Inibição da urease como ferramenta medicinal e agrícola: a influência de átomos de selênio e boro na atividade antiureolítica de inibidores de urease conhecidos

Abstract

The enzyme urease, a metalloprotein that catalyzes the hydrolysis of urea into ammonia and carbon dioxide, plays a crucial role in various biological and pathological processes. Its activity is essential in organisms that use urea as a nitrogen source. It is also associated with numerous human health issues, including infections caused by fungi and bacteria, and agricultural concerns, such as the environmental impact of ammonia release in soil. Therefore, developing effective urease inhibitors is of great interest in medicine and agriculture. This work is divided into three chapters and presents the synthesis and evaluation of the anti-ureolytic potential of three classes of molecules: selenium-derived Biginelli adducts, Biginelli adducts derived from formylphenylboronic acids, and benzoylselenoureas. Selenium-derived Biginelli adducts were identified as potent inhibitors of plant urease (C. ensiformis). The most active compounds displayed CI50 values between 30 and 50 μM, showing greater activity than their urea—and thiourea-derived analogs. Kinetic studies of the most active derivatives were conducted to define the most potent inhibitors' inhibition mechanisms and kinetic parameters. The synthesis of Biginelli adducts derived from formylphenylboronic acids was optimized for nuclei containing urea and thiourea moieties. Enzymatic assays with urease (C. ensiformis) allowed the determination of CI50 (132 μM) and revealed that this compound acts through a mixed inhibition mechanism. Additionally, biophysical studies showed how the most active derivative interacts with the urease active site through the hydroxyl groups of the boronic acid. Finally, the synthesis of benzoylselenoureas was optimized, and these compounds and their sulfur analogs, benzoylthioureas, were evaluated for their anti-ureolytic potential against fungal urease C. neoformans. In vitro activity of these compounds showed that the selenium compounds possess greater antifungal activity (minimum inhibitory concentration - MIC and minimum fungicidal concentration - MFC values ranging from 1 to 16 mg/L) compared to their sulfur counterparts (MIC and MFC values ranging from 8 to 128 mg/L). Furthermore, benzoylselenoureas were tested on urease from the crude protein extract of C. neoformans, where ureCI50 values ranging between 0.95 and 13.95 nM were observed. The results of this research significantly contribute to the field of medicinal chemistry, providing new tools for the potential treatment of fungal infections and mitigation of environmental issues related to urease activity.