Synthesis, antileishmanial activity and structure–activity relationship of 1-N-X-phenyl-3-N′-Y-phenyl-benzamidines

• Antileishmanial activity evaluation of new N,N′-substituted benzamidines series.
• QSAR study involving the hydrophobicity and electronic parameters.
• Synthesis and characterization of N,N′-substituted benzamidines series.

Two series of N,N′-diphenyl-benzamidines were synthesized as part of a study to search potential new drugs with antileishmanial activity. These compounds were obtained by anilides in PCl5 halogenation reaction with generation in situ of the corresponding benzimidoyl chlorides, and subsequently treatment with adequate anilines. The series I showed expressive results of antileishmanial activity, highlighted the compounds 9a with IC50 = 81.28 μM (log IC50 = 1.91 μM) against Leishmania chagasi, 8e with IC50 = 26.30 (log IC50 = 1.52 μM) against Leishmania braziliensis. From the results obtained from SAR study (series I), the series II was planned from Craig 2-dimensional map, in which was possible the discovery of the potent compounds, 9v and 9j with IC50 = 12.60 μM (log IC50 = 1.10 μM) and 13.00 μM (log IC50 = 1.11 μM), respectively, against Leishmania amazonensis. The results obtained from the SAR and QSAR studies indicated the best results when electron-donor groups in the ring attached to amidinic carbon, unlike when electron-withdrawing groups at the phenyl-N ring showing inhibitory activity increased. Furthermore, the QSAR model obtained indicated the hydrophobicity as a fundamental property for antileishmanial activity presented by these series.

Figure optionsDownload as PowerPoint slide