Novos complexos metálicos com derivados do ácido antranílico e cicloserina: síntese, caracterização e avaliação de suas atividades biológicas

Author(s)

Carlos Marrote Manzano

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
• Defense date: 2022-02-21

Examining board members

Pedro Paulo Corbi; Paulo Cesar de Sousa Filho; Wdeson Pereira Barros; Flávia Aparecida Resende Nogueira; Alexandre Cuin

• Advisor: Pedro Paulo Corbi

Abstract

Tuberculosis is a disease caused by the pathogen Mycobacterium tuberculosis. It is one of the infectious diseases that most kills worldwide and the emerging bacterial resistance to the most diverse antibiotics makes it an urgent global health problem. One strategy to overcome this challenge is the development of new metal complexes with antibacterial activity, as metal ions have the potential to effectively affect several molecular targets inside the bacterial cell. For this purpose, fluoroanthranilic acid isomers were selected as ligands due to their activity against resistant and biofilm-forming M. tuberculosis. Four complexes identified as Ag4fa, Ag5fa, Ag6fa and Ag4,5fa were characterized by elemental and thermogravimetric analysis, mass spectrometry (MS), infrared (IR) and 1H, 13C and {15N,1H} nuclear magnetic resonance (NMR) spectroscopy, which revealed a 1:1 metal:ligand ratio and coordination by the nitrogen atoms of the amine moiety and oxygen atoms of the carboxylate group. The crystal structure of the Ag5fa complex was determined by single crystal X-ray diffraction (XRD) confirming the proposed structure and revealing a polymeric structure for this complex. Significant in vitro activity of Ag4fa, Ag5fa and Ag6fa complexes was observed against M. tuberculosis (MIC90 between 2.6 and 4.2 ?g/mL), while the activity was lower against other Gram-positive and Gram-negative bacteria. In addition, the complexes also exhibited in vitro cytotoxicity against several tumor cells, especially colorectal epithelial adenocarcinoma (IC50 = 2.1 ?g/mL and SI >3) and were not mutagenic according to Ames test. Fluoroanthranilic ligands were also object of theoretical study by density functional theory (DFT) by comparing the calculated data with their spectroscopic properties of fluorescence, and also by molecular docking in order to predict distinct interactions of each fluoroanthranilic isomer with target proteins of the tryptophan biosynthesis pathway in M. tuberculosis bacteria. Furthermore, a series of Cu(II) complexes with 6fa and auxiliary ligands (bipyridine, phenanthroline and 4,4’-dimethylbipyridine) and one complex of Pd(II) with the antimycobacterial drug cycloserine were also synthesized. Although the biological activity of these complexes has not yet been evaluated, their characteriza (AU)

• FAPESP's process: 17/25995-6 - New Ag(I), Pd(II) and Pt(II) metal complexes with ligands used for the treatment of Tuberculosis: synthesis and in vitro evaluation of antimicrobial and antiproliferative activities
• Grantee: Carlos Marrote Manzano
• Support Opportunities: Scholarships in Brazil - Doctorate