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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