Banca de DEFESA: ARI SOUZA GUIMARAES

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : ARI SOUZA GUIMARAES
DATE: 31/01/2024
TIME: 09:00
LOCAL: Sala de reuniões do IQB
TITLE:

Exploitation the biological profile of -C=N- compounds: antioxidant, antiproliferative, photoprotective, anti-tyrosinase and anti-ureolytic studies

KEY WORDS:

 

Aminoguanidine hydrazones, pyrazoles hybrids, Schiff base, amines, antiproliferative activity, Urease, Tyrosinase, Factor sun protection, Antioxidants.

PAGES: 120
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUMMARY:

The investigation of different functionalities in small molecules has great contributions in chemistry
medicine, being one of the most important approaches for the treatment of various diseases and
new product developments. In this line, the pharmacophoric fraction -C=N- stands out, which when
linked to other groups or molecules, can lead to different biological activities, including
antioxidant, antimalarial, antitumor, antibacterial, antiviral, antifungal, among others. In this regard,
considering the importance of bioactive molecules with such potential, this work aimed to carry out a
synthetic exploration and applications of three classes of compounds that have this pharmacophoric moiety.
Initially, four aminoguanidine hydrazone derivatives with different nuclei were evaluated.
aromatics. Of the compounds evaluated, AGH-3 with the indole nucleus showed the greatest capacity
antioxidant with results comparable to those of Trolox compared to traditional DPPH radical methods•,
ABTS•+, FRAP and sequestration of the radical •NO. Furthermore, AGH-3 showed the highest activity of
antiproliferative against human kidney cancer cells (786-0) with IC50 = 6.56 M. Additionally,
in biophysical studies, the compound interacted with ctDNA (biological target model) forming a
fluorescent supramolecular complex with a binding constant of 2.89×103 M-1 and acting as a ligand
interleaving. Thus, these compounds show the potential of aminoguanidine hydrazones as a class  strategy of compounds to act on biological multitargets. Subsequently, considering the importance of new urease enzyme inhibitors, the inhibitory profile of a class of hybrid pyrazoles with thiosemicarbazides (Fig. A). Derivative 312 showed the highest activity (IC50 = 24.72±1.09), being superior to the Thiourea standard (p ≤ 0.05, Tukey test). Furthermore, 312 presented a type of competitive inhibition with Km = 0.015 (± 0.009) mM and Vmax = 0.690 (±0.098) µmol NH4+ min−1 mg−1 of protein. The interaction of 312 with urease led to the formation of a non-fluorescent supramolecular complex (Fig. D) with a Ksv = 1.93(±0.07) x104, Kb = 5.98(±0.01) x102 M and n = 0.66 (±0.03). The formation of the complex was proven by UV-vis, where at the same concentration, Acomplex – A307 ≠ Aurease. Furthermore, Kq = 1.94x1012 M s−1 indicating that the dominant quenching in the supramolecular system is static. At FRET E = 43 % R0 = 1.97 nm and r0 = 2.15 nm, indicating a high efficiency in energy transfer between species. 3D fluorescence indicated changes in the native structure of urease, mainly in the microenvironment close to Trp residues and Tyr. Finally, in molecular docking, 312 showed a higher affinity to the active site (fitScore = 61.9) of urease, corroborating the experimental data. Finally, the synthesis, characterization and application were carried out of compounds analogous to resveratrol and hybrids with lipoic acid, using Schiff bases and their

corresponding amines as model structures. Thus, the 22 compounds were obtained with yields of
which ranged from 49 to 98% yields, which were characterized by 1H, 13C, Noesy and FTIR NMR. Like this,
for the results of in vitro inhibition of the tyrosinase enzyme, the compound ESS02 showed an activity 

higher than the kojic acid standard. As for the FPS-UVB results, the imine derivatives showed a
FPS similar to the BZF-3 standard (p < 0.05 for the Tukey test), with ASG51 having the highest FPS (23.4±1.0),
which complies with ANVISA and FDA standards. For antioxidant assays, compounds
showed a capacity comparable to the standards Trolox, caffeic acid, ferrulic acid and resveratrol
for traditional methods of inhibiting the radical DPPH•, ABTS•+, FRAP and Piacetannal for the method
CUPRAC (p < 0.05 for the Tukey test), however, the compounds were not active for the
Fe(II) complexation method. Furthermore, ADMET in silico studies demonstrated that compounds
have low skin permeability (Kp), in addition to corroborating antioxidant studies,
demonstrating a greater hydrophilic character of the evaluated compounds. Furthermore, theoretical calculations of
molecular docking, demonstrated a preference for compounds to interact with the enzyme carried out
hydrophobic interactions. Finally, these results highlight the bioactive potential of the evaluated compounds
capable of being explored in subsequent studies.

COMMITTEE MEMBERS:
Externo(a) à Instituição - FERNANDA ANDREIA ROSA - UEMG
Interno(a) - 2089941 - DIMAS JOSE DA PAZ LIMA
Interno(a) - 3182336 - EDEILDO FERREIRA DA SILVA JUNIOR
Presidente - 1820117 - ISIS MARTINS FIGUEIREDO
Externo(a) à Instituição - LUZIA VALENTINA MODOLO - UFMG
Interno(a) - 2120103 - MARILIA OLIVEIRA FONSECA GOULART