From 4,4′-dichloro-3,3′-diquinolinyl sulfide (11) A solution of sulfide 11 (0.18 g, 0.5 mmol) and p-fluoroaniline (0.17 g, 1.5 mmol) in MEDG (5 mL) was refluxed for 3 h. After cooling, the solution was poured into water (20 ml) and alkalized with 5 % aqueous sodium hydroxide to pH

10. The resulting solid was filtered off, washed with water and purified by column BAY 73-4506 chromatography (Al2O3, CHCl3) to give 0.17 g (86 %) of 14-(p-fluorophenyl)diquinothiazine (12c), beige, mp 315–316 °C. 1H NMR (CDCl3) δ: 6.43 (dd, 2H, C6H2), 6.77 (m, 2H, C6H2), 7.75 (t, 2H, H-2, H-12), 7.85 (t, 2H, H-3, H-11), 8.34 (d, 2H, H-4, H-10), 8.39 (d, 2H, H-1, H-13), 9,06 (s, 2H, H-6, H-8). 13C NMR (CDCl3) δ: 115.75 (J = 22.5 Hz, m-C of C6H4F), 116.30 (J = 7.5 Hz, o-C of C6H4F), 122.87 (C-1, C-13), check details 126.82 (C-13a, C-14b), 128.51 (C-2, C-12), 129.89 (C-6a, C-7a), 130.13 (C-3, C-11), 130.25 (C-4, C-10), 140.57 (J = 2.5 Hz, ipso-C

of C6H4F), 145.54 (C-13b, C-14a), 147.98 (C-4a, C-9a), 149.49 (C-6, C-8), 158.07 (J = 238.5 Hz, p–C of C6H4F). EIMS m/z: 395 (M+, 100), 363 (M-S,20), 300 (M-C6H4F, 17). Anal. Calcd. for C24H14FN3S: C, 72.89; H, 3.57; N, 10.63. Found: C, 72.77; H, 3.59; N, 10.46. In vitro lipid peroxidation Heat-inactivated hepatic microsomes from untreated rats were prepared as described (Rekka et al., 1989). The incubation mixture contained microsomal fraction (corresponding to 2.5 mg of hepatic protein per ml or 4 mM fatty acid residues), ascorbic acid (0.2 mM) in Tris–HCl/KCl buffer (50 mM/150 mM, pH 7.4), and the studied

compounds (50–1 μM) dissolved in DMSO. The reaction was initiated by addition of a freshly prepared FeSO4 solution (10 μΜ), and the mixture was incubated at 37 °C for 45 min. Lipid peroxidation of aliquots was assessed spectrophotometrically (535 against 600 nm) as TBAR. Both compounds and solvents were found not to interfere with the assay. Each assay was performed in duplicate, and IC50 values represent the mean concentration of compounds that inhibit the peroxidation of control microsomes by 50 % after 45 min of incubation. All standard errors are within 10 % of the respective reported values. Calculation of lipophilicity, molecular mass, surface area, and molecular volume Lipophilicity (as cLogP), molecular mass Bcl-w (M), surface area (S), and molecular volume (VM) were calculated using CS Chem 3D Ultra 7.0 (CambridgeSoft) and Spartan’04 (Wavefunction, Inc. Irvine, CA). Results and discussion Synthesis The synthesis of the title azaphenothiazines was based on the reactions of isomeric diquinodithiins, dichlorodiquinolinyl sulfides, and disulfide with amines, ammonia, and acetamide. The fusion reactions of linearly condensed diquinodithiin 1 with hydrochlorides of aniline and its p-substituted derivatives such as p-chloroaniline and p-methoxyaniline led to tetracyclic 9-substituted 6H-quinobenzothiazines 3a–c (Scheme 1).