Synthesis, biological evaluation, and structure-activity relationship of clonazepam, meclonazepam, and 1,4-benzodiazepine compounds with schistosomicidal activity.
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 [N(1) H-C(2) (=O)] is the principal pharmacophoric unit of 1,4-benzodiazepine schistosomicidal compounds and that substitution on the amide nitrogen atom (N(1)  position) is not tolerated.
Laboratório de Avaliação e Síntese de Substâncias Bioativas, Universidade Federal do Rio de Janeiro, P O Box 68024, 21944-971, Rio de Janeiro, RJ, Brazil.
Carla M S
CM
Menezes
Gildardo
G
Rivera
Marina A
MA
Alves
Daniel N
DN
do Amaral
Jean Pierre B
JP
Thibaut
François
F
Noël
Eliezer J
EJ
Barreiro
Lídia M
LM
Lima
D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001570:Benzodiazepinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002998:Clonazepam / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000031:analogs & derivatives; D006801:Humans; D008958:Models, Molecular; D012547:Schistosoma / Q000187:drug effects; D012552:Schistosomiasis / Q000469:parasitology / Q000473:pathology; D012556:Schistosomicides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001570:Benzodiazepinones; D012556:Schistosomicides; D001569:Benzodiazepines; D002998:Clonazepam; C020602:meclonazepam