Heterocyclic chemistry and epigenetic for the development of library of compounds for medicinal chemistry purposes.

• Grant number: 17/21146-4
• Support type: Regular Research Grants
• Duration: February 01, 2018 - January 31, 2020
• Field of knowledge: Health Sciences - Pharmacy
• Principal researcher: Flavio da Silva Emery
• Grantee: Flavio da Silva Emery
• Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated grant(s): 18/08398-7 - Next generation inhibitors of switch region RNA polymerase, AP.R SPRINT

Abstract

This proposal describes the strategies for the synthesis and chemical reactivity studies of heterocycles aiming at the development of a small library of structurally innovative fragments. Furthermore, the proposal approaches fragment-based drug discovery studies toward epigenetic inhibitors. Pyrazole-pyridone, pyrido-pyridone and pyrido-pyridazone will be deeply studied in terms of synthesis and functionalization, in order to expand the heterocyclic chemical espace. Saturated synthetic intermediates will also be studied. The project involves new efficient synthetic methodologies for the heterocycles under study, as well as the study of chemical reactivity of these compounds, targeting regioselectivity and diverse types of functionalization. This part of the project is fundamental for studies of drug discovery based on fragments, since it predicts the usefulness of these heterocycles as a starting point for the development of structurally more complex compounds according to the vectorial functionalization. The second part of the project involves the application of drug-discovery studies based on fragments, aimed at the discovery of inhibitors of the enzyme histone deacetylase 6 (HDAC6), an enzyme that plays an important role in the progression of cancer. The project will have as its starting point a fragment of the aromatic sulfonamide type, recently characterized as a hit for inhibition of HDAC6. From this fragment, a series of compounds was planned and selected, via molecular docking, as potential inhibitors. In this proposal the strategic development of this series of fragments is described, aiming the beginning of the studies of FBDD for HDAC6. Thus, in general, this proposal intends to study the usefulness of structural fragments as a starting point for the development of a library of compounds for medicinal chemistry studies. (AU)

Scientific publications

(9)

(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)

VAIDERGORN, MIGUEL M.; EMERY, FLAVIO DA SILVA; GANESAN, A. From Hit Seeking to Magic Bullets: The Successful Union of Epigenetic and Fragment Based Drug Discovery (EPIDD plus FBDD). Journal of Medicinal Chemistry, v. 64, n. 19, p. 13980-14010, OCT 14 2021. Web of Science Citations: 0.

SILVA, DANIEL G.; FEIJENS, PIM-BART; HENDRICKX, RIK; MATHEEUSSEN, AN; GREY, LUCIE; CALJON, GUY; MAES, LOUIS; EMERY, FLAVIO S.; JUNKER, ANNA. Development of Novel Isoindolone-Based Compounds against Trypanosoma brucei rhodesiense. CHEMISTRYOPEN, v. 10, n. 9, p. 922-927, SEP 2021. Web of Science Citations: 1.

SILVA, DANIEL G.; JUNKER, ANNA; DE MELO, SHAIANI M. G.; FUMAGALLI, FERNANDO; GILLESPIE, J. ROBERT; MOLASKY, NORA; BUCKNER, FREDERICK S.; MATHEEUSSEN, AN; CALJON, GUY; MAES, LOUIS; EMERY, FLAVIO S. Synthesis and Structure-Activity Relationships of Imidazopyridine/Pyrimidine- and Furopyridine-Based Anti-infective Agents against Trypanosomiases. CHEMMEDCHEM, v. 16, n. 6 NOV 2020. Web of Science Citations: 0.

GIL DE MELO, SHAIANI MARIA; DIAS DE REZENDE, LUCAS CUNHA; PETRILLI, RAQUEL; VIANNA LOPEZ, RENATA FONSECA; GOULART, MARILIA O. F.; EMERY, FLAVIO DA SILVA. Nitrosation of BODIPY dyes and their applications in the development of thiol sensors. DYES AND PIGMENTS, v. 173, FEB 2020. Web of Science Citations: 1.

FUMAGALLI, FERNANDO; GIL DE MELO, SHAIANI MARIA; RIBEIRO, CAMILA MARINGOLO; SOLCIA, MARIANA CRISTINA; PAVAN, FERNANDO ROGERIO; EMERY, FLAVIO DA SILVA. Exploiting the furo [2,3-b]pyridine core against multidrug-resistant Mycobacterium tuberculosis. Bioorganic & Medicinal Chemistry Letters, v. 29, n. 8, p. 974-977, APR 15 2019. Web of Science Citations: 0.

CALIL, FELIPE A.; DAVID, JULIANA S.; CHIAPPETTA, ESTELA R. C.; FUMAGALLI, FERNANDO; MELLO, RODRIGO B.; LEITE, FRANCO H. A.; CASTILHO, MARCELO S.; EMERY, FLAVIO S.; CRISTINA NONATO, M. Ligand-based design, synthesis and biochemical evaluation of potent and selective inhibitors of Schistosoma mansoni dihydroorotate dehydrogenase. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, v. 167, p. 357-366, APR 1 2019. Web of Science Citations: 0.

DA SILVA JUNIOR, PAULO ELIANDRO; AMIN, HAWRAZ I. M.; NAUTH, ALEXANDER M.; EMERY, FLAVIO DA SILVA; PROTTI, STEFANO; OPATZ, TILL. Flow Photochemistry of Azosulfones: Application of ``Sunflow{''} Reactors. CHEMPHOTOCHEM, v. 2, n. 10, SI, p. 878-883, OCT 2018. Web of Science Citations: 8.

FREIRE FRANCO, MARCIA SILVANA; DE PAULA, MURILO HELDER; GLOWACKA, PAULINA CECYLIA; FUMAGALLI, FERNANDO; CLOSOSKI, GIULIANO CESAR; EMERY, FLAVIO DA SILVA. Palladium-catalyzed C-H alkenylation of quinoxaline N-oxide enabled by a mono-N-protected amino acid. Tetrahedron Letters, v. 59, n. 26, p. 2562-2566, JUN 27 2018. Web of Science Citations: 1.

SILVA, DANIEL GEDDER; EMERY, FLAVIO DA SILVA. Strategies towards expansion of chemical space of natural product-based compounds to enable drug discovery. Brazilian Journal of Pharmaceutical Sciences, v. 54, n. SI 2018. Web of Science Citations: 1.