Evaluation of the in vivo therapeutic effect, mutagenicity and search for the mechanism of action of the compound 1-[1-(4-chlorophenyl)-2,5-dimethyl-pyrrole-3-yl]-N-(cyclohexylmethyl) methanamine, a derivative of N-phenyl-2,5-dimethylpyrrole

• Grant number: 22/03511-5
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2023
• End date: July 19, 2026
• Field of knowledge: Biological Sciences - Microbiology - Applied Microbiology
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Giulia Polinário
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Associated scholarship(s): 23/16045-5 - Development and characterization of microcarriers for pulmonary administration of 1-[1-(4-chlorophenyl)-2,5-dimethyl-pyrrol-3-yl]-N-(cyclohexylmethyl)methanamine against Mycobacterium tuberculosis, BE.EP.DR

Abstract

Tuberculosis (TB) has the bacillus Mycobacterium tuberculosis as its main etiological agent and, until the Covid-19 pandemic, led for several years the cause of death by a single infectious agent, surpassing HIV/AIDS. At best, the bacillus can be fought with a treatment regimen lasting 6 months, but in cases of resistance, treatment can take up to 2 years, with no guarantee of success. The compound 1-[1-(4-chlorophenyl)-2,5-dimethyl-pyrrol-3-yl]-N-(cyclohexylmethyl)methanamine, a C3-modified N-phenyl-2,5-dimethylpyrrole derivative of the pyrrole ring, in a previous work by our group, has already demonstrated promising extra and intracellular activity against M. tuberculosis at concentrations similar to isoniazid and moxifloxacin, as well as inhibitory activity of an MDR strain. It also has low toxicity both in vitro and in vivo in a larval model of Galleria mellonella. The compound is considered a promising candidate in the development of a new therapy for tuberculosis and computational studies already indicate that a mycolic acid transporter may be its target for its mechanism of action, as well as that of its precursors SQ109 and BM212, two antibiotics already used in the tuberculosis treatment. In this project, through a collaboration with the King's College of London, we aim to direct the experiments in order to expand the studies of activity in resistant strains, deepen the knowledge of toxicogenicity and absorption, in addition to evaluating the therapeutic effect in vivo in BALB/c mice, and understand the mechanism of action through complete genome sequencing (SGC) of naturally resistant mutants. (AU)