Synthesis, characterization and evaluation of the in vitro activity of benzofuroxan derivatives against Mycobacterium tuberculosis.

• Grant number: 23/13946-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2024
• End date: December 31, 2024
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Rafaela Melo Pogianeli
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Tuberculosis (TB), triggered by the aerobic, acid-alcohol resistant bacillus Mycobacterium tuberculosis (Mtb), stands as one of the leading causes of death worldwide due to a single infectious agent. In the face of antibiotic resistance in the treatment of the disease, Medicinal Pharmaceutical Chemistry is dedicated to the development of new drugs. The compound BZ8, a benzofuroxane derivative developed by our research group, has shown highly promising in vitro and in vivo results against the bacillus. The known mechanism of action is attributed to the compound's interaction with the mycobacterial ribosome, inhibiting the initiation of the translation process and consequently interfering with the synthesis of mycobacterial proteins. Considering these background details, the current project aims at the synthesis, characterization, and evaluation of the in vitro anti-Mycobacterium tuberculosis activity of four new derivativesof BZ8, obtained through bioisosterism. The synthesis aims to reduce the instability of the N-acylhydrazone function in acidic conditions exhibited by the initial compound. Microbiological experiments, on the other hand, will determine the potency, toxicity, and the compound's action inside macrophages by determining the Minimum Inhibitory Concentration against H37Rv and two clinical isolates (CF110 and CF169), assessing cytotoxicity against lung fibroblasts, macrophages, and intramacrophagic analysis, respectively. The results will contribute to the design of new studies and the discovery of a new effective and safe drug for patients.