Application of novel organic reactions for the preparation of new heteroaromatic s...
| Grant number: | 17/21146-4 |
| Support type: | Regular Research Grants |
| Duration: | February 01, 2018 - January 31, 2020 |
| Field of knowledge: | Health Sciences - Pharmacy |
| Principal Investigator: | 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)