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