Current Drug Discovery Technologies

Loading....

Loading....

Loading....

Loading....

Loading....

Teks penuh

(1)

Current Drug Discovery Technologies

Drug Discovery Technologies

Curr

ent

Send Orders for Reprints to reprints@benthamscience.ae

Current Drug Discovery Technologies, , 13,

)$""*

($!$(+,,-"!

!"*"+

&",'".

/0,+&,-+1$(2'3("*"*

6XNR+DUGMRQR

6LVZDQGRQR6LVZRGLKDUGMR

3XUZDQWR3UDPRQR

DQG:LQ'DUPDQWR

1Pharmaceutical Chemistry Department, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia; 2Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia

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

UHTXLUHG)URPWKHWHVW5HUDQN6FRUHZKLFKLVWKHHQHUJ\RILQWHUDFWLRQEHWZHHQWKHUHFHSWRUDQG WKH OLJDQG PROHFXOH LV WKHQ REWDLQHG +\GUR[\XUHD GHULYDWLYHV ZHUH V\QWKHVL]HG E\ PRGLI\LQJ 6FKRWWHQ%DXPDQQ¶V PHWKRG E\ WKH DGGLWLRQ RI EHQ]R\O JURXS DQG LWV KRPRORJV UHVXOWHG LQ WKH LQFUHDVH RI OLSRSKLOLF HOHFWURQLF DQG VWHULF SURSHUWLHV DQG F\WRWR[LF DFWLYLW\ 6\QWKHVL]HG FRPSRXQGVZHUHEHQ]R\OR[\XUHDDQGLWVGHULYDWLYHV6WUXFWXUHFKDUDFWHUL]DWLRQZDVREWDLQHGE\ WKHVSHFWUXPRI89,5+105&105DQG0DVV6SHFWURPHWHU$QWLFDQFHUDFWLYLW\ZDVFDUULHG RXWXVLQJ077PHWKRGRQ+H/DFHOOV7KH4XDQWLWDWLYH6WUXFWXUH&\WRWR[LF$FWLYLW\5HODWLRQVKLSV RI EHQ]R\OR[\XUHD FRPSRXQG DQG LWV GHULYDWLYHV ZDV FDOFXODWHG XVLQJ 6366 7KH FKHPLFDO VWUXFWXUHZDVGHVFULEHGQDPHO\&ORJ3ʌı56&05DQG(VZKLOHWKHF\WRWR[LFDFWLYLW\ZDV LQGLFDWHG E\ ORJ ,& 7KH UHVXOWV VKRZ WKDW WKH EHVW HTXDWLRQ RI 4XDQWLWDWLYH 6WUXFWXUH &\WRWR[LF$FWLYLW\5HODWLRQVKLSV46$5RIEHQ]R\OR[\XUHDFRPSRXQGDQGLWVGHULYDWLYHVLV /RJ,& ı±(V±

5 6

5HFHLYHG)HEUXDU\ 5HYLVHG0D\ $FFHSWHG0D\

DOI:

10.2174/15701638136661605251123 27

7+8,(2'43K\VLFRFKHPLFDOSDUDPHWHUVF\WRWR[LFDFWLYLW\EHQ]R\OR[\XUHD46$5

9 53:59

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

$GGUHVV FRUUHVSRQGHQFH WR WKLV DXWKRU DW WKH 3KDUPDFHXWLFDO &KHPLVWU\ 'HSDUWPHQW )DFXOW\ RI 3KDUPDF\ 8QLYHUVLWDV $LUODQJJD 6XUDED\D,QGRQHVLD(PDLOVXNRKDUGMRQR#\DKRRFRP

FRQILUPWKHVWUXFWXUHDQGWRGRELRORJLFDODFWLYLW\ WHVW 7KH ODVW VWHS LV WR IRUPXODWH WKH TXDQWLWDWLYH UHODWLRQVKLS EHWZHHQ VWUXFWXUH SK\VLFRFKHPLFDO SURSHUWLHVDQGELRORJLFDODFWLYLW\46$5E\XVLQJ VWDWLVWLFDO UHJUHVVLRQ DQDO\VLV >@ ,W LV D VWDWLVWLFDO

PRGHOWKDWUHODWHVDVHWRIVWUXFWXUDOGHVFULSWRUV RI

DFKHPLFDOFRPSRXQGWRLWVELRORJLFDODFWLYLW\.7R

SURYLGH VRPH JXLGH LW LV ZLGHO\ DFFHSWHG WKDW EHWZHHQ ILYH DQG WHQ FRPSRXQGV DUH UHTXLUHG IRU

HYHU\GHVFULSWRULQD46$5>@6RPHUHVHDUFKHUVXVH

46$5 DV UHVHDUFK PRGHOV%KDUDWH 63et al VWXGLHG WKHDQWLOHLVKPDQLDODFWLYLW\RIVHYHUDOVWUXFWXUDOO\

VLPLODU QDWXUDOO\ RFFXUULQJ JOREDOV IURP

0\UWDFHDHIDPLO\ZKLFKKDYHDOVREHHQSUHGLFWHG

XVLQJ GHYHORSHG 46$5 PRGHO >@ 5ROOL (et al

VWXGLHG 1SKHQ\O1¶EHQ]RWKLD]RO\OXUHD 3%8 GHULYDWLYHVDQGREVHUYHGWKHDDGYHQWLWLRXVURRWLQJ

(2)

DGMXYDQW DFWLYLW\ ZDV VWULFWO\ GHSHQGHQW RQ WKHLU

FKHPLFDO VWUXFWXUH >@ <DPXQD (et al VWXGLHG

F\FORKHSWD >E@ LQGROH GHULYDWLYHV E\ 46$5 >@

6KDOLQL 6LQJK VWXGLHG FRPSXWDWLRQDO GHVLJQ DQG FKHPRPHWULF 46$5 PRGHOLQJ RI 3ODVPRGLXP IDOFLSDUXPFDUERQLFDQK\GUDVHLQKLELWRUV>@

7RSOLVV SURSRVHG D VFKHPH RU DQ RSHUDWLRQDO GLDJUDP WR V\QWKHVL]H DQDORJV LQ GUXJ GHVLJQ 7KLV GLDJUDP LV EDVHG RQ WKH EDVLF DVVXPSWLRQ RI +lQVFK¶V PHWKRG WKDW D SDUWLFXODU VXEVWLWXHQW PD\ DOWHU WKH UHODWLYH DFWLYLW\ WR WKH PRWKHU FRPSRXQG EDVHG RQ FKDQJHV LQ WKH K\GURSKRELF HOHFWURQLF HIIHFWV DQG VWHULF >@ $ VXEVWLWXWLRQ RQ WKH JXLGLQJ FRPSRXQGV DOWHUV WKH

SK\VLFRFKHPLFDO SURSHUWLHV ZKLFK LQFOXGH

OLSRSKLOLF HOHFWURQLF DQG VWHULF SURSHUWLHV >@ 8QWLO QRZ UHVHDUFKHUV DUH VWLOO XVLQJ WKH 7RSOLVV¶ GLDJUDPIRUGHVLJQLQJDGUXJEHFDXVHWKHWKHRU\LV IRXQG WR EH UHODWLYHO\ XQGHUVWDQGDEOH DQG HDV\ WR IROORZ .DNZDQL VWXGLHG 1DU\OWULD]RO \O &LQQDPDPLGH 'HULYDWLYHV DV 3RWHQWLDO $QWLP\FREDFWHULDO $JHQWV >@ /D]]DURWWR 0 VWXGLHG2SWLPL]HGPRGLILHG7RSOLVVPHWKRG>@

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

DDPLQRSKRVSKRQDWHV>@

7KLV VWXG\ XVHG 7RSOLVV DSSURDFK PRGHO LQ FKRRVLQJ WKH JURXS WKDW ZDV XVHG LQ WKH VWUXFWXUH

PRGLILFDWLRQ +\GUR[\XUHD GHULYDWLYHV ZHUH

V\QWKHVL]HGE\WKHDGGLWLRQRIEHQ]R\OJURXSDQGLWV KRPRORJV 7KLV V\QWKHVLV UHVXOWV LQ WKH LQFUHDVH RI OLSRSKLOLF HOHFWURQLF DQG VWHULF SURSHUWLHV DQG DV D UHVXOW WKH F\WRWR[LF DFWLYLW\ LV DOVR H[SHFWHG WR

LQFUHDVH 6\QWKHVL]HG FRPSRXQGV ZHUH

EHQ]R\OR[\XUHD DQG LWV GHULYDWLYHV QDPHO\

FKORUREHQ]R\OR[\XUHD FKORUREHQ]R\OR[\

XUHD GLFKORUREHQ]R\OR[\XUHD EURPR EHQ]R\OR[\XUHD WULIOXRURPHWK\OEHQ]R\OR[\ XUHD PHWK\OEHQ]R\OR[\XUHD WEXWK\O

EHQ]R\OR[\XUHD PHWKR[\EHQ]R\OR[\XUHD

DQGIOXRUREHQ]R\OR[\XUHD7KHV\QWKHVLVZDV GRQHE\PRGLI\LQJ6FKRWWHQ%DXPDQQPHWKRG> @

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

*HPFLWDELQH 'LSKRVSKDWH *'3 >@

+\GUR[\XUHD KDV D PHFKDQLVP VLPLODU WR JHPFLWDELQH

7KH F\WRWR[LF DFWLYLW\ WHVW ZDV FRQGXFWHG ZLWK FDQFHUFHOONLOOLQJPHWKRGVDQGZKLFKZDVFDUULHG

RXW E\ GHWHUPLQLQJ ,& EDVHG RQ WKH DPRXQW RI

(3)

Quantitative Structure-Cytotoxic Activity Relationship Current Drug Discovery Technologies, , Vol. 13, No. 2

ZLWKLQYLWURXVLQJ077PHWKRG&DQFHUFHOOVXVHG ZHUH +H/D FHOOV +H/D FHOOV DUH FDQFHU FHOOV VHOHFWHG IRU D VWDQGDUG XVHG WR GHWHUPLQH WKH DFWLYLW\ RI +\GUR[\XUHD >@ +H/D FHOOV DUH VDIH IRUKXPDQFHOOVFRPPRQO\XVHGIRUWKHEHQHILWRI FHOO FXOWXUH WKHUHIRU RIWHQ XVHG LQ UHVHDUFK 7R LGHQWLI\ WKH VXUYLYLQJ FHOOV WKH UHVXOW RI UHDFWLRQ

DEVRUEDQFH RI GLPHWLOWLD]ROLO

GLIHQLOWHWUD]ROLXP EURPLGH 077 UHDJHQW ZLWK DOLYH +H/D FHOOV ZDV GHWHFWHG E\ XVLQJ (OL]D 5HDGHUZKLFKZDVUHDGDWDZDYHOHQJWKRIQP DV PHQWLRQHG LQ WKH &DQFHU &KHPRSUHYHQWLRQ 5HVHDUFK &HQWHU &&5& SURWRFROV >@ ,&

YDOXH RI WHVW FRPSRXQGV ZDV REWDLQHG WKURXJK SURELWDQDO\VLV46$5RIEHQ]R\OR[\XUHDDQG LWV GHULYDWLYHV ZHUH GHWHUPLQHG EX XVLQJ

SK\VLFRFKHPLFDO SDUDPHWHUV ZLWK F\WRWR[LF

DFWLYLW\ 3K\VLFRFKHPLFDO SDUDPHWHUV FRQVLVW RI OLSRSKLOLF SDUDPHWHUV QDPHO\ &ORJ3 DQG ʌ HOHFWURQLF SDUDPHWHUV ı DQG 56 DQG VWHULF SDUDPHWHUV &05 DQG (V &\WRWR[LF DFWLYLW\ LV

LQGLFDWHG E\ ,& RU ORJ ,& ,Q DGGLWLRQ WR

GHWHUPLQH WKH 4XDQWLWDWLYH 6WUXFWXUH&\WRWR[LF $FWLYLW\5HODWLRQVKLSV6366SURJUDPZDVXVHG

; 93;53

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

)XUWKHUPRUH V\QWKHVLV ZDV GRQH E\ DGGLQJ

EHQ]R\O FKORULGH RU LWV KRPRORJV LQ

WHWUDK\GURIXUDQ LQWR D PL[WXUH RI K\GUR[\XUHD LQ WHWUDK\GURIXUDQ DQG WULHWK\ODPLQH DV D FDWDO\VW ZKLOH VWLUULQJ >@ 7KH SXULW\ RI WKH V\QWKHVL]HG SURGXFW ZDV GHWHUPLQHG E\ D PHOWLQJ

SRLQW DQG D WKLQ OD\HU FKURPDWRJUDSK\

5HFU\VWDOOL]DWLRQ ZDV GRQH ZLWK KRW HWKDQRO 7R DVFHUWDLQZKHWKHUWKHV\QWKHVL]HGFRPSRXQGVZHUH LQ DFFRUGDQFH ZLWK WKH GHVLUHG FRPSRXQGV VWUXFWXUH FKDUDFWHUL]DWLRQ ZDV FRQGXFWHG E\ XVLQJ VSHFWUDO RI 8OWUD 9LROHW 899,6 ,QIUDUHG )7

,5 +& 1XFOHDU 0DJQHWLF 5HVRQDQFH +& 105DQG0DVV6SHFWURPHWHU06>@

&\WRWR[LF DFWLYLW\ ZDV GHWHUPLQHG E\ LQ YLWUR XVLQJ+H/DFHOOV7KHVWHSVZHUHSHUIRUPHGEDVHG RQ WKH &&5& SURWRFROV >@7KH PRWKHU FRPSRXQG ZDV GLOXWHG LQ VWDJHV ZLWK 'XOEHFFRV 0RGLILHG (DJOH 0HGLXP '0(0 FXOWXUH PHGLD VR D VHULHV RI ZRUNLQJ VWDQGDUG VROXWLRQ ZDV JDLQHG +H/D FHOO FXOWXUHV ZHUH SUHSDUHG LQ D PLFURSODWH ZLWK ZHOOV LQ WKH IRUP RI D FHOO

VXVSHQVLRQZLWKDGHQVLW\RIFHOOVZHOOKHQ

LQFXEDWHG IRU KRXUV LQ &2 LQFXEDWRU

6XUYLYLQJ FDQFHU FHOOV ZHUH LGHQWLILHG E\ XVLQJ D UHGXFHG 077 UHDJHQW LQ WKH PLWRFKRQGULD RI FDQFHU FHOOV WKDW ZHUH VWLOO DOLYH VR DV WR IRUP YLROHW FU\VWDOV 7KH FU\VWDOV ZRXOG EHFRPH SXUSOH VROXWLRQ ZLWK WKH DGGLWLRQ RI 6RGLXP 'HGRF\O 6XOIRQDWH 6'6 UHDJHQW WKDW ZDV GHWHUJHQW 7KH DEVRUEDQFH RI SXUSOH FRORU ZDV UHDG ZLWK (OLVD 5HDGHU RU 0LFURSODWH 5HDGHU DW D ZDYHOHQJWK RI QP 7KH DFWLYLW\ RI WKH WHVW FRPSRXQG ZDV

GHVFULEHG E\ SURELW DQDO\VLV REWDLQHG ,&YDOXH

7R FDOFXODWH WKH 4XDQWLWDWLYH 6WUXFWXUH&\WRWR[LF

$FWLYLW\5HODWLRQVKLS,&ZDVFRQYHUWHGLQWR/RJ

,&

4XDQWLWDWLYH 6WUXFWXUH&\WRWR[LF $FWLYLW\

5HODWLRQVKLS RI EHQ]R\OR[\XUHD DQG LWV GHULYDWLYHV ZDV FDOFXODWHG E\ XVLQJ 6366 7KH FKHPLFDO VWUXFWXUH ZDV GHVFULEHG EDVHG RQ SK\VLFRFKHPLFDOSDUDPHWHUVQDPHO\&ORJ3ʌı 56 &05 DQG (V 3K\VLFRFKHPLFDO SDUDPHWHUV WKHRUHWLFDOO\REWDLQHGIURPWH[WERRNVRU&KHP%LR 'UDZ8OWUDH[FHSW56REWDLQHGIURPWKHLQVLOLFR WHVW &\WRWR[LF DFWLYLW\ ZDV LQGLFDWHG E\ /RJ

,&

:933:59

In Silico'

)URPWKHUHVXOWVRILQVLOLFRWHVWVIRUDOOVXEVWDQFHV RQ (8' WKH QXPEHU RI K\GURJHQ ERQGV DQG WKH YDOXH5HUDQN6FRUHKDYHEHHQREVHUYHGDVVKRZQLQ

7DEOH$QH[DPSOHRIGRFNLQJWKHFRPSRXQG

WEXW\OEHQ]R\OR[\XUHD ZLWK (8' FDQ EH VHHQ LQ

)LJVDQG

+'"'

WHQ FRPSRXQGV LQFOXGLQJ

(4)

K\GUR[\XUHD WR EHQ]R\OFKORULGH DQG LWV GHULYDWLYHV +DYLQJ FKDUDFWHUL]HG WKH VWUXFWXUH FRXOG EH FRQFOXGHG WKDW WKH FRPSRXQGV ZHUH SURGXFHGDFFRUGLQJWRWKHWDUJHW7KHUHVXOWVRIWKH VWUXFWXUH FKDUDFWHUL]DWLRQ FDQ EH VHHQ LQ WKH H[SODQDWLRQEHORZ

1-(benzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

DQG1+1+& 2HVWKHU

& 2 DPLGH & & DURPDWLF DQG

&2 &+ DURPDWLF +105

6SHFWUXP į SSP LQ '062' V+ ± 1+ G- +] +$U+ G P-

+] + $U+ HI V+ 1+&

1056SHFWUXPįSSPLQ'062'&DWRPLQ

DQG I

0DVV 6SHFWURPHWHU 6SHFWUXP PH

&+12&+2&+

1-(4-chlorobenzoyloxy)urea

)LQH ZKLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

DQG &+ DURPDWLF 1+

DQG1+& 2HVWKHU& 2

DPLGH & & DURPDWLF DQG &2

+1056SHFWUXPįSSPLQ'062'V

+ 1+G- +] + $U+ H G - +] + $U+ G DQG V+ 1+

&105 6SHFWUXP į SSP LQ '062' &

DWRP LQ DQG 0DVV6SHFWURPHWHU6SHFWUXPPH+506 P] FDOFXODWHG PDVV IRU &+12&O 0+

DQG PHDVXUHGPDVVIRU

%& ",!"2'("*,&*2"+2(,=%,2"=2 (>!,(,"(!",/%0,"&,>'"1$(2"'2("*"*' 8":3

9, < 6< 6 9< :< (>!,(

+ +

+ &O

+ &+

+ 2&+

+ W&+

+ &)

+ %U

+ )

&O &O

&O +

?"=/17KHSRVLWLRQRIWKHWEXWK\OEHQ]R\OR[\XUHDLQ

(8'

?"= /1 +\GURJHQ ERQG EHWZHHQ W

EXWK\OEHQ]R\OR[\XUHDDQG(8'

Asn 426

eu 427

Cys 218

Gly 247

Ser 217 L 445

Pro 607 Cys 428

(5)

Quantitative Structure-Cytotoxic Activity Relationship Current Drug Discovery Technologies, , Vol. 13, No. 2

1-(4-methylbenzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

QP DQG QP ,5 6SHFWUXP Ȟ FP LQ .%U

SHOOHW 1+ 1+ & 2

HVWKHU& 2DPLGH& &DURPDWLF

DQG&2 &+ DURPDWLF+105

6SHFWUXPįSSPLQ'062'V+1+ G- +]+$U+ HG- +=

+ $U+ G V + 1+ V + &+

J&1056SHFWUXPįSSPLQ'062'&

DWRPLQDQG 0DVV 6SHFWURPHWHU 6SHFWUXP PH +506

P] FDOFXODWHG PDVV IRU &@+12 0+

DQG PHDVXUHGPDVVIRU

1-(methoxybenzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

1+ 1+ &+ DURPDWLF

& 2 HVWKHU & 2 DPLGH &+ DURPDWLF & & DURPDWLF DQG &

2+105 6SHFWUXP į SSP LQ '062'

V + 1+ G- +] + $U+ H G - +] + $U+ G V+ 1+

DQGV+&+&1056SHFWUXPįSSP

LQ '062' & DWRP LQ 0DVV 6SHFWURPHWHU

6SHFWUXP PH P] &+2 P]

&+<2ADQG&+2

1-(4-tertbutylbenzoyloxy)urea

)LQH \HOORZLVK ZKLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ& 89 6SHFWUXP Ȝ PD[

QPLQHWKDQRODQG,56SHFWUXPȞFP

LQ .%U SHOOHW 1+ DQG

1+ & 2 HVWKHU & 2 DPLGH

DQG & & DURPDWLF &2

DQG &+ DURPDWLF+105 6SHFWUXP į

SSP LQ '062' V 1+G - +]+$U+ GG- +]+$U+ H

V + 1+ DQG V + &+ K

&105 6SHFWUXP į SSP LQ '062' &

DWRP LQ SSP SSP SSP SSP SSP SSP DQG SSP 0DVV 6SHFWURPHWHU 6SHFWUXP PH +506

P] FDOFXODWHG PDVV IRU &+120+

DQG PHDVXUHGPDVVIRU

1-(4-trifluoromethylbenzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG ,5 6SHFWUXP Ȟ FP LQ .%U SHOOHW

1+ DQG 1+ & 2

HVWKHU & 2 DPLGH DQG & & DURPDWLF &2 DQG &+

DURPDWLF+1056SHFWUXPįSSPLQ'062

' V+1+ G - +] + $U + G G - +] + $U+ H V +

1+&105 6SHFWUXP į SSP LQ '062

' & DWRP LQ SSP SSP SSP SSP SSP SSP SSP 0DVV 6SHFWURPHWHU 6SHFWUXP PH +506

P] FDOFXODWHG PDVV IRU &@+12)

DQG PHDVXUHGPDVVIRU

1-(4-bromobenzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

1+ 1+ & 2 HVWKHU

& 2 DPLGH & & DURPDWLF

&2&+DURPDWLF+1056SHFWUXP

į SSP LQ '062' V + 1+ G- +]+$U+ GG- +]+

$U+ H V + 1+ &105

6SHFWUXPįSSPLQ'062'&DWRPLQ

DQG DQG

0DVV 6SHFWURPHWHU 6SHFWUXP

PH +506 P] FDOFXODWHG PDVV IRU

&+12%U 0+ DQG PHDVXUHG

PDVVIRU

1-(4-fluorobenzoyloxy)urea

)LQH ZKLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

1+ DQG 1+ & 2

HVWKHU & 2 DPLGH DQG & & DURPDWLF &2 DQG &+

DURPDWLF+1056SHFWUXPįSSPLQ'062

' V+ 1+ P- +]+ $U + GP- +]+$U+ HV+

1+&105 6SHFWUXP į SSP LQ '062

'&DWRPLQSSPSSPSSP SSPSSPSSPSSPDQG SSP 0DVV 6SHFWURPHWHU 6SHFWUXP PH

+506 P] FDOFXODWHG PDVV IRU &+12)

0+ DQG PHDVXUHG PDVV IRU

(6)

1-(2,4-dichlorobenzoyloxy)urea

)LQH \HOORZLVK ZKLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ& 89 6SHFWUXP Ȝ PD[

QPLQHWKDQRODQG,56SHFWUXPȞFP

LQ .%U SHOOHW 1+ DQG

1+ & 2 HVWKHU & 2 DPLGH

DQG & & DURPDWLF &2

DQG &+ DURPDWLF+105 6SHFWUXP į

SSP LQ '062' V+ 1+ G- +] + $U+ H V + $U+ I G- +] + $U+ J V+ 1+

&105 6SHFWUXP į SSP LQ '062' &

DWRPLQDGH K F I J 0DVV 6SHFWURPHWHU 6SHFWUXP PH +506 P] FDOFXODWHG PDVV IRU &+12&O 0

DQGPHDVXUHGPDVVIRU

1-(2-chlorobenzoyloxy)urea

:KLWH FU\VWDO \LHOG PHOWLQJ SRLQW ƒ&896SHFWUXPȜPD[QPLQHWKDQRO

DQG,56SHFWUXPȞFPLQ.%USHOOHW

1+ DQG 1+ & 2

HVWKHU & 2 DPLGH DQG & & DURPDWLF &2 DQG &+

DURPDWLF+1056SHFWUXPįSSPLQ'062

' V+ 1+ SSPG - +]+

$U+ H P- +] + $U+ IJ

V+1+&1056SHFWUXPįSSPLQ

'062' & DWRP LQ SSP SSP SSP SSP SSP DQG SSP 0DVV 6SHFWURPHWHU 6SHFWUXP

PH +506 P] FDOFXODWHG PDVV IRU

&+12&O 0+ DQG PHDVXUHG

PDVVIRU

+,,-"!!"*"+'

7KH SK\VLFRFKHPLFDO SDUDPHWHUV DQG WKH F\WRWR[LF DFWLYLW\ RI EHQ]R\OR[\XUHD DQG LWV

GHULYDWLYHVFDQEHVHHQLQ7DEOH

)URP WKH WDEOH DERYH LW FDQ EH VHHQ WKDW WKH

JUHDWHVW F\WRWR[LF DFWLYLW\ LV VKRZQ E\ WKH t

EXWK\OEHQ]R\OR[\XUHD FRPSRXQG EHFDXVH LW KDV

WKH JUHDWHVW /RJ ,& YDOXH 7KH WDEOH DOVR

VKRZV WKDW WKH FRPSRXQG KDV WKH JUHDWHVW OLSRSKLOLFSDUDPHWHUYDOXHLQGLFDWHGE\&ORJ3WKH VPDOOHVW HOHFWURQLF SDUDPHWHU YDOXH 56 DQG WKH JUHDWHVWVWHULFSDUDPHWHU&05

)$""* ($!$(+,,-"! !"*"+ &",'".

'HWHUPLQHG UHJUHVVLRQ HTXDWLRQV DUH WKH UHJUHVVLRQ HTXDWLRQV ZKLFK KDYH JRRG DQG %& .+'"!,! "!&.( ('2!+,,-"!!"*"+,B/%0,+&,-+1$(2"'2("*"*'

9, < &,=# /&,=#1 C C D ; ' ,=/1

+ +

+ &O

+ &+

+ 2&+

+ W&+

+ &)

+ %U

+ )

&O &O

&O +

(7)

Quantitative Structure-Cytotoxic Activity Relationship Current Drug Discovery Technologies, , Vol. 13, No. 2

PHDQLQJIXO UHJUHVVLRQ FRHIILFLHQWV 7KH HTXDWLRQV

DUHVKRZQLQ7DEOH

%& (=(''", E$",' ,B /%0,+&,-+1$( 2 "'2("*"*'

5#+'"!,! "!&#( (

/RJ,& &/RJ3±

Q 5 ) VLJ V

/RJ,& &/RJ3±

Q 5 ) VLJ V

/RJ,& ʌ±

Q 5 ) VLJ V

/RJ,& ʌ±

Q 5 ) VLJ V

/RJ,& ı±

Q 5 ) VLJ V

/RJ,& 56±

Q 5 ) VLJ V

/RJ,& &05±

Q 5 ) VLJ V

/RJ,& (V±

Q 5 ) VLJ V

8,#+'"!,! "!&#( ('

/RJ,& &/RJ3&/RJ3±

Q 5 ) VLJ V

/RJ,& ʌʌ±

Q 5 ) VLJ V

/RJ,& &/RJ3ı±

Q 5 ) VLJ V

/RJ,& &ORJ3±56±

Q 5 ) VLJ V

/RJ,& &ORJ3±&05±

Q 5 ) VLJ V

/RJ,& &ORJ3±(V±

Q 5 ) VLJ V

/RJ,& ʌ±ı±

Q 5 ) VLJ V

/RJ,& ʌ±56±

Q 5 ) VLJ V

/RJ,& ʌ±&05±

Q 5 ) VLJ V

/RJ,& ʌ±(V±

Q 5 ) VLJ V

/RJ,& ı±&05±

Q 5 ) VLJ V

/RJ,& ı±(V±

Q 5 ) VLJ V

/RJ,& 56(V±

Q 5 ) VLJ V

/RJ,& &05(V±

Q 5 ) VLJ V

2IWKHUHJUHVVLRQHTXDWLRQVDQHTXDWLRQZDV VHOHFWHG EDVHG RQ WKH EHVW FRUUHODWLRQ FRHIILFLHQW YDOXHDQGLWVVLJQLILFDQFH7KHEHVWHTXDWLRQZDV

/RJ,& ı±

(V±

Q 5 ) VLJ V

7KH DERYH HTXDWLRQ ZDV FKRVHQ EHFDXVH LW KDG WKH JUHDWHVW FRUUHODWLRQ FRHIILFLHQW U DQG OLWWOH VLJQLILFDQFH ZKLFK LV § )URP WKHVHOHFWHGHTXDWLRQLWFRXOGEHH[SODLQHGWKDWWKH SK\VLFRFKHPLFDOSURSHUWLHVDIIHFWF\WRWR[LFDFWLYLW\ RI EHQ]R\OR[\XUHD GHULYDWLYHV ZHUH HOHFWURQLF SURSHUWLHVıDQGWKHVWHULFSURSHUWLHV(V

59:59

/DVWDQDO\VLVWKHEHVWHTXDWLRQRI4XDQWLWDWLYH 6WUXFWXUH&\WRWR[LF $FWLYLW\ 5HODWLRQVKLS RI EHQ]R\OR[\XUHDDQGLWVGHULYDWLYHVLV

/RJ ,& ı±

(V ± Q 5 )

VLJ V

59?5?9

$XWKRUVUHSRUWQRFRQIOLFWRILQWHUHVW

795F3G;9

(8)

6LVZDQGRQR $SW 06 IURP WKH )DFXOW\ RI 3KDUPDF\ 8QLYHUVLWDV $LUODQJJD DV D SURPRWHU DQGWKHRQHZKRKDVWKH0ROHJURSURJUDPOLFHQVH 3URI 'U 3XZDQWR $SW IURP WKH )DFXOW\ RI 3KDUPDF\ 8QLYHUVLWDV $LUODQJJD DV FRSURPRWHU 3URI 'UV :LQ 'DUPDQWR 06L 3K' IURP WKH )DFXOW\ RI 6FLHQFH DQG 7HFKQRORJ\ 8QLYHUVLWDV $LUODQJJD DV FRSURPRWHU 3URI +RQGD IURP +RVKL 8QLYHUVLW\ -DSDQ ZKR KDV KHOSHG LQ

LQWHUSUHWLQJ WKH 06 VSHFWUD GDWD 3URI

6XSDUJL\RQR '70 + 68 6S3DU . RI WKH 'HSDUWPHQW RI 3DUDVLWRORJ\ )DFXOW\ RI 0HGLFLQH 8QLYHUVLWDV *DGMDK 0DGD ZKLFK KDV DOORZHG PH

WRVWXG\DQGGHWHUPLQHWKHF\WRWR[LFDFWLYLW\

? 9

>@ 6LVZDQGRQR GDQ %DPEDQJ 6RHNDUGMRKimia Medisinal $LUODQJJD 8QLYHUVLW\3UHVV

>@ 6LVZDQGRQR 0RGLILNDVL 6WUXNWXU GDQ +XEXQJDQ 6WUXNWXU $NWLYLWDV 6HQ\DZDVHQ\DZD %DUX 7XUXQDQ %HQ]R\OXUHD $LUODQJJD 8QLYHUVLW\ 'LVVHUWDWLRQ6XUDED\D

>@ 2NVHO & :DQJ ;= 4XDQWLWDWLYH 6WUXFWXUHǦ$FWLYLW\ 5HODWLRQVKLS 46$5 PRGHOV´ 8QLYHUVLW\ RI /HHGV KWWSTXDOLW\QDQRHXXSORDGV6FKRRO7UDLQLQJ0DWHULDOV46$5V /HFWXUHB&H\GD2NVHOSGI

>@ %KDUDWH6%6LQJK,34XDQWLWDWLYHVWUXFWXUH±DFWLYLW\UHODWLRQVKLSVWXG\ RI SKORURJOXFLQROWHUSHQH DGGXFWV DV DQWLOHLVKPDQLDO DJHQWV %LRRUJ 0HG&KHP/HWWHUV±

>@ 5ROOL ( ,QFHUWL 0 %UXQRQL ) 9LFLQL 3 5LFFL $ 6WUXFWXUH±DFWLYLW\ UHODWLRQVKLSV RI 1SKHQ\O1¶EHQ]RWKLD]RO\OXUHD V\QWKHWLF GHULYDWLYHV&\WRNLQLQOLNHDFWLYLW\DQGGYHQWLWLRXVURRWLQJHQKDQFHPHQW 3K\WRFKHPLVWU\±

>@ <DPXQD(.XPDU5$=HOOHU03UDVDG.-56\QWKHVLVDQWLPLFURELDO DQWLP\FREDFWHULDO DQG VWUXFWXUHDFWLYLW\ UHODWLRQVKLS RI VXEVWLWXWHG S\UD]ROR LVR[D]ROR S\ULPLGR DQG HUFDSWRS\ULPLGRF\FORKHSWD >E@LQGROHV(XU-0HG&KHP

>@ 6LQJK 6 &RPSXWDWLRQDO GHVLJQ DQG FKHPRPHWULF 46$5 PRGHOLQJ RI 3ODVPRGLXP IDOFLSDUXP FDUERQLF DQK\GUDVH LQKLELWRUV %LRRUJ 0HG &KHP/HWWHUV± 6\QWKHVLV DQG 3UHOLPLQDU\ %LRORJLFDO (YDOXDWLRQ RI 1RYHO 1DU\O WULD]RO\O &LQQDPDPLGH 'HULYDWLYHV DV 3RWHQWLDO $QWLP\FREDFWHULDO $JHQWV $Q 2SHUDWLRQDO 7RSOLVV 7UHH DSSURDFK %LRRUJ0HG&KHP/HWWHUV±

>@ /D]]DURWWR 0 +HLQ]HQ 9( <XQHV 5$ 2SWLPL]HG PRGLILHG WRSOLVV PHWKRG D WRRO IRU TXDQWLWDWLYH VWUXFWXUHDFWLYLW\ UHODWLRQVKLS VWXGLHV $U]QHLPLWWHOIRUVFKXQJ

>@ =DFKLIPDQ - (QDP 3 3HQGXGXN 5, 0HQGHULWD . 'HSDUWHPHQ .HVHKDWDQ,QGRQHVLDZZZGHSNHVJRLG'HFHPEHU

>@ 5LVNHVGDV +HDOWK 5HVHDUFK WKH $JHQF\ IRU +HDOWK 5HVHDUFK DQG 'HYHORSPHQW 5HVHDUFK RI WKH 0LQLVWU\ RI +HDOWK 5, KWWSZZZGHSNHVJRLGUHVRXUFHV GRZQORDG JHQHUDO +DVLO5LVNHVGDVSGI

>@ .KD\DW $6 *XLPDUmHV $& &DUGRVR 3&et al 0XWDJHQLFLW\ RI +\GUR[\XUHD LQ /\PSKRF\WHV IURP 3DWLHQWV ZLWK 6LFNOH &HOO 'LVHDVH *HQHW0RO%LRO

>@ &KDEQHU%$5\DQ'33D]$UH]/*DUFLD&DUERQHUR5RFLR&DODEUHVL 3DXO $QWLQHRSODVWLF $JHQW ,Q *RRGPDQ *LOPDQ¶V 7KH 3KDUPDFRORJLFDO%DVLVRI7KHUDSHXWLFV0F*UDZ+LOO1HZ<RUN ±

>@ .\XQJ1R / 'HYHORSPHQW RI 6SHFLILF ,QKLELWRU RI 7UDQVJOXWDPLQDVH 3KHQ\OWKLRXUHD'HULYDWLYHV7KH$PHULFDQ8QLYHUVLW\ >@ +RIV+30F9LH-*(IIHFWVRI%HQ]R\OSKHQ\OXUHDVRQ*URZWKRI%

0HODQRPDV &HOOV LQ YLWUR DQG LQ YLYR ,QYHVWLJDWLRQDO 1HZ 'UXJV

>@ 4LQJ 6RQJ ' 1D 'X 1 0LQJ :<et al 6\QWKHVLV DQG $FWLYLW\ (YDOXDWLRQ RI 3KHQ\OXUHD 'HULYDWLYHV DV 3RWHQW $QWLWXPRU $JHQWV %LRRUJ0HG&KHPH±

>@ 4LQJ6'0LQJ:<1D'1et al6\QWKHVLVDQG$FWLYLW\(YDOXDWLRQRI %HQ]R\OXUHD 'HULYDWLYHV DV 3RWHQWLDO $QWLSUROLIHUDWLYH $JHQWV %LRRUJ0HG&KHP/HWWHUV±

>@ 0DQMXOD 61 1RROYL 10 3DULKDU .9 5HGG\ 6$0 5DPDQL 9 6\QWKHVLV DQG $QWLWXPRU $FWLYLW\ RI 2SWLFDOO\ $FWLYH 7KLRXUHD DQG 7KHLU DPLQREHQ]RWKLD]ROH 'HULYDWLYHV D 1RYHO &ODVV RI $QWLFDQFHU $JHQWV(XU-0HG&KHP

>@ 'HQR\HOOH 6 &KHQ 7 &KHQ /et al ,Q YLWUR LQKLELWLRQ RI WUDQVODWLRQ LQLWLDWLRQ E\ 11GLDU\OXUHDV SRWHQWLDO DQWLFDQFHU DJHQWV %LRRUJ 0HG &KHP/HWWHUV±

>@ .RFD,2]JXU$&RVNXQ.$7XWDU<6\QWKHVLVDQGDQWLFDQFHUDFWLYLW\ RIDF\OWKLRXUHDVEHDULQJS\UD]ROHPRLHW\%LRRUJ0HG&KHP ±

>@ +XDQJ;&:DQJ03DQ<0et al6\QWKHVLVDQGDQWLWXPRUDFWLYLWLHV RIQRYHOWKLRXUHDĮDPLQRSKRVSKRQDWHVIURPGHK\GURDELHWLFDFLG(XU-0HG&KHP

>@ +DUGMRQR 6 0RGLILNDVL 6WUXNWXU EHQ]RLORNVLXUHD GDQ +XEXQJDQ .XDQWLWDWLI 6WUXNWXU$NWLYLWDV 6LWRWRNVLNQ\D 8QLYHUVLWDV $LUODQJJD 'LVVHUWDWLRQ6XUDED\D

>@ &OD\GHQ-*UHHYHV1:DUUHQ6:RWKHUV32UJDQLF&KHPLVWU\2[IRUG 8QLYHUVLW\3UHVV1HZ<RUN

>@ =LQQHU * 6WDIIHO 5 &DUEDPR\ODWLRQ RI +\GUR[\ODPLQH +\GUR[\ODPLQH'HULYDWLYHV$UF3KDUP%HU*HV >@ ,VW\DVWRQR(3KWWSZZZNRPSXWDVLOLSLJRLG >@ -HQ]HQ ) ,QWURGXFWLRQ WR &RPSXWDWLRQDO &KHPLVWU\ QG (GI

2GHQVH'HQPDUN

>@ ;X + )DEHU & 8FKLNL 7 5DFFD - GDQ 'HDOZLV & 6WUXFWXUHV RI (XNDU\RWLF 5LERQXFOHRWLGH 5HGXFWDVH , 'HILQH *HPFLWDELQH 'LSKRVSKDWH %LQGLQJ DQG 6XEXQLW $VVHPEO\ 31$6 ±

>@ +\GUHDKWWSSDFNDJHLQVHUWVEPVFRPSLSLBK\GUHDSGI

>@ &&5& 8*0 KWWSFFUFIDUPDVLXJPZRUGSUHVVFRPSURWRNRO

>@ 6LOYHUVWHLQ 50 :HEVWHU ); .LHPOH '-. 6SHFWURSKRWRPHWULF ,GHQWLILFDWLRQRI2UJDQLF&RPSRXQGWK(G-RKQ:LOH\DQG6RQV,QF 1HZ<RUN

Figur

Memperbarui...

Referensi

Memperbarui...