Preparation and Biological Evaluation of Dehydrozingerone Derivatives as Potential Agents agianst Tuberculosis

• Grant number: 17/08383-7
• Support Opportunities: Scholarships in Brazil - Master
• Start date: August 01, 2017
• End date: February 28, 2019
• Field of knowledge: Health Sciences - Pharmacy
• Agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Luis Octávio Regasini
• Grantee: Gabriela Miranda Ayusso
• Host 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

Abstract

Tuberculostatics are crucial drugs for maintaining life expectancy, mainly for HIV-positive patients. Numerous reasons justify the requirement for novel antimycobacterial agents, including the high resistance rates of Mycobacterium tuberculosis and rates of morbidity and mortality related to tuberculosis. Thus, efforts are need to discover and develop innovative tuberculostatics, which must act against resistant strains, including MDR and XDR. Dehydrozingerone (DZG) is a ginger compound and exhibits several biological activities. In the previous study developed by the candidate, carried out with the support of two Fapesp projects (2014/18719-4 and 2016/07108-0), two DZG derivatives presented activity against M. tuberculosis H37Rv. In the current project, we proposed the synthesis of a series of analogues containing vanilyl subunit (ring A) and ring B substituted by hydrophobic and electron accepting atoms and groups. These compounds will be prepared by a method previously established by the candidate. These experiments uses aldol condensation reactions. Hydrophobicity of DZG derivatives will be determined by octanol/water partition coefficient values (log Po/w), which will be obtained on HPLC. The antimycobacterial activity will be evaluated using susceptible M. tuberculosis H37Rv, as well as clinical isolates strains [susceptible (CF73) and resistant to isoniazid and rifampicin (CF81 and CF104)]. Derivatives with a concentration value capable to inhibit 90% mycobacterial growth (MIC90) equal or below than 12,5 ¼g mL-1 will have their toxicity evaluated against eukaryotic cells, including murine macrophages (J774A.1) and human pneumocytes (MRC-5). The selectivity index (SI) of the substances will be calculated from the concentration values capable of promoting the death of the macrophages or the pneumocytes (IC50) and CIM90, therefore IS = IC50 (eukaryote)/CIM90 (H37Rv). Substances with IS values equal or above than 10 will be submitted to M. tuberculosis Erdman intracellular inhibition assays. In addition, compounds demonstrate activity against resistant clinical isolates will be investigated their inhibitory effect against efflux pump using Mycobacterium smegmatis, as a model of reduced biological risk. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

AYUSSO, Gabriela Miranda. Synthesis and evaluation of monocarbonyl analogues of curcumin as potential agents against tuberculosis. 2019. Master's Dissertation - Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto São José do Rio Preto.