The thermolysis reactions of benzoazacyclodecatrienes under microwave irradiation conditions in toluene at 150 °C afforded complex azabenzo[a]cyclopropa[cd]azulene and (epiminomethano)cyclopenta[a]indene frameworks. Cyclopropanes were established as intermediates of the ultimate thermolysis products.

Benzazecines with an allene fragment were prepared for the first time and in high yields via tandem reaction of 1-phenylethynyl-1-methyl(benzyl)-1,2,3,4-tetrahydroisoquinolines with activated alkynes in trifluoroethanol.

Nature-inspired, bridged polycyclic molecules share low similarity with currently available drugs, containing preferentially planar and/or achiral moieties. This "Escape from Flatland" scenario, aimed at exploring pharmacological properties of atypical molecular scaffolds, finds interest in synthetic routes leading to tridimensional-shaped molecules. Herein we report on the synthesis of N-bridged cyclopenta[a]indene derivatives, achieved through microwave-assisted thermal rearrangement of allene 3benzazecines with high diastereoselectivity. The biological evaluation disclosed selective inhibition of human acetylcholinesterase or butyrylcholinesterase, depending on the substitution around the molecular core, which was rationalized by means of docking simulations. The most potent BChE inhibitor 31 was effective in neuroprotection from glutamatergic excitotoxicity and displayed low intrinsic cytotoxicity and good brain penetration. Overall, compound 31 and its close congeners 34 and 35 acted as multitarget agents addressing different biological events involved in neurodegeneration, particularly in the progression of Alzheimer's disease.

We have elaborated a general and simple microwave-assisted method for the synthesis of original 8-ylidene decorated benzazecines. We have shown that under the action of electron-deficient alkynes in acetic acid the starting benzoannulated azacyclic allenes or 1-alkyl(benzyl)-1-phenylethynylsubstituted isoquinolines underwent transformations leading to benzazecines in high yields. In acetic acid all reactions pro-[a] Dr. A. A. Titov, M. S. Results and DiscussionWe initiated our study with estimating the influence of protonic solvents on the transformations of phenylethynyl decorated isoquinolines 1a-g under the action electron-deficient alkynes. The starting 1-alkyl(benzyl)-1-phenylethynyl-6,7-dimethoxyisoquinolines 1a-g were synthesized according to the previously described procedure [23] from 1-alkyl(benzyl)-3,4-dihydroisoquinolinium methiodide derived via the Bischler-Napieralski reaction followed by alkylation [20] (Scheme 1). Scheme 1. Synthesis of starting 1-alkyl(benzyl)-1-phenylethynyl-6,7-dimethoxyisoquinolines 1a-g.Scheme 3. Reactions of isoquinolines 1b-g with methyl propiolate in HFIP.

Aim: Enamino 3-benzazecine compounds, incorporating the C6-C8 allene system, were synthesized and evaluated in vitro as inhibitors of P-glycoprotein (P-gp) and/or multidrug resistance-associated protein 1 (MRP1), two efflux pumps mainly connected with multidrug resistance (MDR) in cancer cells. Results & methodology: Most of the synthesized compounds were selective P-gp inhibitors in Calcein-AM uptake assay. Structure–activity relationships (SARs) pointed out that CO2Me derivatives are more potent than acetyl derivatives, and 10,11-dimethoxy compounds are five to tenfold more potent inhibitors than the respective unsubstituted compounds, and that the P-gp inhibition potency is mainly related to volume parameters. Conclusion: Nanomolar P-gp inhibitors, such as 23 (IC50 = 4.2 nM), restored the antiproliferative activity of doxorubicin in multidrug-resistant cells. The observed activities showed that 3-benzazecine-based compounds may be promising MDR reversers.