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Synthesis and evaluation of 4-Hydroxyderricini (4-HD) and its analogs as potential agents against tuberculosis

Grant number: 19/11979-4
Support type:Scholarships in Brazil - Master
Effective date (Start): October 01, 2019
Effective date (End): February 28, 2021
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Luis Octávio Regasini
Grantee:Reinaldo dos Santos Theodoro
Home Institution: Instituto de Biociências, Letras e Ciências Exatas (IBILCE). Universidade Estadual Paulista (UNESP). Campus de São José do Rio Preto. São José do Rio Preto , SP, Brazil


Tuberculostatics are crucial drugs to for life expectancy, mainly to HIV-positive patients. Several reasons justify the need for new antimycobacterial, including high morbilitiy and mortality related to tuberculosis. The resurgence of multidrug resistant (MDR-TB) and extensively drug resistant (XDR-TB), typical morphophysiological features of Mycobacterium tuberculosis, as well as phenotypical forms (active and latent), also are challenge to discovery of tuberculostatics. Thus, efforts are necessary to discover and develop tuberculostatic with innovative structural and mechanistic patterns. The current project aims the synthesis and biological evaluation of 4-hydroxyderricin (4-HD), an antibacterial C-isoprenylated chalcone with unexplored tuberculostatic activity. Three series of analogs of IBC will be synthesized. Series I, II and III will exhibit modifications on chalconic ring A, ring B and alpha,beta-unsaturated ketone, respectively. The synthetical strategy will include iodation and Suzuki coupling reactions, allowing C-prenylation at carbon C-3' (ring A). The antimycobacterial potency will be determined against sensitive H37Rv and clinical isolates (MDR-TB and XDR-TB) strains., indicating Minimum Inhibitory Concentration (MIC) values. The n-octanol/water partition coefficient (log Po/w) will be performed by HPLC-DAD experiment, aiming to relate hydrophobicity and antimycobacterial activity of chalcones. The values of log Po/w and melting points of chalcones will be used in the prection of water-solubility (log S), by using of General Solubility Equation. Antimycobacterial compounds (MIC H37Rv < 10 uM) will be submitted to toxicity evaluations against eukaryotic cells, including murine macrophages (J774A.1), human fibroblasts (MRC-5) and human hepatocytes HepG2), stablishing selective index (IS - IC50 eukaryote/MIC H37Rv). Chalcones that exhibited SI (macrophage) > 10 will be selected to evaluation against intramacrophagic forms of Erdman M. tuberculosis. (AU)