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FRONTIERS IN SCIENCE ON NEGLECTED DISEASES
PRODRUG DESIGN AND RATIONAL DRUG DESIGN
ELIZABETH IGNE FERREIRAUniversity of Sao Paulo
School of Pharmaceutical Sciences
November 2014
PRODRUG DESIGN
DRUGS
CURRENTLY USED
NEW
STRUCTURES
PRODRUGS
SECONDARY
USEPRODRUGS
PHARMACOKINETICS
Post hocAd hoc
NEW TARGETS
TARGETED DRUGS
CHAGAS
DISEASELEISHMANIASIS
M ALARIA TUBERCULOSIS
MOLECULARMODELING
ANALOGS
PHARMACODYNAMICS
QSAR 2D, 3D4D
SBDDLBDD
LABORATORY OF DESIGN AND SYNTHESISOF CHEMOTHERAPEUTIC AGENTS
POTENTIALLY ACTIVE IN NEGLECTED DISEASES
RATIONAL DRUG DESIGN
PRODRUG DESIGN LABORATORY OF DESIGN AND SYNTHESIS
OF CHEMOTHERAPEUTIC AGENTS POTENTIALLY ACTIVE IN NEGLECTED DISEASES
C
BIOTRANSFORMATION AND
ELIMINATION
CHEMICAL AND/OR
ENZYMATIC RELEASE
C
PHARMACOLOGICAL
EFFECTS
D
R
E
C
E
P
T
O
R
D
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. (Org.).
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. 290-340.
DRUG/
BIOACTIVE COMPOUND
D
CARRIERC
PRODRUG DESIGN Albert, 1957Harper, 1958
SELECTIVITY
Toxicity
Solubility
Pharmaceutics ADEPTGDEPTVDEPT
Targeted drugs
C
PRODRUG
Selectivity
B
R
R
A
I
E
R
Pharmacokinetics
S
Chung, M.C. PhD Thesis, 1996
Chung et al. J. Pharm. Sci, 1997, 86, 1127-1131.
Highly active compound
Walter ColliMaria Teresa M. Miranda
Mutual prodrugsChagas´ disease
In vitro
In vivo
IC50 cruzain = 10.55±0.81 μMEC50 T. cruzi amastigotes = 3.03 mMCC50 = 52.06 mM (84%)
SI = 17.18Max activity (%) = 100.8
Lethal dosis = 2,000 mg/kg bw
Wistar rats, single oral dose (200 mg/kg)NFOH V distribution 20 times > NFNFOH 50% hydrolised into NF in 24 h
Lucio H. G. Freitas JrCarolina B. Moraes
CNPEM, LNBio
The most active compound
Chung et al. Bioorg. Med. Chem., 2003, 11, 4779-4783
> 20 papers
BIOSOSTERISMHYBRIDIZATION
PRODRUGS
NFOHLEISHMANICIDES
ANTICHAGASIC
ANTIMALARIALS
BIOISOSTERISM
PHARMACEUTICS
PRODRUG DESIGN
ELECTROCHEMISTRY
MOLECULAR MODELING
NATION AL PARTNERSHIP
INTERNATIONALPARTNERSHIP
NET USP DN
PARTNERSHIPS
MEDICINAL CHEMISTRY
BIOLOGICAL ASSAYS
CYTED,UR
PARTNERSHIP WITHPHARMACEUTICAL
INDUSTRY
UNIV. COIMBRA, PT
MEDICINAL CHEMISTRY
SCIENTIFIC PRODUCTION
OTHER INSTITUTIONS
LAPDESF, UNESP
UNICAMP
UNIV. MUENSTER,GE
ANTI-TB
Multidisciplinaryprojects with other
compoundsHUMAN RESOURCES
FORMATION
MONTEIRO, L.M. ; BOU-CHACRA, N. A. ; CHUNG, M.C.; FERREIRA, E.I. ; COTRIM, P.C. Sistema Nanoestruturado Polimérico e seu uso. 2014, Brasil. Patente: Privilégio de Inovação. Número do registro: BR1020140079238, data de depósito: 02/02/2014, título: "Sistema Nanoestruturado Polimérico e seu uso" , Instituição de registro:INPI - Instituto Nacional da Propriedade Industrial.
LABORATORY OF DESIGN AND SYNTHESISOF CHEMOTHERAPEUTIC AGENTS
POTENTIALLY ACTIVE IN NEGLECTED DISEASES
O
O O
O
OH
O O
O
OH
O OH
O
OH
OH
OHOH
OO
O
OHOO
OO
OHO
OHO
OH
O
O
O
OH
O
O
OH
OOH
O
OH
GIAROLLA, 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.Revista da Propriedade Industrial-RPI, N° 2006, pág. 51/52, item3.1, 2009.
Directing group TARGETED DRUGS
Other cores: diamine ethylenebutane diamineethylene glycolglicerol
Inositol as core
Other space group: glutamic acid
L-malic acidas spacer group
3-hydroxyflavoneNFOHPrimaquine
Drug/Bioactive compound
PAMAM – polyamidoamine
RATIONAL DRUG DESIGN
LABORATORY OF DESIGN AND SYNTHESISOF CHEMOTHERAPEUTIC AGENTS
POTENTIALLY ACTIVE IN NEGLECTED DISEASES
DISASSEMBLY STUDIES
MOLSIM 3.2
INTEGRATION DENDRIMER AND MOLECULAR MODELING
1YAJ: ETHYL ACETATE (3.00 Ǻ)(Clustal Omega) (AUTODOCK)
GIAROLLA, J.; PASQUALOTO, K.F.M.; FERREIRA, E.I. Molecular Diversity, v.17, p.711-720, 2013.
SANTOS, S. S. ; GIAROLLA, J. ; PASQUALOTO, K. F. M. ; FERREIRA, E.I. Molecular Simulation (Print), v.39, p. 860-867, 2013.
GIAROLLA, J. ; PASQUALOTO, K. F. M. ; RANDO, D. G. ; ZAIM, M.H. ; FERREIRA, E. I. Journal of Molecular Modeling, v. 18, p. 2257-2269, 2012.
GIAROLLA, J. ; RANDO, D. G. ; PASQUALOTO, K. F.M. ; ZAIM, M. H. ; FERREIRA, E. I. Journal of Molecular Structure. Theochem(Print), v. 939, p. 133-138, 2010.
SEARCHING FOR ANTI-CHAGAS DISEASE AGENTS
144 compounds
LBDD
Docking
SBDDSybyl-X 1.1
Gold 4.1.2GRID v.22.0.3c
EC50 = 5.53 mMIS >36Max activity (%) – 86.99%
Lucio H. G. Freitas JrCarolina B. Moraes
CNPEM, LNBio
LBDDSBDD
CRUZAIN
1
2
R1 = R2 = 6 N-1
14 R1 = N-2R2 =
MOLECULAR HYBRIDIZATIONBIOISOSTERISM
RESEARCH TEAMNATIONAL COLLABORATION
CHUNG MAN CHIN, UNESP/AraraquaraJEAN LEANDRO DOS SANTOS, UNESP/Araraquara
CAROLINA H. ANDRADE, UFGDANIELA G. RANDO, UNIFESP
KERLY F. M. PASQUALOTO, INST. BUTANTANMAURO A. LA SCALEA, UNIFESP
CARLOS MAURÍCIO R. DE SANT´ANNA, UFRRJLUIS CARLOS DIAS, UNICAMP
LUCIO H. G. FREITAS JUNIOR, CNPEM/LNBioCAROLINA B. MORAES, CNPEM/LNBio
PAULO C. COTRIM, IMT/USPLEOBERTO C. TAVARES, FCF/USP
ANTONIA T. AMARAL, IQ/USPSILVIA H. P. SERRANO, IQ/USP
ADRIANO D. ANDRICOPULO, IFSC/USPSILVIA STORPIRTIS, FCF/USP
JOSÉ E. GONÇALVES, FCF/USPANA PAULA M. LOUREIRO, FCF/USP
INTERNATIONAL COLLABORATIONANTHON J. HOPFINGER, UNM, US
ANTONY D´EMANUELE, UCLAN, UKSCOTT FRANZBLAU, ITR, UIC, US
HUGO CERECETTO, UdeLAR, UruguayGALINA LEPESHEVA, VU, USGARY MOLANDER, UP, US
Caminante, no hay camino!Se hace camino al andar!
Antonio Machado, Spanish poet