PRODRUG DESIGN AND RATIONAL DRUG DESIGN

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1 FRNTIERS IN SCIENCE N NEGLECTED DISEASES PRDRUG DESIGN AND RATINAL DRUG DESIGN ELIZABETH IGNE FERREIRA University of Sao Paulo School of Pharmaceutical Sciences November 2014

TUBERCULSIS Ad hoc NEW TARGETS NEW STRUCTURES PRDRUGS SECNDARY USE DRUGS CURRENTLY USED

2 CHAGAS DISEASE LEISHMANIASIS PRDRUG DESIGN LABRATRY F DESIGN AND SYNTHESIS F CHEMTHERAPEUTIC AGENTS PTENTIALLY ACTIVE IN NEGLECTED DISEASES RATINAL DRUG DESIGN M ALARIA SBDD LBDD TUBERCULSIS Ad hoc NEW TARGETS NEW STRUCTURES PRDRUGS SECNDARY USE DRUGS CURRENTLY USED PRDRUGS Post hoc MLECULAR MDELING ANALGS PHARMACKINETICS TARGETED DRUGS QSAR 2D, 3D 4D PHARMACDYNAMICS

3 LABRATRY F DESIGN AND SYNTHESIS F CHEMTHERAPEUTIC AGENTS PTENTIALLY ACTIVE IN NEGLECTED DISEASES PRDRUG DESIGN

PRDRUG DESIGN D C PRDRUG Pharmaceutics Pharmacokinetics B A R R I E R S Solubility CHEMICAL AND/R ENZYMATIC RELEASE C Toxicity Selectivity D R E C E P T R C Albert, 1957 Harper, 1958 PHARMACLGICAL

4 PRDRUG DESIGN D C PRDRUG Pharmaceutics Pharmacokinetics B A R R I E R S Solubility CHEMICAL AND/R ENZYMATIC RELEASE C Toxicity Selectivity D R E C E P T R C Albert, 1957 Harper, 1958 PHARMACLGICAL EFFECTS D ADEPT GDEPT VDEPT Targeted drugs SELECTIVITY DRUG/ BIACTIVE CMPUND Chung, Ferreira. Quím. Nova, 22(1999)75. Chung et al. Rev.Bras.Cienc.Farm., 41(2005)155. Silva et al. Mini Rev. Med. Chem., 5(2005)893. Chung et al. Molecules, 3 (2008)616. Giarolla et al. In: Hugo Cerecetto Meyer, Mercedes González. (rg.). Enfermedad de Chagas: estrategias en la búsqueda de nuevos medicamentos. Una visión iberoamericana. 1ed. México, DF: RIDIMEDCHAG, CYTED, Silanes Laboratorios, SA de CV, 2012, p BITRANSFRMATIN AND ELIMINATIN C CARRIER

Silva et al. Mini Rev. Med. Chem., 5(2005)893. Chung et al. Molecules, 3 (2008)616. Giarolla et al. In: Hugo Cerecetto Meyer, Mercedes González. (rg.). Enfermedad de Chagas: estrategias en la búsqueda de nuevos medicamentos.

5 BISSTERISM HYBRIDIZATIN PRDRUGS The most active compound Mutual prodrugs Chagas disease Lucio H. G. Freitas Jr In vitro Carolina B. Moraes CNPEM, LNBio IC 50 cruzain = 10.55±0.81 μm EC 50 T. cruzi amastigotes = 3.03 mm CC 50 = mm (84%) SI = Max activity (%) = In vivo Chung, M.C. PhD Thesis, 1996 Lethal dosis = 2,000 mg/kg bw Wistar rats, single oral dose (200 mg/kg) NFH V distribution 20 times > NF NFH 50% hydrolised into NF in 24 h Highly active compound Chung et al. Bioorg. Med. Chem., 2003, 11, > 20 papers Chung et al. J. Pharm. Sci, 1997, 86, Walter Colli Maria Teresa M. Miranda

Multidisciplinary projects with other compounds HUMAN RESURCES FRMATIN BIISSTERISM ANTICHAGASIC PRDRUG DESIGN MLECULAR MDELING MEDICINAL CHEMISTRY LABRATRY F DESIGN AND SYNTHESIS F CHEMTHERAPEUTIC

6 Multidisciplinary projects with other compounds HUMAN RESURCES FRMATIN BIISSTERISM ANTICHAGASIC PRDRUG DESIGN MLECULAR MDELING MEDICINAL CHEMISTRY LABRATRY F DESIGN AND SYNTHESIS F CHEMTHERAPEUTIC AGENTS PTENTIALLY ACTIVE IN NEGLECTED DISEASES PARTNERSHIPS NATIN AL PARTNERSHIP SCIENTIFIC PRDUCTIN NFH INTERNATINAL PARTNERSHIP ANTIMALARIALS LEISHMANICIDES ANTI-TB PARTNERSHIP WITH PHARMACEUTICAL INDUSTRY NET USP DN CYTED, UR UNIV. MUENSTER,GE LAPDESF, UNESP UNICAMP THER INSTITUTINS PHARMACEUTICS UNIV. CIMBRA, PT MEDICINAL CHEMISTRY ELECTRCHEMISTRY BILGICAL ASSAYS MNTEIR, L.M. ; BU-CHACRA, N. A. ; CHUNG, M.C.; FERREIRA, E.I. ; CTRIM, P.C. Sistema Nanoestruturado Polimérico e seu uso. 2014, Brasil. Patente: Privilégio de Inovação. Número do registro: BR , data de depósito: 02/02/2014, título: "Sistema Nanoestruturado Polimérico e seu uso", Instituição de registro:inpi - Instituto Nacional da Propriedade Industrial.

INDUSTRY NET USP DN CYTED, UR UNIV. MUENSTER,GE LAPDESF, UNESP UNICAMP THER INSTITUTINS PHARMACEUTICS UNIV. CIMBRA, PT MEDICINAL CHEMISTRY ELECTRCHEMISTRY BILGICAL ASSAYS MNTEIR, L.M. ; BU-CHACRA, N.

GIARLLA, J.; FERREIRA, E.I. Pró-fármaco dendrimérico. Processo para sua preparação e composições contendo os mesmos. Protocolo de nº. 018090032049, junto à delegacia do INPI.

7 GIARLLA, J.; FERREIRA, E.I. Pró-fármaco dendrimérico. Processo para sua preparação e composições contendo os mesmos. Protocolo de nº , junto à delegacia do INPI. Revista da Propriedade Industrial-RPI, N 2006, pág. 51/52, item 3.1, Drug/Bioactive compound Directing group H H H H ther space group: glutamic acid 3-hydroxyflavone NFH Primaquine L-malic acid as spacer group TARGETED DRUGS H H H H H H H H Inositol as core H H H ther cores: diamine ethylene butane diamine ethylene glycol glicerol PAMAM polyamidoamine

Drug/Bioactive compound Directing group H H H H ther space group: glutamic acid 3-hydroxyflavone NFH Primaquine L-malic acid as

8 LABRATRY F DESIGN AND SYNTHESIS F CHEMTHERAPEUTIC AGENTS PTENTIALLY ACTIVE IN NEGLECTED DISEASES RATINAL DRUG DESIGN

9 INTEGRATIN DENDRIMER AND MLECULAR MDELING GIARLLA, J.; PASQUALT, K.F.M.; FERREIRA, E.I. Molecular Diversity, v.17, p , SANTS, S. S. ; GIARLLA, J. ; PASQUALT, K. F. M. ; FERREIRA, E.I. Molecular Simulation (Print), v.39, p , DISASSEMBLY STUDIES GIARLLA, J. ; PASQUALT, K. F. M. ; RAND, D. G. ; ZAIM, M.H. ; FERREIRA, E. I. Journal of Molecular Modeling, v. 18, p , GIARLLA, J. ; RAND, D. G. ; PASQUALT, K. F.M. ; ZAIM, M. H. ; FERREIRA, E. I. Journal of Molecular Structure. Theochem (Print), v. 939, p , MLSIM 3.2 1YAJ: ETHYL ACETATE (3.00 Ǻ) (Clustal mega) (AUTDCK)

G. ; ZAIM, M.H. ; FERREIRA, E. I. Journal of Molecular Modeling, v. 18, p. 2257-2269, 2012. GIARLLA, J. ; RAND, D. G. ; PASQUALT, K. F.M. ; ZAIM, M. H.

10 SEARCHING FR ANTI-CHAGAS DISEASE AGENTS Docking LBDD 144 compounds EC 50 = 5.53 mm IS >36 Max activity (%) 86.99% Lucio H. G. Freitas Jr Carolina B. Moraes CNPEM, LNBio Sybyl-X 1.1 Gold GRID v c SBDD

11 MLECULAR HYBRIDIZATIN BIISSTERISM 1 2 SBDD LBDD 6 R 1 = R 2 = N-1 14 R 1 = N-2 R 2 = CRUZAIN

12 RESEARCH TEAM NATINAL CLLABRATIN CHUNG MAN CHIN, UNESP/Araraquara JEAN LEANDR DS SANTS, UNESP/Araraquara CARLINA H. ANDRADE, UFG DANIELA G. RAND, UNIFESP KERLY F. M. PASQUALT, INST. BUTANTAN MAUR A. LA SCALEA, UNIFESP CARLS MAURÍCI R. DE SANT ANNA, UFRRJ LUIS CARLS DIAS, UNICAMP LUCI H. G. FREITAS JUNIR, CNPEM/LNBio CARLINA B. MRAES, CNPEM/LNBio PAUL C. CTRIM, IMT/USP LEBERT C. TAVARES, FCF/USP ANTNIA T. AMARAL, IQ/USP SILVIA H. P. SERRAN, IQ/USP ADRIAN D. ANDRICPUL, IFSC/USP SILVIA STRPIRTIS, FCF/USP JSÉ E. GNÇALVES, FCF/USP ANA PAULA M. LUREIR, FCF/USP INTERNATINAL CLLABRATIN ANTHN J. HPFINGER, UNM, US ANTNY D EMANUELE, UCLAN, UK SCTT FRANZBLAU, ITR, UIC, US HUG CERECETT, UdeLAR, Uruguay GALINA LEPESHEVA, VU, US GARY MLANDER, UP, US

CTRIM, IMT/USP LEBERT C. TAVARES, FCF/USP ANTNIA T. AMARAL, IQ/USP SILVIA H. P. SERRAN, IQ/USP ADRIAN D. ANDRICPUL, IFSC/USP SILVIA STRPIRTIS, FCF/USP JSÉ E.

13 Caminante, no hay camino! Se hace camino al andar! Antonio Machado, Spanish poet

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