Synthesis and in vitro antiproliferative activity of novel 12(H)-quino[3,4-b][1,4]benzothiazine derivatives

Abstract

Novel method of N-dealkylating quinobenzothiazinium salts 2, promoted by reaction with benzimidazole, led to a series of new azaphenothiazine derivatives having 12(H)-quino[3,4-b][1,4] benzothiazine 4 structure. Reaction of compounds 4 in an alkaline milieu with alkylating agents occur as N-alkylation of the thiazine nitrogen and yields quinobenzothiazine derivatives 7. In vitro antiproliferative activity of compounds 4 and 7 was tested using two cancer cell lines (SNB-19 and C-32) and cisplatin as a reference. Most of the studied azaphenothiazine derivatives showed activity against both cell lines investigated (5.6–12.4 μg/ml concentration range tested). Compounds 4(b–e) containing a halogen atom or methyl group at the 9-position of the quinobenzothiazine ring show activity in the tested concentration range only against C-32 cell line. Compound 4f with methyl group in 11-position of quinobenzothiazine ring lacked activity against either cell line. The presence of additional aminoalkyl substituents at the thiazine nitrogen atom in compounds 7 increases their activity against both examined cell lines, when compared to compounds 4.

Synthesis and biological activity of novel benzoazoles, benzoazines and other analogs functionalized by 2,4-dihydroxyphenyl moiety

“…1) was heated to reflux for 2.5-3 h. The hot mixture was filtered via a Büchner funnel. Next, the formed solid was filtered off (2,(9)(10)(11), and either the filtrate was concentrated (compounds 3-8) or water was added to afford the solid (…”

“…4H-1,4-benzothiazines exhibited antifungal potency against Aspergillus fumigates and Candida albicans [9,10]. The derivatives of 12(H)-quino [3,4-b] [1,4]benzothiazine showed antiproliferative activity against two cancer cell lines, SNB-19 and C-32 [11], while 6-substituted 9-fluoroquino [3,2-b]benzo [1,4]thiazines exhibited cytotoxicity as well as antiproliferative actions against human peripheral blood mononuclear cells stimulated with phytohemagglutinin A (PHA) [12].…”

Synthesis and In Vitro Antiproliferative Activity of Novel Phenyl Ring-Substituted 5-Alkyl-12(H)-quino[3,4-b][1,4]benzothiazine Derivatives

“…In our earlier papers we reported a novel method of synthesizing the 1,4-thiazine ring which proceeds via the substitution of a hydrogen atom with a thiolate sulfur atom. The obtained compounds have demonstrated promising anticancer properties [14,15,16,17,18]. Herein, we report on the synthesis of novel tetracyclic phenothiazine derivatives containing various substituents (aliphatic, aromatic, or heterocyclic) in positions 9, 10, and 11 of the quinobenzothiazine system.…”

Synthesis and biological evaluation of novel propargylquinobenzothiazines and their derivatives as potential antiproliferative, anti-inflammatory, and anticancer agents

“…About 40 types of azaphenothiazines are known as monoaza-, diaza-, triaza-, and tetraazaphenothiazines and their monobenzo-and dibenzo derivatives 16 . Some of these azaphenothiazines being pyridobenzothiazines [17][18][19][20][21] , pyrimidobenzothiazines 22,23 , pyrazinobenzothiazines 24,25 , dipyridothiazines [26][27][28][29][30] , quinobenzothiazines [31][32][33][34][35][36] , quinobenzothiazinium salts [37][38][39] , diquinothiazines 26,27 , and quinonaphthothiazines 36,40 exhibited promising anticancer, antibacterial, antiviral, immunosuppressive, antioxidative anti-inflammatory, and enzyme inhibiting activities.…”