S18uC1u8AL AC1lvl1?

8LLA1lCnSPl
Cnce Lhe sLrucLure of lead compound ls known
SA8 ls nexL sLep lL deflnes Lhe funcLlonal group or
reglons of a lead compound whlch are lmporLanL
for blologlcal acLlvlLy
When a parLlcular funcLlonal group of molecule
ls removed lL ls posslble Lo flnd ouL whlch groups
are essenLlal and whlch are noL lL helps ln LesLlng
all Lhe analogues for blologlcal acLlvlLy and
comparlng wlLh Lhe orlglnal compound
lnulnC 8CLL Cl ALCCPCLS Anu
PLnCLS
1hese groups are lnvolved ln hydrogen bondlng
C2 acL as P bond accepLor and P acL as Pu
roLon of orlglnal CP group ls lnvolved as Pu
and lf lL ls removed P bond ls losL Suppose C
aLom ls acLlng as PA o ls sLlll presenL ln eLher so
lL could Lake parL ln bondlng
ConL
1he exLra bulk of meLhyl group should hlnder Lhe
close and should dlsrupLed P bondlng
1he P bondlng may noL compleLely prevenLed buL
lL may weakened
An esLer analogue cannoL acL as PulL acL as PA
buL exLra bulk of acyl grp ls even greaLer Lhan
meLhyl grp of eLhLhls may hlnder P bondlng
lnulnC 8CLL Cl A8CMA1lC
8lnCS
AromaLlc rlngs are planar hydrophoblc sLucLures
are lnvolved ln vandervaal and hydrophoblc
lnLeracLlons wlLh flaL hydrophoblc reglons slLe
An analogue conLalnlng a cyclohexane rlng ln
place of aromaLlc rlng ls less llkely Lo blnd so
wellas Lhe rlng
ConL
AromaLlc rlngs could also lnLeracL wlLh
AMMCnluM lon Lhrough lnducrd
dlpole lnLeracLlons or P bondlL ls noL
plsslblr wlLh cyclohexane
lnulnC 8CLL Cl kL1CnL and
ALuLP?uLS
W kL1CnL ls planar grp LhaL can lnLeracL wlLh
blndlng slLe by P CnulnC where CC grp
oxygen acL as PA
W 1wo lone palr of elecLron on CC has speclflc
dlpole momenL so dlpoledlpole lnLeracLlons
wlLh blndlng slLe ls also posslble
lnulnC 8CLL Cl LS1L8S
LS1L8 acL as PA only 1he CC oxygen acL
as PA Lhan alkoxy C as lL sLerlcally less
hlndered wlLh greaLer elecLron denslLy
LsLers are hydrolyse by esLerases1hey may
pose a problem lf Lhe lead compound conLalns
an esLer LhaL ls lmporLanL Lo blndlng lL means
LhaL drug have shorL half llfe
ConL
W Asplrln has anLllnflammaLory acLlon ablllLy Lo
lnhlblL cyclooxygenase whlch ls requlred for
C synLhesls Asplrln acLs as acylaLlng agenL
lLs aceLyl grp as covalenLly aLLached Lo serlne
resldue ln acLlve slLe of CCx
ldenLlflcaLlon of pharmacophore
W PA8MACCPC8L ls lmp blndlng grp whlch ls
requlred for acLlvlLy Lhelr relaLlve poslLlon ln
space wlLh respecL Lo each oLher
W Cllplne has Lwo phenol grps aromaLlc grp n
aLom
W henol grp acLs as PAaromaLlc rlng can
parLlclpaLe ln vW lnLeracLlon amlne acLs as
PA or as lonlc cenLre lf lL ls proLonaLed
u8uC C1lMMlSA1lCn
W Cnce Lhe lmp blndlng grps pharmacophore
of Lhe lead compd have been ldenLlfledlL ls
posslble Lo synLheslze analogues conLaln Lhe
same pharmacophore
W very few lead compds are ldeal mosL are
llkely Lo have varlous adr's so Lhere ls an
advanLage ln flndlng analogues wlLh lmproved
properLles
varlaLlon of subsLlLuenLs
W 1 Alkyl subsLlLueLs alkyll subs of eLheramlne
esLers amldes are easlly varled
W eglsoprenallne ls analogue of Adr where a
meLhyl grp ls replaced by lsopropyl grp
resullng good selecLlvlLy for adrenerglc beLa
recepLors over alpha
2AromaLlc subsLlLuenLs
W lf a drug conLalns aromaLlc rlng Lhe poslLlon of
subs can be varled Lo flnd beLLer lnLeracLlons
resulLed ln beLLer acLlvlLy
W LlecLron wlLhdrawlng grp nlLro wlll affecL Lhe
baslclLy of aromaLlc amlne lf lL ls ln para
poslLlon raLher Lhen meLa nlLro wlll make Lhe
amlne a weaker base easlly proLonaLe Lhls
would decrease Lhe amlne ablllLy Lo lnLeracL
wlLh blndlng grps ln slLe dec acLlvlLy