Synthesis and Evaluation of Antifungal and Antitrypanosomastid Activities of Symmetrical 1,4-Disubstituted-1,2,3-Bistriazoles Obtained by CuAAC Conditions.

BACKGROUND: The trypanosomatids, such as the protozoan Leishmania spp., have a demand by ergosterol, which is not present in the membrane from mammal cells. The suppression of the synthesis of ergosterol would be a new target of compounds with leishmanicidal activity, and bistriazole has shown trypanocidal activity by this mechanism. The incidence of fungal infections has increased at an alarming rate over the last decades. This is related both to the growing population of immune-compromised individuals and to the emergence of strains that are resistant to available antifungals. Therefore, there is a challenge for the search of potential new antifungal agents. OBJECTIVE: The study aimed to synthesize 1,4-disubstituted-1,2,3-bistriazoles by optimized copper( I)-catalyzed alkyne-azide cycloaddition (CuAAC) and evaluate their antifungal and antitrypanosomastid activities. METHOD: The synthesis of symmetrical bistriazoles with diazides as spacers was planned to be performed following the CuAAC reaction strategy. For evaluation of best conditions for the synthesis of symmetrical bistriazoles hex-1-yne 2 was chosen as leading compound, and a variety of catalysts were employed, choosing (3:1) alkyne:diazide stoichiometric relationship employing CuSO4.5H2O as the best condition. For the preparation of diversity in the synthesis of symmetrical bistriazoles, a 1,3-diazide-propan-2-ol 1a and 1,3-diazidepropane 1b were reacted with seven different alkynes, furnishing eleven symmetrical bistriazoles 9-13a,b and 14a. All compounds were essayed to cultures of promastigotes of L. amazonensis (1 x 106 cells mL-1) in the range of 0.10 - 40.00 µg mL-1 and incubated at 25ºC. After 72 h of incubation, the surviving parasites were counted. For antifungal assay, the minimum inhibitory concentrations (MIC) for yeasts and filamentous fungi were determined. Each compound was tested in 10 serial final concentrations (64 to 0.125 µg mL-1). RESULTS: Eleven 1,4-disubstituted-1,2,3-bistriazoles were synthesized and their structures were confirmed by IR, 1H and 13C-NMR and Mass spectral analysis. The antifungal and antitrypanosomastid activities were evaluated. The best result to antifungal activity was reached by bistriazole 11a that showed the same MIC of fluconazole (32 µg mL-1) against Candida krusei ATCC 6258, an emerging and potentially multidrug-resistant fungal pathogen. Due to their intrinsically biological activity versatility, five derivatives compounds showed leishmanicidal inhibitory activity between 15.0 and 20.0% at concentrations of 20 and 40.0 µg mL-1. Among these compounds the derivative 13a showed best IC50 value of 63.34 µg mL-1 (182.86 µM). CONCLUSION: The preliminary and promising results suggest that bistriazole derivatives, especially compound 13a, could represent an innovative scaffold for further studies and development of new antifungal and anti-parasitic drug candidates.

Triagem fitoquímica, atividade antioxidante e leishmanicida do extrato hidroetanólico 70% (v/v) e das frações obtidas de (Annona crassiflora Mart. ) / Phytochemical screening, antioxidant and leishmanicidal activity of the hydroethanolic extract 70% (v / v) obtained from fractions (Annona crassiflora Mart. )

A fitoterapia é uma prática sociocultural presente ao longo dos anos e utilizada para tratar enfermidades que acometem o ser humano. Nesse contexto, a Annona crassiflora Mart. destaca-se por ser uma das espécies utilizadas na fitoterapia pouco estudada química e biologicamente. Conhecida popularmente como marolo denota, segundo a literatura científica, uma constituição química composta por ácidos fenólicos, alcaloides, flavonoides, taninos, terpenoides e acetogeninas. Esses ativos são responsáveis pelo grande potencial farmacológico da espécie onde se destacam as atividades antimicrobianas, antioxidantes, citotóxicas, leishmanicidas e hipoglicêmicas. Considerando o exposto, este estudo propôs investigar do ponto de vista químico e biológico a espécie Annona crassiflora. Para esse fim, foi obtido o extrato hidroetanólico 70% (v/v) e frações hidroetanólicas das folhas de marolo. Com essas amostras realizou-se uma triagem fitoquímica que permitiu a detecção de compostos como: alcaloides, flavonoides, taninos, terpenos, ácidos fenólicos e catequinas. Avaliou-se, também, a atividade antioxidante pelo método sequestrante do radical DPPH, e os valores das frações hidroetanólicas revelaram-se mais significativos comparados ao extrato hidroetanólico. A atividade leishmanicida foi executada utilizando placas de 96 poços e os resultados mostraram que o extrato e as frações apresentaram-se inativos contra as formas promastigotas de Leishmania amazonensis.(AU)

Phytotherapy is a sociocultural practice present over the years and used to treat diseases that affect humans. In this context, Annona crassiflora Mart. is notable for being one of the species used in phytotherapy, seldom studied chemically or biologically. Popularly known as "marolo", its chemical constitution is composed of phenolic acids, alkaloids, flavonoids, tannins, terpenoids and acetogenins, according to scientific literature. The presence of these actives is responsible for the great pharmacological potential of this species, where the antimicrobial, antioxidant, cytotoxic, leishmanicidal and hypoglycemic activities stand out. Considering this, the present study proposes to investigate the Annona crassiflora species from the chemical and biological point of view. For this purpose, we obtained hydroethanolic extract 70% (v / v) and fractions from the marolo leaves. With these samples, a phytochemical screening was carried out, which allowed us to detect compounds such as: alkaloids, flavonoids, tannins, terpenes, phenolic acids and catechins. We also assessed the antioxidant activity using the DPPH radical capturing method, where the values ​​of the hydroethanolic fractions were more significant compared to its extract. The leishmanicidal activity was performed using 96-well plates and the results show that both the extract and the fractions were inactive against the promastigote forms of Leishmania amazonensis.(AU)