Exam 2- Lecture 8: Hydrogen Bonding

What is a hydrogen bond?

Reversible, non-covalent electrostatic interaction b/w H atom that is covalently bonded to an electronegative atom (X-H; HBD) & lone pair of electrons on another electronegative atom (:Y; HBA)

What do FG interactions depend on in med chem?

• # of interactions

• Type & strength

What are the most common X-H as HBD?

• O-H

• N-H

• S-H (less common)

What are the most common :Y as HBA?

• :O

• :N

• :S (less common)

• :F (less common)

What happens in cases where one lone pair of electrons is involved in resonance & not available as a HBA?

Other lone pair can act as a weak HBA

What does lone pair electron availability of N or O big general increase?

HBA strength

Alcohol

HBA & HBD

Phenol

HBD & weak HBA

Ether

HBA

Aromatic ether

Weak HBA

Ester

HBA & weak HBA

CA

HBA, weak HBA, HBD

Carboxylate ion

HBA

Aldehyde

HBA

Ketone

HBA

1 & 2 amine

HBA & HBD

3 amine

HBA

Aromatic 2 amine

HBD

Aminium ions

HBD

3 amide

HBA

1 & 2 amide

HBA & HBD

Beta-lactam

HBA

What is aromaticity?

Unusual thermodynamic stability that arises when a cyclic, planar fully conjugated system contains (4n+2) pi electronics, allowing continuous delocalization of electron density around ring (“Huckel’s rule”)

What if lone pair of electrons are required to maintain aromaticity (to satisfy Huckel’s rule)?

Those lone pair electrons are NOT available/CANNOT act as HBA

What are the most common lipid-soluble FGs?

• Aromatic rings & ring systems

• Alkyl chains (aliphatic)

• Alicylic rings

• Alkenes

• Alkynes

• Halogens

What are the lipid soluble FGs capable of?

• NOT H2O soluble

1. Cannot ionize

2. Cannot participate in H bonding

CANNOT form productive interactions/bonds w/ H2O

What do these factors effect H2O solubility?

• FG ionization (charge formation): increase very strongly

  • Charged species interact strongly w/ polar H2O molecules (via ion-dipole int)

• HBD: increase

  • Donate H bonds to H2O

• HBA: increase

  • Accept H bonds from H2O

• Polarity/dipole moment: increases Donate

  • Polar bond improve interactions w/ H2O (via dipole-dipole int)

• EWG: often increase

  • Can increase polarity & sometimes ionization of acidic FGs via decreased pKa

• Molecular size/ MW: decrease

  • Large SA increases hydrophobic character

• Lipophilicity (cLogP): decrease

  • Higher cLogP= prefers lipid over H2O

• Aromatic rings: decrease

  • Large hydrophobic pi-systems reduce polarity

• Alkyl groups: decrease

  • Increase hydrophobic SA

• Intramolecular H bonding: decrease

  • Reduces ability to intereact w/ H2O intermolecularly

What do Intramolecular H bonds prevent?

Intermolecular H bonds w/ H2O

What do you want a balance b/w?

H2O & lipid solubility

What is tetracycline?

20 mines more H2O soluble than doxycycline

What are the properties of doxycycline?

• Oral abs into systemic bloodstream: high (~90-100% due to balance)

• Effect of food on oral abs: minimal effect

• Tissue penetration: high

• Plasma t1/2: ~16-22 hrs

• Kidney/renal elim: minimal

What are the properties of tetracycline?

• Oral abs into systemic bloodstream: moderate (~60-70%)

• Effect of food on oral abs: food strongly decreases oral abs

• Tissue penetration: moderate

• Plasma t1/2: due to inc. H2O solubility ~6-8 hrs

• Kidney/renal elim: significant

What is the meaning of doxycycline vs. tetracycline?

• Doxy absorbs better orally

• Tetra must be taken on empty stomach to maximize efficacy

• Doxy penetrates tissues better to treat bacterial infection

• Doxy dosed less frequently/ better patient compliance

• Doxy is safer in kidney/renal failure patients

What is the critical principal that increases drug lipophilicity can improve?

Oral absorption & pharmacokinetics even if H2O solubility decreases

What is drug design almost always about?

1. Balancing H2O & lipid solubility

2. Permeability of cell membranes

What is the primary role of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: allows drug to dissolve in aqueous biological fluids (blood)

• Lipid: allows drug to cross lipid membranes via passive diffusioN

• Drugs must dissolve & permeate lipid membranes

What is the drug absorption into systemic bloodstream of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: required for drug dissolution in GI fluids or plasma

• Lipid: required for membrane permeability during absorption

• Oral drugs require both!

What is the drug distribution of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: promotes drug distribution in blood & extracellular fluid

• Lipid: promotes drug penetration into cells, tissues, & membranes

• Influences tissue distribution of drugs (intracellular drug target)

What is the BBB penetration of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: high H2O solubility → poor BBB penetration

• Lipid: high lipid solubility → better BBB penetration

• Key for CNS-based drugs

What is the drug target/ receptor binding of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: often contributed H bonding & ionic interactions w/ drug target

• Lipid: often contributes hydrophobic interactions w/ drug target

• Stabilization of drug*drug target binding interactions

What is the drug metabolism of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: highly H2O-soluble drugs are often cleared rapidly by body

• Lipid: lipophilic drugs often require metabolic conversion (by liver) to polar metabolites

• Affects drug t1/2

What is the drug excretion of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: facilitates renal (kidney) elimination

• Lipid: lipophilic drugs may undergo reabsorption in kidneys from urine back into blood

• Polar drug metabolites are excreted more easily from body

What is the typical drug structure features of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: polar functional groups

• Lipid: non polar functional groups

• Medicial chemists can tune these FGs

What is the drug design challenge of H2O solubility (hydrophilicity) vs. lipid solubility (lipophilicity)?

• H2O: too hydrophilic → poor membrane permeability

• Lipid: too lipophilic → poor H2O solubility (dissolution) & also high toxicity risk (hERG channel binding)

• Balance is essential (LogP =1-3)