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Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors

Grant number: 13/18009-4
Support type:Research Projects - Thematic Grants
Duration: May 01, 2014 - April 30, 2020
Field of knowledge:Physical Sciences and Mathematics - Chemistry
Principal Investigator:Carlos Alberto Montanari
Grantee:Carlos Alberto Montanari
Home Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
Co-Principal Investigators:Antonio Carlos Bender Burtoloso ; Sérgio de Albuquerque
Assoc. researchers:Andrei Leitão ; João Santana da Silva
Associated grant(s):18/21749-3 - Computational study of cruzain enzyme by reversible covalent inhibitors, AV.BR
17/13344-0 - Molecular design of cysteine protease reversible covalent inhibitors, AV.EXT
15/24455-2 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.EMU
15/24453-0 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, AP.EMU
14/06941-4 - Hypothesis-driven molecular design based on cruzain reversible covalent inhibitors, AV.EXT
Associated scholarship(s):19/06271-2 - Synthesis of novel anti-Trypanosoma cruzi agents, BP.DD
18/03985-1 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme, BP.PD
18/09961-7 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme, BP.PD
+ associated scholarships 18/03279-0 - Anti-Trypanosoma cruzi activity of non-Peptidic agents as inhibitors of cysteine protease cruzain, BP.MS
17/02092-0 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.PD
16/12047-0 - Planning, synthesis and trypanosomicidal activity of enzyme cruzain reversible covalent inhibitors, BP.IC
16/04096-0 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.PD
16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme, BP.DD
15/22003-7 - Asymmetric Aza-Michael addition from unsaturated diazoketones, BP.PD
15/20084-0 - Total synthesis of (-)-Brussonol, (+)-Komaroviquinona and its analogs targeting potential candidates with trypanocidal activity, BP.PD
16/01375-6 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.IC
15/14304-7 - Design, synthesis and trypanocidal activity of covalent reversible inhibitors of the enzyme cruzain. molecular hybridization, BP.PD
15/22133-8 - Analysis of cysteine protease activity in Trypanosoma Cruzi and Leishmania spp, BP.IC
15/04947-8 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.PD
14/07292-0 - Molecular design, trypanocidal and anticancer activities of covalent reversible inhibitors of cysteine proteases, BP.DR
14/18443-9 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.PD - associated scholarships

Abstract

Cruzain, the main cysteine protease of Trypanosoma cruzi, is an essential enzyme for the life cycle of the parasite and has been used as a viable target for searching for enzyme inhibitors as drug candidates. The peptide mimetic compound K11777 inhibits cruzain at nanomolar concentrations, and acts by an irreversible inhibition mechanism. Analogs or derivatives K11777 usually contain electrophilic functional groups known as "warheads" that can bind covalently to the active site of cruzain via nucleophilic attack promoted by catalytic cysteine. Although this mechanism has been extensively studied, few other studies have explored the influence of the nature of the covalent bond in the process of reversible covalent inhibition in cruzain. The Medicinal Chemistry Group of IQSC / USP began studying this mechanism through FAPESP 2011/01893-3 and 2011/20572-3 projects, with great success using nitriles as warheads to form covalent-reversible dipeptidyl nitriles with cysteine proteases. Inhibitors similar to the prototypical inhibitors of cathepsin K (which has been used in the pharmaceutical industry as a target) were selected to contain a skeleton susceptible to chemical optimization processes. All the synthesised NEQUIMED compounds were active against cruzain in the range of low- to sub-micromolar concentrations. The most potent compound, Nequimed409 (Neq409), inhibited the enzyme with IC50 of 1.89 ± 0.11 µM (pIC50 = 5.7). These compounds showed trypanocidal activity against the trypomastigote infective form Tulahuen lacZ strain at concentrations less than 50 µM. The prototype compound Neq409, potent against cruzain is also a trypanocidal agent (concentration-dependent response) with IC50 of 2.7 ± 0.3 µM (pIC50 = 5.6). Neq409 is 9 times more potent than the drug benznidazole (BZ), which was used as control (pIC50 = 4.6) and has minimal cytotoxicity in mice spleen (> 500 µM, comparable to the BZ which is > 500 µM). The dipeptidyl nitriles exhibit characteristics of leads that can be optimized for drug candidates: T. cruzi pIC50 > 5 (pIC50 (Neq409) = 5.6) with SI > 10 (SI ratio = IC50(cyto)/IC50(T. cruzi) = 185, BZ = 20.6); PFI < 8 (PFINeq409 = 3.7); # Ar rings < 5 and MW 500 < Da. The Aims of this proposal are (i) determine the in silico docking poses with molecular dynamics simulation and calculation of the free energy of interaction (MM-PBSA) and to obtain structure-activity relationships (SAR) to identify new drug candidates; (ii) synthesise Neq409 analogues/derivatives with three different objectives: (1) optimising the potency of dipeptidyl nitriles as cruzain nanomolar inhibitors (2) identification of new warheads as alternatives to nitrile and (3) substitution of the amide group by heterocycles to tailor the ligands to have less peptidic character and reduced hydrolytic instability; (iii) determine the potency against cruzain; (iv) obtaining X-ray data of the crystallographic structure of ligand-cruzain co-crystal; (v) evaluating of trypanocidal activity in vitro and in vivo; (vi) evaluating of cytotoxic activity and (vii) determining the in vivo pharmacokinetic profile. (AU)

Articles published in Agência FAPESP about the research grant
Promising novel compounds for treatment of the acute phase of Chagas disease 

Scientific publications (30)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
QUILLES JR, JOSE C.; TEZUKA, DAIANE Y.; LOPES, CARLA D.; RIBEIRO, FERNANDA L.; LAUGHTON, CHARLES A.; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS A.; LEITAO, ANDREI. Dipeptidyl nitrile derivatives have cytostatic effects against Leishmania spp. promastigotes. Experimental Parasitology, v. 200, p. 84-91, MAY 2019. Web of Science Citations: 0.
GALLO, RAFAEL D. C.; CAMPOVILLA, JR., ORLANDO C.; AHMAD, ANEES; BURTOLOSO, ANTONIO C. B. Synthesis of Oxazinanones: Intramolecular Cyclization of Amino Acid-Derived Diazoketones via Silica-Supported HClO4 Catalysis. FRONTIERS IN CHEMISTRY, v. 7, FEB 8 2019. Web of Science Citations: 0.
SANTIAGO, JOAO VICTOR; BURTOLOSO, ANTONIO C. B. Synthesis of Fused Bicyclic [1,2,3]-Triazoles from gamma-Amino Diazoketones. ACS OMEGA, v. 4, n. 1, p. 159-168, JAN 2019. Web of Science Citations: 0.
QUILLES JR, JOSE C.; BERNARDI, MURILLO D. L.; BATISTA, PEDRO H. J.; SILVA, SAMELYN C. M.; ROCHA, CAMILA M. R.; MONTANARI, CARLOS A.; LEITAO, ANDREI. Biological Activity and Physicochemical Properties of Dipeptidyl Nitrile Derivatives Against Pancreatic Ductal Adenocarcinoma Cells. ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY, v. 19, n. 1, p. 112-120, 2019. Web of Science Citations: 1.
TALERO, ALEXANDER GARAY; MARTINS, BRUNA SIMOES; BURTOLOSO, ANTONIO C. B. Coupling of Sulfoxonium Ylides with Arynes: A Direct Synthesis of Pro-Chiral Aryl Ketosulfoxonium Ylides and Its Application in the Preparation of alpha-Aryl Ketones. ORGANIC LETTERS, v. 20, n. 22, p. 7206-7211, NOV 16 2018. Web of Science Citations: 2.
DOS SANTOS, ALBERTO MONTEIRO; CIANNI, LORENZO; DE VITA, DANIELA; ROSINI, FABIANA; LEITAO, ANDREI; LAUGHTON, CHARLES A.; LAMEIRA, JERONIMO; MONTANARI, CARLOS A. Experimental study and computational modelling of cruzain cysteine protease inhibition by dipeptidyl nitriles. Physical Chemistry Chemical Physics, v. 20, n. 37, p. 24317-24328, OCT 7 2018. Web of Science Citations: 1.
AMARANTE, GIOVANNI W. . Journal of Organic Chemistry, v. 83, n. 18, p. 11399-11406, SEP 21 2018. Web of Science Citations: 0.
GALLO, RAFAEL DOUGLAS C.; BURTOLOSO, ANTONIO C. B. Silica-supported HClO4 promotes catalytic solvent- and metal-free O-H insertion reactions with diazo compounds. GREEN CHEMISTRY, v. 20, n. 19, p. 4547-4556, SEP 7 2018. Web of Science Citations: 2.
CIANNI, LORENZO; SARTORI, GERALDO; ROSINI, FABIANA; DE VITA, DANIELA; PIRES, GABRIEL; LOPES, BIANCA REBELO; LEITAO, ANDREI; BURTOLOSO, ANTONIO C. B.; MONTANARI, CARLOS A. Leveraging the cruzain S3 subsite to increase affinity for reversible covalent inhibitors. BIOORGANIC CHEMISTRY, v. 79, p. 285-292, SEP 2018. Web of Science Citations: 0.
SANTIAGO, JOAO VICTOR; BURTOLOSO, ANTONIO C. B. Rapid Synthesis of Bicyclic N-Heterocyclic Cores from N-Terminal ,-Unsaturated Diazoketones. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, n. 22, p. 2822-2830, JUN 15 2018. Web of Science Citations: 1.
METZKER, GUSTAVO; DIAS, RAFAEL M. P.; BURTOLOSO, ANTONIO C. B. Iron-Catalyzed Reductive Amination from Levulinic and Formic Acid Aqueous Solutions: An Approach for the Selective Production of Pyrrolidones in Biorefinery Facilities. CHEMISTRYSELECT, v. 3, n. 2, p. 368-372, JAN 17 2018. Web of Science Citations: 3.
Traditional and New methods for the Preparation of Diazocarbonyl Compounds. Anais da Academia Brasileira de Ciências, v. 90, n. 1, p. -, 2018.
BURTOLOSO, ANTONIO C. B.; MOMO, PATRICIA B.; NOVAIS, GRAZIELE L. Traditional and New methods for the Preparation of Diazocarbonyl Compounds. Anais da Academia Brasileira de Ciências, v. 90, n. 1, 1, p. 859-893, 2018. Web of Science Citations: 5.
GALLO, RAFAEL D. C.; AHMAD, ANEES; METZKER, GUSTAVO; BURTOLOSO, ANTONIO C. B. alpha,alpha-Alkylation-Halogenation and Dihalogenation of Sulfoxonium Ylides. A Direct Preparation of Geminal Difunctionalized Ketones. CHEMISTRY-A EUROPEAN JOURNAL, v. 23, n. 67, p. 16980-16984, DEC 1 2017. Web of Science Citations: 6.
SILVA, DANIEL G.; RIBEIRO, JEAN F. R.; DE VITA, DANIELA; CIANNI, LORENZO; FRANCO, CAIO HADDAD; FREITAS-JUNIOR, LUCIO H.; MORAES, CAROLINA BORSOI; ROCHA, JOSMAR R.; BURTOLOSO, ANTONIO C. B.; KENNY, PETER W.; LEITAO, ANDREI; MONTANARI, CARLOS A. A comparative study of warheads for design of cysteine protease inhibitors. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 22, p. 5031-5035, NOV 15 2017. Web of Science Citations: 5.
POSSATO, BRUNA; CARNEIRO, ZUMIRA APARECIDA; DE ALBUQUERQUE, SERGIO; NIKOLAOU, SOFIA. New uses for old complexes: The very first report on the trypanocidal activity of symmetric trinuclear ruthenium complexes. Journal of Inorganic Biochemistry, v. 176, p. 156-158, NOV 2017. Web of Science Citations: 1.
TALERO, ALEXANDER G.; BURTOLOSO, ANTONIO C. B. Sharpless Asymmetric Dihydroxylation on ,-Unsaturated Diazoketones: A New Entry for the Synthesis of Disubstituted Furanones. Synlett, v. 28, n. 14, p. 1748-1752, SEP 2017. Web of Science Citations: 4.
SILVA, DANIEL G.; GILLESPIE, J. ROBERT; RANADE, RANAE M.; HERBST, ZACKARY M.; NGUYEN, UYEN T. T.; BUCKNER, FREDERICK S.; MONTANARI, CARLOS A.; GELB, MICHAEL H. New Class of Antitrypanosomal Agents Based on Imidazopyridines. ACS Medicinal Chemistry Letters, v. 8, n. 7, p. 766-770, JUL 2017. Web of Science Citations: 5.
DIAS, RAFAEL M. P.; MOMO, PATRICIA B.; BURTOLOSO, ANTONIO C. B. One-step syntheses of substituted 2-pyrrolidinones and 3-pyrrolidinones from alpha,beta-unsaturated diazoketones and amines. Application in the synthesis of barmumycin. Tetrahedron, v. 73, n. 26, p. 3720-3729, JUN 29 2017. Web of Science Citations: 7.
SANTA CRUZ, ELISA C.; CARECHO, ADRIEL R.; SAIDEL, MARTA E.; MONTANARI, CARLOS ALBERTO; LEITAO, ANDREI. In silico selection and cell-based characterization of selective and bioactive compounds for androgen-dependent prostate cancer cell. Bioorganic & Medicinal Chemistry Letters, v. 27, n. 3, p. 546-550, FEB 1 2017. Web of Science Citations: 2.
BORGES, NADIA MELO; KENNY, PETER W.; MONTANARI, CARLOS A.; PROKOPCZYK, IGOR M.; RIBEIRO, JEAN F. R.; ROCHA, JOSMAR R.; SARTORI, GERALDO RODRIGUES. The influence of hydrogen bonding on partition coefficients. Journal of Computer-Aided Molecular Design, v. 31, n. 2, p. 163-181, FEB 2017. Web of Science Citations: 6.
BURTOLOSO, ANTONIO C. B.; DE ALBUQUERQUE, SERGIO; FURBER, MARK; GOMES, JULIANA C.; GONCALEZ, CRISTIANA; KENNY, PETER W.; LEITAO, ANDREI; MONTANARI, CARLOS A.; QUILLES JUNIOR, JOSE CARLOS; RIBEIRO, JEAN F. R.; ROCHA, JOSMAR R. Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors. PLoS Neglected Tropical Diseases, v. 11, n. 2 FEB 2017. Web of Science Citations: 2.
SILVA, DANIEL GEDDER; ROCHA, JOSMAR RODRIGUES; SARTORI, GERALDO RODRIGUES; MONTANARI, CARLOS ALBERTO. Highly predictive hologram QSAR models of nitrile-containing cruzain inhibitors. JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, v. 35, n. 15, p. 3232-3249, 2017. Web of Science Citations: 0.
KAWAMURA, MEIRE Y.; TALERO, ALEXANDER G.; SANTIAGO, JOAO V.; GARAMBEL-VILCA, EDSON; ROSSET, ISAC G.; BURTOLOSO, ANTONIO C. B. Six-Step Syntheses of (-)-1-Deoxyaltronojirimycin and (+)-1-Deoxymannonojirimycin from N-Z-O-TBDPS-L-serinal. Journal of Organic Chemistry, v. 81, n. 21, p. 10569-10575, NOV 4 2016. Web of Science Citations: 4.
DIAS, RAFAEL M. P.; BURTOLOSO, ANTONIO C. B. Catalyst-Free Insertion of Sulfoxonium Ylides into Aryl Thiols. A Direct Preparation of beta-Keto Thioethers. ORGANIC LETTERS, v. 18, n. 12, p. 3034-3037, JUN 17 2016. Web of Science Citations: 25.
KENNY, PETER W.; MONTANARI, CARLOS A.; PROKOPCZYK, IGOR M.; RIBEIRO, JEAN F. R.; SARTORI, GERALDO RODRIGUES. Hydrogen Bond Basicity Prediction for Medicinal Chemistry Design. Journal of Medicinal Chemistry, v. 59, n. 9, SI, p. 4278-4288, MAY 12 2016. Web of Science Citations: 17.
BERNARDIM, BARBARA; COUCH, ERICA D.; HARDMAN-BALDWIN, ANDREA M.; BURTOLOSO, ANTONIO C. B.; MATTSON, ANITA E. Divergent Roles of Urea and Phosphoric Acid Derived Catalysts in Reactions of Diazo Compounds. SYNTHESIS-STUTTGART, v. 48, n. 5, p. 677-686, MAR 2016. Web of Science Citations: 11.
LEITAO, RENAN C. F.; TRUJILLO, LOREN N.; LEITAO, ANDREI; ALBUQUERQUE, RODRIGO Q. On the use of porous nanomaterials to photoinactivate E. coli with natural sunlight irradiation. Solar Energy, v. 122, p. 1117-1122, DEC 2015. Web of Science Citations: 1.
AVELAR, LEANDRO A. A.; CAMILO, CRISTIAN D.; DE ALBUQUERQUE, SERGIO; FERNANDES, WILLIAM B.; GONCALEZ, CRISTIANA; KENNY, PETER W.; LEITAO, ANDREI; MCKERROW, JAMES H.; MONTANARI, CARLOS A.; MENACA OROZCO, ERIKA V.; RIBEIRO, JEAN F. R.; ROCHA, JOSMAR R.; ROSINI, FABIANA; SAIDEL, MARTA E. Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors. PLoS Neglected Tropical Diseases, v. 9, n. 7 JUL 2015. Web of Science Citations: 11.
BURTOLOSO, ANTONIO C. B.; SANTIAGO, JOAO V.; BERNARDIM, BARBARA; TALERO, ALEXANDER G. Advances in the Enantioselective Metal-catalyzed N-H and O-H Insertion Reactions with Diazocarbonyl Compounds. CURRENT ORGANIC SYNTHESIS, v. 12, n. 5, p. 650-659, 2015. Web of Science Citations: 7.

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