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Abstract
A novel approach for the synthesis of unsymmetrically substituted dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones has been developed. This facile three-step method uses variously substituted 1H-benzo[d][1,3]oxazine-2,4-diones (isatoic anhydrides) and 2-aminobenzoic acids as a starting materials. The obtained products were further transformed into N-alkyl-, N-acetyl- and dithio analogues. Developed procedures allowed the synthesis of unsymmetrical dibenzo[b,f][1,5]diazocine-6,12(5H,11H)diones and three novel heterocyclic scaffolds: benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)dione, pyrido[3,2-c][1,5]benzodiazocine-5,11(6H,12H)-dione and pyrazino[3,2-c][1,5]benzodiazocine-6,12(5H,11H)dione. For 11 of the compounds crystal structures were obtained. The preliminary cytotoxic effect against two cancer (HeLa, U87) and two normal lines (HEK293, EUFA30) as well as antibacterial activity were determined. The obtained dibenzo[b,f][1,5]diazocine(5H,11H)6,12-dione framework could serve as a privileged structure for the drug design and development.
Highlights
Tricyclic dibenzodiazepines and their structural analogues having two non-polar, aromatic benzene or heterocyclic rings separated by a seven-membered ring containing heteroatoms such as sulfur, nitrogen or oxygen (1, Figure 1), are very popular, privileged structures, useful for the development of drugs, as well as compounds with various biological activities and applications (Figure 1)
Modulation of biological properties is possible by skillful chemical modifications, and variation of substituents and functional groups located in the six-membered benzene rings and the seven-membered heterocyclic ring
We focused on the search for the the synthesis of unsymmetrical dibenzo[b,f ][1,5]diazocines 10 (R, R, R, R )
Summary
Tricyclic dibenzodiazepines and their structural analogues (dibenzoazepines, dibenzothiazepines and others) having two non-polar, aromatic benzene or heterocyclic rings separated by a seven-membered ring containing heteroatoms such as sulfur, nitrogen or oxygen (1, Figure 1), are very popular, privileged structures, useful for the development of drugs, as well as compounds with various biological activities and applications (Figure 1). Modulation of biological properties is possible by skillful chemical modifications, and variation of substituents and functional groups located in the six-membered benzene rings and the seven-membered heterocyclic ring This group of compounds includes such important drugs as imipramine (2; a dibenzoazepine with antidepressant activity and a serotonin and norepinephrine reuptake inhibitor) [1], clobenzepam (3; dibenzodiazepine; antihistaminic and anticholinergic) [2], quetiapine (4; dibenzothiazepine; antipsychotic activity; dopamine, serotonin, and adrenergic receptors antagonist) [3], oxcarbazepine (5; dibenzoazepine; anticonvulsant activity; voltage-sensitive sodium channels blocker) [4,5], and nevirapine (6; dipyridodiazepine; anti-HIV; non-nucleoside reverse transcriptase inhibitor) [6]. We recently reported [7] the synthesis of structurally related, tricyclic pyrazinebenzodiazepines type 7 [6].,we werecently recentlyreported reported[7]
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