ABSTRACT
Homologation is a concept introduced by Gerhard in 1853 to describe a homologous series in organic chemistry. Since then, the concept has been adapted and used in medicinal chemistry as one of the most important strategies for molecular modification. The homologation types, their influence on physico-chemical properties and molecular conformation are presented and discussed. Its application in lead-identification and lead optimization steps, as well as its impact on pharmacodynamics/pharmacokinetic properties and on protein structure is highlighted from selected examples. ⢠Homologation: definition and types ⢠Homologous series in nature ⢠Comparative physico-chemical and conformational properties ⢠Application in lead-identification and lead-optimization ⢠Impact on pharmacodynamic property ⢠Impact on pharmacokinetic property ⢠Impact on protein structure ⢠Concluding remarks ⢠Acknowledgment ⢠References.
Subject(s)
Drug Discovery , Pharmaceutical Preparations/chemistry , Molecular ConformationABSTRACT
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.