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Medicinal Chemistry > Introduction > Flashcards

Introduction Flashcards

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1
Q

What is medicinal chemistry?

A

A large field that encompasses many disciplines (synthetic organic chemistry, enzymology, biochemistry metabolism, etc.)

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2
Q

What do medicinal chemists do? What do they produce?

A

Medicinal chemists discover new chemical entities with pharmacological effects and, by a process of chemical modification, produce lead compounds and from the lead compounds produce new, safe and effective drugs to treat disease

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3
Q

What’s a chemical entity?

A

Any (likely organic) chemical

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4
Q

What is a lead compound?

A

A chemical compound with the desired pharmacological effect that can be modified chemically to improve its potency, absorption, distribution, metabolic profile (or any aspect of the drug)

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5
Q

How do you improve a drug?

A

By utilizing the knowledge of, or determining the Structure Activity Relationship (SAR), a medicinal chemist can turn lead compounds into safe and effective drugs

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6
Q

Describe the quantitative SAR. Why is it important?

A

Generating a mathematical relationship between physicochemical properties of a series of compounds and their pharmacologic activity. In this case the “compounds” are modifications to the lead. This mathematical relationship can predict the most potent structure

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7
Q

Describe the qualitative SAR.

A

The relationship between the structure and the pharmacological activity of the drug, i.e., how arrangement of functional groups on the drug molecule effect pharmacological activity (absorption, secretion, etc.)

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8
Q

What is an important chemical property of drugs?

A

Electronegativity

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9
Q

What is electronegativity? Why is it important?

A

Electronegativity is a measure of the tendency of an atom to attract a bonding pair of electrons (basically: what would the electrons do?)
Electronegative atoms can polarize a molecule resulting in a permanent dipole

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10
Q

How do functional groups affect electrons?

A

Electrons can move around (delocalize) depending on functional groups.

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11
Q

What are the two ways that electrons move?

A

There are two ways electron density can move through a molecule: resonance and induction

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12
Q

Define resonance

A

The movement of electron density through pi-bonds (i.e., though alliterating single and double bonds aka conjugated systems)

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13
Q

Define induction

A

The movement of electron density through sigma-bonds (i.e, through saturated carbons)

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14
Q

How do functional groups affect the movement of electrons (through resonance and/or induction)?

A

A functional group may be electron donating (ED) or electron withdrawing (EW) depending on if ED or EW happens by resonance (pi-bond) or by induction (sigma-bonds). Therefore the same functional group may be ED or EW depending on if it happens through pi or sigma-bonds.

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15
Q

Besides the type of bonds, what else affects ED and EW?

A

ED and EW also depends on electronegativity, the presence of lone pair electrons, multiple bonds and the geometry of the molecule

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16
Q

In resonance, how does delocalization happen?

A

Delocalization happens through a series of pi-bones = conjugation. There’s a hydride structure, which has partial double bon character

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17
Q

In induction, how does delocalization occur?

A

Delocalization happens because of the distribution of electron density over the molecule through sigma-bonds

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18
Q

Where do we find EW inductively but ED by resonance?

A

In electronegative atoms with a lone pair (-OH, -NH2)

Exceptions are halogens, which are EW but usually do not participate in ED

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19
Q

Where do we find ED by induction?

A

Alkyl groups, the more branched, the more donating

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20
Q

Where do we find EW only by induction?

A

Atoms with no lone pair of electrons but have partial positive charge or a charge of +1 (-CF3, -NH3+, halogens)

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21
Q

Where do we find EW inductively and by resonance?

A

Attached group with a double bond O or N or triple bond N (NO2, CN, SO2R, SO2NHR)

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22
Q

Where do we find EW or ED by resonance?

A

CH2=CHR

When attached to a benzene ring

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23
Q

What is acid/free acid?

A

Protonated acid (HA)

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24
Q

What is conjugate base?

A

Deprotonated acid (A-)

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25
What is free base?
Deprotonated base (B)
26
What is conjugate acid?
Protonated base (HB+)
27
What is the ratio ionization based on?
The pKa and the pH of the solution
28
To estimate the ratio of ionization, to significantly ionize HA to A-:
Need pH > pKa
29
To estimate the ratio of ionization, to minimize the ionization of HA to A-:
Need pH
30
To estimate the ratio of ionization, to significantly ionize B to HB+:
Need pH
31
To estimate the ratio of ionization, to minimize the ionization of B to HB+:
Need pH > pKa
32
What happens when pH = pKa
You get 50% ionization
33
What happens when a drug contains both HA and B in the structure and the pKa of HB+ is greater than the pKa of HA?
Example: glycine, where the pKa of HA = 2.5 and pKa of HB+ = 9. In solid form or water at pH 7, it is a zwitterion (positively and negatively charged). In strong acid (pH 9), it is negatively charged
34
What do we mean when we talk about the pKa of a base?
We will almost always be talking about a 1st, 2nd or 3rd amine, and specifically the pKa of its conjugate acid
35
Carboxylic acids are weak acids. Explain
Both the inductive effects in the neutral form and the resonance effects in the ionized form explain why its COOH proton is acidic Inductively withdraws electrons from H, thus making the H acidic. A stable carboxylate anion is resulted after H+ departs. The negative charge is stabilized through resonance
36
Why are acids and bases important in medicinal chemistry? Give some examples
Acids and bases are commonly used to ionize and make salts of drugs. Drugs are usually marked in a salt form because they are easier to make into a solid dosage form and they dissolve more readily in water. Unionized drugs are typically oils and are not easy with which to work. Example: Warfarin sodium (warfarin + NaOH) is much more water soluble than warfarin Example: Pseudoephedrine HCl
37
What are the advantages to salts?
Drugs is water soluble and will dissolve in the gut The free acid/base is often an oil and the conjugate base/acid is a crystalline form Oils are notoriously impossible to tablet and are often hydroscopic and therefore very difficult to measure by weight The conjugate acid/base can be weighed and tableted more easily In many cases the conjugate acid/base as a solid crystalline form is more stable while the free base/acid as an oil is less stable
38
What is a substituent?
An atom or group of atoms substituted in place of a hydrogen atom on the parent organic compound (very important). Also known as moiety, side-chain, functional group, group, or branch.
39
Describe alcanes
``` Tetrahedral carbon centre sp3 hydrbidization Bond angle: 109.5º C-C bond length: 1.5 A or 150 pm Non polar Always ED Methane, Ethane, Propane Substituent: Methyl, Ethyl ```
40
Describe alkenes
``` Planar geometry sp2 hybridization Bond angle: 120º C=C bond length: 1.3 A or 130 pm Non polar ED/EW depending on substituents Ethene, Propene, Butene Substituents: Ethenyl, propenyl, butenyl ```
41
Describe alkynes
``` sp hydridization Bone angle: 180º Bond length: 1.2 A or 120 pm Non polar Mostly EW Ethyne Rare ```
42
Describe alkanes and alkenes
They cannot form ionic, hydrogen or ion-dipole bonds with themselves or water, only van der Waals is possible They cannot break and form bonds between and with water so they are not water soluble The larger or more branched the alkyl, the less hydrophilic or more lipophilic the group becomes Halogenated hydrocarbons (CH3F, CCl4) are generally less hydrophilic than the alkyl form
43
Describe alcohols
They can form H-bonds with water and are polar, so they therefore increase solubility They can be ED via resonance or EW via induction They are H-bond donors and acceptors sp3 hybridization Tetrahedral geometry There is a permanent dipole Not very acidic
44
What are phenols?
A special type of alcohol (alcohol + benzene) | Generally they are more acidic than aliphatic alcohols (pKa between 9-10) but it depends on other substituents
45
Describe aromatic hydrocarbons
Names: phenyl, naphthyl Hydrophobic ED/EW depending on substituents
46
Describe thiols and thiophenols
SH (sulfhydryl) group is only weakly acidic SH is always ED R-SH is more acid than R-OH E.g., CH3-SH (methanethiol or methyl mercaptan)
47
Describe Ethers and thioethers
Only weakly polar O-R (alkoxy) is ED/EW SR (thioalkoxy) is ED E.g., Diethyl ether aka ethoxyethain, methoxybenzene, diethyl thioether
48
Describe sulfoxides
``` Always EW S centre is tetrahedral Lone pair of electrons Chiral if R doesn't equal R' Highly polar Famous solvent: DMSO ```
49
Describe sulfones
Always strongly EW S centre is tetrahedral Highly polar
50
Describe aldehydes and ketones
Carbonyl (C=O) is polar, can form H-bonds with water (dipole-dipole interaction) Always EW They are in rapid equilibrium with alcohol to form hemiacetal and hemiketal
51
Describe amines
An important functional group Polar, can form H-bonds with water (dipole-dipole or ion-dipole) Neutral forms of amines are ED (resonance) and EW (induction) The N of amine is basic (loan pair)
52
Describe carboxylic acid
A very important group Polar, H-bonding, dipole-dipole, ion-diple EW (neutral form), ED (anion form) Acidic, readily deprotonated at physiological pH
53
Describe esters
Important group Polar, H-bonding with water Always EW Susceptible to hydrolysis (major route of metabolism, catalyzed by esterases; frequently incorporated to facility the absorption of carboxylic acid drugs - act as a pro-drug
54
Describe amides
Important group Polar, H-bonding with water, dipole-dipole Planar Always EW The N is not basic (forms resonance structures) VERY weakly acidic Neutral at physiological pH
55
What are nitriles and carbonates similar to?
Similar properties to esters
56
What are carbamates similar to?
Properties in between esters and amides
57
Describe ureas
Properties similar to amides | Very stable
58
Describe amidines and guanidines
Highly polar, H-bonding, dipole-dipole, ion-dipole with water In neutral form, amidine is EW but guanidine is weakly ED and weakly EW (due to electronegative nature of N) In ionized form, EW Multiple tautomeric forms are possible More basic than amine. Usually fully protonated at pH 7.4 (depends on substitution) sp2 hybridization
59
Descibre Nitro
Although nitro group is charged, it is only slightly polar (electrically neutral because of + and - charges) Highly EW The negative charge on O is unable to accept a proton
60
Describe sulfonic acids
Properties similar to carboxylic acids Highly polar EW More acidic than carboxylic acids
61
Describe sulfonamides
Properties similar to amides Polar EW More acidic than amides
62
What are the requirement for aromaticity?
Cyclic Planar Delocalized conjugated (every atom in the ring has p-orbitals that can form pi-bonds and every atom is sp2 hybridized) Number of p-orbitals capable of forming pi-bonds satisfies this relationship: 4n+2 where n=1,2,3
63
Describe the aromaticity charge distribution
There is potential for interaction between aromatic groups. This is not technically a dipole-dipole interaction because the aromatic ring has more than two poles.
64
What is aromatic stacking interactions?
Aromatic stacking interactions are also called pi-stacking interactions. They are important for drug receptor interactions and for protein folding and DNA and RNA interactions
65
What are the different types of aromatic stacking interactions?
T-shaped stacking interaction aka Edge to face interaction Parallel displaced interaction Sandwich interaction

Medicinal Chemistry (13 decks)

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