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.