o recognize the amine and amide functional groups • Learn the Nitrogen-Containing Functional Groups • Nitrogen is in Draw structural formulas for the following molecules:
Cité 25 fois — Most importantly, amides are characterized by a "conjugated system" in which the NBEs of nitrogen can delocalized into the adjacent carbonyl (C=O) group
nal group Structure Suffix Prefix General form acid R OH O –oic acid –carboxylic acid
- try to draw 3D structures in a zig-zag shape C R C R H H H H C C C NH2 Br Functional groups 1 carboxylic acid 2 amide 3 bromo 4 alkene 5 amine 6 nitrile c
ructure Activity Relationships Acetylcholine agonists: Identification of acidic / basic functional groups Amide 6 2 - 3 Ex monofuctional comp methanol - pentanol/hexanol
Cité 3 fois — which functional groups are important for binding and for binding and activity • 1o and 2o amines are converted to 2o and 3o amides respectively • amides cannot
nal Groups functional group: an atom, or group of atoms (with specific connectivity), exhibiting
r percentage of amide functional groups in nylon molecules' structures leads to stronger hydrogen
[PDF] amide hydrolysis mechanism
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Drug Design:
Functional groups / Pharmacological Activity
Structure - Mechanism of action
(Interaction with target) Structure - Physiochemical properties (Bioavailability etc) •Acid / base properties •Water solubility •Partition coefficient •(Crystal structure) •Stereochemistry ADME
Absorbtion. Distribution, Metabolism, Excretion
(ADMET, ADMEtox)
Structure - Mechanism of action
N O O O H ca. 5Å
Acetylcholin
(Neurotransmittor) N O O H 2 N
Carbacholin
N N H N N Me H O O
Acetylcholin Agonists
Nicotine
Pilocarpine
Protonated av phys. pH (pH≈7.4)
Acetylcholin Antagonists
N O O OH
Atropin
O O N OH
Cyclopentolat
MeO O HO O OH OMe N H Me N Me Me
Tubocurarin
CNS
Effektor celle
Reseptor
Synapse
Acetylkolin
Noradrenalin
Det somatiske nervesystemDet autonome nervesystem
CNSCNS
Det sympatiske
nervesystem
Det parasympatiske
nervesystem ganglion
Structure - Mechanism of action
SAR: Structure Activity Relationships
Acetylcholine agonists: Small N-quartenary compds. Acetylcholine antagonists: Larger N-quartenary compds. N CO 2 Me O O
Cocaine
O O N NH 2
Procaine
(1905) N H N
Lidocaine/Xylocaine
(1946) O
Acid labile ester
Hydrophilic
Aminogroup
(can be protonated)
Spacer
-C n -X-
X: -CO
2 -CONH- -NHCO-
Lipophilic
(Aryl)
Active compound identified
Target?
Target identified
Ligand?
Structure - Physiochemical properties
•Acid / base properties •Water solubility •Partition coefficient •(Crystal structure) •Stereochemistry
Human body: ca 75% water
pH blood ca 7.4 (physiolog. pH) pH stomach 1 - 3.5 pH duodenum ca. 4 pH urine ca. 6 Identification of acidic / basic functional groups pKa determines degree of ionization different places in the body N O O O H ca. 5Å
Acetylcholin
(Neurotransmittor)
Acetylcholin Antagonists
Possible atropine analogs?
O O N OH
Cyclopentolat
O O N OH O O N OH O O N OH O
Cyclopentolate - tertiary amine, pKa ca. 10
[acid form] [base form]
At pH 7.4
10 = 7.4 + loglog
[acid form] [base form] = 2.6 [acid form] [base form] = 398; 99.75% acid form O O N OH H = active form O O N OH H acid form + H 2 0 O O N OH baseform + H 3 O pKa = pH + log [acid form] [base form]
Henderson Hasselbach
pH=pKa; [acid]= [base] pH
pKa; basic form dominates Antibacterial sulfonamides
Old compound
NH 2 S O O H 2 N Acid form - neutral
Low watersol. - crystals -
Kidney damage
[acid form] [base form] At pH 6 (urine)
10.4 = 6 + log
[acid form] [base form] ≈ 25000 Modern compound
ArS O O HN Sulfametoksasol
pKa 6.1 ArS O O N - H ArS O O N ArS O O N N O N O N O N O ArS O O N N O At pH 6 (urine)
[acid form] [base form] ≈ 1 base form, ionic, water sol. Structure - Physiochemical properties
•Acid / base properties •Water solubility •Partition coefficient •(Crystal structure) •Stereochemistry Ionisation -permanent charge
-acid / base properties Hydrogen bonds
Ion - dipole bonds
H NHR H Acidic form of amines
H O H R O O Basic form of carboxylic acid
(carboxylate) H O H Intramoleculare interact. reduce water sol.
R CO 2 NH 3 Strong intramolec interact.
O HH O HH Salts between weak organic acids and weak organic bases does not dissolve well in water The more H-bonds possible - the more water sol.
R O H Alchohol
O H H H O H O H H 3 H-Bonds
O Aldehyde / ketone
H H O H O H 2 H-Bonds
RR' O Ester H H O H O H 3 H-Bonds
RO R H O H Primary amine
3 H-Bonds
RN H H O O H O H H H H H Secondary amine
2 H-Bonds
RN R' HO H O H H H Secondary amine
1 H-Bonds
RN R' R'' H O H Prediction of water solubility - Empirical
Water solubilization of functional groups
Functional groupMonofunctional comp.Polyfunctional comp. Alchohol5 - 6 carbons3 - 4 carbons
Phenol6 - 73 - 4
Ether4 - 52
Aldehyde4 - 52
Ketone5 - 62
Amine6 - 73
Carboxylic acid5 - 63
Ester63
Amide62 - 3
Ex. monofuctional comp.
methanol - pentanol/hexanol are solubile Charge: 1 charge - 20-30 C
N Terbinafine
Antifungal agent
21 C-atom, tertiary amine solubilize 6 - 7 C atoms
Insolubile (neutral form)
Corresponding acid (cationic) solubile
(solubile: >10 mg/mL) Water solubilization of functional groups
Functional groupMonofunctional comp.Polyfunctional comp. Alchohol5 - 6 carbons3 - 4 carbons
Phenol6 - 73 - 4
Ether4 - 52
Aldehyde4 - 52
Ketone5 - 62
Amine6 - 73
Carboxylic acid5 - 63
Ester63
Amide62 - 3
Ex. polyfunctional comp.
Charge: 1 charge - 20-30 C
O O N H OH Betaxolol
Betablokker
18 C-atomer
Ether: 2
Ether: 2
Alchohol: 3-4
Amine 2
Tot: 9 - 10
(not solubile) logP Experimental: MlogP or logP
meas P: Partition coefficient between n-octanol and water Fragment
π-value
C (aliphatic+0.5
Phenyl+2.0
-Cl+0.5 -ONO 2 +0.2 -S-0.0 O=C-O- (carboxyl)-0.7
O=C-N- (amide)-0.7
-O- (hydroxyl, ether)-1.0 N (amine)-1.0
-NO 2 (aliphat.)-0.85 -NO 2 (aromat.)-0.28 O O N H OH Betaxolol
Betablokker
12 x C aliphat: +6.0
Ph: +2.0
3 x O: -3.0
N: -1.0
logP +4.0 ClogP (SciFinder): 2.69
π-value: hydrophilic - lipophilic value
logP ∝ Rt (HPLC, TLC reverse phase) Structure - Physiochemical properties
•Acid / base properties •Water solubility •Partition coefficient •(Crystal structure) •Stereochemistry Calcd: ClogP
Absorbtion of Bioactive Compounds
Absorbtion from GI tract
Stomach
pH 1-3 Duodenum
pH 5-7 Jejunum
Ileum pH 7- 8 Smallquotesdbs_dbs17.pdfusesText_23
Chapter 6 Amines and Amides - Angelo State University