BR-102024017758-A2 - Pyridyl-thiazolidinone derivative JC-21A with fungicidal activity against Candida auris and dermal toxicity in rats.

Abstract

The present invention relates to the JC-21A molecule active against the fungus Candida auris. More specifically, the molecule of the present invention relates to a pyridyl-thiazolidinone derivative JC-21A - (E)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidine-4-one useful in the decolonization or treatment of infection caused by the fungus C. auris and applied in the following technical sectors: chemical processes and compounds, pharmaceuticals and therapies. Tests in in vitro experimental models showed a significant reduction in the fungus. Based on the results of the dermal toxicity study of the compound (E)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidine-4-one in rats, it was observed that the compound did not induce significant adverse effects during the toxicity test, presenting a classification in category 5 of OECD 402, indicating low potential for acute and subacute toxicity of the compound. From the experiments performed, it was evidenced that this compound can be considered safe for topical application. The results from the in vitro and in vivo experimental models place the pyridyl-thiazolidinone derivative as a candidate for a new agent for the treatment of infection caused by C. auris.

Inventors

• ANA CRISTINA LIMA LEITE
• REGINALDO GONÇALVES DE LIMA NETO
• RICARDO BRANDÃO
• ANDRÉ DE LIMA AIRES
• RAQUEL FEITOSA DE ALBUQUERQUE
• JULIANA MARIA DA CONCEIÇÃO
• BRUNA RODRIGUES DE SOUSA
• LUIZ ALBERTO BARROS
• ANA CAROLINA LOPES CERQUEIRA

Assignees

• UNIVERSIDADE FEDERAL DE PERNAMBUCO

Dates

Publication Date

20260310

Application Date

20240829

Claims (5)

1. 1. PYRIDIL-THIAZOLIDINONE DERIVATIVE JC-21A WITH FUNGICIDAL ACTIVITY AGAINST CANDIDA AURIS AND DERMAL TOXICITY IN RATS, characterized by containing the synthesis of the pyridyl-thiazolidinone derivative compound as active pharmaceutical ingredients; this derivative is chemically named: (E)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one (JC-21A).
2. 2. PYRIDILYL-THIAZOLIDINONE JC-21A DERIVATIVE WITH FUNGICIDAL ACTIVITY AGAINST CANDIDA AURIS AND DERMAL TOXICITY IN RATS, according to claim 1, characterized by having the pyridyl-thiazolidinone derivative compound, tested in an in vitro antifungal experimental model, which allows us to observe that there was a significant reduction in the fungus.
3. 3. PYRIDILYL-THIAZOLIDINONE JC-21A DERIVATIVE WITH FUNGICIDAL ACTIVITY AGAINST CANDIDA AURIS AND DERMAL TOXICITY IN RATS, according to claims 1 and 2, characterized by having the pyridyl-thiazolidinone derivative compound, tested in an in vivo experimental model for acute and subacute dermal toxicity in rats, which shows that there were no adverse effects on the animal.
4. 4. PYRIDILYL-THIAZOLIDINONE DERIVATIVE JC-21A WITH FUNGICIDAL ACTIVITY AGAINST CANDIDA AURIS AND DERMAL TOXICITY IN RATS, according to claims 1 to 3, characterized by having the pyridyl-thiazolidinone derivative compound to be used individually or in combination with other antifungal agents, for the purpose of decolonization and treatment of infection caused by the yeast C. auris.
5. 5. PYRIDILYL-THIAZOLIDINONE JC-21A DERIVATIVE WITH FUNGICIDAL ACTIVITY AGAINST CANDIDA AURIS AND DERMAL TOXICITY IN RATS, according to claims 1 to 4, characterized for the production of pharmaceutical preparations in the form of: powders, granules, coated tablets, capsules, oral and/or injectable solutions, ointments, creams, elixirs, syrups, emulsions, suspensions, lotions, plasters, gels, controlled release systems such as micro and nanocapsules, micro and nanoparticles, inclusion complexes, micro and nanoemulsions, liposomes and hydrogels, together with one or more adjuvants and/or vehicles.

Description

Field of invention [001] The present invention relates to a pyridyl-thiazolidinone derivative with code JC-21A, whose official name is (E)-2-((E)-(1-(pyridin-2-yl)ethylidene)hydrazono)thiazolidin-4-one, active against the fungus Candida auris and with dermal toxicity in rats, being useful in the treatment of infection caused by C. auris and applied in the following technical sectors: chemical processes and compounds, pharmaceuticals and therapies. Fundamentals of the invention [002] Candida auris is an emerging opportunistic pathogen that was first reported in Japan in 2009, causing otomycosis (Satoh et al., 2009). Since then, it has been reported on every continent except Antarctica, both as a causative agent of invasive infections and as a colonizer (Lone; Ahmad, 2019; Sabino et al., 2020). Associated with healthcare-related outbreaks in hospital settings, C. auris is reported as a public health problem due to the high mortality rates associated with bloodstream infection (Shastri et al., 2020; Briano et al., 2022). [003] Since the initial report, C. auris has grown to represent a “serious threat” in healthcare settings, as indicated by the U.S. Centers for Disease Control and Prevention (CDC, 2019) and is now on the World Health Organization’s (WHO, 2022) list of priority fungal pathogens, described as one of the critical “most wanted” pathogens. [004] In Brazil, C. auris was first reported in 2020, where it was isolated as a colonizer of two hospitalized patients with COVID-19, caused by the SARS-CoV-2 coronavirus, in the city of Salvador. The colonization of the first patient originated from the tip of a central venous catheter and the other from a blood culture (De Almeida et al., 2021). In general, bloodstream infection (candidemia) caused by C. auris occurs secondary to colonization. Thus, identifying this species at this stage, as well as understanding the risk factors among colonized patients, can aid in early diagnosis and prevent invasive infections (Prestel et al., 2021; Briano et al., 2022). [005] C. auris is best known for its strong resistance to a wide variety of fungicidal therapies. Based on the provisional limits proposed by the CDC, C. auris strains are resistant to major antifungal drugs. About 90% are resistant to fluconazole (FLU), 30% to amphotericin B (AMB), and 2% to 10% to echinocandins (CDC, 2020). Overall, about 90% of C. auris strains have acquired resistance to at least one drug; 30% to 41% are resistant to two drugs, and about 4% are resistant to all three antifungals (CDC, 2020). [006] Unlike most environmental fungi, C. auris is thermotolerant, growing between 37°C and 42°C. Furthermore, it has a remarkable ability to survive adverse environmental conditions for long periods, adapting outside the human host (Allert et al., 2022). These facts increase the risk of hospital outbreaks, as colonization and infections can originate from environmental sources, such as contaminated medical devices and the hands of healthcare professionals (Ruiz-Gaitán et al., 2019; Prestel et al., 2021). [007] Among healthcare-associated infections (HAIs), invasive fungal infections (IFIs) are responsible for more than 1.6 million deaths per year (Bongomin et al., 2017). In Intensive Care Units (ICUs), candidemia – the most common clinical manifestation of invasive candidiasis – predominates, with an estimated incidence of 3.5 and 4.6 per 1,000 admissions to medical and surgical ICUs, respectively (Bienvenu et al., 2020). [008] According to Pappas et al. (2016), four pharmacological classes can be used in the treatment of invasive candidiasis: echinocandins, azole derivatives, polyenes, and pyrimidine analogs. Azole derivatives are synthetic fungistatic compounds that act by blocking ergosterol biosynthesis, by inhibiting the lanosterol-14α-demethylase enzyme, encoded by the ERG11 gene (Houst; Spízek; Havlícek, 2020). [009] Despite advances in diagnostic procedures, the implementation of strategies to prevent candidemia, and the development of new antifungal agents in recent years, the phenomenon of resistance in Candida species has been expanding primarily due to incorrect treatment and/or the use of inactive agents in resistant strains (Bassetti et al., 2018; Tsay et al., 2020). [0010] In clinical practice, both in the prophylaxis and therapy of Candida infections, the use of fluconazole stands out from other drugs, mainly due to its low cost, which has led to increased fungal resistance to this drug over the years, resulting in numerous cases of therapeutic failure (Bassetti et al., 2018) and making it necessary to search for new treatments. [0011] The molecule's design was based on the work of Cardoso et al. (2014), as well as Silva et al. (2017), who identified 2-(pyridin-2-yl)-1,3-thiazole derivatives as antiparasitic agents. In both cases, some compounds showed trypanocidal properties superior to or similar to the reference drug Benzonidazole (BZN) for the trypomastigote form. In other stud