, 1991; Isaacson, 1998), and anti-inflammatory (Sharma et al., 2005) activities. Modification of basic structural fragments of drugs, by altering molecular conformation, introducing additional

substituents into aromatic or heterocyclic rings can Tipifarnib manufacturer affect drug-receptor interactions, as well as drug body distribution and metabolism (Patrick, 2005). In our previous papers, we reported a novel method of synthesizing quinoline fragment-containing phenothiazine derivatives that possess the structure of 5-alkyl-12(H)-quino[3,4-b][1,4] benzothiazinium salts 2. These compounds contain a totally planar tetracyclic fragment and have interesting antimicrobial and antiproliferative properties (Zięba et al.,2010, 2012). In this study, we present details of synthesis of novel quinobenzothiazine

derivatives as free quinoline bases, and their derivatives containing aminoalkyl substituents at the thiazine nitrogen atom. We also demonstrate their antiproliferative activity. Results and discussion Chemistry 5-Alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts 2 were obtained by cyclization of 1-alkyl-4-(arylamino)quinolinium-3-thiolates 1 in the presence of HCl donor (aniline learn more hydrochloride) and atmospheric oxygen (Scheme 1) (Zięba et al., 2000; Zięba and Suwińska, 2006). 3-Thiolates 1 were obtained by reacting thioquinanthrenediinium salts with aromatic amines (Maślankiewicz and Zięba, 1992). Scheme. 1 Synthesis of compounds 2 Phenothiazine derivatives with aminoalkyl substituents at the thiazine nitrogen atom constitute an important group of neuroleptic drugs (Isaacson, 1998), they also possess other interesting biological properties, such as antimicrobial and antiproliferative activity. Compounds having such structure are obtained by alkylating phenothiazine derivatives in an alkaline environment. Quinoselleck compound benzothiazine derivatives with such substituents at the thiazine nitrogen atom cannot be obtained directly from Orotic acid salts 2 using this method, like 3-azaphenothiazine salts (Clarke et al., 1961), they do not form sodium salts in the presence of bases. Instead, they split off hydrogen

chloride and form respective 5-alkyl-5(H)-quino[3,4-b][1,4]benzothiazine 3 derivatives (Scheme 2) (Zięba et al., 2000; Zięba and Suwińska, 2006). Scheme. 2 Reaction of salts 2 with bases We attempted, therefore, to perform N-dealkylation of salts 2 to obtain quinobenzothiazine derivatives 4 as free quinoline bases. There are no data available concerning N-dealkylation of azaphenothiazine salts. In an earlier publication, we described N-dealkylation of 1-alkylquinolinium salts achieved by heating their pyridine or DMF solutions (Maślankiewicz and Zięba, 1994). However, under such conditions salts 2 do not undergo the N-dealkylation reaction. On the other hand, by carrying the reaction of 5-alkyl-12(H)-quino[3,4-b][1,4]benzothiazinium salts 2 with benzimidazole at 200 °C, the expected 12(H)-quino[3,4-b][1,4]benzothiazines 4 were obtained (Scheme 3) with good yield.