Synthesis and activity of novel tetrazole compounds and their pyrazole-4-carbonitrile precursors against Leishmania spp

• Published in: Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (23), p.6310-6312
• Main Authors: Faria, Jéssica V., dos Santos, Maurício S., Bernardino, Alice M.R., Becker, Klaus M., Machado, Gérzia M.C., Rodrigues, Raquel F., Canto-Cavalheiro, Marilene M., Leon, Leonor L.
• Format: Article
• Language: English
• Subjects: Animals; Antileishmanial activity; antileishmanials; Antiprotozoal Agents; Cell Line; chemistry; cytotoxicity; Dose-Response Relationship, Drug; drugs; Leishmania - drug effects; Leishmania amazonensis; Leishmania braziliensis; Mice; Nitriles - chemistry; promastigotes; Pyrazoles - chemistry; Stereoisomerism; Structure-Activity Relationship; Tetrazole; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.09.062

A series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a–m) and their 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a–m) precursors were synthesized and evaluated for their antileishmanial activity. A new series of 5-(1-aryl-3-methyl-1H-pyrazol-4-yl)-1H-tetrazole derivatives (4a–m) and their precursor 1-aryl-3-methyl-1H-pyrazole-4-carbonitriles (3a–m) were synthesized and evaluated as antileishmanials against Leishmania braziliensis and Leishmania amazonensis promastigotes in vitro. In parallel, the cytotoxicity of these compounds was evaluated on the RAW 264.7 cell line. The results showed that among the assayed compounds the substituted 3-chlorophenyl (4a) (IC50/24h=15±0.14μM) and 3,4-dichlorophenyl tetrazoles (4d) (IC50/24h=26±0.09μM) were the most potent against L. braziliensis promastigotes, as compared the reference drug pentamidine, which presented IC50=13±0.04μM. In addition, 4a and 4d derivatives were less cytotoxic than pentamidine. However, these tetrazole derivatives (4) and pyrazole-4-carbonitriles precursors (3) differ against each of the tested species and were more effective against L.braziliensis than on L. amazonensis.