Structural features which influence drug action
© Oldřich Farsa 2012
Stereochemistry: Space arrangement of the atoms or three-dimensional
structure of the molecule.
Stereochemistry plays a major role in the pharmacological properties because:
(1) Any change in stereospecificity of the drug will affect its pharmacological
activity
(2) The isomeric pairs except the enantiomeric ones have different physical
properties (partition coefficient, pKa
, etc.) and thus differ in pharmacological
activity.
The following steric factors markedly influence pharmacological activity:
Geometric isomerism
Optical isomerism
Conformational versatility
Geometric isomerism (cis-trans or E/Z-isomerisms).
Occur as a result of restricted rotation about a chemical bond, owing to double
bonds or rigid ring system in the molecule.
They are not mirror images and have different physicochemical properties and
pharmacological activity. Because different distances separate the functional groups
of these isomers.
They generally do not fit to the same receptor equally well and if these functional
groups are pharmacophores the isomers will differ in biologic activity.
●2 pairs of the same substituents or situation on a ring or on a system of saturated
fused rings ⇒ cis/trans
●
all the 4 substituents are different ⇒ E/Z must be used; then is necessary to order the
substituents in the sequence of decreasing atomic weights of the atoms bond directly to
the multiple bond; if 2 heavier substituents are on the same side, then Z, if they are on
different sides, then E; if the first atoms are the same, further ones have to be
compared
Z assigned to German zusamen = together
E entgegen = opposite
●cis-diethylstilbestrol has only 7 % of estrogenic activity of its trans-isomer
CH3
CH3
OH
OH
CH3
CH3
OH
OH
13
149
8
10
17
12
11
15
16
7
5
6
CH3
18
1
4
2
3
HH
H
OH
OH
trans-diethylstilbestrol cis-diethylstilbestrol
estradiol
●the distance between -OH groups of trans-diethylstilbestrol is approx. the same as in
estradiol, it is differnt in cis-isomer
●tricyclic antipsychotics of thioxanthene series: Z-configuration is much more active
9
S
10
8
7
6
5 4
3
2
1
Cl
N
N
OH
9
S
10
8
7
6
5 4
3
2
1
Cl
N
N
OH
●mixture E/Z:
clopenthixol
●Z-isomer: zuclopenthixol
●highly active
Cisordinol ®
E-isomer: weakly active
●situation on a ring: MAO inhibitor tranylcypromine
NH2
NH2
trans- 1-amino-2-phenylcyclopropane
tranylcypromine
●non-selective MAO inhibitor
●geometry similar to prefered dopamine
conformation
cis- 1-amino-2-phenylcyclopropane
●nearly inactive
●situation on a ring: a fibrinolysis inhibitor tranexamic acid
H
H
NH2
OH
O
trans-4-(aminomethyl)cyclohexanecarboxylic acid
tranexamic acid
●inhibits transformation of plasminogene into plasmine
●used in conditions with increased fibrinolysis – bleeding conditions after adenectomy or
tonsilectomy, hemorrhage due to the application of a fibrinolytic, primarirly generalized
fibrinolytic conditions
Exacyl ® inj. sol.
●cis-isomer much less active
●situation on a ring: antiectoparazitic lindane
Cl
H
H
H
H
Cl
H
H
Cl
Cl
Cl
Cl
Cl
H
H
H
H
Cl
H
H
Cl
Cl
Cl
Cl
1,2,3,4,5,6-hexachlorocyclohexane
●
5 stereoisomers assigned α - ε
(1α,2α,3β,4α,5α,6β)hexachlorocyclohexane
= γ-isomer
lindane
●the most active and the only one
used in therapeutics
●pediculicide, scabicide (eg.
treatment of lice and scabies)
Skabicid ®
Conformation formulas of all the stereoisomers of 1,2,3,4,5,6-hexachlorocyclohexane
●inorganic coordination compounds: cisplatin and transplatin
●neutral square planar coordination complexes
Pt
Cl
Cl
NH3
NH3
Pt
Cl
NH3
NH3
Cl
cisplatin
cis-diamminedichloroplatinum(II)
●antineoplastic
●forms intra- and interstrand cross-links
namely between N(7) of imidazole rings
of adenins and guanins
●intrastrand cross-links are difficult to
repair by cellular reparation mechanisms
trans-diamminedichloroplatinum(II)
●active in vitro, but not in vivo
●forms namely interstrand cross-links
which are easy to repair
Optical isomerism and pharmacological activity
Chiral compounds are compounds that are able to rotate the plane
of polarized light. It is due to some molecular asymmetry.
The (+) or dextrorotatory: isomer rotates light to the right
(clockwise). The (-) or levorotatory: isomer rotates light to the left
(counterclockwise). If isomers are mirror images which cannot be
superimposed they are called enantiomers. Enantiomers have the
same physical (melting or boiling point, density, viscosity, IR, NMR,
UV-VIS, MS) and chemical properties. They have also the same
absolute value of optical rotation but different signs (+) or (-).
Optical isomers which are not mirror images are called
diastereomers. Optical isomers very often differ in biological activity,
because all their target structures (active sites of enzymes and
receptors, nucleic acids etc.) transport systems (proteins) and
enzymes taking part in their metabolism are chiral.
Useful terms in optical isomerism
●eutomer – more active (or less toxic) isomer
●distomer – less active (or more toxic) isomer
●racemate – mixture of equimolar amounts of enatiomers which does not show optical
rotation
Main types of optical isomerism
1. Central chirality
For total number of optical isomers n = 2m
where m is number of chiral centres (except
of chiral compounds with symmetry axis)
2. Atropoisomerism
3. Axial chirality
4. Helical chirality
1. Central chirality
● occurs in compounds which contain at least one central atom (C, S, P, N …) with four
different substituents attached which is the chiral centre
●
a free electron pair can in some cases also act as one of four substituents (S in H+
-pump
inhibitors)
● the Cahn – Ingold – Prelog (CIP) convention is used for description of absolute
configuration on every chiral centre (the R, S system)
● the atoms attached to a chiral centre are ranked as per their atomic number according
to the following laid-down norms:
– Maximum (highest) priority is given to the atom with highest atomic number and
subsequent atoms are ranked accordingly from highest to lowest
– In a situation when a decision cannot be reached with respect to 'priority', i.e. 2
atoms having the same atomic number attached to the chiral centre, the process
continues to the next atom until a decision could be arived
● the molecule is then viewed from the side opposite to the lowest priority atom so that
the bond between the central atom and the atom of the lowest priority can be
considered to be an imaginary steering-wheel axis; and the sequence of priority form
highest to lowest is determined
– In case, the sequence is to the right, or clockwise, the chiral centre is designated
as the R absolute configuration; when the priority sequence is to the left, or
anticlockwise, the designation is S
● do not forget that CIP system is conventional and the thus the R configuration need not
indicate that the compound is dextrorotatory just as the S isomer need not be levorotatory !
Drugs with one chiral carbon atom
α-methyldopa – antihypertensive, α-adrenolytic
Dopegyt ® contains (-)-(S) sesquihydrate
OH
O
OH OH
CH3
NH2
OH
O
OH OH
CH3
NH2
2-amino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
(-)-(S) (+)-(R) - inactive
decarboxylase
OH OH
CH3
NH2
H
β -hydroxylase
OH OH
CH3
NH2
H
OH
α-methylnoradrenaline – metabolite active as α1
antagonist
α-methyldopamine
O
NH CH3
Cl
2-(2-chlorophenyl)-2-(methylamino)cyclohexanone
O
NH CH3
Cl
O
NH CH3
Cl
Drugs with one chiral carbon atom
ketamine – intravenous general anaesthetic
(S)-(+) base (R,S)-(±) racemate (R)-(-) base
(S)-(-) hydrochloride
syn. esketamine [INN] (R)-(+) hydrochloride
hypnotic, analgesic > >
unwanted effects < <
Unwanted effects: post operative restlessness, combativeness, loss of selfcontrol,agitation,
disorientation
Calypsol ® inj. sol. and Narkamon ® 1% inf. sol. contain racemate
Drugs with one chiral carbon atom
●loop diuretics: etozoline
S
H
O
N CH3
O
OH
N
S
H
O
N CH3
O
O
N
CH3 metabolism
(esterase)Z Z
(±)-(R,S) etozoline
●used as diuretic and antihypertesive
●prodrug
(+)-(S) dexetozoline
●patented as an antihypertensive
DE 2911296 (1980)
●
significantly more active diuretic than (±)(R,S)
and more than 2x active than (-)-(R)
(±)-(R,S) ozolinone
●experimental drug
(-) active as diuretic
(+) not diuretic; inhibits low
doses of (-) and furosemide
Diuretic effects of etozoline enantiomers in rats
A - (±)-(R,S) etozoline
B - (+)-(S) dexetozoline
C - (-)-(R)
Drugs with one chiral carbon atom
Anxiolytics: 2,3-benzodiazepins
5
H
4
CH3
N
3
N
2
1
O
CH3
O
CH3
CH3
6
7
O
CH3
8
O
CH3
(R,S)-(±): tofisopam
Grandaxin®
(R)-(+): dextofisopam
●anxiolytic, therapeutic of irritable colon and Crohn disease
(S)-(-): levotofisopam
●anxiolytic
Drugs with one chiral carbon atom
Local anaesthetics of anilide series: prilocaine
●anaesthetic activity of R and S enantiomers does not markedly
differ
NH
CH3
NH
CH3
O
CH3
S-(+)
NH2
CH3
NH
CH3
O
CH3
OH
(2R)-2-(propylamino)propanoic acid
R-(-)
hydrolase
oxidation metabolism
NH2
CH3OH
NH2
CH3
OH
+
+
●toxic metabolites
●methemoglobinemia
●administration of the pure S-(+)
enantiomer can eliminate the toxicity
Drugs with two chiral carbon atoms
●adrenolytic for hypertension treatment: labetalol
OH
NH2
O
H
OH NH
H
CH3
OH
NH2
O
H
OH NH
H
CH3
OH
NH2
O
H
OH NH
H
CH3
OH
NH2
O
H
OH NH
H
CH3
2-hydroxy-5-[1-hydroxy-2-{(4-phenylbutan-2-yl)amino}ethyl]benzamide
R,R α 1 0.15 β 1
2.27 β 2 2.18
syn. dilevalol
S,S α 1 0.39 β 1 0.03 β 2 <0.02
R,S α 1 0.23 β 1 0.15 β 2 0.09 S,R α 1 1.74 β 1 0.04 β 2 0.02
●the equimolar mixture of all the four optical isomers has all the inhibiting activities defined as
equal to one
●activities on α1
and β1
receptors are desirable while activity on β2
unwanted
(bronchoconstriction)
O
CH3
O
H N
CH3
CH3
CH3
O
CH3
O
H N
CH3
CH3
CH3
Drugs with two chiral carbon atoms
Synthetic opioids: phenylbutylamine derivatives
dextropropoxyphene
(+)-(2S, 3R)-analgesic; 1/10 of methadone
activity
Darvon ® (USA)
levopropoxyphene
(-)-(2R, 3S)-antitussive
●no analgesic activity
Novrad ® (USA)
●(2S, 3S) and (2R, 3R) isomers have no important effects
Drugs with chiral sulphur atom
●
H+
/K+
-ATPase (or proton pump) inhibitors: omeprazole
●a free electron pair on the sulphur atom is rigid and acts as the fourth substituent
N
S
NNH
O
CH3
O
CH3
O
CH3
CH3
N
S
NNH
O
CH3
O
CH3
O
CH3
CH3
N
S
NNH
O
CH3
O
CH3
O
CH3
CH3
(R,S)-(±)-omeprazole
(S)-(-)-omeprazole
esomeprazole (R)-(+)-omeprazole
●both enantiomers have the same inhibition activity in vitro, but R-isomer is rapidly metabolized
by CYP2C19 metabolizing enzyme ⇒ S-isomer reaches higher plasmatic levels and longer
lasts in the body ⇒ it is more effective in the treatment
Preparations: (R,S)-(±)-omeprazole Asilar ® , Helicid ® , Lomac ® , …
(S)-(-)-esomeprazol Emanera ® , Emozul ® , Prazectol ® , ...
Drugs with chiral phosphorus atom
●antineoplastics – alkylating agents: cyclophosphamide
N
Cl
Cl
P
O
N
H O
NH
Cl
P
O
N
H O +
H
Cl
O
N-deschloroethylated metabolite
●inactive
(R,S)-(±)-cyclophosphamide
●both enantiomers are equally active in vitro
●R- enantiomer is about twice more rapidly changed in N-deschloroethylated metabolite
and 2-chloroacetaldehyde ⇒ it is less active and more neurotoxic
2. Atropoisomerism
●occurs namely in moleculs of biphenyl type substituted at least in one position
corresponding to o-positin of every of both rings with bulky substituents
●free rotation around the single bond between both rings is here restricted so that two
rotation isomers which are mirror images which cannot be superimposed can arise
●such isomers are then called atropoisomers
●antihypertensives – Ca2+
channel blockers of dihydropyridine series: nifedipine
●in 3,5-disubstituted-4-(2-nitrophenyl)-1,4-dihydropyridines meet atropoisomerism and chiral
conformerism
N
H
N
+
O
-
O
O
O
O
O CH3
CH3
H
dimethyl 4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate
nifedipine
Cordipin ® , Nifecard ®
●
nifedipine and other 1,4-dihydropyridine Ca2+
antagonists exist in 2 atropoisomers; the first
one corresponds to antiperiplanar (ap) conformation and the second one to synperiplanar (sp)
conformation
●sp isomer is 50times more active than ap
●the stereochemistry of 1,4-dihydropyridines has in its relationship to their chiral
conformerism its special „sailing ship nomenclature“ which refers to parts of a ship