Synthesis, pharmacology and molecular modeling of  N-substituted 2-phenyl-indoles and benzimidazoles as potent GABA A agonists

Among the known non-benzodiazepine hypnotic drugs, Zolpidem ( 1a), Indiplon ( 2a) and Zaleplon ( 2b) have shown high affinity and selectivity for the α 1 subunit of the GABA-A receptor. Our group has performed pharmacophoric and ADMET-prediction studies to evaluate a virtual library of new molecules based on privileged structures. Among these, we have synthesized a library of N-substituted indoles and a library of N-substituted benzimidazoles. Afterwards, in vitro screening and in vivo spontaneous motor activity in mice has revealed molecules with good in vitro affinities for the α 1 receptor and potent in vivo induction of sedation. The synthesis of N-substituted indoles ( 10) and benzimidazoles ( 14) as potent GABA A agonists is reported.