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811 > Lecture 2 > Flashcards

Lecture 2 Flashcards

Med Chem Basics

1
Q

Drug + Receptor Interactions

A

Simplified: “Lock & Key,” drug interlocks with receptor to exert therapeutic effect

Complex: Drug contains interacting groups held in place by a scaffold to bind to receptor

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2
Q

Functional Groups + Scaffolds

A
  • Scaffolds hold chemical in 3D space
  • Interacting groups interact with receptor
  • Sometimes groups are both scaffold and an interacting groups (EX: phenyl = hydrophobic interactor and a scaffold holding phenolic -OH at right distance from aliphatic -OH)
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3
Q

Alkane

A
  • single bonded C & H
  • flexible (rotates around C-C bond)
  • Hydrophobic
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4
Q

Alkane Properties

A

Solubility- hydrophobic, so soluble in lipids, not water
Interactions- hydrophobic bond
Ionization states- none at biological pH
Chemical stability- very stable
Biological Reactivity- broadly unreactive, oxidized by P450
Uses in drug structures- very common, but not only scaffold
How common- very

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5
Q

Alkene

A

C=C

  • no rotation around double bond
  • cis and trans isomers
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6
Q

Alkene Properties

A

Chemical stability susceptible to oxidation
Uses in drug structures- scaffold & interacting group (polyene antifungals)
How common- moderate

Properties not included are the same as alkane

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7
Q

Alkyne & Properties

A

-Triple C-C bond

Chemical stability less susceptible to oxidation
Biological Reactivity- often used to inhibit P450 through reactive intermediates
Uses in drug structures- scaffold & interacting group
How common- rare

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8
Q

Cycloalkanes

A
  • relatively flexible (boat and chair)
  • RARE except in natural products
  • All other properties are the same as acyclic alkanes
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9
Q

Aromatics

A
  • Hydrophobic (unless heterocyclic)

- Totally flat and no chirality

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10
Q

Aromatic Properties

A

Solubility- hydrophobic, so soluble in lipids, not water
Interactions- hydrophobic bond
Ionization states- none at biological pH
Chemical stability- stable
Biological Reactivity- broadly unreactive, oxidized by P450 occasionally
Uses in drug structures- scaffold & interacting group
How common- exceedingly common

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11
Q

Scaffold/Interactors: Heterocycles

A
  • Both scaffold and interacting groups, very common as high atom efficiency
  • Properties - similar to linear analogs
  • Except when aromatics, pKa is usually very similar
  • Exceedingly common, found in almost ALL drugs
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12
Q

Halocarbons

A

Hydrogen of a hydrocarbon bond replaced by a halogen

  • Usually interacting groups (aromatic Br, I, Cl)
  • Replacement of metabolic susceptible H by F
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13
Q

2-trifluoromethyl

A
  • Powerful effects on acidity/bascity of groups
  • Effects solubility, bioavailability, and metabolic stability
  • Adding to a compound greatly helps solubility of carbon
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14
Q

Hydroxyl (Alcohol)

A
  • An oxygen single-bonded to a carbon
  • Other valence site of O binds a H
  • Can be primary, secondary, tertiary, or phenolic
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15
Q

Hydroxyl Properties

A

Solubility- hydrophilic – promotes water solubility
Interactions- hydrogen bond
Ionization states- none at biological pH (except 1% -ve or so for phenols)
Chemical stability stable, but can be oxidized
Biological Reactivity- easily oxidized by P450, often site of Phase 2 metabolism
Uses in drug structures- hydrogen bond donor/acceptor: ↑H2O solubility
How common- very
Prodruggability easy conversion to ester

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16
Q

Halocarbon Properties

A

Solubility- aromatic I, Br & Cl hydrophobic
but aliphatic F and especially trifluoromethyl quite
polar Interactions- depends, usually hydrophobic, some H bonding (esp F)
Ionization states- none at biological pH
Chemical stability stable (but not aliphatic Cl, Br, I)
Biological Reactivity- broadly unreactive, especially fluoro
Uses in drug structures- interacting group
How common- common

17
Q

Carbonyl

A
  • Oxygen double bonded to carbon
  • If carbon is primary = aldehyde
  • If carbon is secondary = ketone
18
Q

Carbonyl Properties

A

Solubility- weakly hydrophillic
Interactions- hydrogen bond
Ionization states- none at biological pH
Chemical stability Unstable, reacts with amines and other groups, can be oxidized
Biological Reactivity- oxidized and reduced, reacts with proteins, DNA etc.
Uses in drug structures- H bond acceptor, reactive group.
How common- rare: DNA and protein reactivity makes it a liability
Prodruggability- not easy.

19
Q

Carboxylic Acid

A
  • RC(O)OH
  • Not simple combination of ketone and alcohol
  • Special properties of its own
20
Q

Carboxylic Acid Properties

A

Solubility- very hydrophillic
Interactions- both ionic and hydrogen bond, depending on pH
Ionization states- pKa 3-6 so >99% -ve at pH7, neutral at pH 1 this drives differential ionization in stomach (pH 3- 5) vs intestine (pH 6-7.5) and can be important
Chemical stability- very stable
Biological Reactivity- site of phase 2 metabolism
Uses in drug structures- ionic bonder, H bond acceptor & donor: ↑H2O solubility
How common- relatively common
Prodruggability- easy conversion to ester or amide

21
Q

Ester

A
  • RO-C=O

- Formed by reversible dehydration reaction with carboxylic acid and alcohol

22
Q

Ester Properties

A

Solubility- very hydrophobic
Interactions- hydrogen bond acceptor
Ionization states- none
Chemical stability- Stable unless water present, if not dry hydrolysis occurs
Biological Reactivity- usually converted to acid and alcohol by esterase enzymes
Uses in drug structures- To “hide” polar groups as prodrug to increase permeability across membranes
How common- quite common
Prodruggability- it IS a prodrug form of alcohol & acid

23
Q

Ether

A
  • R-O-R’
  • Oxygen linking two carbons
  • Carbons can be aromatic or aliphatic
24
Q

Ethers Properties

A

Chemical stability very stable
Biological Reactivity- often converted to alcohol by– O demethylation, by P450 enzymes
Uses in drug structures- hydrophobic H bond acceptor
How common- not so much
Prodruggability- none

Properties not included are the same as esters

25
Q

Amine

A
  • N-R
  • Nitrogen single bonded to a carbon
  • Can be primary, secondary, tertiary, or quaternary
26
Q

Amine Properties

A

Solubility- very hydrophillic
Interactions- both ionic and hydrogen bond
Ionization states- pKa 9-11 99% + ve at pH7, 100 % +ve at pH 1
Chemical stability- Pretty stable
Biological Reactivity- can be site of phase 2 metabolism, deamination, N-demethylation by enzymes such as P450
Uses in drug structures- ionic bonder, H bond acceptor & donor: ↑H2O solubility
How common- very common
Prodruggability- easy conversion to amide

27
Q

Amide

A
  • Similar to ester, except a dehydration of an amine and an alcohol
  • R’NH-C=O
28
Q

Amide Properties

A

Solubility- amphiphilic
Interactions- hydrogen bond donor & acceptor
Ionization states- none at biological pH
Chemical stability- Stable unless water present, hydrolysis
Biological Reactivity- Hydrolysis but Much less than esters (why)
Uses in drug structures- To “hide” polar groups as prodrug to increase permeability across membranes. Also as H bond donor & acceptor in molecules that are not prodrugs
How common- quite common
Prodruggability- it IS a prodrug form of amine & acid

29
Q

Aromatic Nitrogen Heterocycles Properties

A 
Solubility- moderate hydrophobic, much less than aliphatic amine
Interactions- hydrogen bond
Ionization states- generally non
Chemical stability- stable
Biological Reactivity- generally low
Uses in drug structures- structural element also containing H bond acceptor & some are donor: can prevent metabolic toxicity as phenyl bioisostere
How common- very common
Prodruggability- none

811 (38 decks)

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