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 three-dimensional 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 (geometricisomers) 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 three-dimensional 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 interactionsrequire 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 loss (e.g., adipose tissue) or excretion.

• 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 electron-rich 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) anaestesiTocainide R>S (3:1) antiarythmicWarfarin S>R (8:1) anticoagulantTerbutaline ->+ (3000:1)trachea relaxantPindolol ->+ (200:1) inhibit tachycardi

Biomolecules (reseptors, enzymes): Asymmetric

Enantiomers may behave differently:

• Absorbtion (membrane selectivity)

• Metabolism

• Binding to other reseptors than target

(loss, side effects)

• Binding to target reseptor

A

BC

D

Drug

Biomolecular target

Desired responce

D

BC

A

No desired resonceSide effects??

Lock and Key ModelLock and Key Model

CH2OH

C

CHO

H

H

OH

OH

CHO

CH2OH

C

CHO

H

H OH

OH

CHO

Discrimination of Enantiomers byBiological Molecules

Discrimination of Enantiomers byBiological Molecules

KJM5230-H06

Restricted rotation - optically active rotamers

P

P

(R)-(+)-BINAP

P

P

(S)-(-)-BINAP

I I

I

NH2

O

CO2H*

Chiral C-atom

Chiral axis (restrict. tot.)4 stereoisomers

X-ray contrast agent

KJM5230-H06

•Screening/Design/Serendipity/Natural products •Lead compound

•Structure Optimisation•Actual Drug

Refinement of lead structure:• Determining pharmacophore• Functional group modification

Pharmacophore: The part of the molecule that contains the functional groups that actually binds to the reseptor

Morfin

O

OHN

OH

N

O

O

Petidine

N

O

O

Dextropropoxyphene

KJM5230-H06

N

N N

N

O

Cl

Lead compoundN

N N

N

Ar

X

Y

Z

Rel high activity

N

N N

N

O

R

R ° CH2Ph

N

N N

N

R

R=H, alkyl

Inactive

N

N N

N

Ar

Pharmacophore??

Azapurines??

Deazapurines?? N

N N

Ar

R

??

N

N

Ar

??

Antimycobacterials

??

X

Ar

KJM5230-H06

Improvement of lead by functional group modification

•Activity•Toxicity•Bioavailability•Metabolism

Isosters:Functional groups that results in approx. the same propertiesSteric and electronic similarities

S

bp 81 oC bp 84 oC

-CH=CH- and -S- are isosters

N

bp 116 oC

-C= and -N= not isosters

(at least with respect to bp)

KJM5230-H06

Bioisosters:Functional groups that results in approx. the same biological properties

Classical bioisostersSteric 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=C-

Trivalente-CH=, -N=

Tetravalente

Rings

N S O

N C

KJM5230-H06

N

N N

N

O

X

-X p % Inhib at6.25 g/mL

MIC(g/mL)

-H 0 0 >90 3.13-F 0.15 0.06 >90 6.25-OH -0.61 -0.37 79 n.d.-NH2 -1.23 -0.66 23 n.d.-CH3 0.60 -0.17 >90 3.13Bioisosters

: electronic effects; >0 electron withdrawing, <0 electron donating: Lipophilicity, >0 increased lipophil. rel to H

Non-classical bioisostersNot strong steric or electronic similarities

N

N

NNHO

O

N

N

NN

NH

N

O

HO2C

Angiotensin II antagonists(Hypertention)

N

NH

pKa 14.2

N

N

NH

pKa 9.2

N

N

NH

pKa 10.3

N

NN

NH

pKa 4.9 karboksylsyrer

• Adanya gugus spesifik tidak berarti punya akt. farmakologi, krn aktivitas tergantung pd molekul obat secara keseluruhan

• Mengapa penting:1. untuk menghasilkan reaktivitas atau karena stereokimianya2. cepat mengubah intensitas aktivitas karena karakteristiknya Gugus yang reaktif banyak, mudah bereaksi dg konstituen sel dpt mencegah dimana ia hrs bereaksiGugus yg relatif kurang aktif, tidak mmberikan aktivitas

Aktivitas biologi, memerlukan:• reaktivitas optimal dan sifat fisika optimal• Modifikasi struktur, penemuan obat baruAriens :1. Gugus chemofunctional2. Gugus biofunctionala. Gugus esensialb. Gugus non-esensial

Gugus pembawaGugus yang mudah terusikGugus critical dan non-criticalGugus bioisostereGugus haptophoric dan pharmacophoric

A. Gugus PembawaStruktur kimia dalam obat:• Mengaktivasi, perlu latensasi obat: mengubah

menjadi aktif melalui modifikasi kimia• Mendeaktivasi1. Modifikasi durasi obat2. Intekonversi dpt terlokalisasi dalam sel/otot yg

dituju3. Untuk mengatasi kesukaran selama formulasi

farmasetika4. Modifikasi transpor obat dan distribusi bat5. Mengurangi tksisitas senyawa senyawa tertentu

Contoh: protonsil rubrum, menjadi sulfanilamid

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 pada intestine sajaUrasil mustard

N

N

N

O

OCH2-CH2-Cl

CH2-CH2-Cl

N=N-

NH2

H2N SO2NH2

HOOC-H2C-H2C-OC-HN SO2-NH-

S

N

• Beberapa obat aktif dan

Obat aktif Transport inaktif

R-OH 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

I. Nonplanar II. Planar

III. Planar IV. Nnplanar

RN

RN RN

H3C

RN

Siklofosfamida Melfalan

Kloramfenicol palmitat

NCH2-CH2-Cl

CH2-CH2-Cl

HOOC-(H2N)HC-H2CNH

O

CH2-CH2-Cl

CH2-CH2-Cl

P

O

N

Oglucoronic acid

O2N CHOH-CH-NH-CO-CHCl2CH2-O-CO-C15H31

II. Gugus yang mudah terusikKarena resistensi atau kepekaan gugus-gugus fungsi terhadap enzim, mengurangi atau memperpanjang aksinya, aktivasi or inaktivasi

H3C SO2-NH-CHO-NH

H2N

H3C SO2-NH-CH2O-NH-

Cl SO2-NH-CH2O-NH-

Menstabilkan gugus yang mudah terusik:Memasukkan gugus alkil, asetilkolin esteraase

Struktur Nama Senyawa Kecepatan hidrolisis oleh Asetilkolin esterase

CH3-CO-O-CH2-CH2-N-(CH3)3 Asetilkoline 100

CH3-CO-O-CH(CH3)CH2-N-(CH3)3 L(+)-Asetil-Ƀ-metilkoline 54.5

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

Tingkat stabilisasi thd hidrolisisR1 R2 R3 Kecepatan

Hidrolisis

H H NH2 500

H CH3 NH2 15

CH3 CH3 NH2 0

H H H 3000

R3 CO-O-C

R1

R2

CH2-N(C2H5)2

• Lidokain dan tolikain

• III. Gugus Critical dan Non-critical• Critical: terlibat dalam interaksi O-R• Non-critical: tidak terlibat O-R

CH3

CH3

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

CH3

CO-OCH3

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

N=N-

NH2

H2N 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 84.4°C.

• 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 bioisostereGugus bioisostere penting untuk disain obat baru.1919 Langmuir, gugus dari atom-atom yang mempunyai konfigurasi elektron yang samaContoh: CO dgn N2: COO dgn N3 atau NCOKarakterisasi isostere ialah sifat fisikanya sama

Grimm, konsep isosterisme dgn pemindahan hidrida, dan disebut pseudo atom

Erlenmeyer, konsep isostere , atom-atom, ion-ion atau molekul yang elektron perifer identik.

Pemindahan hidrida dari GrimmE total 6 7 8 9 10 11

C N O F Ne Na+

CH NH OH FH -

CH2 NH2 OH2 FH2+

CH3 CH3 OH3+

CH4 NH4+

Contoh : aminopirin (antipiretik)

+ +

N (CH3)2

O

H3CCH3

CH(CH3)2

O

H3CCH3

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

Atom-atom, ion-ion atau molekul yang elektron perifer identik

E perifer 4 5 6 7 8

N+ P S Cl ClH

P+ As Se Br BrH

S+ Sb Te I IH

As+ - FH SH SH2

Sb - - FH2 FH3

Gugus-gugus jg disebut isostere, contoh:-COO : -CO-: Cl-SO2NH: SO2- : CF3Obat /antihistamin;

X dpt diganti O, NH or CH2Inhibisi kolinergik: X diganti COO, -CONH atau –COSFriedman: senyawa yang mempunyai isostere menunjukkan antagonistik

NR1

R2

CH2-CH2-X-R

Isostere klasik: spt definisi Erlenmeyer, yaitu pemindahan hidrida, unsur dalam sistem periodik, dan ekivalensi annular

Monovalen Bivalen Trivalen Tersubttetra

Ekiv. Annular

F, OH, NH2, CH3

-O- -N= =C= -CH=CH-

Cl, SH, PH2 -S- -P= =N+= -S-

Br -Se- -As= =P+= -O-

I -Te- -Sb= =As+= -NH-

-CH= =Sb+=

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

-CO -COOH -SO2NH2 H Str. anul -O-CO- -H

-SO2 -SO3H -PO(OH)NH2 F Open -CO-O- -NH2

N

N

OH

HO

BrN

N

OH

HO

CH3

Penggantian gugus isostere kadang-kadang menjadi antagonis yang kompetitif

Contoh:Atom/gugus Atom/gugus pengganti Contoh metabolis kompetitif

H- -F, -Br, -CH3 As. Fluorositrat-, 5-Fluoro urasil

-OH -NH2 Aminopterin

-NH2 -OH, -Cl, -NH-NH2 Oksitiamin, Ƀ-feniletilhidrazine

-CH3 -Cl, -C2H5, 2-kloronaftokuinon, Etionin

S -O, NH-, CH2-CH2-, -CH=CH- Metionin, Tiamin, biotin, prirtiamin

-COOH -SO2NH2, -SO3H, -CO-CH3 Sulfanilamid, asam nikotinat, Ƀ-asetilpiridin

-CO -CH2 Deoksipiridoksal

V. Gugus Haptoforik dan FarmakoforikGugus haftoforik ialah gugus yg menolong dalam pengikatan obat ke reseptorGugus 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 berbedaContoh: derivat sulfonat sebagai antibakteri

Derivat sulfonat Antidiabet Bakteriostatik

Inhibitor Karbonik anhidrase

Salure-tik

Tolbutamid +++ _ _ _

Karbutamid +++ ++ _ _

Sulfadiamin _ +++ _ _

Sulfanilamide _ ++ ++ +

Carzenide _ _ +++ -

Klortiazide _ _ ++ +++

H3C NHOSO

CO H

N (CH2)3 CH3

H2N NHOSO

CO H

N (CH2)3 CH3

H2N NHOSO N

N

H2N NH2

OSO

HOOC NH2

OSO

NH2

OSO

N

N

OS

O

Efek dari gugus-gugus spesifik

Pengaruh yang cukup besar dari molekul obat dalam menjalankan fungsinya yaitu1. Efek elektronik (induktif)2. Efek halogen (sterik)Gugus yang menarik elektron > at. H: induksi negatifGugus yang menarik elektron < at. H: induksi positifEfek 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 +

-CHO -OH -CH3

-NR3 +

>C=O -SH -CH2R

-NO2 F -SR -CHR2

-CN Cl -CH=CH2 -CH3

-COOH Br -CR=CR2

-COORC CH

CO–

O

Gugus yang meningkatkan kerapatan e dalam sistem terkonjugasi mempunyai karakter +R dan menurunkan kerapatan e , -R

+R, -I -R, -I +R, +I-F, -Cl, -Br, -I -NO2 - O-

-OH, -OR -S-

-O-CO-R -C-N=O -CH3-SH, -SR -CRO -CR3

-NH2 -COOH, -COOR-NR2 -COONH2

-NH-CO-R -SOR, CF3

C N

2. Efek halogenHalogen sering digunakan dalam sintesis karenaa. Mudah diperolehb. Digunakan sebagai gugus penghambat juga

pengarahc. Me too drug, tujuan komersild. Berpengaruh pada sifat kimia dan fisika

Komersil bukan tujuan ahli medisinal, namun:Mendapatkan seny dgn struktur analog dgn aktivitas yang lebuh tinggi.

Atom Jari-jari Ikatan Jarak Kek. Ikatan

H 0.29 C-H 1.14 93

F 0.64 C-F 1.45 114

Cl 0.99 C-Cl 1.74 72

Br 1.14 C-Br 1.90 59

I 1.33 C-I 2.12 45

Halogen dapat mengakibatkan pengaruha. Sterikb. Elektronik danc. Merintangi/menghalangi

a. Efek sterikEfek sterik dari mengakibatkan perubahan aktivitas, misalnya pada fludcortisone

Gugus I mencegah terjadinya rotasi bebas pada ikatan O

O

HO

F

OHCO-CH2OH

H<F<Cl<Br<I

OHO

I

I

I

I

CH2 CHCOOH

NH2

b. Efek elektronik dari halogenEfek elektronik (induksi) dari halogen menyebabkan aktivitas berbeda, misalnya pada anestetika lokal

Senyawa Hidrolisis Aktivitas biologi

100 +

20 +

9 _

1 _

H2N N(CH2CH2Cl)2

Cl N(CH2CH2Cl)2

N(CH2CH2Cl)2

N(CH2CH2Cl)2O2N

NO2

Kecepatan hidrolisis dari derivat prokain

Senyawa Kecepatan hidrolisisProkain 1.002-kloroprokain 4.632-bromoprokain 2.443,5-dikloroprokain 0.26

3. 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 induknya.

Apabila gugus metil diganti klor pada tolbutamida, maka akan meningkatkan waktu paruh dari 5-7 jam menjadi 33 jam, aksi ini karena atom klor yang merintangi.

NH

NHC2H5

C2H5

O

OO

H3C NHOSO

CO H

N (CH2)3 CH3

Efek gugus alkilGugus alkil dapat memnyebabkan 1. efek sterik (kelarutan dalam air) 2. Elektronik (permukaan yg komplemen O-R),

mengurangi reaksitivitas ikatan kovalen

Obat R1 R2 pKa %ionisasi , pH 5.2 Solubilitas

Sulfadiazin H H 6.5 3.9 0.0005

Sulfamerazin H CH3 7.1 1.4 0.0013

Sulfamethazin CH3 CH3 7.4 0.7 0.024

H2N NH

O

S

O HN

HN

R1

R2

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

N N N NCH3 CH3