A.

HUBUNGAN
STEREOKIMIA TERHADAP
AKTIVITAS OBAT
KULIAH 3

 Stereoisomers are compounds containing

the same number and kinds of atoms, the
same arrangement of bonds, but different
three-dimensional structures: in other
words. they only differ in the threedimensional arrangements of atoms in
space
Stereoisomers are subdivided into two
types, enantiomers and diastereoisomers.
Enantiomers are compounds for which the
three-dimensional arrangement of atoms is
such that they are nonsuperimposable
mirror images

 Diastereoisomers are all stereoisomer

compounds that are not enantiomers.
Thus, the term "diastereoisomer" includes
compounds containing double bonds (geometric
isomers) as well as ring systems.
Unlike enantiomers diastereoisomers exhibit
different physicochemical properties,
including, but not limited to, melting point,
boiling point, solubility, and chromatographic
behavior
Enantiomers cannot be separated using such
techniques unless a chiral environment is
provided or they are converted to
diastereoisomers

 These differences in physicochemical

properties allow the separation of
diastereoisomers from mixtures
utilizing standard chemical separation
techniques, such as column
chromatography or crystallization.

 The phisicochemical properties of a drug

molecule are dependent not only on what
functional groups are present in the molecule
but also on the spatial arrangement of these
groups
This becomes an especially important factor
when a molecule is subjected to an asymmetric
environment, such as the human body.
Because proteins and other biological
macromolecules are asymmetric in nature, how
a particular drug molecule interacts with these
macromolecules is determined by the threedimensional orientation of the organic
functional groups that are present.

 If crucial functional groups are not

occupying the proper spatial region
surrounding the molecule, then
productive bonding interactions with
the biological macromolecule (or
receptor) will not be possible,
potentially negating the desired
pharmacological effect.
If however, these functional groups are
in the proper three-dimensional
orientation, the drug can produce a
very strong interaction with its receptor

 It therefore is very important for the

medicinal chemist developing a new
molecular entity for therapeutic use to
understand not only what functional
groups are responsible for the drug's
activity but also what three-dimensional
orientation of these groups is needed.
Approximately one in every four drugs
currently on the market can be considered
to be an isomeric mixture, yet for many of
these compounds, the biological activity
may reside in only one isomer (or at least
predominate in one isomer).

 The majority of these isomeric mixtures are

what are referred to as "racemic mixtures" (or
"racemates").
These are compounds, usually synthetic, that
contain equal amounts of both possible
enantiomers, or optical isomers.
Enantiomers also are referred to as chiral
compounds, antipodes, or enantiomorphs.
When introduced into an asymmetric, or
chiral. environment, such as the human body,
enantiomers will display different
physicochcmical properties, producing
significant differences in their pharmacokinetic
and pharmacodynamic behavior.

 Such differences can result in adverse

side effects or toxicity, because one or
more of the isomers may exhibit
significant differences in absorption
(especially active transport), serum
protein binding, and metabolism.
With the latter, one isomer may be
converted into a toxic substance or may
influence the metabolism of another drug.
The basic concepts of stereochemistry
will be not reviewed as previously studied
in the organic chemistry course.

 In 1886, Piutti reported different

physiologic actions for the enantiomers of
asparagine, with (+)-asparagine having a
sweet taste and (-)-asparagine a bland
one.
This was one of the earliest olbservations
that enantiomers can exhibit differences in
biological action.
In 1933. Easson and Stedman reasoned
that differences in biological activity
between enantiomers resulted from
selective reactivity of one enantiomer with
its receptor

They postulated that such interactions

require a minimum of a three-point fit to the
receptor.

Stereochemistry and Biological Activity:

Easson-Stedman Hypothesis
The Easson-Stedman Hypothesis states that the
more potent enantioimer must be involved in a
minimum of three intermolecular interactions
with the receptor surface and that the less
potent enantiormer only interacts with two sites.
This can be illustrated by looking at the
differences in vasopressor activity of (R)-(-)Epinephrine, (S)-(+)-epinephrine and the achiral
N-methyldopamine. With (R(-(-)-Epinephrine, the
three points of interaction with the receptor site
are the substituted aromatic ring, B-hydroxyl
group, and the protonated secondary
ammonium group.

 All three functional groug interact with their

complementary binding sites on the receptor
surface, producing the necessary interactions
that stimulate the receptor.
With (S)- (+)-Epinephrine, only two interactions
are possible (the protonatcd secondary
ammonium and the substituted aromatic ring).
The B-hydroxyl group occupies the wrong
region of space and therefore, cannot interact
properly with the receptor. Nmethyldopamine
can achieve the same interactions with the
receptor as (S(-(+ )-Epinephrine: therefore it is
not surprising that its vasopressor response is
the same as that of (S)-(+)-Epinephrine and
less than that of (R)-(-)-Epinephrine.

 Not all stereoselectivity seen with

enantiomers can be attributed to
differences in reactivity at the receptor
site.
Differences in biological activity also
can result from differences in the ability
of each enantiomer to reach the
receptor site.
Because the biological system
encountered by the drug is asymmetric,
each enantiomer may experience
selective penetration of membranes,
metabolism, and absorption at sites of

 Not all of these processes may be

encountered by a particular
enantiomer, but such processes may
provide enough of an influence to
cause one enantiomer to produce a
significantly better pharmacologic
effect than the other.
Conversely, such processes also may
contribute to untoward effects of a
particular enantiomer.

The neurotransmitter
acetylcholine can be
used to demonstrate
the concept of
conformational isomers

 With conformational isomerism, we are

dealing with a dynamic process that is,
isomerization takes place via rotation about
one or more single bonds.
Such bond rotation results in nonidentical
spatial arrangement of atoms in a molecule.
Changes in spatial orientation of atoms
because of bond rotation results in different
conformations (or rotamers), whereas
conversion of one enamiomer into another (or
diastereoisomer) requires the breaking of
bonds, which has a much higher energy
requirement than rotation around a single
bond.

 Each single bond within the acetylcholine

molecule is capable of undergoing rotation, and
at room temperature, such rotations readily
occur.
Even though rotation around single bonds was
shown by Kemp and Pitzer in 1936 not to be
free but, rather, to have an energy barrier, this
barrier is sufficiently low that at room
temperature, acetylcholine exists in many
interconvertible conformations.
Close observation reveals that rotation around
the central Ca-Cb bond produces the greatest
spatial rearrangement of atoms compared to
rotation around any other bond within the
molecule.

 In fact, several rotatable bonds in

acetylcholine produce redundant
structures, because all of the atoms
attached to one end of some bonds are
identical, resulting in no change in spatial
arrangement of atoms (methyls).
When viewed along the Ca-Cb bond,
acetylcholine can be depicted in the
Newman projections. When the ester and
trimethylammonium group are 180 apart,
the molecule is said to be in the anti or
staggered, conformation (or conformer or
rotamer).

 This conformation allows maximum

separation of the functional groups
and, therefore, considered to be the
most stable conformation energetically.
Other conformations possibly are more
stable if factors other than steric
interactions come into play (e.g.,
intramolecular hydrogen bonds).
Rotation of one end of the Ca-Cb bond
by 120 or 240 results in the two
gauche, or skew, conformations

 These are considered to be less stable than the

anticonformer, although some studies suggest
that an electrostatic attraction between the
electron-poor trimethylammonium and electronrich ester oxygen stabilizes this conformation.
Rotation by 60, 180, and 240 produce
conformations in which all of the atoms overlap,
or what are referred to as eclipsed
conformations.
These are the least stable conformers. An
interesting observation can be made with the
two gauche conformers.
These conformers are not distinct molecules,
and they only exist for a transient period of time
at room temperature

 If these could be "frozen" into the

conformations shown, however, they would be
non-superimposable mirror images or
enamiomers. Thus, a compound that is achiral,
such as acetylcholine, can exhibit prochirality if
certain conformational isomers can be formed.
It is quite possible that such a situation could
exist when acetylcholine binds to one of its
receptors.
Studies have suggested that the gauche
conformation is the form that binds to the
nicotinic receptor, whereas the anti form,
which is achiral, binds to the muscarinic
receptor

S (+)-Ketamin > R-(-) Ketamin (4:1)

anaestesi
Tocainide R>S (3:1) antiarythmic
Warfarin S>R (8:1) anticoagulant
Terbutaline ->+ (3000:1)trachea

Biomolecules(reseptors,enzymes):Asymmetric

D
A

Drug

C
B

Biomolecular
target

Desiredresponce

Nodesiredresonce
Sideeffects??

Enantiomersmaybehavedifferently:
Absorbtion(membraneselectivity)
Metabolism
Bindingtootherreseptorsthantarget
(loss,sideeffects)
Bindingtotargetreseptor

Lock
Lockand
andKey
KeyModel
Model

CHO

CH2OH
H
H

OH

CHO OH

CHO

OH

CH2OH
CHO

OH

Discrimination
Discriminationof
ofEnantiomers
Enantiomersby
by
Biological
BiologicalMolecules
Molecules

Restrictedrotationopticallyactiverotamers

(S)-(-)-BINAP

(R)-(+)-BINAP

X-ray contrast agent

* CO2H

Chiral C-atom

O
I

Chiral axis (restrict. tot.)

NH2

KJM5230H06

4 stereoisomers

Screening/Design/Serendipity/Naturalproducts
Leadcompound

StructureOptimisation

Refinementofleadstructure:
Determiningpharmacophore
Functionalgroupmodification

ActualDrug

Pharmacophore:
Thepartofthemoleculethatcontainsthefunctionalgroupsthatactuallybindstothereseptor

Morfin

Dextropropoxyphene

Petidine

OH

OH

O
O

KJM5230H06

Antimycobacterials

Ar

Lead compound

Rel high activity

N
Cl

N
O

R CH2Ph

R=H, alkyl

Inactive

Pharmacophore??
Ar

N
N

Azapurines??
Deazapurines??

??

KJM5230H06

N
N

Ar

Ar

Ar

N
??

??

Improvementofleadbyfunctionalgroupmodification
Activity
Toxicity
Bioavailability
Metabolism

Isosters:
Functionalgroupsthatresultsinapprox.thesameproperties
Stericandelectronicsimilarities
N
S
bp 81

oC

bp 84

oC

-CH=CH- and -S- are isosters

bp 116 oC

-C= and -N= not isosters

(at least with respect to bp)

KJM5230H06

isosters:
nctional groups that results in approx. the same biological properties

Classical bioisosters
Steric and electronic similarities

Monovalent
F,H
OH,NH2
H,F,OH,NH2,CH3
SH,OH
Cl,Br,CF3

Divalent
-C=S, -C=O, -C=NH, -C=CTrivalente
-CH=, -N=

Tetravalente
N

Rings
N

KJM5230H06

O
N

H
F
OH
NH2
CH3
Bioisosters

0
0.15
0.61
1.23
0.60

0
0.06
0.37
0.66
0.17

%Inhibat
6.25g/mL
>90
>90
79
23
>90

MIC
(g/mL)
3.13
6.25
n.d.
n.d.
3.13

:electroniceffects;>0electronwithdrawing,<0electrondonating
:Lipophilicity,>0increasedlipophil.reltoH

AngiotensinIIantagonists
(Hypertention)
Non-classical bioisosters
Not strong steric or electronic similarities

N
N

N
N
H

pKa 14.2

N
N
H

pKa 10.3

N
H

N
N

pKa 9.2

N N
N
N
H

pKa 4.9

N
NH

HO2C

N
N

karboksylsyrer
HO

KJM5230H06

 Adanya gugus spesifik tidak berarti punya akt.

farmakologi, krn aktivitas tergantung pd
molekul obat secara keseluruhan
Mengapa penting:
1. untuk menghasilkan reaktivitas atau karena
stereokimianya
2. cepat mengubah intensitas aktivitas karena
karakteristiknya
Gugus yang reaktif banyak, mudah bereaksi dg
konstituen sel dpt mencegah dimana ia hrs
bereaksi
Gugus yg relatif kurang aktif, tidak mmberikan
aktivitas

Aktivitas biologi, memerlukan:

reaktivitas optimal dan sifat fisika optimal
Modifikasi struktur, penemuan obat baru
Ariens :
1. Gugus chemofunctional
2. Gugus biofunctional
a. Gugus esensial
b. Gugus non-esensial
Gugus
Gugus
Gugus
Gugus
Gugus

pembawa
yang mudah terusik
critical dan non-critical
bioisostere
haptophoric dan pharmacophoric

A. Gugus Pembawa
Struktur kimia dalam obat:
Mengaktivasi, perlu latensasi obat: mengubah
menjadi aktif melalui modifikasi kimia
Mendeaktivasi
1. Modifikasi durasi obat
2. Intekonversi dpt terlokalisasi dalam sel/otot
yg dituju
3. Untuk mengatasi kesukaran selama formulasi
farmasetika
4. Modifikasi transpor obat dan distribusi bat
5. Mengurangi tksisitas senyawa senyawa
tertentu

Contoh: protonsil rubrum, menjadi

sulfanilamid
N=N-

H2N

SO2NH2

NH2

Gugus terbatas, gugus yg besar dan

cenderung terakumulasi dalam
kompartemen yang lipofilik.
Contoh suksinil sulfatiasol, gugus
pembawa yang anionik, sukar
terabsorbsi, shg aksinya hanya terbatas
SO -NH
HOOC-H C-H C-OC-HN
O
N
pada intestine
CH -CHsaja
-Cl
N
O
CH -CH -Cl
N
Urasil mustard
2

 Beberapa obat aktif dan

Obat aktif
R-OH

Transport
inaktif
R-O-CO-X

R-OH

R-fosfat

R-SH

R-fosfat

R-SH

R-S-CO-X

R-COOH

R-CO-O-X

R2NH

R2-N-CO-X

 Faktor sterik diperlukan untuk

mengurangi atau menambah volume
gugus pembawa
Untuk mencegah atau memudahkan
rotasi disekitar, agar struktur
datar/planar or tidak datar
RN

RN

H3C
RN

I.

Nonplanar

II. Planar
RN

NH
P

CH2-CH2-Cl

HOOC-(H2N)HC-H2C

CH2-CH2-Cl
CH2-CH2-Cl

O O CH2-CH2-Cl

Siklofosfamida

Melfalan

N
O

glucoronic acid
O2N

CHOH-CH-NH-CO-CHCl2
CH2-O-CO-C15H31

Kloramfenicol palmitat

II. Gugus yang mudah terusik

Karena resistensi atau kepekaan gugusgugus fungsi terhadap enzim,
mengurangi atau memperpanjang
aksinya, aktivasi or inaktivasi
H3C

SO2-NH-CH2O-NH-

Cl

SO2-NH-CH2O-NH-

H3C
H2N

SO2-NH-CHO-NH

Menstabilkan gugus yang mudah terusik:

Memasukkan gugus alkil, asetilkolin
esteraase
Struktur

CH3-CO-O-CH2-CH2-N(CH3)3

Nama
Senyawa

Asetilkoline

Kecepatan
hidrolisis oleh
Asetilkolin
esterase
100

CH3-CO-O-CH(CH3)CH2-N- L(+)-Asetil-(CH3)3
metilkoline

54.5

CH3-CO-O-CH(CH3)CH2-N- D(+)-Asetil-(CH3)3
metilkoline

Inhibisi

R3

Tingkat stabilisasi thd

hidrolisis
R1

R2

R3

Kecepat
an
Hidrolisi
s

NH2

500

CH3

NH2

15

CH3

CH3

NH2

3000

R1
CO-O-C CH2-N(C2H5)2
R2

 Lidokain dan tolikain

CH3

CH3

NH-CO-CH2-N-(C2H5)2

NH-CO-CH2-N-(C2H5)2

CH3

CO-OCH3

III. Gugus Critical dan Non-critical

Critical: terlibat dalam interaksi O-R
Non-critical: tidak terlibat O-R
H2N

N=NNH2

SO2NH2

4. Gugus bioisostere
These may include undesirable side effects,
physicochemical properties, other factors that
affect oral bioavailability and adverse
metabolic or excretion properties. These
undesirable properties could be the result of
specific functional groups in the molecule.
The medicinal chemist therefore must modify
the compound to reduce or eliminate these
undesirable features without losing the desired
biological activity. Replacement or modification
of functional groups with other groups having
similar properties is known as "isosteric
replacement" or "bioisosteric replacement

 Allen, in 1918 defined the molecular number of a

compound in a similar way of the atomic number:
N = aN1 + bN2 + cN3 + - + zNi
where N = molecular number
N1, N2, N3, . . . Ni = respective atomic numbers of
each element of the molecule.
a, b, . . . z = number of atoms of each element
present in the molecule.
Example: Comparison of the ammonium and the
sodium cations.
The atomic number of nitrogen is 7 and that of
hydrogen is 1. Thus the molecular number of the
ammonium cation can be calculated and
compared to that of the sodium ion.

 In a biologically active molecule the

replacement of an atom or a group of
atoms by another one presenting the
same physiochemical properties is based
on the concept of isosterism.
The notion of isosterism was introduced in
1919 by Langmuir who was mainly
focused in the similarities of electronic
and steric arrangement of atoms, groups,
radicals, and molecules

 The concept of isosters was then

broadened by Grimm in 1925 with the
statement of Hydride Displacement Law,
and, further on,
Erlenmeyer extended Grimm's
classification defining isosters as atoms,
ions, and molecules in which the peripheral
layers of electrons can be considered
identical. The extensive application of
isosterism to modify a part of a biologically
active molecule to get another one of
similar activity, has given rise to the term
of bioisosterism or non-classical isosterism.

 As initially defined by Friedman,

bioisosters include all atoms and molecules
which fit the broadest definition for isosters
and that elicit the similar biological activity.
In medicinal chemistry, the concept of
bioisosterism is a research tool of the
utmost importance widely used in
analogs design
In 1919 Langmuir first developed the
concept of chemical isosterism to describe
the similarities in physical properties
among atoms, functional groups, radicals,
and molecules.

 The similarities among atoms described by

Langmuir primarily resulted from the fact that
these atoms contained the same number of
valence electrons and came from the same
columns within the periodic table.
This concept was limited to elements in
adjacent rows and columns, inorganic
molecules, ions, and small organic molecules,
such as diazomethane and ketene
To account for similarities between groups with
the same number of valence electrons but
different numbers of atoms.
Grimm developed his hydride displacement
law.

 This is not a "law" in the strict sense but.

rather, more an illustration of similar physical
properties among closely related functional
groups.
Descending diagonally from left to right in the
table, hydrogen atoms are progressively added
to maintain the same number of valence
electrons for each group of atoms within a
column.
Within each column, the groups are considered
to be "pseudoatoms with respect to one
another. This early view of isosterism did not
consider the actual location, motion, and
resonance of electrons within the orbitals of
these functional group replacements.

 He further deduced from the octet theory

that the number and arrangement of
electrons in these molecules are the same.
Thus, isosteres were initially defined as
those compounds or groups of atoms that
have the same number and arrangement of
electrons. Then, he defined other
relationships in a similar manner. Argon was
viewed as an isostere of K+ ion and
methane as an isostere of NH4+ ion.
He deduced that K+ ions and NH4+ ions
must be similar because argon and
methane are very similar in physical
properties

 The biological similarity of molecules

such as CO2 and N2O was later
coincidentally acknowledged as both
compounds were capable of acting as
reversible anes-thetics to the slime
mold Physarum plycephalum.

 Instead of considering only partial structures.

Hinsberg applied the concept of isomerism to
entire molecules.
He developed the concept of "ring equivalents
that is groups that can be exchanged for one
another in aromatic ring systems without
drastic changes in physicochemical properties
relative to the parent structure.
Benzene, thiophene, and pyridine illustrate this
concept. A -CH=Chgroup in benzene ts replaced
by the divalent sulfur -S- in thiophene, and a
-CH= is replaced by the trivalent -N= to give
pyridine

 The physical properties of benzene and

thiophene are very similar. For example, the
boiling point of benzene is 81.1 C and that of
thiophene is 84.4C.
Pyridine, however, deviates, with a boiling point
of
115 C.
Hinsberg therefore concluded that divalen sulfur
(-S- or thioether) must resemble -C=C- in shape,
and these groups were considered to be isosteric.
Note that hydrogen atoms are ignored in this
comparison.
Today this isosteric relationship is seen in many
drugs.

 It is difficult to relate biological

properties to physicochemical
properties of individual
atoms, functional groups, or entire
molecules, because many
physicochemical
parameters are involved
simultaneously and, therefore, are
difficult to quantitate.

IV. Gugus bioisostere

Gugus bioisostere penting untuk disain obat
baru.
1919 Langmuir, gugus dari atom-atom yang
mempunyai konfigurasi elektron yang sama
Contoh: CO dgn N2: COO dgn N3 atau NCO
Karakterisasi isostere ialah sifat fisikanya sama
Grimm, konsep isosterisme dgn pemindahan
hidrida, dan disebut pseudo atom
Erlenmeyer, konsep isostere , atom-atom, ionion atau molekul yang elektron perifer identik.

Pemindahan hidrida dari Grimm

E
total

10

11

Ne

Na+

CH

NH

OH

FH

CH2

NH2

OH2

FH2+

CH3

CH3

OH3+

CH4

NH4+

Contoh : aminopirin (antipiretik)

O

CH(CH3)2

N (CH3)2
H3 C

H3C
CH3

CH3- COO- CH2- CH2- N( CH3) 3

CH3

NH2- COO- CH2- CH2- N( CH3) 3

Atom-atom, ion-ion atau molekul yang

elektron perifer identik
E
perifer

N+

Cl

ClH

P+

As

Se

Br

BrH

S+

Sb

Te

IH

As+

FH

SH

SH2

Sb

FH2

FH3

Gugus-gugus jg disebut isostere, contoh:

-COO : -CO-: Cl
-SO2NH: SO2- : CF3
R1
Obat /antihistamin; N CH -CH -X-R
2

R2

X dpt diganti O, NH or CH2

Inhibisi kolinergik:
X diganti COO, -CONH atau COS
Friedman: senyawa yang mempunyai
isostere menunjukkan antagonistik

Isostere klasik: spt definisi Erlenmeyer,

yaitu pemindahan hidrida, unsur dalam
sistem periodik, dan ekivalensi annular
Monoval
en

Bivalen

Trivalen

Tersubt
tetra

Ekiv.
Annular

F, OH,
NH2, CH3

-O-

-N=

=C=

-CH=CH-

Cl, SH,
PH2

-S-

-P=

=N+=

-S-

Br

-Se-

-As=

=P+=

-O-

-Te-

-Sb=

=As+=

-NH-

-CH=

=Sb+=

OH
Br

N
HO

OH

CH3

N
HO

Bromourasil antagonis Timin

Isostere non-klasik: yg terbustitusi dlm
molekul ttt, memberikan senyawa yg
susunan sterik dan elektroniknya sama
dgn seny induknya:
-CO

-COOH

-SO2NH2

-SO2 -SO3H

PO(OH)NH2

Str.
anul
Open

-O-CO-

-H

-CO-O-

-NH2

Penggantian gugus isostere kadang-kadang

menjadi antagonis yang kompetitif

Contoh:
Atom/gug
us

Atom/gugus
pengganti

H-

-F, -Br, -CH3

-OH

-NH2

-NH2

-OH, -Cl, -NH-NH2

-CH3

-Cl, -C2H5,

-O, NH-, CH2-CH2-,

-CH=CH-

-COOH

-SO2NH2, -SO3H, -COCH3

-CO

-CH2

Contoh metabolis
kompetitif
As. Fluorositrat-, 5-Fluoro
urasil
Aminopterin
Oksitiamin, feniletilhidrazine
2-kloronaftokuinon, Etionin
Metionin, Tiamin, biotin,
prirtiamin
Sulfanilamid, asam nikotinat,
-asetilpiridin
Deoksipiridoksal

V. Gugus Haptoforik dan Farmakoforik

Gugus haftoforik ialah gugus yg menolong
dalam pengikatan obat ke reseptor
Gugus farmakoforik ialah gugus yang
bertanggung jawab atas aksi biologik.
Variasi aksi yang dilakukan gugus tersebut
membentuk kompleks dgn reseptor dgn
mekanisme yg berbeda dan tipe reseptor
yg berbeda
Contoh: derivat sulfonat sebagai
antibakteri

Derivat sulfonat
O
O H
S NH C N (CH2)3 CH3
O

H3C

Tolbutamid

+++

++

+++

++

++

O
S NH2
O

+++

O
S NH2
O

O
N
S NH
N
O

Sulfanilamide

H2N

Carzenide
HOOC

Klortiazide

N
N S
O O

Inhibitor SalureKarboni tik

k
anhidra
se

+++

O
O H
Karbutamid
S NH C N (CH2)3 CH3
H2N
O

Sulfadiamin
H N

Antidiab Bakterio
et
statik

O
S NH2
O

++ +++

Efek dari gugus-gugus spesifik

Pengaruh yang cukup besar dari molekul obat
dalam menjalankan fungsinya yaitu
1. Efek elektronik (induktif)
2. Efek halogen (sterik)
Gugus yang menarik elektron > at. H: induksi
negatif
Gugus yang menarik elektron < at. H: induksi
positif
Efek yang sama yang dilancarkan melalui ruang
diantara dipol dan substituen disebut field effect
-I, acceptor e dan +I, donor e

Gugus
I

Gugus
I

Gugus
I

+ Gugus
I

-NH3
+
-NR3
+
-NO2

-CHO

-OH

-CH3

>C=O

-SH

-CH2R

-SR

-CHR2

-CN

Cl

-CH=CH2

-CH3
O

-COOH

Br

-CR=CR2

-COOR

C
O

C CH

Gugus yang meningkatkan kerapatan e

dalam sistem terkonjugasi mempunyai
karakter +R dan menurunkan

+R, -I
-F, -Cl, -Br, -I
-OH, -OR
-O-CO-R
-SH, -SR
-NH2
-NR2
-NH-CO-R

-R, -I
-NO2
C N

-C-N=O
-CRO
-COOH,
-COOR
-COONH2
-SOR, CF3

+R, +I
- O-S-CH3
-CR3

2. Efek halogen
Halogen sering digunakan dalam sintesis
karena
a. Mudah diperoleh
b. Digunakan sebagai gugus
penghambat juga pengarah
c. Me too drug, tujuan komersil
d. Berpengaruh pada sifat kimia dan
fisika
Komersil bukan tujuan ahli medisinal,
namun:

Ato
m
H
F
Cl
Br
I

Jarijari
0.29
0.64
0.99
1.14
1.33

Ikatan

Jarak

C-H
C-F
C-Cl
C-Br
C-I

1.14
1.45
1.74
1.90
2.12

Halogen dapat mengakibatkan

pengaruh
a. Sterik
b. Elektronik dan
c. Merintangi/menghalangi

Kek.
Ikatan
93
114
72
59
45

a. Efek sterik
Efek sterik dari mengakibatkan perubahan
aktivitas, misalnya pada fludcortisone
CO-CH2OH
OH

HO

H<F<Cl<Br<I
F
O

Gugus I mencegah terjadinya rotasi bebas

pada ikatan O I
I

HO
I

CH2 CHCOOH
NH2

b. Efek elektronik dari halogen

Efek elektronik (induksi) dari halogen
menyebabkan aktivitas berbeda,
misalnya pada anestetika lokal
Senyawa
H2N

N(CH2CH2Cl)2

N(CH2CH2Cl)2

Cl

N(CH2CH2Cl)2

NO2
O2N

N(CH2CH2Cl)2

Hidrolisis
100

Aktivitas
biologi
+

20

Kecepatan hidrolisis dari derivat prokain

Senyawa

Kecepatan
hidrolisis
1.00
4.63
2.44
0.26

Prokain
2-kloroprokain
2-bromoprokain
3,53. dikloroprokain
Efek halogen yang merintangi

Pada peristiwa detoksikasi, cincin aromatis

terhidroksilasi kemudian terkonjugasi dengan
asam glukoronat

Adanya halogen pada cincin pada posisi

para, maka akan merintangi proses ini,
misalnya obat antikonvulsan
(fenobarbital), mempunyai aksi perintang
yang lebih besar daripada
senyawa
O
C2H5
induknya.
NH
C2H5
O

N
H

Apabila gugus metil diganti klor pada

tolbutamida, maka akan meningkatkan
waktu paruh dari 5-7 jam menjadi 33 jam,
O Hyang merintangi.
aksi ini karena atom Oklor
H3C

S NH C N (CH2)3 CH3
O

Efek gugus alkil

Gugus alkil dapat memnyebabkan
1. efek sterik (kelarutan dalam air)
2. Elektronik (permukaan yg komplemen
O-R), mengurangi reaksitivitas ikatan
kovalen
R1

O
S

H2N

HN

NH
HN
R2

Obat

R1

R2

pKa

%ionisasi ,
pH 5.2

Solubilitas

Sulfadiazin

6.5

3.9

0.0005

Sulfamerazin

CH3

7.1

1.4

0.0013

Sulfamethazin

CH3

CH3

7.4

0.7

0.024

CH3

CH3

inaktif
aktif
Efek seri homolog (alkana, polimetilen
dan siklopolimetilen) akan mempengaruh
sifat farmakologi:
1. Aktivitas naik pada obat berstruktur
non spesifik (hipnotika,