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

• Grant number: 13/18009-4
• Support Opportunities: Research Projects - Thematic Grants
• Duration: May 01, 2014 - November 30, 2020
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Carlos Alberto Montanari
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Pesquisadores principais: Antonio Carlos Bender Burtoloso ; Sérgio de Albuquerque
• Associated researchers: Andrei Leitão ; João Santana da Silva
• Associated grant(s): 20/04653-2 - Molecular design and synthesis of coronavirus SARS-CoV-2 main protease (SARS CoV-2 Mpro) inhibitors, AP.R; 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; + associated grants 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 grants
• Associated scholarship(s): 19/14836-0 - Synthesis of 2-aminoacetonitriles derivatives as molecular fragments of reversible covalent inhibitors of cruzain enzyme, BP.IC; 19/06070-7 - On the Synthesis of New Trypanocidal Agents for the Treatment of Chagas Disease., BP.PD; 19/06271-2 - Synthesis of novel anti-Trypanosoma cruzi agents, BP.DD; + associated scholarships 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; 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; 15/20084-0 - Total Synthesis of (-)-Brussonol, (+)-Komaroviquinona and its analogs targeting potential candidates with trypanocidal activity, BP.PD; 15/22003-7 - Asymmetric Aza-Michael Addition from unsaturated diazoketones., BP.PD; 15/14304-7 - Design, Synthesis and Trypanocidal Activity of Covalent Reversible Inhibitors of the Enzyme Cruzain. Molecular Hybridization, BP.PD; 16/01375-6 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors, BP.IC; 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)

Scientific publications

(60)

(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)

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. (15/20084-0, 17/23329-9, 13/18009-4)

FURNIEL, LUCAS G.; BURTOLOSO, ANTONIO C. B.. Copper-catalyzed N-H insertion reactions from sulfoxonium ylides. Tetrahedron, v. 76, n. 51, SI, DEC 18 2020. (13/18009-4, 17/23329-9, 18/17800-3)

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. (13/18009-4, 13/25504-1, 17/23329-9)

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.; et al. Anti-trypanosomal activity of non-peptidic nitrile-based cysteine protease inhibitors. PLoS Neglected Tropical Diseases, v. 11, n. 2, FEB 2017. (13/18009-4)

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.; et al. 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. (13/18009-4, 13/01128-0, 16/10362-5, 15/14304-7)

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. (13/18009-4, 13/01128-0, 16/10362-5)

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. (13/18009-4, 15/20302-7)

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. (13/50312-9, 13/18009-4, 12/22274-2, 13/25504-1)

SANTIAGO, JOAO VICTOR; BURTOLOSO, ANTONIO C. B.. Rapid Synthesis of Bicyclic N-Heterocyclic Cores from N-Terminal ,-Unsaturated Diazoketones. EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, v. 2018, n. 22, p. 2822-2830, JUN 15 2018. (13/18009-4)

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. (13/18009-4)

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. (13/18009-4, 12/22274-2, 13/25504-1)

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. (13/18009-4, 13/25504-1)

CIANNI, LORENZO; ROCHO, FERNANDA DOS REIS; BONATTO, VINICIUS; PRADO MARTINS, FELIPE CARDOSO; LAMEIRA, JERONIMO; LEITAO, ANDREI; MONTANARI, CARLOS A.; SHAMIM, ANWAR. Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L. Bioorganic & Medicinal Chemistry, v. 29, JAN 1 2021. (13/18009-4, 18/03985-1, 16/07946-5)

TEZUKA, DAIANE YUKIE; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS ALBERTO; LEITAO, ANDREI. Discovery of 2-aminopyridine Derivatives with Antichagasic and Antileishmanial Activity Using Phenotypic Assays. LETTERS IN DRUG DESIGN & DISCOVERY, v. 17, n. 7, p. 867-872, 2020. (13/18009-4, 18/15904-6)

CIANNI, LORENZO; ROCHO, FERNANDA DOS REIS; ROSINI, FABIANA; BONATTO, VINICIUS; RIBEIRO, JEAN F. R.; LAMEIRA, JERONIMO; LEITAO, ANDREI; SHAMIM, ANWAR; MONTANARI, CARLOS A.. Optimization strategy of single-digit nanomolar cross-class inhibitors of mammalian and protozoa cysteine proteases. BIOORGANIC CHEMISTRY, v. 101, AUG 2020. (13/18009-4, 16/07946-5, 18/03985-1)

LAMEIRO, RAFAEL DA FONSECA; SHAMIM, ANWAR; ROSINI, FABIANA; CENDRON, RODRIGO; JATAI BATISTA, PEDRO HENRIQUE; MONTANARI, CARLOS ALBERTO. Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds. Future Medicinal Chemistry, v. 13, n. 1, p. 25-44, JAN 2021. (18/03279-0, 18/03985-1, 13/18009-4)

ROCHO, FERNANDA R.; BONATTO, VINICIUS; LAMEIRO, RAFAEL F.; LAMEIRA, JERONIMO; LEITAO, ANDREI; MONTANARI, CARLOS A.. A patent review on cathepsin K inhibitors to treat osteoporosis (2011-2021). EXPERT OPINION ON THERAPEUTIC PATENTS, v. 32, n. 5, p. 13-pg., 2022-03-12. (13/18009-4)

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. (17/23329-9, 13/18009-4)

CIANNI, LORENZO; FELDMANN, CHRISTIAN WOLFGANG; GILBERG, ERIK; GUETSCHOW, MICHAEL; JULIANO, LUIZ; LEITAO, ANDREI; BAJORATH, JUERGEN; MONTANARI, CARLOS A.. Can Cysteine Protease Cross-Class Inhibitors Achieve Selectivity?. Journal of Medicinal Chemistry, v. 62, n. 23, p. 10497-10525, DEC 12 2019. (13/18009-4, 16/07946-5)

RIBEIRO, JEAN F. R.; CIANNI, LORENZO; LI, CHAN; WARWICK, THOMAS G.; DE VITA, DANIELA; ROSINI, FABIANA; ROCHO, FERNANDA DOS REIS; MARTINS, FELIPE C. P.; KENNY, PETER W.; LAMEIRA, JERONIMO; et al. Crystal structure of Leishmania mexicana cysteine protease B in complex with a high-affinity azadipeptide nitrile inhibitor. Bioorganic & Medicinal Chemistry, v. 28, n. 22, NOV 15 2020. (13/18009-4)

CIANNI, LORENZO; LEMKE, CARINA; GILBERG, ERIK; FELDMANN, CHRISTIAN; ROSINI, FABIANA; ROCHO, FERNANDA DOS REIS; RIBEIRO, JEAN F. R.; TEZUKA, DAIANE Y.; LOPES, CARLA D.; DE ALBUQUERQUE, SERGIO; et al. Mapping the S1 and S1' subsites of cysteine proteases with new dipeptidyl nitrile inhibitors as trypanocidal agents. PLoS Neglected Tropical Diseases, v. 14, n. 3, MAR 2020. (13/18009-4, 17/17386-0, 16/07946-5)

BONATTO, VINICIUS; JATAI BATISTA, PEDRO HENRIQUE; CIANNI, LORENZO; DE VITA, DANIELA; SILVA, DANIEL G.; CEDRON, RODRIGO; TEZUKA, DAIANE Y.; DE ALBUQUERQUE, SERGIO; MORAES, CAROLINA BORSOI; FRANCO, CAIO HADDAD; et al. On the intrinsic reactivity of highly potent trypanocidal cruzain inhibitors. RSC MEDICINAL CHEMISTRY, v. 11, n. 11, p. 1275-1284, NOV 1 2020. (18/21749-3, 18/15904-6, 13/18009-4)

QUILLES, JR., JOSE C.; SHAMIM, ANWAR; TEZUKA, DAIANE Y.; BATISTA, PEDRO H. J.; LOPES, CARLA D.; DE ALBUQUERQUE, SERGIO; MONTANARI, CARLOS A.; LEITAO, ANDREI. Dipeptidyl nitrile derivatives suppress the Trypanosoma cruzi in vitro infection. Experimental Parasitology, v. 219, DEC 2020. (13/18009-4, 18/15904-6, 18/03985-1, 14/07292-0)

AMARANTE, GIOVANNI W.. Metal-Free Insertion Reactions of Diazo Carbonyls to Azlactones. Journal of Organic Chemistry, v. 83, n. 18, p. 11399-11406, SEP 21 2018. (17/23329-9, 13/18009-4)

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. (13/18009-4, 11/07025-3)

FURNIEL, LUCAS G.; BURTOLOSO, ANTONIO C. B.. Copper-catalyzed N-H insertion reactions from sulfoxonium ylides. Tetrahedron, v. 76, n. 51, p. 10-pg., 2020-12-18. (17/23329-9, 18/17800-3, 13/18009-4)

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, p. 11-pg., 2016-05-12. (13/18009-4)

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. (13/18009-4, 13/01128-0, 16/10362-5)

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. (13/18009-4, 13/25504-1, 15/22003-7)

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. (13/18009-4, 13/25504-1)

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. (12/02955-5, 13/18009-4)

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. (13/18009-4)

LAMEIRO, RAFAEL DA FONSECA; SHAMIM, ANWAR; ROSINI, FABIANA; CENDRON, RODRIGO; JATAI BATISTA, PEDRO HENRIQUE; MONTANARI, CARLOS ALBERTO. Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds. Future Medicinal Chemistry, DEC 2020. (18/03279-0, 18/03985-1, 13/18009-4)

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. (13/18009-4)

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. (13/18009-4)

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. (13/18009-4, 14/07292-0)

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. (13/18009-4, 13/17271-7)

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. (13/18009-4, 13/25504-1, 15/22003-7)

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.; et al. Molecular Design, Synthesis and Trypanocidal Activity of Dipeptidyl Nitriles as Cruzain Inhibitors. PLoS Neglected Tropical Diseases, v. 9, n. 7, JUL 2015. (13/18009-4)

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. (13/18009-4, 13/26399-7, 13/25504-1)

SILVA, JOSE ROGERIO A.; CIANNI, LORENZO; ARAUJO, DEBORAH; JATAI BATISTA, PEDRO HENRIQUE; DE VITA, DANIELA; ROSINI, FABIANA; LEITAO, ANDREI; LAMEIRA, JERONIMO; MONTANARI, CARLOS A.. Assessment of the Cruzain Cysteine Protease Reversible and Irreversible Covalent Inhibition Mechanism. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 3, p. 1666-1677, MAR 23 2020. (13/18009-4, 18/21749-3)

MOMO, PATRICIA B.; LEVEILLE, ALEXANDRIA N.; FARRAR, ELLIOT H. E.; GRAYSON, MATTHEW N.; MATTSON, ANITA E.; BURTOLOSO, ANTONIO C. B.. Enantioselective S-H Insertion Reactions of alpha-Carbonyl Sulfoxonium Ylides. ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, v. 59, n. 36, MAY 2020. (18/19105-0, 13/18009-4, 17/23329-9)

SARTORI, GERALDO RODRIGUES; LEITAO, ANDREI; MONTANARI, CARLOS A.; LAUGHTON, CHARLES A.. Ligand-induced conformational selection predicts the selectivity of cysteine protease inhibitors. PLoS One, v. 14, n. 12, DEC 19 2019. (13/18009-4)

GOMES, JULIANA C.; CIANNI, LORENZO; RIBEIRO, JEAN; ROCHO, FERNANDA DOS REIS; MARTINS SILVA, SAMELYN DA COSTA; JATAI BATISTA, PEDRO HENRIQUE; MORAES, CAROLINA BORSOI; FRANCO, CAIO HADDAD; FREITAS-JUNIOR, LUCIO H. G.; KENNY, PETER W.; et al. Synthesis and structure-activity relationship of nitrile-based cruzain inhibitors incorporating a trifluoroethylamine-based P2 amide replacement. Bioorganic & Medicinal Chemistry, v. 27, n. 22, NOV 15 2019. (13/18009-4, 16/07946-5)

QUILLES JUNIOR, JOSE C.; ROCHO CARLOS, FERNANDA DOS REIS; MONTANARI, A.; LEITAO, ANDREI; MIGNONE, VIVIANE W.; ARRUDA, MARIA AUGUSTA; TURYANSKA, LYUDMILA; BRADSHAW, TRACEY D.. Apoferritin encapsulation of cysteine protease inhibitors for cathepsin L inhibition in cancer cells. RSC ADVANCES, v. 9, n. 63, p. 36699-36706, NOV 11 2019. (13/18009-4, 14/07292-0)

LAMEIRA, JERONIMO; BONATTO, VINICIUS; CIANNI, LORENZO; ROCHO, FERNANDA DOS REIS; LEITAO, ANDREI; MONTANARI, CARLOS A.. Predicting the affinity of halogenated reversible covalent inhibitors through relative binding free energy. Physical Chemistry Chemical Physics, v. 21, n. 44, p. 24723-24730, NOV 28 2019. (13/18009-4, 18/21749-3)

BRITO MATOS, THIAGO KELVIN; JATAI BATISTA, PEDRO HENRIQUE; ROCHO, FERNANDA DOS REIS; DE VITA, DANIELA; PEARCE, NICHOLAS; KELLAM, BARRIE; MONTANARI, CARLOS ALBERTO; LEITAO, ANDREI. Synthesis and matched molecular pair analysis of covalent reversible inhibitors of the cysteine protease CPB. Bioorganic & Medicinal Chemistry Letters, v. 30, n. 18, SEP 15 2020. (16/07946-5, 18/15904-6, 13/18009-4)

ALVES, LUANA; SANTOS, DEBORAH A.; CENDRON, RODRIGO; ROCHO, FERNANDA R.; MATOS, THIAGO K. B.; LEITAO, ANDREI; MONTANARI, CARLOS A.. Nitrile-based peptoids as cysteine protease inhibitors. Bioorganic & Medicinal Chemistry, v. 41, JUL 1 2021. (13/18009-4, 18/15904-6, 18/09961-7)

LIN, CHI-CHUAN; SUEN, KIN MAN; STAINTHORP, AMY; WIETESKA, LUKASZ; BIGGS, GEORGE S.; LEITAO, ANDREI; MONTANARI, CARLOS A.; LADBURY, JOHN E.. Targeting the Shc-EGFR interaction with indomethacin inhibits MAP kinase pathway signalling. Cancer Letters, v. 457, p. 86-97, 2019. (13/18009-4)

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. (13/18009-4, 14/07292-0)

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LEMKE, CARINA; CIANNI, LORENZO; FELDMANN, CHRISTIAN; GILBERG, ERIK; YIN, JIAFEI; ROCHO, FERNANDA DOS REIS; DE VITA, DANIELA; BARTZ, ULRIKE; BAJORATH, JUERGEN; MONTANARI, CARLOS A.; et al. N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design, synthesis and biochemical characterization. Bioorganic & Medicinal Chemistry Letters, v. 30, n. 18, p. 6-pg., 2020-09-15. (13/18009-4)

AHMAD, ANEES; BURTOLOSO, ANTONIO C. B.. Total Synthesis of (+/-)-Brussonol and (+/-)-Komaroviquinone via a Regioselective Cross-Electrophile Coupling of Aryl Bromides and Epoxides. ORGANIC LETTERS, v. 21, n. 15, p. 6079-6083, AUG 2 2019. (15/20084-0, 17/23329-9, 13/18009-4)

DA COSTA, CLAUBER H. S.; BONATTO, VINICIUS; DOS SANTOS, ALBERTO M.; LAMEIRA, JERONIMO; LEITAO, ANDREI; MONTANARI, CARLOS A.. Evaluating QM/MM Free Energy Surfaces for Ranking Cysteine Protease Covalent Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 2, p. 880-889, FEB 2020. (13/18009-4, 18/21749-3)

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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. (17/02092-0, 17/23329-9, 13/18009-4)

DOS SANTOS, ALBERTO M.; SANTANA OLIVEIRA, AMANDA RUSLANA; DA COSTA, CLAUBER H. S.; KENNY, PETER W.; MONTANARI, CARLOS A.; VARELA, JALDYR DE JESUS G.; LAMEIRA, JERONIMO. Assessment of Reversibility for Covalent Cysteine Protease Inhibitors Using Quantum Mechanics/Molecular Mechanics Free Energy Surfaces. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 62, n. 17, p. 12-pg., 2022-09-12. (18/21749-3, 13/18009-4)

LAMEIRO, RAFAEL F.; MONTANARI, CARLOS A.. Investigating the Lack of Translation from Cruzain Inhibition to Trypanosoma cruzi Activity with Machine Learning and Chemical Space Analyses. CHEMMEDCHEM, v. N/A, p. 13-pg., 2023-02-03. (21/01633-3, 13/18009-4)

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