipophilicity: πamine = -1.0

Amines - Properties Acidity / Basicity

:

Simple amines NH3 + H3O+ Base

NH4+

+

H2 O

Conjugate Acid

:

Typically, we talk about the Deprotonation of the Conjugate acid: NH4+

+ H2O

NH3 pKa

+

H 3 O+

Amines - Properties Amine NH3 CH3NH2 (CH3)2NH (CH3)3N

Conjugate Acid N+H4 CH3N+H3 (CH3)2N+H2 (CH3)3N+H

pKa (BH) 9.2 10.6 10.7 9.8

Little change in basicity of amines with alkyl substitution.

Amines - Metabolism: Oxidation: N

N

Amine oxide

O

enzyme OH

OH

O

O O

O

Atropine

Atropine N-oxide

Methylation / N-dealkylation

N

N CH3

Nicotine

enzyme enzyme

N

N+ CH3 H3C

Quaterary Ammonium ion

N-methylnicotine

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, which allows for interaction with receptors (and improved water solubility). • The relative insensitivity of pKa to substitutent effects allows for a wide variety of structural variation in amine-containing drugs while maintaining desired pKa and lipophilic/hydrophilic balance.

Amine Groups in Drugs Summary: Analysis of Amine Functional Group: Shape: N is similar in size to CH2 group, tetrahedral hydrophilic (πamine = -1) very polar basic Binding Interactions: ionic, H-Bond, Can be metabolically unstable.

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

:

Anilines: Properties

N(CH3)

2

N,N-Dimethylaniline Solubility = 1.4g/100mL H2O

Solubilization, Hydrophilicity similar to amines

:

Anilines: Properties H N+(CH2CH3)

N(CH2CH3) 2

Conjugate Acid

> = <

pKa ~ 4

2

N,N-Diethylaniline +

Compare to simple amines with pKa of 9-10!

H+

:

Anilines: Resonance Effects N(CH2CH3)

+ N(CH2CH3)

2

N,N-Diethylaniline

+ N(CH2CH3)

–

–

2

–

2

+ N(CH2CH3) 2

Anilines - Metabolism Conjugation: H2N

enzyme OH

CO2 H

HO2C HO HO

O

H N

OH OH

CO2 H

Anilines as Drugs The aniline functional group occurs in a number of drugs. Although the analine group is similar to the amino group In hydrophilicity and solubilzation, it is only very weakly basic The aniline group can be metabolically unstable.

Aniline Groups in Drugs Summary: Analysis of Aniline Functional Group: Shape: N is similar in size to CH2 group, planar hydrophilic (πaniline = -1) polar weakly basic Binding Interactions: H-Bond, dipolar, ionic Can be metabolically unstable.

Review of Functional Group pKa (In units of Fives) Functional Group Alcohols Phenols Amines Anilines

Approx. pKa ROH PhOH RNH3+ PhNH3+

~15 ~10 ~10 ~5

Neutral Weak Acids Bases Weak Bases

Other Basic Functional Groups : N

Pyridine pKa = 5

Is the nitrogen lp involved In (aromatic) resonance?

N H

:

:

N

Imidazole pKa = 7

Is this nitrogen lp involved in (aromatic) resonance?

Why is this “amine” so different Why is imidazole so different From pyridine? From trimethyl amine?

Other Basic Functional Groups H

H

N+

N

N H

N+ H

Resonance stabilization of the protonated form Increases the pKa relative to pyridine

Other Basic Functional Groups NH R

R

NH2

Amidine pKa ~ 12

H

+H

N

R

N H

N H

NH2

Guanidine pKa ~ 12

H H

NH

N

H +H

R N H

Resonance stabilization Of the protonated form Increases the pKa Relative to simple amines

What is the pKa of N-methylnicotine?

N

N+ CH3 H3C

Identify the basic functional group(s). Pyridines have pKa’s ~ 5–6

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Carbonyl Compounds

O

'R

R’

R

O–

R

+

R’

R

O

Aldehydes and Ketones - Properties O

O

Formaldehyde Benzaldehyde

H

Acetaldehyde H

Me

H

O H

bp 179 °C, 0.3g/100 mL H2O Compare benzyl alcohol

In simple carbonyl compound Aldehyde and ketone groups Solubilize 4-6 carbons. In polyfunctional drugs, each aldehyde or ketone group can solubilize 2 carbons.

OH H H

bp 205 °C, 4g/100 mL H2O

Aldehydes and Ketones - Chemistry: Hydration O Cl3 C

H

chloral O– Cl3 C

+

H

+

H2O :

OH Cl3C

OH H

chloral hydrate

Aldehydes and Ketones - Chemistry: Hydration OH

O R

R’

carbonyl

+ H2 O

OH R

R’

Carbonyl hydrate

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

Aldehydes and Ketones - Chemistry: Acetal/Ketal Formation O R

H

+

aldehyde

H

R'OH

+

+

alcohol

R'O

OH

R

H

R'OH

H+

hemiacetal

R'O

OR'

R

H

acetal

Intramolecular: H H HO H H

O OH H OH OH CH2OH

H+

OH HO HO

O OH

H OH

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

Aldehydes and Ketones - Chemistry: Hydration Bacterial Enzyme

NH2 HO HO

H2N HO O HO

OR

NH2 –O

NH2

–O

Aminoglycoside Antibiotic

H2N HO O HO

O

H2N HO O HO

OR

NH2

INACTIVE

NH2 HO O

P

HO O

H2O OR

NH2

NH2 HO HO H2N OH O HO HO

OR

NH2

Bacterial Enzyme

Spontaneous

–  HPO42­ NH2 HO O H2N OH P O HO –O HO O –O

OR

NH2

Aldehydes - Chemistry: Reactivity Air

O R

O R

H

OH

Acid R O R

O O

R

:

Aldehydes /Ketones - Chemistry: Tautomers O R

OH

R'

H

R

H

Keto

Enol

O–

+ R H

R'

O+ R'

H

R

H

–

R'

Tautomers: Differ only in the attachment of one proton

Aldehydes /Ketones - Chemistry: Enolization O R

O R'

H

Keto

R'

R

H

Enolate

pKa ~ 20 BUT: if R’ is also C=O, pKa ~ 10.

–

O R

–

R'

+ H+

Aldehydes /Ketones - Chemistry: Imine formation

"R

O R'

R

Ketone or Aldehyde (R = H)

N

NH2 R'

R"

R

Imine (Shiff’s Base)

Aldehydes /Ketones - Metabolism: Oxidation/Reduction

R

OH R'

Alcohol

Oxidation

Reduction

R' = H

R

O R'

Oxidation Reduction

R' = H  Aldehyde R ≠ H  Ketone

R

O OH Acid

Aldehydes / Ketones in Drugs Very few drugs possess the aldehyde functional group due To 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 OH

O

Nabilone

OH

O

∆9­THC

Ketone/Aldehyde Groups in Drugs Summary: Analysis of Ketone and Aldehyde Functional Groups: Shape: C=O is similar is size to C=CH2 group, planar hydrophilic polar neutral or weakly acidic Binding Interactions: dipolar, H-Bond, covalent Can be chemically and metabolically unstable.

Functional Groups Halogens Alcohols Ethers Phenols Thiols Thioethers Sulfoxides Sulfones Amines Amine oxides Quaternary Ammonium ions Anilines Amidines Guanidines

Aldehydes Ketones Imines Carboxyic Acids Esters Amides Sulfonic Acids Sulfonamides

Carboxylic Acids O

Acetic acid H3 C

OH

O

Benzoic acid

OH

bp = 250 °C, 0.34g/100 mL H2O In simple carboxylic acids the carboxylic acid group Can solubilize 5-6 carbons. In polyfunctional drugs, each carboxylic acid group can solubilize 3 carbons.

Carboxylic Acids O

O OH

NaOH

0.34g/100 mL H2O

O– Na+

55 g/100 mL H2O

Carboxylic acid salts are much more soluble than Carboxylic acids.

O

pKa = 3.75

OH

H O

OH

H3 C

pKa = 4.76

O OH

O

pKa = 3.50 OH

O2 N

pKa = 4.21

Review of Inductive Effect Carbocation Stability: H

Least Stable

Primary

+ H

H H

H3C

+

Secondary CH3

CH3

Most Stable

Tertiary

+ H3C

CH3

Ion–Dipole Interactions An ionic center interacts favorably with a properly aligned dipole. +q’

-q

+q

-q’

+q

-q

PEIon-Dipole ∝   q / r2

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

H

Inductive effect is an Ion–bond dipole effect H + H

H

=

CH 3

+

+ H3 C

CH 3

=

+

CH bond Inductive Effect Stabilizes Positive charges CH3 + H3C

CH3

=

Good

+

CH bond Inductive Effect Destabilizes Negative charges

CH3 H3C

–

CH3

=

–

Bad

Review of the Inductive Effect: Which is more inductively Stabilized? O O F F

C

H

–

O

or F

H

C H

What are the bond dipoles involved?

O–

Review of the Inductive Effect: Which is more inductively Stabilized? (Least inductively de-stabilized) O

O H H

–

O

or

H

O–

H

What are the bond dipoles involved? What is the magnitude of this effect? SMALL PEIon-dipole ∝   q / r2

C–H bond = 0.2 D 1 debye (D) = 3.336 x 10-30 coulomb meters

Carboxylic Acids - Properties

O R

H O

H

Hydrogen bonding (2-3) Polar πcarboxyl = -0.7

O

R O

Carboxylic Acids - Metabolism Conjugation: O R

O

enzyme OH

R

N H

CO2H

And other conjugation reactions β-oxidation: O R

O

enzyme OH

R

OH

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.

Carboxylic Acid Groups in Drugs Summary: Analysis of Carboxyl Functional Group: Shape: Similar in size to -CH(Me)2 group , planar hydrophilic (πcarboxyl = -0.7) polar weakly acidic Binding Interactions: ionic (metal ion coordination), H-Bond, Can be metabolically unstable.

Esters - Properties O

Methyl benzoate

O

CH3

bp = 199 °C 0.016g/100 mLH2O

In simple esters the ester functional group Can solubilize 5-6 carbons. In polyfunctional drugs, each ester group can solubilize 3 carbons. Each ester functional group can accept up to 2 Hydrogen bonds Polar, but neutral πester = -0.7

Me

OH

N

Me

O

OH

N O

H

O

O

codeine

morphine logP = 0.89

logP = 1.19

O

Me

Me

CH3

O

N O O O

Heroin

CH3

logP = 1.58

Esters - Properties 'R

'R

O

O R

O

O

R

Tetrahedral O–R Oxygen Relatively free rotation about the C–O bond

Esters - Chemistry/Metabolism: Hydrolysis Acid, base or enzyme

O R'

O

R

H2O

–

OH

–

O

R '

OH O

R

Tetrahedral Intermediate

O R'

HO OH

R

Amides - Properties O

Benzamide

NH2

bp = 288 °C 1.35 g/100 mL H2O

In simple amides the amide functional group Can 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 πamide = -0.7

Amides vs. Esters 'R

'R

O

O

O R

R

'R H

O

N R

N is planar Restricted rotation about C–N bond

O

O–

O 'R

N

R

'R

+

N

R

H

H

Resonance - NOT tautomerization

N

OH

N H

Tautomerization

O

Amides - Chemistry/Metabolism: Hydrolysis H

'R

O

+ N H

R

Strong Acid or enzyme H2O

H2O HO

OH

+ R R N ' HH Tetrahedral Intermediate

O 'R

H2N OH

R

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 the corresponding carboxylic acids. Cyclic esters are more stable to hydrolysis, and can be found in a variety of drugs. Both acyclic and cyclic amide functional groups are found in a number of drugs. Pro-Drug: a compound that is inactive, but which undergoes metabolic transformation to an active form.

Easter and Amide Groups in Drugs Summary: 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 bond rotation hydrophilic (πester = -0.7) polar neutral Binding Interactions: H-Bond, dipolar Is chemically, metabolically unstable.

Easter and Amide Groups in Drugs Summary: Analysis of Amide Functional Group: Shape: Similar in size to -CH(Me)2 group , planar, restricted C–N bond rotation hydrophilic (πester = -0.7) polar neutral Binding Interactions: H-Bond, dipolar Can be metabolically unstable.

QUIZ O

Amide

N Me

Insoluble (simple amide -> 6 carbons) logPpred. = (2*2)+0.5+(-0.7) = 3.8

Ether O O

Alcohol / Hydroxyl group OH

Insoluble (OH -> 3-4 C’s, two ethers -> 2* 2 C’s) logPpred. = (2*2)+(4*0.5)+(2*-1) = 4.0

O Me Me

Ketone - Carbonyl group Alkene

Me

CO2 H

Insoluble (simple ketone -> 5-6 C’s) logPpred. = (13*0.5)+(-0.7) = 5.8 Carboxylic Acid - Carboxyl group Insoluble (simple carboxylic acid -> 6-7 C’s) logPpred. =2+ (6*0.5)+(-0.7) = 4.3

O MeO2 C O

Me

Ester - Carbomethoxy group Borderline Soluble (two esters -> 2*3 C’s) logPpred. = (2*2)+(2*0.5)+(2*-0.7) = 3.6

Functional Groups Halogens Alcohols Aldehydes Ethers Ketones Phenols Imines Thiols Carboxyic Acids Thioethers Esters Sulfoxides Amides Sulfones Sulfonic Acids Amines Sulfonamides Amine oxides Quaternary Ammonium ions Anilines Amidines Read Lemke p 77-78 Guanidines