TY - JOUR
T1 - Synthesis, Biological Evaluation, and Structure-activity Relationship of Clonazepam, Meclonazepam, and 1,4-Benzodiazepine Compounds with Schistosomicidal Activity
AU - Menezes, Carla M.S.
AU - Rivera, Gildardo
AU - Alves, Marina A.
AU - Do Amaral, Daniel N.
AU - Thibaut, Jean Pierre B.
AU - Noël, François
AU - Barreiro, Eliezer J.
AU - Lima, Lídia M.
PY - 2012/6
Y1 - 2012/6
N2 - 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 1H-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.
AB - 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 1H-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.
KW - 1,4-benzodiazepine
KW - Clonazepam
KW - Meclonazepam
KW - Pharmacophoric unit
KW - Schistosomiasis
KW - Structure-activity relationship
UR - http://www.scopus.com/inward/record.url?scp=84860481848&partnerID=8YFLogxK
U2 - 10.1111/j.1747-0285.2012.01354.x
DO - 10.1111/j.1747-0285.2012.01354.x
M3 - Artículo
C2 - 22321778
AN - SCOPUS:84860481848
SN - 1747-0277
VL - 79
SP - 943
EP - 949
JO - Chemical Biology and Drug Design
JF - Chemical Biology and Drug Design
IS - 6
ER -