DESIGN, SYNTHESIS AND EVALUATION OF NEW THIAZOLES AS PROMISING ANTI- SPOROTHRIX AGENTS

DESIGN, SYNTHESIS AND EVALUATION OF NEW THIAZOLES AS PROMISING ANTI- SPOROTHRIX AGENTS

• Author
• Lucas Manoel da Silva Sousa
• Co-authors
• Robert da Silva Tibúrcio , Vanessa Gouveia de Melo Silva , Reginaldo Gonçalves de Lima Neto , Valéria Pereira Hernandes , Policarpo Ademar Sales Júnior , Ana Cristina Lima Leite
• Abstract

•  

  DESIGN, SYNTHESIS AND EVALUATION OF NEW THIAZOLES AS PROMISING ANTI- SPOROTHRIX AGENTS

  Lucas Manoel da Silva Sousa¹; Robert da Silva Tibúrcio¹; Vanessa Gouveia de Melo da Silva¹; Reginaldo Gonçalves de Lima Neto²; Valéria Pereira Hernandes³; Policarpo Ademar Sales Júnior³; Ana Cristina Lima Leite^1*.

  ¹ Laboratory of Planning in Medicinal Chemistry, Department of Pharmaceutical Sciences, Center for Health Sciences, Federal University of Pernambuco, Recife, PE, Brazil.

  ² Post-Graduate Program in Tropical Medicine, Center for Medical Sciences, Federal University of Pernambuco, Recife, PE, Brazil.

  ³ Laboratory of Immunopathology and Molecular Biology, Department of Immunology, Aggeu Magalhães Institute, Fundação Oswaldo Cruz, Recife, PE, Brazil.

   

  lucas.manoels@ufpe.br; ana.lleite@ufpe.br

   

  ABSTRACT

  INTRODUCTION: The genus Sporothrix comprises important human dimorphic fungal pathogens responsible for causing sporotrichosis, a neglected mycosis with a worldwide distribution.  The major species within this genus include S. brasiliensis, S. schenckii, S. globosa, S. mexicana, S. chilensis, S. luriei, and S. pallida. The pathogenic form of Sporothrix spp. is the yeast phase, which is located in the infected tissues of mammalian hosts.  S. brasiliensis and S. schenckii stand out as the most virulent species within the Sporothrix genus in the Americas. In Brazil, S. brasiliensis is the predominant etiological agent [1].  The most common clinical presentation of sporotrichosis is the lymphocutaneous form, followed by the fixed cutaneous form. However, extracutaneous and more severe forms can also occur, including cutaneous disseminated, pulmonary, osteoarticular, and neurological manifestations. The primary treatment for sporotrichosis involves the use of itraconazole and terbinafine. In severe cases of sporotrichosis, amphotericin B is the most commonly treatment option [2].  The Existing antifungals presents some limitations, highlighting the need for new, less toxic treatment options. Recent research has uncovered antifungal compounds derived from thiazole, showing a promising antifungal activity profile characterized by effective MICs combined with low cytotoxicity [3,4]. This work represents significant advancements in medicinal chemistry in the novel antifungal agents. AIMS: In this study, performed the antifungal evaluation of 20 new thiazoles. Clinical isolates of S. Brasiliensis and S. schenckii were used using the broth microdilution technique (M27-S4 – CLSI). METHODS: The synthesis of compounds involved three steps process, by using the thin-layer chromatography (TLC), visualized under UV light at 365 nm and 254 nm to monitoring the reaction progress. The compounds were identified using ¹H and ¹³C NMR. For the antifungal assays Sporothrix spp. Yeasts (URM 176 and URM 258) were cultured, washed, and subjected to varying drug concentrations to determine MIC values based on growth inhibition.  RESULTS AND DISCUSSION: In general, observing the average MICs of the tested isolates, 45% (n=9/20) of the thiazole derivatives were effective, showing lower inhibition concentrations. The best compounds exhibited fungicidal and antifungal activity, inhibiting 100% of fungal growth. The most active compounds of all series were compounds VM04 and VM06. The compound VM04 showed MICs values of 15,62 µg/mL (URM176) and 15,62 µg/mL (URM 258). Compound VM06 exhibited MIC values of 7,81 µg/mL (URM176) and 62,5 µg/mL (URM 258). Concerning the cytotoxicity profile of compounds, the best compounds exhibited cytotoxicity values (CC50%) of 58,6 ?M (VM04) and 54,1 ?M (VM06) in L929 cells. CONCLUSION: Among the synthetic molecule derived from thiazole ring categorized as effective, the compounds VM06 and VM04 shows promising profile of antifungal activity, due to the effective combination of MICs and tolerable toxicity profile. These results represent advances in the medicinal chemistry in the field of new antifungal agents. ACKNOWLEDGEMENT: The authors would like to thank CAPES, CNPq, FACEPE and UFPE.

  Keywords: Thiazole Derivatives, Anti-Sporothrix Compounds, Drug Design.

   

  REFERENCES

  [1] RODRIGUES, Anderson Messias et al. The threat of emerging and re-emerging pathogenic Sporothrix species. Mycopathologia, v. 185, p. 813-842, 2020.

  [2] OROFINO-COSTA, Rosane et al. Sporotrichosis: an update on epidemiology, etiopathogenesis, laboratory and clinical therapeutics. Anais brasileiros de dermatologia, v. 92, p. 606-620, 2017.

  [3] KAUFFMAN, Carol A. et al. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clinical Infectious Diseases, v. 45, n. 10, p. 1255-1265, 2007.

  [4] BONIFAZ, Alexandro; TIRADO-SÁNCHEZ, Andrés. Cutaneous disseminated and extracutaneous sporotrichosis: current status of a complex disease. Journal of Fungi, v. 3, n. 1, p. 6, 2017.

• Keywords
• Thiazole Derivatives, Anti-Sporothrix Compounds, Drug Design
• Modality
• Pôster
• Subject Area
• Drug Design and Discovery, Synthesis and Natural Products