Synthesis, Biological Evaluation, and Structure-activity Relationship of Clonazepam, Meclonazepam, and 1,4-Benzodiazepine Compounds with Schistosomicidal Activity

• Published in: Chemical biology & drug design 2012-06, Vol.79 (6), p.943-949
• Main Authors: Menezes, Carla M. S., Rivera, Gildardo, Alves, Marina A., do Amaral, Daniel N., Thibaut, Jean Pierre B., Noël, François, Barreiro, Eliezer J., Lima, Lídia M.
• Format: Article
• Language: English
• Subjects: 4-benzodiazepine; Animals; Benzodiazepines - chemical synthesis; Benzodiazepines - chemistry; Benzodiazepines - pharmacology; Benzodiazepinones - chemical synthesis; Benzodiazepinones - chemistry; Benzodiazepinones - pharmacology; clonazepam; Clonazepam - chemical synthesis; Clonazepam - chemistry; Clonazepam - pharmacology; Humans; meclonazepam; Models, Molecular; pharmacophoric unit; Schistosoma; Schistosoma - drug effects; schistosomiasis; Schistosomiasis - parasitology; Schistosomiasis - pathology; Schistosomicides - chemical synthesis; Schistosomicides - chemistry; Schistosomicides - pharmacology; Structure-Activity Relationship
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/j.1747-0285.2012.01354.x

The inherent morbidity and mortality caused by schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutic use, leading to a permanent risk of parasite resistance. In search for new schistosomicidal drugs, meclonazepam, the 3‐methyl‐derivative of clonazepam, is still considered an interesting lead‐candidate because it has a proven schistosomicidal effect in humans but adverse effects on the central nervous system did not allow its clinical use. Herein, the synthesis, in vitro biological evaluation, and molecular modeling of clonazepam, meclonazepam, and analogues are reported to establish the first structure–activity relationship for schistosomicidal benzodiazepines. Our findings indicate that the amide moiety [N1H‐C2(=O)] is the principal pharmacophoric unit of 1,4‐benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N1 position) is not tolerated. Schistosomiasis is a serious public health problem in developing countries. Praziquantel is the only drug in therapeutics. Taking into account the schistosomicidal activity of clonazepam and meclonazepam, the objective of present work was to establish a structure‐activity relationship for 1,4‐benzodiazepine compounds with schistosomicidal activity. Our findings indicate that the amide moiety (N1H‐C2(=O)) is the principal pharmacophoric unit and that substitution on the amide nitrogen atom (N1 position) is not tolerated.