Kelompok 10 - Metode Optimasi Senyawa Penuntun

8/9/2019 Kelompok 10 - Metode Optimasi Senyawa Penuntun

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KIMIA MEDISINAL

METODE OPTIMASI SENYAWA PENUNTUN

(MODIFIKASI STRUKTUR MODEL PENDEKATAN TOPLISS

DAN METODE RANGKAIAN OPTIMASI SIMPLEKS)

NIKE MARDIANA MARBUN 08111006056

RONNY S E 08111006058DEBIE YOLANDA 08111006059

APRIDINATA 08111006060

COSMALINDA KURNIA P 08111006063



H! " L#$% C&'&*%+++(1)

A ,H!, C&'&*% is a chemical compound that produces a result in a preliminary biochemical test

indicating that the compound merits further study as part

of a drug discovery project.

A -.#$%, C&'&*% is a compound that has been

selected from a group of hit compounds based on qualities

such as the intensity of the biochemical effect that occurs

when the compound is present (efficacy), or the absence of

coincidental effects (specificity).

Sumber:



N#/ '&.#.# /!2 &!#*!$. 2$'$#!$. *!##!4 -2!4

$# natural products, or compounds generated by computational

chemistry, or compounds from screening of chemical libraries,

from combinatorial chemistry, and from pharmaceutical

biotechnology.

T2# ,2! &'&*% '&7#% for its pharmacologic,

pharmacodynamic and pharmacokinetic properties by chemical

or functional group modifications, transforming it into $ .#$%

&'&*%.

Sumber:

H! " L#$% C&'&*%+++()



lead compound should :

have a known !!#

have a known '#2$*' & $!&*

H! " L#$% C&'&*%+++(3)



pakah yang dimaksud dengan optimasi senyawa

penuntun!

"he lead compounds identified from the #ypothesis

$eneration stage must be refined

and optimi%ed prior to continuation of research, so

that the value of research e&penses are ma&imi%ed.

"his process is called L#$% O!':$!&*.

'ippincott illiams ilkins. *++. -emington; "he Science nd ractice /f harmacy

L#$% &!':$!&*+++(1)



pakah yang dimaksud dengan optimasi

senyawa penuntun!

'ead optimi%ation is a multi0parametric process

aimed at simultaneously optimi%ing several

features such as on target activity, bioactivity

and stability.

1ohn iley Sons. *+22. picomple&an arasites: 3olecular pproaches toward "argeted 4rug 4evelopment

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L#$% &!':$!&*+++(3)

5apankah optimasi senyawa penuntun dapat

dilakukan!

"he optimi%ation of a lead compound can be

made $!# $ ,2! &'&*% &*%

!2&<2 =&.&<$. #7$.$!&*+



3engapa optimasi senyawa penuntun perlu dilakukan!

to be $ %< $*%%$!# !2$! $# to use in

human clinical trials

to '&7# ADME (absorption, distribution,

metabolism and e&cretion) of the drug

#%!&* & !2# !&>!?

'&7#'#*! & !2# #$?

S'=#

L#$% &!':$!&*+++(3)



3engapa optimasi senyawa penuntun perlu dilakukan!

"he analogs of the lead compound will 2$7# $ 2<2# 2$*# &

&#*< $ '.$ $!7!? !& .#$% &'&*% than if othercompounds were prepared on a random basis

T& #$# &'&*% /!2 <#$!# &!#*# than the lead

compound ant to have more desirable features in terms of the

following characteristics : reduced to&icity, greater specificity of

drug action, improved duration of action compared to the leadcompound, improved stability, and reduced cost of the production

"o %#7#.& !!# $!7!? #.$!&*2

S. 6. andeya, 1. -. 4immock . 2778. n 9ntroduction "o 4rug 4esign.

L#$% &!':$!&*+++(@)



L#$% O!':$!&* M#!2&%

3etode optimasi senyawa penuntun diantaranya :

1+ M&%$ !! '&%#. #*%#$!$* T&.

+ M#!&%# &!'$ $*<$$* S'.#. 3etode pencarian ;ibonacci

<. nalisis 5laster

&2* G+ T&.4 P2+D+



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"he "opliss decision tree is essentially a flow

diagram that in a series of steps directs the medicinal

chemist to produce a series of analogues, some ofwhich should have a greater activity than the lead

used to start the tree. 9t is emphasi%ed that &*.? &'#

& !2# &'&*% /.. =# '&# $!7# !2$* !2# .#$%

&'&*%.

$areth "homas 0 ;undamentals of 3edicinal =hemistry



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"he "opliss scheme is an empirical method inwhich each compound is tested before an analog

is planned, and is compared in terms of its

physical properties with analogs already planned.

"homas 6ogrady. 277*. 3edicinal =hemistry 0 3olecular and >iochemical pproach



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3emasukkan gugus0gugus yang mempunyai sifat lipofilik,

elektronik dan sterik tertentu, pada posisi tertentu senyawa penuntun,

dengan ramalan akan menghasilkan senyawa yang memberikan

aktivitas lebih tinggi, sama atau lebih rendah dibanding aktivitas

senyawa penuntun, dan kemudian di cari jalur sintesis yang paling

menguntungkan.

Siswandono. *+++. 5imia 3edisinal



M&%$ S!!

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lasan penggunaan model pendekatan "opliss :

L$ & #$? $# !& &'!# by chemists in the early

278+

S?*!2# & .$<# *'=# & &'&*% %.! (but

biological testing of compounds is readily available)

/ptimi%ation of the potency of a lead compound is '&#

##*!

M*':$!&* of the number of compounds needed to be

synthesi%ed.

?lsevier. 4rug 4iscovery, 4esign and 4evelopment.



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5riteria suatu senyawa yang dapat dimodifikasi

menggunakan model pendekatan "opliss :

"he lead compound 2$ =##* !#!#% & =&.&<$.

$!7!? ( screened for its desired biological activity)

"he lead compound must C&*!$* $ '&*&=!!!#%

$&'$! *< (unfused aromatic ring system)



a. 3odifikasi struktur $%$ ** $&'$!

b. 3odifikasi struktur pada $*!$ $'*<<< $..

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M&%$ S!!

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shutosh 5ar. *++8. 3edicinal =hemistry, ;ourth ?dition



M&%$ S!!

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;undamentals of 3edicinal =hemistry 0 $areth "homas



'angkah pertama dalam pendekatan "opliss adalah

mensintesis turunan <0kloro (>) dari . 3isalkan

aktivitas > lebih besar daripada , maka setelah cabang

3, analog berikutnya adalah turunan ,<0dikloro (=) (anggaplah bahwa uji biologis = kurang dari >).

4alam contoh ini, "opliss menunjukkan bahwa

analog paling menjanjikan berikutnya adalah turunan

<0trifluromethyl dari (4) . ada titik ini kita juga akan

mensintesis dan menguji biologis analog *,<0dikloro

(?) dan < 0 nitro (;) dari .

M&%$ S!!

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<0chloro derivative happens to be the ‘first structural analogue’ in

this particular scheme perhaps because it is easy to synthesi%e.

"he @ (sifat lipofilik) and A (elektronik) values are both positive

by virtue of the fact that the chloro substituent is much more

hydrophobic and electron0withdrawing than hydrogen0atom.

"he synthesi%ed chloro0analogue is subjected to the biological

activity measurements accordingly.

"hree situations may arise, namely : (a) analogue possessing lessactivity (L) ; (b) equal activity (?) B and (c) more activity (M).

Ashutosh ar .!""#. Medicinal $hemistry% &ourth 'dition.

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;urther line of action towards the synthesis of structural

analogues of <0chloro aromatic substituents are entirely

guided and based on the following three options% namely

Ashutosh ar .!""#. Medicinal $hemistry% &ourth 'dition.

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Biological Activity Series Followed Next AnaloguesSynthesized

Increases M-series 3, 4-Dichloro substituted

derivatives

Same profle E-series 4-Methyl derivatives

Decreases L-series 4-Methoxy derivatives



;ollowed by synthesi%ing different analogs

containing electron withdrawing or donating

functional groups such as =l0, ;0, 6/*0, 3e0,

and 3e/0 and comparing biological activity to

the unsubstituted molecule of interest

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9nterpretasi : peningkatan aktivitas disebabkan oleh

peningkatan sifat lipofilik dan elektronik, sehingga

substitusi selanjutnya masih meningkatkan kedua

sifat tersebut, yaitu dengan mensintesis turunan ,<0dikloro

Substituen dikelompokkan berdasarkan @, A, atau @*

dan keragaman kombinasi &@ atau y@

endekatan dimulai dengan mensintesis lima turunan,

senyawa disubstitusi dengan (<0#)B <0chloroB ,<0

dichloroB <0methylB <0metho&y.

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C&*!&2 M&%$ S!!

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2,*,,<0tetrahydroacridone



Substituen -l disintesis pada senya!a inti "#$%&pada posisi 4 atau '4 dari cincin aromati()

Substituen yan* berbeda dicipta(an sesuaiden*an a(tivitas l- pada '

4)

+i(a l- di '4 menampil(an a(tivitas sama "E&pada yan* #$% tersubstitusi, ma(a lan*(ahselanutnya adalahmenambah(an *u*us

un*sional -Me (e inti #$% untu( men*ui apa(ah(elompo( ini memili(i & a(tivitas yan* sama "E&,lebih "M&, atau "L& dari senya!a disintesissebelumnya)

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C&*!&2 M&%$ S!!

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da hubungan antara gugus fungsional =l0 dan "# pada posisi0posisi tertentu)



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.erubahan a(tivitas dipen*aruhisiat lipoili( "/&, ele(troni( "0& dansteri( "Es& substituen)

Senya!a yan* di(emban*(anmen*andun* *u*us 1, 2$,12$, atau -1-', -12$-' dan

2$1-') "' adalah variabelsubstituen&

S



5) 6anti *u*us metil den*an *u*us isopropil laluui a(tivitasnya

) 7ila a(tivitas hasil sintesis lebih tin**i artinyanilai "8& / yan* berpen*aruh, adi *antiden*an *u*us yan* nilai "8& / lebih besartetapi nilai Es hampir sama "*u*us si(lopentil&

3) 7ila a(tivitas hasil sintesis lebih a(ti,

lanut(an modif(asi den*an turunansi(loheptil, ben9il dan eniletil "(arena a(anmenin*(at(an nilai nilai / san*at besar dannilai Es moderat)

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M#!&%# R$*<$$* O!'$ S'.#



4asar :

Cengaturan tertentu dari struktur senyawa yang

mempunyai aktivitas biologis samaD

rinsip :

C Senyawa hipotetik diplot dalam sistem koordinat 4D

M#!&%# '.# && %<*$$* *! '&%$ #

#*?$/$ ?$*< *!#*?$ '#'#.$* /$! #.$!

.$'$ #%$*< $!7!$ =&.&<*?$ #.$! #$!+

M#!&%# R$*<$$* O!'$ S'.#



M#!&%# R$*<$$* O!'$ S'.#

Kelompok 10 - Metode Optimasi Senyawa Penuntun

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