Synthesis and Antiprotozoal Profile of 3,4,5-Trisubstituted Isoxazoles

Abstract

A series of 60 4-aminomethyl 5-aryl-3-substituted isoxazoles were synthesized by an efficient method and evaluated in vitro against Leishmania amazonensis and Trypanosoma cruzi, protozoa that cause the neglected tropical diseases leishmaniasis and Chagas disease, respectively. Thirteen compounds exhibited a selective index greater than 10. The series of 3-N-acylhydrazone isoxazole derivatives bearing the bithiophene core exhibited the best antiparasitic effects.

Keywords: N-acylhydrazone derivatives; antileishmanial drugs; antiprotozoal agents; cyclocondensation reactions; isoxazoles.

Scheme 1

Antiprotozoal activities of isoxazole core (a) and pyrazolo[3,4‐d]pyridazin‐7‐one‐N‐acylhydrazone (b). Compounds synthesized and evaluated in this work (c).

Scheme 2

One‐pot synthesis of 3‐carboxyethyl‐4‐[(aryl)aminomethyl]‐5‐arylisoxazoles 2. [a] Reaction conditions: β‐enamino diketone 1 a–d (1.0 mmol), t‐Bu‐amine (1.05 mmol), MeCN (4.0 mL), hydroxylamine hydrochloride (1.2 mmol), BF₃OEt₂ (2.0 mmol), arylamine (3.0 mmol), NaBH₃CN (1.2 mmol). [b] Isolated yield after recrystallization in ethanol or purification by column chromatography.

Scheme 3

Synthesis of 3‐carbohydrazide derivatives 3. [a] Reaction conditions: Isoxazole 2 (1.0 mmol, 1.0 equiv.), hydrazine monohydrate (20.0 mmol, 20.0 equiv.), EtOH (4.0 mL). [b] Isolated yield after filtration and washed with cold water.

Scheme 4

Synthesis of 3‐N‐acylhydrazone derivatives 4, 5, and 6. [a] Reaction conditions: Isoxazole 3 (1.0 mmol), benzaldehyde, 2‐formylpyridine or 2,2'‐bithiophene‐5‐carboxaldehyde (1.0 mmol), DMSO (2.0 mL), Two drops of hydrochloric acid (37 %). [b] Isolated yield after filtration and washed with cold water.