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

作者：Insuasty Braulio^*; Ramirez Juan; Becerra Diana; Echeverry Carlos; Quiroga Jairo; Abonia Rodrigo; Robledo Sara M; Dario Velez Ivan; Upegui Yulieth; Munoz July A; Ospina Victoria; Nogueras Manuel; Cobo Justo

来源：European Journal of Medicinal Chemistry, 2015, 93: 401-413.

DOI：10.1016/j.ejmech.2015.02.040

• Caffeine
• Chalcones
• Pyrazolines
• Diazepines
• Antimicrobial activity

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 803 +/- 13.5 to 94.2 +/- 0.2% when were tested at 20 mu g/mL. Compounds 5b, 5e, 7c and 7f showed remarkable activities against Leishmania panamensis with growth inhibition of 883 +/- 1.5, 82.6 +/- 2.2, 82.8 +/- 1.7 and 87.6 +/- 0.5% respectively, at 20 mu g/mL. In vitro assays against Trypanozoma cruzi showed that pyrazoline 6d displayed a growth inhibition of 61.9 +/- 7.8% at 20 mu g/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 mu g/mL.

• 出版日期2015-3-26