Details

Autor(en) / Beteiligte

• Carvalho, Diego B.
• Costa, Pedro A.N.
• Portapilla, Gisele B.
• das Neves, Amarith R.
• Shiguemoto, Cristiane Y.K.
• Pelizaro, Bruno I.
• Silva, Fernanda
• Piranda, Eliane M.
• Arruda, Carla C.P.
• Gaspari, Priscyla D.M.
• Cardoso, Iara A.
• Luccas, Pedro H.
• Nonato, M. Cristina
• Lopes, Norberto P.
• de Albuquerque, Sergio
• Baroni, Adriano C.M.

Titel

Design, synthesis and antitrypanosomatid activity of 2-nitroimidazole-3,5-disubstituted isoxazole compounds based on benznidazole

Ist Teil von

• European journal of medicinal chemistry, 2023-11, Vol.260, p.115451, Article 115451

Ort / Verlag

Elsevier Masson SAS

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Chagas disease and leishmaniasis are neglected diseases of high priority as a public health problem. Pharmacotherapy is based on the administration of a few drugs, which exhibit hazardous adverse effects and toxicity to the patients. Thus, the search for new antitrypanosomatid drugs is imperative to overcome the limitations of the treatments. In this work, 46 2-nitroimidazole 3,5-disubstituted isoxazole compounds were synthesized in good yields by [3 + 2] cycloaddition reaction between terminal acetylene (propargyl-2-nitroimidazole) and chloro-oximes. The compounds were non-toxic to LLC-MK2 cells. Compounds 30, 35, and 44 showed in vitro antichagasic activity, 15-fold, 12-fold, and 10-fold, respectively, more active than benznidazole (BZN). Compounds 30, 35, 44, 45, 53, and 61 acted as substrates for the TcNTR enzyme, indicating that this might be one of the mechanisms of action involved in their antiparasitic activity. Piperazine series and 4-monosubstituted compounds were potent against T. cruzi parasites. Besides the in vitro activity observed in compound 45, the in vivo assay showed that the compound only reduced the parasitemia levels by the seventh-day post-infection (77%, p > 0.001) compared to the control group. However, 45 significantly reduced the parasite load in cardiac tissue (p < 0.01) 11 days post-infection. Compounds 49, 52, and 54 showed antileishmanial activity against intracellular amastigotes of Leishmania (L.) amazonensis at the same range as amphotericin B. These findings highlight the antitrypanosomatid properties of 2-nitroimidazole 3,5-disubstituted isoxazole compounds and the possibility in using them as antitrypanosomatid agents in further studies. [Display omitted] •46 novel 2-nitroimidazole-3,5-isoxazole-based derivatives of benznidazole (BZN) have been synthesized.•Isoxazole-piperazine series were active against T. cruzi and L. amazonensis.•Several compounds showed in vitro antichagasic activity and four of them exhibited activity <1 μM.•Correlation of a threshold value of optimal lipophilicity and antichagasic potency in piperazine series.•Electron-donating substituents in position 4 provided potent monosubstituted compounds against T. cruzi parasites.•In vivo study with compound 45 (25 mg/kg/day) promoted the reduction of parasite load in cardiac tissue.•Type I nitroreductases (TcNTR) might be one of the action mechanisms involved in their antiparasitic activity.•The in vitro antileishmanial assay (L. amazonensis) showed that different compounds were more active than the reference drugs tested as a control.