N-[4-(9-Chloro­quino[3,2-b]benzo[1,4]thia­zin-6-yl)but­yl]acetamide

Małgorzata Jeleń; Kinga Suwińska; Krystian Pluta; Beata Morak-Młodawska

doi:10.1107/S1600536812045680

. 2012 Nov 10;68(Pt 12):o3324–o3325. doi: 10.1107/S1600536812045680

N-[4-(9-Chloroquino[3,2-b]benzo[1,4]thiazin-6-yl)butyl]acetamide¹

Małgorzata Jeleń ^a, Kinga Suwińska ^b,^c, Krystian Pluta ^a,^*, Beata Morak-Młodawska ^a

PMCID: PMC3588930 PMID: 23476166

Abstract

In the title molecule, C₂₁H₂₀ClN₃OS, the tetracyclic system is close to planar [r.m.s. deviation = 0.110 (4) Å]. The dihedral angle between the quinoline ring system and the benzene ring is 178.3 (1)° and the angle between two (S—C=C—N) halves of the thiazine ring is 173.4 (1)°. In the crystal, molecules are arranged via π–π interactions [centroid–centroid distances = 3.603 (2)–3.739 (2) Å] into slipped stacks extending along [010]. Intermolecular N—H⋯O hydrogen bonds link the amide groups of neighbouring molecules along the stack, generating a C(4) motif. The title compound shows promising antiproliferative and anticancer activity.

Related literature

For recent literature on biological activity of phenothiazines, see: Aaron et al. (2009 ▶); Pluta et al. (2011 ▶). For the synthesis and biological activity of 6-substituted quinobenzothiazines, see: Jeleń & Pluta (2009 ▶); Pluta et al. (2012 ▶). For the folded structures of similar tetracyclic systems, see: Jeleń et al. (2012 ▶); Luck et al. (2003 ▶); Yoshida et al. (1994 ▶). For crystal structures of phenothiazines, see: Chu (1988 ▶). For information on azaphenothiazines, and their nomenclature and synthesis, see: Pluta et al. (2009 ▶).

Experimental

Crystal data

C₂₁H₂₀ClN₃OS
M _r = 397.92
Monoclinic,
a = 12.7800 (4) Å
b = 4.9530 (11) Å
c = 28.781 (2) Å
β = 97.726 (5)°
V = 1805.3 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.35 mm⁻¹
T = 100 K
0.60 × 0.10 × 0.05 mm

Data collection

Nonius KappaCCD diffractometer upgraded with an APEXII detector
17434 measured reflections
3032 independent reflections
1987 reflections with I > 2σ(I)
R _int = 0.121

Refinement

R[F ² > 2σ(F ²)] = 0.067
wR(F ²) = 0.127
S = 1.10
3032 reflections
245 parameters
H-atom parameters constrained
Δρ_max = 0.32 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: COLLECT (Nonius, 1998 ▶); cell refinement: DENZO and SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEPIII (Burnett & Johnson, 1996 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: publCIF (Westrip, 2010 ▶).

Supplementary Material

Click here for additional data file.^{(25KB, cif)}

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536812045680/gk2524sup1.cif

e-68-o3324-sup1.cif^{(25KB, cif)}

Click here for additional data file.^{(148.8KB, hkl)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536812045680/gk2524Isup2.hkl

e-68-o3324-Isup2.hkl^{(148.8KB, hkl)}

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N18—H18⋯O21ⁱ	0.88	1.97	2.819 (4)	163

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Symmetry code: (i) Inline graphic .

Acknowledgments

The work was supported by the National Centre of Science (grant No. N405 101739).

supplementary crystallographic information

Comment

Classical phenothiazines are widely recognized as neuroleptic, antihistaminic and antitissive drugs. New phenothiazines are obtained by the introduction of new pharmacophoric substituents at the thiazine nitrogen atom and the substitution of the benzene ring with an azine ring (Pluta et al., 2009, 2011). Both classical and newly synthesized phenothiazines exhibit valuable anticancer, antibacterial and reversal multidrug resistance (Aaron et al., 2009; Pluta et al., 2011). We modified the phenothiazine structure via the substitution of the benzene ring with the quinoline ring to form linear fused quinobenzothiazines. The title compound (Fig. 1) was obtained in a few step synthesis starting from the reaction of diquinodithiin or 2,2'-dichloro-3,3'-diquinolinyl disulfide with p-chloroaniline. The obtained 6H-9-chloroquinobenzothiazine via thiazine ring formation (Pluta et al., 2009) was next alkylated with phthalimidobutyl bromide, hydrolyzed with hydrazine and acetylated with acetic anhydride (Pluta et al., 2012). The structure elucidation was based on the ¹H NMR spectrum which did not take all the doubts away. These reactions may lead to alternative products (II-V) (Fig. 1) as the results of other ring closure reaction, the Smiles rearrangement, tautomeric forms and competitive N-alkylation. The X-ray analysis fully confirmed the proposed structure as [3,2-b], the chlorine atom in position 9 and the acetylaminobutyl substituent at the thiazine nitrogen atom N6. The tetracyclic ring system (the plane from C1 atom up to C12A atom) in title molecule is unexpectedly almost planar [r.m.s. deviation 0.110 (4) Å]) with the dihedral angle between the quinoline and the benzene ring of 178.3 (1)° and the angle between two halves of the thiazine ring of 173.4 (1)°. All the classical neuroleptic phenothiazines are folded along theN–S axis with the angle of 134.0–153.6 ° (Chu, 1988) and the title molecule is the first example of planar azaphenothiazine with the aminoalkyl group at the thiazine nitrogen atom. Other similar tetracyclic compounds with the thiazine ring, 6-benzyl-10-trifluoromethylquinobenzothiazine (Pluta et al., 2012), 6-methyldihydroquinobenzothiazine (Luck et al., 2003) and 5H-naphthobenzothiazine (Yoshida et al., 1994) were also folded. Close to planar structure was 6H-8-trifluoromethylquinobenzothiazine (Pluta et al., 2012). The C10A–S11–C11A and C5A–N6–C6A bond angles are quite large, 102.2 (2)° and 123.8 (3)° and enable the thiazine ring to adopt the flat conformation. Both the thiazine N6 and the amide N18 nitrogen atoms do not show pyramidality as the sum of C–N–X bond angles (X = C or H) is 360.1 (5)° and 360°, repectively. The side chain is not coplanar with the tetracyclic system. The torsion angles involving the butyl group (C14–C17) show the antiperiplanar arrangement of the carbon chain. The torsion angle C16–C17–N18–C19 [135.2 (4)°] describes the anticlinal arrangement of these atoms. In the crystal, molecules are arranged into stacks viaπ–π interactions with centroid-to-centroid distances in the range of 3.603 (2)–3.739 (2) Å and extending along the b crystallographic axis ( Fig. 3). N–H···O hydrogen bond (Table 1) connects adjacent molecules along the stacks via catemeric C(4) motif (Fig. 4). The significant antiproliferative and anticancer activities of the title molecule most probabably result from intercalation of specific DNA by the planar azaphenothiazine system.

Experimental

The title compound was obtained in a few step synthesis starting from the reaction of diquinodithiin or 2,2'-dichloro-3,3'-diquinolinyl disulfide with p-chloroaniline (Jeleń et al., 2009). The obtained 6H-9-chloroquinobenzothiazine was alkylated with phthalimidobutyl bromide in dry toluene in the presence of sodium hydride, hydrolyzed with hydrazine in ethanol and acetylated with acetican hydride in pyridine. The title compound has melting point 417-418 K (Pluta et al., 2012). X-ray quality crystals were grown from chloroform-ethanol mixture by slow evaporation.