Medchem midterms 2

Oxa

Common prefix for heterocycle with O

Thia

Common prefix for heterocycle with S

AZA

Common prefix for heterocycle with N

Unsaturated ( has pi bonds) cycle suffix

ole

Saturated ring suffix

olane

Why are most 5-membered heterocycles electron rich?

Have 6 pi electrons between 5 atoms (vs 6 in arenes)

A 5 membered aromatic heterocycle is [ ] to oxidative metabolism

MORE SUSCEPTIBLE (more electron rich)

Why’re aromatic compounds flat and rigid?

symmetrical pi density from both top and bottom, have to be flat to share the pi electrons

The only 5-membered heterocycle with the opposite dipole:

pyrrole ( in resonance structures, + charge mostly on N-H)

N 5-membered heterocycles are mostly acid or bases?

Weak bases

Conjugate acids of N aromatic heterocycles?

Strong, pka (-1 - 5 )

Oxygen/sulfur heterocycle acidic/basic properties:

No acid/base property

S heterocycles are [ ] than N heterocycles

MORE HYDROPHOBIC

What increases logP in heterocycles?

↑ ring size, electronegativity, aromaticity

Why is furan the least common 5-membered heterocycle in drugs?

lowest resonance NRG - > more prone to oxidative metabolism (eg CYP)

Why would you add a fused phenyl ring to a 5- membered heterocycle? (eg. indole, benzofuran)

More metabolically stable

A greater MW → [ ] diffusion

slower diffusion

What affects diffusion through cell membrane?

lipophilicity, # H bond donators/acceptors, TPSA, MW

Surface area of all polar parts of a molecule (N, O)

TPSA

TPSA for a drug that is poorly membrane permeable

TPSA < 140 Angstroms

TPSA for a badly BBB permeable drug?

TPSA < 90

How does stackable packing of planar aromatics affect dissolution?

More and denser packing, SLOWER dissolution

When is a heteroatom not a H bond acceptor?

S (not donor or acceptor)

Amides, aromatic amines/ethers

Which heterocycles are most instable and causes allergic reactions?

3-membered + 4-membered (mostly beta-lactams)

Lactone/thiolactone reactivity vs Lactams?

Lactones/thiolactones more REACTIVE than lactams, except beta lactams

How does height of N pyramid in beta-lactams affect reactivity?

Higher height greater reactivity:

order the reactivity of the common beta lactams

monobactam < cephem < penam < carbapenem < clavam

(MoCePeCaCl)

Why does height of N in beta-lactam pyramid increase reactivity?

More distorted amide bond → less planar → weaker bond → easier for nucleophiles (like Ser) to attack

Exceptions to reactive 4- membered cycles?

Oxetane , azetidine

What’s the Lipinski Rule of 5?

If at least 2 of these, poorly absorbed:

1) MW > 500

2) log P > 5 (

3) > 10 H bond acceptors

4) >5 H bond donors

5) doesn’t apply to antibiotics, antifungals, vitamins, cardiac glycosides

Permeability (P) relationship with K, D, x

↑with K (slippery coefficient) and D (diffusion coefficeint)

Decrease with membrane thickness (x)

Plasma bonding and logP increases with?

electronegativity, N < O < S

What in heterocycles increase logP?

Bigger ring size, unsaturated > saturated (5-membered), N<O<S

Why does pyridine have lower logP then its saturated form?

Electron deficient heterocycle, 5-membered are electron rich

How does LogP change when adding heterocycles to a benzene?

Adding benzene to saturated heterocycle INCREASES logP

logP is [ ] to plasma binding

log P/lipophilicity is proportional to plasma binding

Which drugs bind to albumin?

Acidic + neutral drugs

Why’re acidic and neutral drugs not available in plasma but basic drugs are ?

Albumin makes up 60% of plasma proteins, while AGP is only 3%

Basic drugs bind to []

Basic →> alpha1- acid glycoprotein, less in blood so more free basic drug available

How does plasma binding, logP, and Vd relate?

High logP → high protein binding → LOW Vd

Fsp3 (fraction of sp3 hybridized C) =

#Csp3 C / total C

Higher Fsp3 = [ ] solubility

More Fsp3, higher soluble

What affects binding of drug to the receptor?

Solvation/desolvation (Receptor-ligand bonding needs to be lower NRG than H bonding with environment)

Less rotatable bonds (<10)

7-membered ring metabolism?

MORE susceptible to metabolism- not aromatic, hard time holding e-

epine / epane suffix?

7 membered

epINE (unsaturated)

epANE (saturated)

ocine / ocane suffix?

8 membered

ocINE (unsaturated)

ocANE (saturated)

onine/ onane suffix

9 membered

onine (unsaturated)

onANE (saturated)

ecine/ ecane suffix

10 membered

ecINE (unsaturated)

ecANE (saturated)

What’re privileged scaffolds and their two types?

• mimic common receptor folds in biological targets

• In natural products or in inspired drugs

Oligopeptide PEPT1,PEPT2 transporters enhance uptake of?

dipeptides/tripeptides mimetics (ACE inhibitors, valtrex)

LAT1 transporters?

Large neutral AA transpoter

• large hydrophobics sidechain (Leu, Phe, tyr)

MCT1 transporters:

MONOcarboxylic acid transporter

OAT / OATPs

organic anion transporters

If drug 1 is a poor substrate / blocker of OAT, [drug2 Oat substrate]?

[drug 2] will increase, slow membrane permeability, is not cleared

uptake transporters?

PEPT1, PEPT2, OAT, GLUT1, vitamin transporters, bile acid transporters, etc

Protein-ligand binding occurs if ∆∆Gbinding is?

Negative ∆∆Gbinding

∆∆Gbinding =

(∆Gproteinligand+ ∆Gsolvent2 ) - (∆Gprotein/s + ∆Gligand/S + ∆Gsolvent1 )

(∆G bound pdt) - (∆G reactants)

If the system gains ∆G, the proteinligand complex?

Complex forms (system gains = -∆G); (uses NRG for +∆G)

What’re the differences between the 2 types o drug-receptor inhibitors?

Noncovalent = no bond formed, dissociates

Covalent (irreversible/reversible) = new bond formed

How does reversible / irreversible covalent inhibitors differ?

Irreversible - binds with active site residue, stays in binding site (beta lactam + DD transpeptidase)

Reversible- complex dissociates without other species coming in to help

Psuedo/quasi irreversible covalent inhibitors

Pseudo-irreversible - their effect doesn’t last full time of the target’s life → active protein can be restored by outside RXN like hydrolysis/nucleophilic attack

Covalent suicide inhibitors?

1) prodrug activated to reactive intermediate

2) reacts with a non catalytic residue in another active site

(beta lactamase Ser attacks beta lactam → clavulanic acid attacks → reacts with different Ser → inactivates it)

Water released from binding site in hydrophobic effect helps the binding by?

increase entropy, 10X potency increase

Noncovalent interactions for ligand-protein complex peaks at?

10 pM, ∆∆G binding of 15 kcal/mol

What does better potency of drug mean?

Better binding = better potency = less drug needed to have same inhibitory effect = lower IC50

10X fold increase in potency =?

1.37 kcal/mol lower

100X fold increase in potency =?

2.74 kcal/mol

1000-fold potency, ∆G is?

4.11 kcal/mol lower in more potent drug

Why are racemic/chiral switches being made?

• More potency

• reduced side effects

• different pharmacokinetics

• lower dose requirements

What are enantiomeric purity requirements for single enantiomer drugs?

• undesired enantiomer treated as impurity, controlled

• enantiomer stable during storage, manufacturing, administration

• >98% enantiomeric excess

What is the 3 pt drug-target interaction ?

there is a preferred isomer that has more interactions with target → greater potency

If there is not big difference in potency between different enantiomer binding, chiral center not pharmacophore

Eutomer

More potent isomer

Distomer

Less potent isomer

High eudimisic ratio =

eutomer > distomer ratio → drug has chiral center pharmacophore

Constitutional isomer

Same connectivity

Enantiomers

Same constitution (connetivity), different spatial configuration

Conformers

Same configuration, different conformation (rotation)