Synthesis and Biological Evaluation of Ferrocene-Based Cannabinoid Receptor 2 Ligands

Abstract

Ferrocene analogs of known fatty acid amide hydrolase inhibitors and CB ligands have been synthesized and characterized spectroscopically and crystallographically. The resulting bio-organometallic isoxazoles were assayed for their effects on CB and CB receptors as well as on fatty acid amide hydrolase. None had any fatty acid amide hydrolase activity but compound 3, 5-(2-(pentyloxy)phenyl)-N-ferrocenylisoxazole-3-carboxamide, was found to be a potent CB ligand (K = 32.5 nM).

Ferrocenes in medicinal chemistry; a personal perspective

“…In this regard, we recently continued a very fruitful collaboration with colleagues at Lille-2 University, France, which focussed on the design of inverse agonists of the canabinnoid CB2 receptor, a well-studied G-protein coupled receptor (GPCR), as well as of ligands acting on fatty acid amide hydrolase (FAAH). [21][22][23] , [24] Our efforts culminated in a suitable illustration of aminoferrocene as a 3D-bioisostere of adamantlyamine in CB2. During these early studies, we were effectively conducting "fishing" exercises with little structural or mechanistic know-how and conducting random kinase assay screens.…”

Metallodrug Profiling against SARS‐CoV‐2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain‐like Protease PLpro

“…Some tested compounds are commercially available and they were purchased from Sigma Aldrich (sodium aurothiomalate hydrate, gold(III) chloride hydrate, chloro(triethylphosphine)gold(I), chloro(triphenylphosphine)gold(I), thiomersal), Acros Organics (silver sulfadiazine, titanocene dichoride, cisplatin, disulfiram), Adipogen‐Biomol (chloroquine diphosphate) and Enzo Life Sciences (auranofin). The following complexes were prepared as previously described in the literature: Au‐7 [51] , Au‐8 [52] , Au‐9 , Au‐11 [53] , Au10 [54] , Au‐12 , Au‐13 [55] , Au‐15 [52] , Au‐20 , Au‐25 , Au‐26 [56] , Au‐27 [57] , Au‐31 – Au‐32 [55] , Au‐33 , Au‐34 [58] , Ru‐1 , Ru‐4 – Ru‐8 , [59] , Ru‐10 [60] , Ru‐11 [61] , Ru‐12 [62] , Ru‐13 [63] , Ru‐14 , Ru‐15 , Ru‐16 [64] , Mn‐1 , Mn‐2 [65] , Re‐1 [66] , Re‐2 [67] , Pt‐2 [68] , Pt‐3 , Pt‐4 , Pd‐1 , Pd‐2 [69] , Fe‐1 , Fe‐2 , Fe‐3 , Fe‐4 [70] , Fe‐5 [71] , Fe‐6 [72] , Fe‐7 , Fe‐8 [73] Fe‐9 [74] , Fe‐10 [75] , Fe‐11 [76] , Fe‐13 [77] , POM‐1 , POM‐2 [27] , POM‐3 [28] , POM‐4 [29] , POM‐5 [30] , POM‐6 , POM7 [31] , POM‐8 , POM‐9 , POM‐10 [32] , POM‐11 [33] . For preparation and characterization of all other complexes see the supporting information.…”

Has Ferrocene Really Delivered Its Role in Accentuating the Bioactivity of Organic Scaffolds?

“…Encouraged by the optimiztic results from previous studies, 146 the same research group later extended the work on the ferrocene-based derivatization of CB 2 ligand 273 and fatty acid amide hydrolase (FAAH) inhibitor 274 to obtain better pharmacological results (Figure 81). 147 Substituting adamantyl with ferrocene was anticipated to increase the CB2 binding affinity, but no substantial change was observed. However, there was a significant improvement in cAMP formation.…”