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

Abstract

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.

Molecular Cloning and Characterization of Novel Glutamate-Gated Chloride Channel Subunits from Schistosoma mansoni

“…However, these BZD binding sites were discarded as putative molecular targets for meclonazepam, since neither exhibited significant affinity for meclonazepam [51], [53]. In agreement with the evidence for a low-affinity meclonazepam binding site, a recent study in in vitro cultures of S. mansoni reported half maximal lethal concentrations (LC 50 ) of 3 µM for meclonazepam and 10 µM for clonazepam [28]. These LC 50 values correlate with in vitro studies on S. mansoni adult males, which showed that 1–10 µM meclonazepam induces immediate, Ca 2+ -dependent spastic paralysis and extensive tegumental disruption, leading to parasite death [54]–[56].…”

“…Unfortunately, the drug was later discarded as a lead candidate due to its lack of selectivity; sedative and hypnotic effects were seen in humans at therapeutic doses [26]. There is hope that medicinal chemistry efforts, combined with a better understanding of the molecular target of meclonazepam, could lead to the development of derivatives with greater selectivity towards schistosomes and minimal adverse effects in patients [27], [28].…”

In vitro and in vivo anthelmintic activity of (−)-6,6′-dinitrohinokinin against schistosomula and juvenile and adult worms of Schistosoma mansoni

“…Several structure-activity relationship (SAR) studies have been conducted (Menezes et al, 2012;Wang et al, 2013) to identify the best candidates to treat schistosomiasis. Considering the results obtained here, it might be interesting to explore the structure-activity relationship of its antischistosomal activity.…”

Synthesis and Evaluation of Anticonvulsant Activity of Some Schiff Bases of 7‐Amino‐1,3‐dihydro‐2H‐1,4‐benzodiazepin‐2‐one

“…In addition to their established anticonvulsant activity, 1,3‐Dihydro‐2 H ‐1,4‐benzodiazepin‐2‐one also demonstrates many other important biological activities such as anti‐anxiety, hypnotic, NNRTI of HIV‐1 reverse transcriptase, anti‐arrhythmic agents, antiproliferative, anti‐platelet anti‐ulcer, vasopressin antagonist activity, as well as anti‐inflammatory agents . The early structure−activity relationship (SAR) study indicated that the potency of benzodiazepine is mainly determined by substitution at the 7 th position, whereas any substitutions at positions 6, 8 and 9 may decrease the activity. The SAR study also promotes the presence of a carbonyl function at the 2 nd position, a phenyl ring at the 5 th position, the presence of a double bond between the 4 th and the 5 th position in diazepine ring B and no alkyl substitution or a less bulky alkyl group at N‐1, as shown in Figure .…”