Design, Synthesis, and Biological Evaluation of Imidazo[1,5-a]quinoline as Highly Potent Ligands of Central Benzodiazepine Receptors

Abstract

A series of imidazo[1,5-a]quinoline derivatives was designed and synthesized as central benzodiazepine receptor (CBR) ligands. Most of the compounds showed high CBR affinity with K i values within the submicromolar and subnanomolar ranges with interesting modulations in their structure−affinity relationships. In particular, fluoroderivative 7w (K i = 0.44 nM) resulted in the most potent ligand among the imidazo[1,5-a]quinoline derivatives described so far. Overall, these observations confirmed the assumption concerning the presence of a large though apparently saturable lipophilic pocket in the CBR binding site region interacting with positions 4 and 5 of the imidazo[1,5-a]quinoline nucleus. The in vivo biological characterization revealed that compounds 7a,c,d,l,m,q,r,w show anxiolytic and antiamnestic activities without the unpleasant myorelaxant side effects of the classical 1,4-BDZ. Furthermore, the effect of 7l,q,r, and 8i in lowering lactate dehydrogenase (LDH) release induced by ischemia-like conditions in rat brain slices suggested neuroprotective properties for these imidazo[1,5-a]quinoline derivatives.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…The desired aminoindane derivatives were obtained with good regio-and enantioselectivity, (product A/ product B was observed in a ratio higher than 19:1, Scheme 5C). It is worth mentioning that aminoindanes are scaffolds also present in biologically active molecules that may present, for example, antipsychotic (12) [54], anticonvulsant (13) [55], and antiparkinsonian activities (14) [56,57] (Scheme 5A).…”

“…The discovery of new biologically active substances represents not only an advance in the chemistry field but also offers innovative chances for pharmacological and biomedical sciences. Every year, several molecules are discovered and studied against different types of diseases, such as cancer [1,2], malaria [3,4], Chagas disease [5,6], HIV [7,8], depression [9,10], amnesia [11], Alzheimer [12], and maybe even in a more recent scenario, COVID-19 [13]. Even though many compounds are found to present activity against these diseases, only a few of them become approved, due to their toxicity or other issues Scheme 1: Schematic overview of transition metals studied in C-H activation processes.…”

Recent Advances in the Chemistry of Isocyanides with Activated Methylene Group

“…[47] Ethyl and tert-butyl isocyanoacetates 1b,d, were used for synthesis of imidazo[1,5-a]quinolines 70 as ligands of central benzodiazepine receptors. [48] The reaction proceeded in the presence of potassium tert-butoxide and yields the target com- Analogues approach was applied for building imidazo-[1,5-a]pyridine core 72 using interaction of substituted benzyl, furylmethyl and -styrylmethyl isocyanides 1 with 2-chloropyridines, 2-chloroquinolines, 2-chloropyrimidines and imidoyl chlorides 71 in the presence of potassium bis(trimethylsilyl)amide (KHDMS) or butyllithium (Scheme 38). [49] The authors established that the reaction proceeds though addition of isocyanides to the substrate followed by elimination of chlorine salt and cyclization.…”

“…Ethyl and tert ‐butyl isocyanoacetates 1b,d , were used for synthesis of imidazo[1,5‐ a ]quinolines 70 as ligands of central benzodiazepine receptors. [ 48 ] The reaction proceeded in the presence of potassium tert ‐butoxide and yields the target compounds from 2‐chloroquinoline derivatives 69 . The authors performed in vivo biological testing of the prepared compounds and established their anxiolytic and antiamnestic activities (Scheme 37).…”

Synthesis of Imidazo[1,5-a]quinolines via Metal-Free Oxidative Amination of sp3 C–H Bonds

“…Some imidazo[1,5-a]quinoline derivatives showed neuroprotective properties because they reduced LDH release induced by an ischemia-like condition. 2 In addition, N- [3,5bis(trifluoromethyl)benzyl]-5-phenylimidazo[1,5-a]quinoline-4-carboxamide was identified as a neurokinin antagonist with potential for alleviating the side effects from chemotherapy and surgery. 3 Furthermore, a ligand that contained the imidazo[1,5-a]quinoline fragment was used for the asymmetric 1,2-silylation of N-tosylaldimines.…”