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eliezer©2008
Estratégias de desenho molecular
Estratégias de desenho
molecular
The concept of bioisosterism refers to frameworks, fragments, atoms, and groups presented
in the structures of bioactive compounds that have similar molecular volume, shape, electronic
distribution, and physical–chemical properties. It is a molecular modification
strategy, based on the replacement of interchangeable molecular fragment(s) (atoms,
functional groups, subunits) having similar steric–electronic profile and comparable
physical–chemical properties. In Beyond Bioisosterism: New Concepts in Drug Discovery, 2017
BioisosterismBioisosterism
https://doi.org/10.2174/0929867053363540
1919
1979
1991
1996
2011
Bioisóstero (Bio + isóstero)Adaptado do “Glossary of Terms Used in Medicinal Chemistry”
•As propriedades biológicas similares referem-se ao
reconhecimento pelo mesmo biorreceptor, podendo ser
agonista ou antagonista.
Pontos
farmacofóricos
Similaridade
molecular
Grupos
funcionais
OH NH2
Monovalentes Divalentes Trivalentes Tetravalentes
F, OH, NH2, CH3, OR -CH2- +CH- =C=
CI, SH, PH2, Si3, SR -O- =N- =Si=
Br -S- =P- =N+=
I -Se- =As- =P+=
-Te- =Sb- =As+=
=Sb+=
-CO- -COOH -SO2NH2 -H -CONH- -COOR- -CONH2
-CO2- -SO3H -PO(OH)NH2 -F -NHCO- -ROCO- -CSNH2
-SO- Tetrazola
-SO2NR- -SO2NHR -OH -catecol
-CON- -3-hidroxiisoxazola -CH2OH -benzimidazol
-CH(CN)- -2-hidroxicromano -NHCONH2
R-S-R’ =N- -NH-CS-NH2 -C5H4N
(R-O-R’)
R-N(CN)-R’ -C(CN)= -NH-C(=CHNO2)-NH2 -C6H5
R-C(CN)(CN)-R’ -C4H4N
_halogeneo C4H4S
-CF3
-CN
-N(CN)2
-C(CN)3
11Na+
FH2+
OH3+
NH4+
10NeFHOH2
NH3
CH4
9FOHNH2
CH3
NH4+
8ONHCH2
NH3
CH4
7NCHCH2
NH3
CH4
6CNHCH2
NH3
CH4
nº de e-
CNHCH2
NH3
CH4
H
HH
H
Grupo 4A
Grupo 5A
Grupo 6A
Grupo 7A
GasesNobres
Grimm, 1925.
The Hydride Displacement Law
Lima & Barreiro, Curr. Med. Chem. 2005, 12, 23
Bioisosterismo
Isósteros
purinas
pirimidinas
carboidratos
N
N
NH2
O
H
N
N
NH2
N
N
O
OHHO
HOH
N
N
NH2
O
O
OH
HO
HO
N
N
OH
O
H
N
N
OH
N
N
O
OHHO
HONH2
adenina guanina
citosinanucleosídeo "uracilo"
guanosinaadenosina
OH
O
H2N
O
NH2
OHH3C
O
NH2
CH3
valina
OH
O
H3C
CH3
NH2
isoleucina (Ile)
OH
O
NH
H2N
NH
NH2arginina
OH
O
NH2
fenilalanina (Phe)
OH
O
NH2HO
tirosina (Tyr)
prolinaOH
O
NH
OH
O
HO
NH2
serina
OH
O
H3C
OH
NH2
treonina (Thr)
asparagina (Asn)
OH
O
NH2
HS
cisteína (Cys)
OH
O
HO
O NH2
ácido aspártico
OH
O
HO
O
NH2
ácido glutâmico
OH
O
H2N
NH2
lisina (Lys)
H3C
OH
O
NH2
alanina
H2N
OH
O
leucina
OH
O
H3C
CH3 NH2
glicina (gly)
HN
NH2
OH
Otriptofano (Trp)
OH
O
SH3C
NH2
metionina
OH
O
HN
N NH2
histidina
glutamina (Gln)
O
OH
NH2O
H2N
Bioisosterismo
Modulação do perfil molecular
Volume molecular (PD)
Polarizabilidade (PD)
Estéreo-eletrônicas (PD/PK)
Solubilidade (PK)
Reatividade química (PK)
Ligação-H (PD>PK)
pKa (PD/PK)
Modulação de propriedades moleculares
propriedades farmacocinéticas (PK);
propriedades farmacodinâmicas (PD; GF);
propriedades toxicofóricas (GT);
HN
N
N
N
N
NN
N
S
NH
O
O
N
NH
S
N
NH
N
O
NH
N
O
N
N
S
N
N
N
NH
benzeno
piridina
tiofeno
furana
1,4-piridazina
pirimidina 1,2-piridazina
benzofurana
naftaleno
antraceno
tienopiridina
quinolina
indol
pirazoloquinolina
fenantreno acridina
isoxazola tiazola oxazola imidazola pirazola
Bioisosterismo de anéis aromáticos
Molecular dissection
Volume 13, 167-198, 2006
In this article we provide an overview on the medicinal chemistry of new
bioactive N-acylhydrazone (NAH) derivatives designed through the structural
optimization of N-arylhydrazone precursors, originally planned by molecular
hybridization of two known 5-lipoxygenase inhibitors, i.e. CBS-1108 and
BW-755c. The analgesic, antiedematogenic and platelet anti-aggregating
profile of several isosteric NAH compounds was investigated by using
classical in vivo and ex-vivo pharmacological assays, which allowed the
identification of new potent centrally and peripherically-acting analgesic
leads, new antiinflammatory agents and new antithrombotic prototypes.
During this study, dozens of active NAH compounds were discovered,
clarifying the structure-activity relationships for this series of derivatives
and indicating the pharmacophoric character of the N-acylhydrazone
moiety for its biological profile.
Carlos A.M. Fraga and Eliezer J. BarreiroAr N
O
H
N Ar'
http://dx.doi.org/10.2174/092986706775197881
N
CO2H
CH3
O
Cl
H3CON
CO2H
CH3
O
H3CO
Cl
indometacina clometacina
Retroisosterismo
regioisomêros retroisósteros
A. M. Jordan & S. D. Roughley, Drug discovery chemistry: a primer for a non-specialist, Drug Discovery Today, 2009, 14, 731.
7-1H-pirazolo[4,3-d]pirimidinona 4-imidazo[5,1-f][1,2,4]triazinone
2003 – ca. US$ 2 bilhões
2013 – ca. US$ 3,5 bilhões
Similaridade MolecularSimilaridade Molecular
Ciprofloxacina
1987
fluoroquinolone
Levofloxacina
1996
2003
gefitinibeerlotinibe
2005
AZGenentech
N
N
O
HN
HN
CH3
N
N
N
H3C
HN
CH3
N
N
3-Py
NH
O
N
CF3
N
H3C
NH
N
O
imatinibe
nilotinibe
para/meta
retroisósterismo
bioisosterismoclássico de anel
CH3
Bioisosterismo
clássico de anel
Bioisosterismo não-clássico
arilógo
fenílogo
Bioisosterismo
funcional clássico
N
H
OH
O
OH
O
N
H
ON
ácido hidroxâmico
acil-cianamida
NN
N
HN
N
NH
O
O
oxo-oxadiazola
N
NH
S
O
oxo-tiadiazola
O
N
OHS
N
OH
NS
N
OH
P
O
OHNH2
SNH
O O
R
O
O
OH
SOH
O O
O
N
H
S
O O
R
tetrazola hidroxi-cromona
acil-sulfonamida
sulfonamida
ácido
sulfônico
fosfonamidahidroxi-tiadiazola
hidroxi-isoxazola
hidroxi-
isotiazola
ácido carboxílico
Todas as funções orgânicas têm a mesma diversidade de isósteros ?
Bioisosterismo funcional
Exemplo de bioisosterismo funcional
eliezer © 2005
safrol
Bióforo natural
indanona benzodioxola
aceptor-H
aceptor-H
aceptor-H
O
O
O
O início……. a literatura de patentes !
LASSBio-349: novo tipo de bioisosterismo
a) Khanapure SP et al., Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (COX-2) selective inhibitors, J Med Chem. 2003, 46, 5484 (A)
b) Khanapure SP et al., 3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)(2-pyridyl) phenyl ketone as a potent and orally active cyclooxygenase-2 selective inhibitor: synthesis and biological evaluation, J Med Chem. 2005,48, 3930 (B)
A B
O
O
NH S
O O
CH3
W
LASSBio-466
a) M P Veloso, Tese de Doutoramento, Instituto de Química, UFRJ, 2000
unidade
farmacofórica
UF
sistema terfenílico
sistema
bisfenilpirazólico
Transposição
(aparente)
da UF
celecoxibe
N
N
S
NH2O
O
CH3
F3C
NN
N
H3C
N
NH
S
OO
CH3
CH3
retroisosterismo
bioisosterismo
novo padrão
molecular
bispirazolaretroisosterismo
Série congênere dos novos COX-2i bispirazólicos
LASSBio-445
LASSBio-446
MP Veloso, Tese de Doutoramento, Instituto de Química, UFRJ, 2000
NN
N
H3C
N
NH
S
OO
CH3
CH3
NN
N
H3C
N
NH
S
OO
CH3
NN
N
H3C
N
CH3
NH
S
OO
CH3
CH3
NN
N
H3C
N
CH3
NH
S
OO
CH3
LASSBio-715
Série congênere dos novos COX-2i bispirazólicos
ABSTRACT: This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1H-pyrazol-1-
yl)-1-phenyl-1H-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as anti-
inflammatory agents. The 1H-NMR spectra obtained in the presence of a chiral lanthanide shift salt associated to
chiral HPLC analysis, X-ray diffraction and molecular modeling tools confirmed that ortho bis-functionalized
bipyrazole 2d exists as a mixture of aR,aS-atropisomers. These results provide useful information to understand
the pharmacological profile of this derivative and of other 4-aminobipyrazole analogues.
aR-(2d) aS-(2d)
Chirality 2012, 24, 463-470
LASSBio-456
N
N
H3C NH2
N
N
CH3
N
N
CH3H2N
N
N
H3C
Determinação da configuração absoluta
Lichosorb (N. 738342) RP-18 column (250 mm x 4 mm x 5 µm) L-7450A diode array detector (DAD)
acetonitrile and water (adjusted to pH 3 with TFA 0.1%) gradients[CH3CN:HOH (pH 3) from 20:80 to 80:20]
LASSBio-775
1H- and 13C-NMR spectra
Derivatização
MP Veloso et al., Chirality 2012, 24, 463
δ 2,29 ppm
δ 2,39 ppm
(+)-Yb(hfc)3
Enraf-Nonius Kappa-CCD difractometer
ORTEP view of P-atropisomer
Atropoisomerismo embispirazóis bioativos
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