Banca de DEFESA: HENRIQUE JEFFERSON DE ARRUDA

SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF ZnII AND AgI COMPLEXES DESIGNED AS PROTOTYPES FOR THE CHEMOTHERAPIC TREATMENT OF INFECTIONS USING HYBRID LIGANDS

zinc complexes, coumarin hybrids, anti-cruzi activity, antiviral activity

Neglected diseases are diseases caused by infectious agents and/or parasites and are considered endemic in low-income populations. These diseases have unacceptable indicators and reduced investments in research, drug production and their control, because of this, it is necessary to search for new drugs that cause better treatment for patients, in addition to being less toxic. Among the neglected diseases that will be addressed in this work are Chagas disease, Zika and Chikungunya, diseases with few or no drugs available. Within the context of medicinal chemistry, coordination compounds gained prominence due to their biological applications, for example, the treatment of cancer and arthritis, antimicrobial agents and enzyme inhibitors. Structural knowledge and understanding of the mechanisms of pharmacological action of these compounds are of fundamental importance in the development of new, more efficient and safer drugs for the human body. Coumarin and quinolone derivatives and various metal complexes have been studied for their potential as agents against neglected diseases. Thus, coumarin-imidazopyridine hybrid linkers of the ethyl 2-(R)-2-oxo-2H-chromen-3-yl)imidazo[1,2-a]pyridine-3-carboxylate (R = 7-Et2N) (HL1), 7-OCH3 (HL2), 8-OCH3 (HL3) and 6-CH3 (HL4)) and 2-(R)-2-oxo-2H-chromen-3-yl)imidazo[1,2- a]pyridine (R = 7-OCH3 (HL5), 8-OCH3 (HL6)) plus four quinolone-derived linkers of the 3-carboethoxy-4-oxo-1,4-dihydroquinoline type (R = 6-H (HL7 ), (6-F (HL8), (6-Cl (HL9) and (6-Br (HL10)) were synthesized. Reactions between ligands (HL1-HL6) and zinc chloride resulted in neutral complexes of the type [ZnCl₂(HL1-6)2](C1-C6), and reactions between HL1-HL3 ligands with AgNO₃ resulted in charged complexes [Ag(HL1-3)₂]NO₃ (C1Ag-C3Ag). Syntheses involving Zn(NO₃)₂, phenanthroline and the quinolone-derived ligands (HL7-HL10) resulted in the charged complexes [Zn(phen)(HL7-10)]NO₃ (C7-C10). The crystal structures of the C2 complexes [ZnCl₂(HL₂)₂] and C3 [ZnCl₂(HL₃)₂] were determined by single crystal X-ray diffraction (XRD), which reveals showed the coordination of two ligands through the nitrogen of the imidazopyridine group, with two chlorines completing the metal coordination sphere and thus exhibiting a distorted tetrahedral geometry. In this work, the anti-cruzi, anti-zika and anti-chikungunya evaluation of four pairs of ligands (HL1-HL4) and complexes (C1-C4) was carried out. The anti-t.cruzi evaluation showed that, initially, the C4 complex was the most active molecule, having twice the activity of its corresponding ligand HL4 (12.4 and 22.8 µM), indicating that coordination can be be favoring the biological activity and even helping to make the ligand bioavailable in the biological environment. Furthermore, the antiviral evaluation of the ligands (HL1-HL4) and respective complexes (C1-C4) against Chikungunya (CHIKV) and Zika (ZIKV) showed that, in general, all compounds exhibited excellent antiviral activity, with highlight for the C2-C4 complexes, which were more active for ZIKV than their parent ligands (IC50 C2-C4 = 0.8 µM, IC50 HL2-HL4 between 1.2 and 4.8 µM) and about 4x more active than the Ribavirin control (IC50 = 3.95 mM). Against CHIKV, the HL3 ligand stood out, which exhibited higher activity than the control and very low cytotoxicity (IC50 = 0.67 µM and CC50 = 910 µM vs IC50 Ribavirin = 2.42 uM and CC50 = 297 µM ), resulting in excellent selectivity index (SI). Unlike what was observed for ZIKV, the activity of the ligands did not increase with complexation when it comes to CHIKV, however, all compounds are eligible to have their mechanisms of action studied, which is in progress.