An efficient synthesis of new caffeine-based chalcones, pyrazolines and pyrazolo[3,4-b][1,4]diazepines as potential antimalarial, antitrypanosomal and antileishmanial agents.
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.
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia. Electronic address: braulio.insuasty@correounivalle.edu.co.
Braulio
B
Insuasty
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia.
Juan
J
Ramírez
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia.
Diana
D
Becerra
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia.
Carlos
C
Echeverry
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia.
Jairo
J
Quiroga
Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia.
Rodrigo
R
Abonia
PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, PO Box 1226, Medellín, Colombia.
Sara M
SM
Robledo
PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, PO Box 1226, Medellín, Colombia.
Iván Darío
ID
Vélez
PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, PO Box 1226, Medellín, Colombia.
Yulieth
Y
Upegui
PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, PO Box 1226, Medellín, Colombia.
July A
JA
Muñoz
PECET, Instituto de Investigaciones Médicas, Facultad de Medicina, Universidad de Antioquia, PO Box 1226, Medellín, Colombia.
Victoria
V
Ospina
Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain.
Manuel
M
Nogueras
Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain.
Justo
J
Cobo
D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001381:Azepines / Q000737:chemistry*; D002110:Caffeine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D047188:Chalcones / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D020128:Inhibitory Concentration 50; D007891:Leishmania / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D011720:Pyrazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects; D020298:U937 Cells
D000962:Antimalarials; D001381:Azepines; D047188:Chalcones; D011720:Pyrazoles; D014344:Trypanocidal Agents; D002110:Caffeine
Antimicrobial activity; Caffeine; Chalcones; Diazepines; Pyrazolines