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

• Grant number: 23/16045-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: April 12, 2024
• End date: March 30, 2025
• Field of knowledge: Health Sciences - Pharmacy - Pharmaceutical Technology
• Principal Investigator: Fernando Rogério Pavan
• Grantee: Giulia Polinário
• Supervisor: Sergio Enrique Moya
• Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Institution abroad: Centre for Cooperative Research in Biomaterials (CIC biomaGUNE), Spain
• Associated to the scholarship: 22/03511-5 - 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, BP.DR

Abstract

Tuberculosis (TB) has as its main etiological agent the bacillus Mycobacterium tuberculosis and, until the Covid-19 pandemic, it was the leading cause of death from a single infectious agent for many years, surpassing HIV/AIDS. In the best scenario, the bacillus can be combated with a 6-month treatment regimen, but in cases of resistance, treatment can last up to 2 years. The abandonment of the therapy due to high rates of systemic adverse effects is one of the main reasons for the lack of efficacy of the treatment. The main goal of our develop a formulation capable of being delivered via the intrapulmonary route, for local action with a high contact surface and avoiding systemic absorption and its adverse effects. The compound 1-[1-(4-chlorophenyl)-2,5-dimethyl-pyrrol-3-yl]-N-(cyclohexylmethyl) methanamine, a derivative of N-phenyl-2,5-dimethylpyrrole with modification at the C3 position of the pyrrole ring, synthesized in a previous work by our group, has already demonstrated bacteriostatic and intracellular activity against M. tuberculosis at concentrations similar to isoniazid and moxifloxacin, as well as inhibitory activity against MDR strains. It also presents low toxicity both in vitro and in vivo in a larval model of Galleria mellonella. The compound is considered a promising candidate for the development of a new therapy for tuberculosis with no mutagenic potential and a low rate of resistance mutations. However, its low aqueous solubility makes its administration difficult. We will encapsulate the compound in different carriers: poly lactic co glycolic (PLGA) nanoparticles, cyclodextrin sponges, and assemblies of cyclodextrin sponges and PLGA nanoparticles, we will characterize the nanoparticles and formulations with the methanamine compound by a battery of techniques (Transmission electron microscopy, dynamic light scattering, zeta potential, HPLC, UV, etc); we will evaluate the in vitro activity of the nanoformulations and we will perform in vivo biodistribution studies by Positron Emission Tomography to assess carriers' fate following inhalation.