An efficient synthesis of new caffeine-based chalcones, pyrazolines and pyrazolo[3,4-b][1,4]diazepines as potential antimalarial, antitrypanosomal and antileishmanial agents

• New series of pyrazolines and diazepines were synthesized from caffeine.
• Antimalarial activity was evaluated against Plasmodium falciparum.
• Antileishmanial activity was evaluated against Leishmania panamensis.
• Antitrypanosomal activity was evaluated against Trypanosoma cruzi.
• Diazepines 10a–f were highly active against P. falciparum.

A new series of chalcones 5a–f were synthesized from caffeine-based aldehyde 3 and substituted acetophenones 4a–f. Treatment of compounds 5a–f with hydrazine hydrate led to pyrazolines 6a–f, and their subsequent reaction with acetic anhydride or formic acid afforded the corresponding N-substituted pyrazolines 7a–f and 8a–f respectively. Additionally, the regioselective cyclocondensation reaction of chalcones 5a–f with 4,5-diaminopyrazole 9 afforded the diazepine derivatives 10a–f. Synthesis of the above novel compounds was carried out through a simple procedure involving an easy work-up and mild reaction conditions. In vitro antimalarial activity against Plasmodium falciparum was evaluated for the obtained compounds. Among of them, just pirazoline 6a showed an outstanding growth inhibition percentage 85.2 ± 5.4%, while diazepines 10a–f showed remarkable growth inhibitions in the range of 80.3 ± 13.5 to 94.2 ± 0.2% when were tested at 20 μg/mL. Compounds 5b, 5e, 7c and 7f showed remarkable activities against Leishmania panamensis with growth inhibition of 88.3 ± 1.5, 82.6 ± 2.2, 82.8 ± 1.7 and 87.6 ± 0.5% respectively, at 20 μg/mL. In vitro assays against Trypanozoma cruzi showed that pyrazoline 6d displayed a growth inhibition of 61.9 ± 7.8% at 20 μg/mL while chalcone 5f was considered especially active with a growth inhibition of 9.7 ± 1.5% for a very low concentration of 1.0 μg/mL.

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