Synthesis and evaluation of BacPROTACs designed as anti-Mycobacterium tuberculosis agents

• Grant number: 22/15844-9
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: March 01, 2023
• End date: August 29, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Jean Leandro dos Santos
• Grantee: Andressa Francielli Bonjorno
• Supervisor: Daniele Castagnolo
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: University College London (UCL), England
• Associated to the scholarship: 21/14973-7 - Synthesis and evaluation of new nitroimidazooxazine derivatives designed to act against drug-resistant Mycobacterium tuberculosis, BP.MS

Abstract

The rising number of tuberculosis (TB) cases and the emergence of resistant strains particularly multidrug-resistant TB [MDR-TB] and extensively drug-resistant TB (XDR-TB) have been motivated the search for new safe and effective drugs. Nitroreductases comprises enzymes responsible for defending Mtb's against exogenous small molecules contributing to the antinitrosative defenses on which Mtb relies by detoxifying chemicals encountered in the host. Such enzyme is involved in the anaerobic metabolism for non-replicant (dormant) bacilli within hypoxic conditions and it has been explored as target by drugs that includes pretomanide and delamanide. Approaches to promote nitroreductase degradation using Bac-PROTAC was not investigated. We hypothesized that the degradation of nitroreductase through BacPROTAC approach could dismantle its adaptive condition under hypoxic environment leading to the Mtb death, even under dormant/latent conditions, and it could be useful to treat MDR-TB and XDR-TB. In this project we aim to synthesize and characterize new BacPROTAC compounds. In addition, we aim to evaluate the anti-Mycobacterium tuberculosis effects against H37Rv and resistant clinical isolates. We expect to discovery the meaning of nitroreductase degradation using such compounds in order to explore new therapeutic approaches to mitigate TB in the future according to goals established by World Health Organization. (AU)