422 Exam2 3 and 4 membered heterocycles

3 membered ring

unsaturated suffix

irene

3 membered ring

saturated suffix

irane

4 membered ring

unsaturated suffix

ete

4 membered ring

saturated suffix

etane

5 membered ring

unsaturated suffix

ole

5 membered ring

saturated suffix

olane

6 membered ring

unsaturated suffix

ine

6 membered ring

saturated suffix

inane

7 membered ring

unsaturated suffix

epine

7 membered ring

saturated suffix

epane

8 membered ring

unsaturated suffix

ocine

8 membered ring

saturated suffix

ocane

3 member N heterocycle

saturated suffix

iridine

4 member N heterocycle

saturated suffix

etidine

5 member N heterocycle

saturated suffix

olidine

-penem definition/purpose

antibacterial antibiotics (carbapenem derivatives)

-cillin definition/purpose

penicillins

-bactam definition/purpose

beta-lactamase inhibitors (mostly monomactams)

reactivity order of beta lactams (highest to lowest)

CLavams (h=0.5)

CArbapenems

PEnams

CEphems

MOnobactams (h=0.05)

Cl-Ca-Pe-Ce-Mo

h

height of triangular pyramid with N at apex

3 points forming plane base are the 3 C attached to N

higher h: less planar, more distortion/strain, more reactive

what is the result of distortion of the amide bond planar geometry?

* makes the amide bond weaker and primes it for reaction with nucleophiles

* weaker C-N bond makes it easier to open b-lactam ring

* amide bond is supposed to have double bond character, needs to be planar for sp2 orbital overlap

other reasons for beta lactam reactivity

* if product has tetrahedral geometry, a distorted b-lactam will better resemble target, more easily forming an early transition state, react faster

* lower conjugation of C=O with N increases partial charge on C, making it a better target for nucleophiles

beta lactam reactivity and antibiotic drug properties

reactivity directly correlates with rate of antibiotic effect & metabolic degradation

what enzyme are low reactivity beta lactams more likely to inhibit?

beta lactamase

beta lactamase definition/purpose

* cleaves beta lactam ring of beta lactam antibiotics

*an enzyme responsible for antibiotic resistance in bacteria

4 membered heterocycles such as azetidine and oxetane are (more/less) reactive than beta lactam rings?

less reactive, more stable

have 4 membered N-containing rings without carbonyl in ring

what is the most common purpose of three membered heterocycle drugs?

DNA alkylating agents due to the reactivity of the aziridine ring

examples: chemotherapeutic agents

why are 3 membered heterocycles highly reactive?

higher ring strain makes them more susceptible to nucleophilic attack

what might make 3 membered heterocycles unusually stable?

steric hindrance

are 3 membered heterocycles more stable or reactive?

reactive

are 4 membered heterocycles more stable or reactive?

stable

are lactones more stable or reactive?

reactive

are thiolactones more stable or reactive?

reactive

are lactams more stable or reactive?

more stable than O & S-containing heterocycles

except for b lactams in antibiotics

are saturated carbocycles (no heteroatoms) more stable or reactive?

stable

which has conformers: 3-membered or 4-membered heterocycles?

4 membered heterocycles

(have 2 envelope conformers)

TRUE OR FALSE: all four membered O-containing heterocycles are highly reactive

FALSE

steric hindrance may make unreactive

lactones (similar to lactams) are generally reactive though

what is the main reason for 3 and 4 membered heterocycles' immunogenic properties?

their relative instability from their ring strain

TRUE OR FALSE: all 3 membered heterocycles in drugs are reactive

TRUE

unless indicated otherwise

what might be the pharmaceutical result(s) of a 3 or 4 membered heterocycle functional group in a drug?

high reactivity may complicate:

* storage

* formulation

* route of administration

* off-target effects in body

beta lactam immunogenic response

* reactive beta lactam and hapten antibiotics form covalent adducts with human proteins

* xenobiotic adduct may trigger production of antibodies

why are penam antibiotics recommended to take on an empty stomach?

1. can covalently react with chemicals in food decreasing effective dose
2. can non-covalently bond to food, delaying absorbtion

If Fsp3 is less than ______ it is poorly soluble

3

how many HB donors are there in this molecule? 

4

which aromatic ring is more susceptible to oxidative metabolism?

5-membered heterocycle

how many HB acceptors are there in this molecule?

6

which molecule cannot serve as a HB acceptor

A

what is a potential way to prevent rapid metabolism of the thiazole group?

Add protecting group

which molecules can't serve as HB acceptors

A and B

what types of drugs are the exception to the lipinski rules?

antibiotics, antifungals, vitamins, and cardiac glycosides

which molecule will have higher plasma binding?

azepane

which heterocycle will have lower anticipated plasma binding?

azetidine

which molecule is more soluble in water?

azetidine

which heterocycles will readily react with cysteine side chain (nucleophile) 

aziridine, furan, oxirane

which drug is less likely to cross the blood-brain barrier

B

aromatic N containing heterocycles are weakly _________

1. acidic
2. basic
3. neutral

basic

why does pyrrole have more electron rich character than benzene 

benzene has 6e per 6 atoms
pyrrole has 6e per 5 atoms

in which of these β-lactam scaffolds is the height of the pyramid the largest? 

carbapenems and clavams (0.5-0.6 angstrom)

assign the following molecule to a class of β-lactams

monobactams
cephems
penams
clavams
carbapenems

cephem

which molecule is most likely to improve dissolution? why?

C, it is non-planar

rank the reactivity of β-lactams in order of most reactive to least reactive

cephems
penams
carbapenems
monobactams
clavams

clavam=carbapenem > penams > cephems > monobactams

what is the correct dipole moment?

D3

beta-lactam antibiotics inhibit what enzyme?

DD-transpeptidase

which drug is a better candidate for CNS application? 

deloxetine

pKa < pH

Protonated or Deprotonated

deprotonated (ionized if COOH)

T or F? this molecule is a hydrogen bond donor 

false

T or F? 3 & 4 membered saturated heterocycles are planar

false they are non-planar

T or F? aromatic N,O,S containing 5-membered heterocycles are never used to build drug molecules.

False, we just have to minimize their reactivity/metabolism

which aromatic compound is most likely to undergo rapid metabolism? 

furan

predict the dipole moments of these heterocycles 

furan: points down
thiophene: points down
pyrrole: points up

does hydrolysis in vivo occur more rapidly in lactams or lactones? why? 

lactones, C-O is a weaker bond than C-N

which of these heterocycles will have a higher anticipated plasma binding?

molecule with thiotane

match the these heights with the following β-lactams

1. cephems
2. monobactams
3. penams 

monobactams 0.05-0.1
cephems 0.2-0.25
penams 0.4-0.5

what are the lipinski rules?

MW > 500
Log P > 5
More than 5 HB donors
More than 10 HB acceptors

which aromatic compound is least likely to undergo rapid metabolism? 

napthalene

Is this molecule aromatic? 

no

Are these 4-membered heterocycles generally reactive or non-reactive? 

non-reactive

are these carbocycles generally reactive or non-reactive? 

non-reactive

predict if the indicated epoxide will be reactive or non-reactive. why? 

non-reactive, steric hinderance

predict if the indicated epoxide will be reactive or non-reactive. why? 

non-reactive, steric hinderance

which of the following heterocycles are prone to causing allergic rxns

oxirane

what type of heterocycles do NOT have acidic or basic properties?

oxygen and sulfur containing heterocycles

assign the following molecule to a class of β-lactams

monobactams
cephems
penams
clavams
carbapenems 

penam

which of these heterocycles will have a higher anticipated plasma binding? 

piperidine

pKa > pH

Protonated or Deprotonated

protonated (ionized if amine)

which heterocycle is more lipophilic?

pyrrole

rank these heterocycles from least lipophilic to most lipophilic

pyrrole < furan < thiophene

which molecule is likely to have the least plasma binding? 

pyrrolidine

Are these 3-membered heterocycles generally reactive or non-reactive? 

reactive

predict if the indicated epoxide will be reactive or non-reactive. why?

reactive, open to nucleophilic attack

are these lactones and lactams generally reactive or non-reactive? why?

reactive, readily hydrolyzable

how do you calculate Fsp3?

sp3 carbons/total carbons

Name the heterocycle indicated in red and predict if it will be reactive or non-reactive. why? 

taxol: oxetane, non-reactive, steric hinderance
docetaxel: oxetane, non-reactive, steric hinerance
orlistat: lactone, reactive, readily hydrolyzable

which molecule is less soluble in water? 

tetrahydrofuran

Which heterocycle should be used instead of the carboxylic acid to mimic its electronic and acidic properties? 

tetrazole

which heterocycles can serve as both a HB donor and HB acceptor

tetrazole and imidazole

which molecule is likely to have the highest plasma binding? 

thiophene

what TPSA corresponds to drugs that tend to be poorly blood-brain barrier permeable?

TPSA > 90

what TPSA corresponds to drugs that tend to be poorly cell membrane permeable?

TPSA > 140

T or F? 5-membered heterocycles are universal building blocks in drug molecules

true