Banca de QUALIFICAÇÃO: SINDY VANESA ACOSTA RODEZNO
Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.STUDENT : SINDY VANESA ACOSTA RODEZNO
DATE: 19/12/2022
TIME: 14:00
LOCAL: Exame remoto através da plataforma Google Meet em https://Meet.google.com/swk-zmwj-arr
TITLE:
Antimicrobials, antivirals, covid-19, organoselenides, organotellurides, and chalcogen compounds.
PAGES: 35
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUMMARY:
The medicinal chemistry of organochalcogen compounds is related to the biological role of selenium in living organisms. Selenium in the amino acid selenocysteine is incorporated into various enzymes with assorted functions, and Glutathione peroxidase is the most prominent of them. Organoselenium and organotellurium compounds can mimic the antioxidant activity of that selenoenzyme to reduce Reactive Oxygen Species (ROS). This reactivity is observed when the chalcogen is in the divalent form, with the +2 oxidation state. That bioactivity increased the interest in this class of compounds as reflected in the diversity of molecules studied and reported in the literature in the last decades of the past century.
The bioactivity in their hypervalent state, the +4 oxidation state, has been explored most recently. In this form, they can react against nucleophiles and act as inhibitors of enzymes dependent on endogenous thiols, i.e., cysteine proteases. These enzymes are recognized therapeutic targets in pathogens such as viruses, protozoa, and parasites responsible for many infectious diseases. The design, synthesis, and antimicrobial evaluation of new organoselenium and organotellurium molecules are the main focus of the present work.
Our research group has been working with the synthesis of cysteine protease inhibitors, finding some promising molecules for chemotherapy. Therefore, studying an expanded structural diversity can lead us to potential inhibitors, offering new approaches for chemotherapy, such as Neglected Tropical Diseases (NTDs) — a class of diseases of particular interest to our group.
The current project is divided into three phases: (I) synthesis and characterization, (II) biological evaluation, and (III) structural modifications to improve bioactivity. Firstly, we synthesize selenides and tellurides by functionalizing benzaldehydes that have been synthesized with organochalcogenyl groups (selenium and tellurium) and boronic acids. Subsequently, the formyl group in ortho and para positions is functionalized into amines, amides, sulfonamides, oximes, benzyl alcohols, and drug-like molecules. Later, the hypervalent derivatives, selenuranes, and telluranes were obtained by oxidation reactions of previous selenides and tellurides with hydrogen peroxide or sulfuryl chloride to give oxides or dichlorides, respectively.
Secondly, the evaluation of biological activity as antimicrobials or antivirals. On the primary screening, four tellurium-containing molecules, SV09, SV13, SV15, and SV17, were active against Gram-negative bacteria, i.e., E. coli. All four compounds, designed as hits, confirmed activity in dose-response assays to determine the Minimum Inhibitory Concentration (MIC). Noteworthy in those assays, the selenium-containing compounds were inactive. Even more interesting, the active compounds showed better inhibition values against Multidrug-resistant (MDR) strains with modified membrane proteins of those bacteria. They were also assessed as antifungals showing moderate to good activity against C. neoformans (SV17) and C. albicans (SV09).
Lastly, as part of academic contribution related to the COVID-19 Pandemic, compounds were evaluated in a high throughput screening to identify coronavirus antiviral agents. Since the main proteases of SARS-CoV-2 belong to the cysteine proteases family and selenides, tellurides and telluranes have been demonstrated to be inhibitors of this enzyme, and we suggest the evaluation of our synthesized compounds. Among them, amines SV12 (Se) and SV13 (Te) were identified with potential antiviral activity and moderate toxicity to Huh-7 cells collected from infected patients. They were also assessed against the Chikungunya virus in a two steps workflow. In the initial screening, organoselenides SV10, SV11, SV12, and organotelluride SV16 were active and tested in a dose-response test. In this confirmatory assay, only SV11 showed potential activity. Those results lead to the study and design of structural modifications to enhance any presented biological activity.
At present, characterization of the ortho- and para-substituted hypervalent compounds from the complete collection is underway. The reaction conditions study to obtain propargyl amines by multicomponent reactions A3 is also ongoing. The molecules are dispatched to in vitro SARS-CoV-2 and Chikungunya antiviral assays as soon as they are characterized.
COMMITTEE MEMBERS:
Presidente - Interno ao Programa - 1623562 - RODRIGO LUIZ OLIVEIRA RODRIGUES CUNHA
Membro Titular - Examinador(a) Externo à Instituição - SUMBAL SABA - UFG
Membro Titular - Examinador(a) Externo à Instituição - THAYSA PASCHOALIN - UNIFESP
Membro Suplente - Examinador(a) Externo à Instituição - MARCOS LEONI GAZARINI DUTRA - UNIFESP