Estratégias de desenho molecular

Estratégias de desenho molecular eliezer 2008

Estratégias de desenho molecular

Bioisosterism https://doi.org/10.2174/0929867053363540 The concept of bioisosterismrefers 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: ew Concepts in Drug Discovery, 2017

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. Grupos funcionais 2 Pontos farmacofóricos Similaridade molecular

Monovalentes Divalentes Trivalentes Tetravalentes F,, 2, C 3, R -C 2 - +C- =C= CI, S, P 2, Si 3, SR -- =- =Si= Br -S- =P- = + = I -Se- =As- =P + = -Te- =Sb- =As + = =Sb + = -C- -C -S 2 2 - -C- -CR- -C 2 -C 2 - -S 3 -P() 2 -F -C- -RC- -CS 2 -S- Tetrazola -S 2 R- -S 2 R - -catecol -C- -3-hidroxiisoxazola -C 2 -benzimidazol -C(C)- -2-hidroxicromano -C 2 R-S-R =- --CS- 2 -C 5 4 (R--R ) R-(C)-R -C(C)= --C(=C 2 )- 2 -C 6 5 R-C(C)(C)-R -C 4 4 _halogeneo C 4 4 S -CF 3 -C -(C) 2 -C(C) 3

Bioisosterismo The ydride Displacement Law Grupo 4A Grupo 5A Grupo 6A nº de e - C 6 C 7 8 C C 2 C 2 C 2 C 2 3 3 3 3 C 4 C 4 C 4 C 4 Grupo 7A 9 F 2 C 3 4 + Gases obres 10 e F 2 3 C 4 11 a + F 2 + 3 + 4 + Grimm, 1925. Lima & Barreiro, Curr. Med. Chem. 2005, 12, 23

Isósteros

purinas pirimidinas carboidratos 2 2 2 2 adenina guanina citosina nucleosídeo "uracilo" guanosina adenosina

2 2 prolina glicina (gly) 2 serina 2 lisina (Lys) triptofano (Trp) 3 C 2 2 alanina S 2 3 C 2 cisteína (Cys) glutamina (Gln) 2 C 3 arginina 2 valina 2 fenilalanina (Phe) 3 C 2 2 3 C C 3 2 isoleucina (Ile) 2 treonina (Thr) 2 tirosina (Tyr) 2 ácido glutâmico 2 3 C 2 3 C S C 3 2 leucina metionina 2 2 ácido aspártico asparagina (Asn) 2 histidina

Bioisosterismo Modulação de propriedades moleculares Volume molecular (PD) Polarizabilidade (PD) Estéreo-eletrônicas (PD/PK) Solubilidade (PK) Reatividade química (PK) Ligação- (PD>PK) pka (PD/PK) Modulação do perfil molecular propriedades farmacocinéticas (PK); propriedades farmacodinâmicas (PD; GF); propriedades toxicofóricas (GT);

Bioisosterismo de anéis aromáticos pirazoloquinolina fenantreno acridina S antraceno pirimidina 1,2-piridazina tienopiridina naftaleno 1,4-piridazina benzeno piridina quinolina benzofurana furana S tiofeno indol S isoxazola tiazola oxazola imidazola pirazola

Molecular dissection

Ar Ar' Carlos A.M. Fraga and Eliezer J. Barreiro Volume 13, 167-198, 2006 Inthisarticleweprovideanoverviewonthemedicinalchemistryofnew bioactive -acylhydrazone(a) derivatives designed through the structural optimization of -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 A 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 A compounds were discovered, clarifying the structure-activity relationships for this series of derivatives and indicating the pharmacophoric character of the -acylhydrazone moiety for its biological profile. http://dx.doi.org/10.2174/092986706775197881

Retroisosterismo regioisomêros retroisósteros 3 C C 2 C 2 C 3 3 C C 3 Cl Cl indometacina clometacina

7-1-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 Molecular A. M. Jordan& S. D. Roughley, Drug discovery chemistry: a primer for a non-specialist, Drug Discovery Today, 2009, 14, 731.

1987 1996 fluoroquinolone Ciprofloxacina Levofloxacina

2003 2005 gefitinibe AZ erlotinibe Genentech

3 C C 3 imatinibe retroisósterismo para/meta bioisosterismo clássico de anel CF 3 C 3 3 C nilotinibe C 3 3-Py

Bioisosterismo clássico de anel

Bioisosterismo não-clássico arilógo fenílogo

Bioisosterismo funcional clássico

Bioisosterismo funcional acil-cianamida hidroxiisotiazola S hidroxi-isoxazola ácido hidroxâmico S hidroxi-tiadiazola oxo-oxadiazola tetrazola ácido carboxílico S oxo-tiadiazola hidroxi-cromona acil-sulfonamida P 2 sulfonamida S R S fosfonamida S R ácido sulfônico Todas as funções orgânicas têm a mesma diversidade de isósteros?

Exemplo de bioisosterismo funcional

Bióforo natural aceptor- aceptor- safrol indanona aceptor- benzodioxola eliezer 2005

LASSBio-349: novo tipo de bioisosterismo início. a literatura de patentes!

S C 3 W a) Khanapure SP et al., Synthesis and structure-activity relationship of novel, highly potent metharyl and methcycloalkyl cyclooxygenase-2 (CX-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

F 3 C sistema terfenílico S 2 celecoxibe C 3 unidade farmacofórica UF bioisosterismo 3 C novo padrão molecular retroisosterismo S C 3 C 3 LASSBio-466 Transposição (aparente) da UF sistema bisfenilpirazólico retroisosterismo bispirazola a) M P Veloso, Tese de Doutoramento, Instituto de Química, UFRJ, 2000

Série congênere dos novos CX-2i bispirazólicos S C 3 S C 3 C 3 3 C C 3 LASSBio-445 C 3 C 3 3 C S C 3 3 C C 3 LASSBio-446 LASSBio-715 S C 3 MP Veloso, Tese de Doutoramento, Instituto de Química, UFRJ, 2000

Série congênere dos novos CX-2i bispirazólicos

Chirality 2012, 24, 463-470 ABSTRACT: This work describes the atropisomeric relationships of 3-methyl-5-(3-methyl-5-phenyl-1-pyrazol-1- yl)-1-phenyl-1-pyrazol-4-amine (2d), which belongs to series 4-aminobipyrazole derivatives designed as antiinflammatory agents. The 1-MR spectra obtained in the presence of a chiral lanthanide shift salt associated to chiral PLC 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. LASSBio-456 ar-(2d) as-(2d)

3 C 2 2 C 3 C 3 3 C

Determinação da configuração absoluta Derivatização 1 - and 13 C-MR spectra LASSBio-775 Lichosorb(. 738342) RP-18 column (250 mm x 4 mm x 5 µm) L-7450A diode array detector (DAD) acetonitrile and water (adjusted to p 3 with TFA 0.1%) gradients [C 3 C: (p 3) from 20:80 to 80:20] MP Veloso et al., Chirality2012, 24, 463

(+)-Yb(hfc) 3 δ 2,39 ppm δ 2,29 ppm Enraf-onius Kappa-CCD difractometer

Atropoisomerismo em bispirazóis bioativos RTEP view of P-atropisomer