Lecture 2 Flashcards
Med Chem Basics
Drug + Receptor Interactions
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
Functional Groups + Scaffolds
- 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)
Alkane
- single bonded C & H
- flexible (rotates around C-C bond)
- Hydrophobic
Alkane Properties
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
Alkene
C=C
- no rotation around double bond
- cis and trans isomers
Alkene Properties
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
Alkyne & Properties
-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
Cycloalkanes
- relatively flexible (boat and chair)
- RARE except in natural products
- All other properties are the same as acyclic alkanes
Aromatics
- Hydrophobic (unless heterocyclic)
- Totally flat and no chirality
Aromatic Properties
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
Scaffold/Interactors: Heterocycles
- 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
Halocarbons
Hydrogen of a hydrocarbon bond replaced by a halogen
- Usually interacting groups (aromatic Br, I, Cl)
- Replacement of metabolic susceptible H by F
2-trifluoromethyl
- Powerful effects on acidity/bascity of groups
- Effects solubility, bioavailability, and metabolic stability
- Adding to a compound greatly helps solubility of carbon
Hydroxyl (Alcohol)
- An oxygen single-bonded to a carbon
- Other valence site of O binds a H
- Can be primary, secondary, tertiary, or phenolic
Hydroxyl Properties
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
Halocarbon Properties
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
Carbonyl
- Oxygen double bonded to carbon
- If carbon is primary = aldehyde
- If carbon is secondary = ketone
Carbonyl Properties
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.
Carboxylic Acid
- RC(O)OH
- Not simple combination of ketone and alcohol
- Special properties of its own
Carboxylic Acid Properties
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
Ester
- RO-C=O
- Formed by reversible dehydration reaction with carboxylic acid and alcohol
Ester Properties
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
Ether
- R-O-R’
- Oxygen linking two carbons
- Carbons can be aromatic or aliphatic
Ethers Properties
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
Amine
- N-R
- Nitrogen single bonded to a carbon
- Can be primary, secondary, tertiary, or quaternary
Amine Properties
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
Amide
- Similar to ester, except a dehydration of an amine and an alcohol
- R’NH-C=O
Amide Properties
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
Aromatic Nitrogen Heterocycles Properties
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
