phthalazinedione derivatives

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Design, synthesis and antibacterial activity of new
phthalazinedione derivatives
ABD EL-GALIL M. KHALIL, MOGED A. BERGHOT and MOSTAFA A. GOUDA*
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516,
Egypt.
* Corresponding author. E-mail: [email protected]
(Received 22 November 2009, revised 15 July 2010)
Abstract: Dibenzobarrelene (1) was utilized as the key intermediate for
the synthesis of some new 2-substituted (1,4-dioxo-3,4,4e,5,10,10ahexahydro-1H-5,10-benzeno-benzo[g]phthalazine: 2, 5a–d, 8a–c and 10.
Condensation of 2 with benzaldehyde or anisaldehyde gave the
corresponding acrylonitrile derivative 3a, b, respectively. Thiophene
derivatives 4a, b were obtained via the Gewald reaction of 2 with
cyclohexanone or pentanone, respectively. Treatment of 5d with acetyl
chloride or p-toluenesulfonyl chloride afforded the corresponding esters 6,
7, respectively. Cyclization of 8a–c with formalin afforded the
corresponding triazine derivatives 9a–c. Ring opening of 10 with sodium
hydroxide gave the corresponding triazole derivative 11, which when
alkylated with pentyl bromide afforded the pentylsulfanyl derivative 12.
Representative compounds of the synthesized products were established
and evaluated as antibacterial agents.
Keywords: Dibenzobarrelene, Phthalazine, Thiophene, Triazine, Triazole,
Antibacterial Agents.
INTRODUCTION
In the past decades, the synthesis of heterocyclic compounds was a
subject of great interest due to their wide applicability. Heterocyclic
compounds occur very widely in nature and are essential to life. Among a
large variety of heterocyclic compounds, heterocycles containing the
phthalazine moiety are of interest due to their pharmacological and
biological activities (Fig. 1).1–3
The phthalazine nucleus has pronounced pharmacological applications
due to its anticonvulsant,4 cardiotonic,5 and vasorelaxant,6 activities. In
continuation of efforts7–8 to identify new candidates that may be of value in
designing new, potent, selective and less toxic antimicrobial agent, herein
the syntheses of some new heterocycles incorporating the phthalazine moiety
starting from dibenzobarallene are reported.9
Fig. 1
RESULTS AND DISCUSSION
Analytical and spectral data of the synthesized compounds
Compound 3a: Yellow crystals; Yield: 65 %, 2.89 g; m.p. 330 °C;
Calcd. for C28H19N3O3 (445.47): C, 75.49, H; 4.30; N, 9.43 %. Found: C,
75.57; H, 4.38; N, 9.50 %; IR (KBr, cm–1): 3345 (NH), 2856 (aliphatic C–
H), 2214 (CN), 1718 (2CO), 1662 (CO); 1H-NMR (? MHz, CDCl3, δ /
ppm): 3.2 (2H, s , C11–H, C12–H), 4.7 (2H, s, C9–H, C10–H), 7.5–7.7 (13H,
m, Ar-H), 7.8 (1H, s, C=CH–Ar), 10.5 (1H, s, NH); 13C-NMR (? MHz,
DOI:10.2298/JSC091122028K
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CDCl3, δ / ppm): 173.8, 163.6, 145.1, 142.3, 139.4, 133.3, 129.9, 129.0,
128.5, 126.1, 125.8, 124.5, 123.7, 118.3, 112.4, 44.6, 44.4; MS (m/z,
(relative abundance, %)): 445 [M+, 0.6], 378 (0.15), 347 (0.1), 275 (5.3), 204
(0.9), 202 (3.5), 178 (100), 101 (3.5), 89 (11.5), 76 (6.2), 44 (2.0).
Compound 3b: pale yellow powder; Yield: 60 %, 2.85 g; m.p. 324 °C;
Calcd. for C29H21N3O4 (475.49): C, 73.25; H, 4.45; N, 8.84 %. Found: C,
73.20; H, 4.39; N, 8.97 %; IR (KBr, cm–1): 3330 (NH), 2863 (aliphatic C–
H), 2220 (CN), 1721 (2CO), 1658 (CO); 1H-NMR (? MHz, CDCl3, δ /
ppm): 3.2 (2H, s, C11–H, C12–H), 3.8 (3H, OCH3), 4.7 (2H, s, C9–H, C10–
H), 7.0–7.5 (12H, m, Ar-H), 7.7(1H, s, C=CH–Ar), 10.5 (1H, s, NH); 13CNMR (? MHz, CDCl3 δ / ppm): 174.0, 163.8, 160.8, 144.6, 142.2, 139.2,
131.1, 126.3, 126.0, 123.2, 124.7, 124.0, 119.1, 114.3, 109.7, 55.3, 44.6,
44.5.
Compound 4a: Yield: 61 %, 1.01 g; m.p. 303 °C; Calcd. for
C33H31N3O3S (549.68): C, 72.11; H, 5.68; N, 7.64 %. Found: C, 72.28; H,
5.74; N, 7.76 %; IR (KBr, cm–1): 3270 (NH), 2939 (aliphatic C–H), 1718
(2CO), 1652 (CO); 1H-NMR (? MHz, CDCl3, δ / ppm): 1.4–2.9 (19H, m,
9CH2, NH), 3.2–3.3 (2H, s, C11–H, C12–H), 4.8 (2H, s, C9–H, C10–H), 7.1–
7.8 (8H, m, Ar-H); 13C-NMR (? MHz, CDCl3, δ / ppm): 194.8, 174.6, 173.7,
141.3, 139.5, 138.3, 128.2, 127.1, 126.9, 126.6, 125.2, 125.0, 124.2, 78.5,
45.3, 45.0, 41.8, 38.3, 32.0, 26.9, 25.7, 25.3, 24.9, 24.5, 23.8, 23.1, 22.1,
21.8; MS (m/z, (relative abundance, %)): 549 [M+, 27.0], 506 (9.8), 493
(3.5), 451 (0.1), 371 (7.9), 328 (8.8), 275 (1.7), 259 (9.7), 193 (5.3), 178
(100), 151 (26.5), 123 (2.6), 78 (15.0), 44 (6.6).
Compound 4b; Yield: 67 %, 1.05 g; m.p. 274 °C; Calcd. for
C31H27N3O3S (521.63): C, 71.38; H, 5.22; N, 8.06 %. Found: C, 71.45; H,
5.31; N, 8.17 %; IR (KBr, cm–1): 3266 (NH), 2945 (aliphatic C–H), 1725
(2CO), 1660 (CO); 1H-NMR (? MHz, CDCl3, δ / ppm): 1.4–3.0 (15H, m,
7CH2, NH), 3.4 (2H, s, C11–H, C12–H), 4.9 (2H, s, C9–H, C10–H), 7.1–7.7
(8H, m, Ar-H).
Compound 5a: Yield: 75 %, 3.07 g; m.p. 306 °C; Calcd. for
C25H18N2O4 (410.42): C, 73.16; H, 4.42; N, 6.83 %. Found: C, 73.21; H,
4.53; N, 6.92 %; IR (KBr, cm–1): 3387 (OH), 3260 (NH), 1724 (2CO), 1659
(CO); 1H-NMR (? MHz, DMSO-d6, δ / ppm): 3.2 (2H, s, C11–H and C12–
H), 4.9 (2H, s, C9–H and C10–H), 7.0–7.8 (12H, m, Ar-H), 10.8 (1H, s, OH),
11.4 (1H, s, NH); 13C-NMR (? MHz, DMSO-d6, δ / ppm): 177.4, 173.8,
159.1, 142.3, 139.4, 135.2, 129.4, 127.2, 126.8, 125.3, 124.7, 119.6, 117.7,
114.3, 44.9, 44.7.
Compound 5b: Yield: 77 %, 3.3 g; m.p. 328 °C; Calcd. for
C25H17ClN2O3 (428.87): C, 70.01; H, 4.00; N, 6.53 %. Found: C, 70.08; H,
4.06; N, 6.61 %; IR (KBr, cm–1): 3374 (NH), 2964, 2927 (aliphatic C–H),
1727 (2CO), 1661 (CO); MS (m/z, (relative abundance, %)): 430 [M++2,
2.6], 428 [M+, 8.0], 383 (0.7), 319 (2.7), 277 (1.8), 253 (1.1), 204 (1.2), 202
(6.2), 178 (100), 139 (40.7), 105 (17.6), 77 (8.0), 55 (1.7).
Compound 5c: Yield: 86 %, 3.4 g; m.p. 322 °C; Calcd. for C24H17N3O3
(395.41): C, 72.90; H, 4.33; N, 10.63 %. Found: C, 72.96; H, 4.38; N, 10.74
%; IR (KBr, cm–1): 3163 (NH), 2996 (aliphatic C–H), 1729 (2CO), 1660
(CO); MS (m/z, (relative abundance, %)): 395 (M+, 10.6), 370 (0.2), 316
(0.4), 275 (0.3), 231 (0.1), 202 (3.5), 178 (100), 152 (1.7), 106 (3.5), 78
(1.7).
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Compound 5d: Yield: 72 %, 3.1 g; m.p. 250 °C; Calcd. for
C24H18N2O4S (430.48): C, 66.96; H, 4.21; N, 6.51 %. Found: C, 67.04; H,
4.33; N, 6.68 %; IR (KBr, cm–1): 3166 (NH), 2959 (aliphatic C–H), 1718,
1662 (2CO), 1357 (SO2N); 1H-NMR (? MHz, DMSO-d6, δ / ppm): 3.1 (2H,
s, C11–H, C12–H), 4.8 (2H, s, C9–H, C10–H), 7.1–7.8 (13H, m, Ar-H), 10.8
(1H, s, NH).
Compound 6: Yield: 93 %, 0.75 g; m.p. 282 °C; Calcd. for
C26H20N2O5S (472.51): C, 66.09; H, 4.27; N, 5.93 %. Found: C, 66.12; H,
4.30; N, 5.98 %; IR (KBr, cm–1): 2880 (aliphatic C–H), 1707, 1673 (2CO),
1380 (SO2N).
Compound 7: Yield: 82 %, 1.4 g; m.p. 269 °C; Calcd. for
C31H24N2O6S2 (584.66): C, 63.68; H, 4.14; N, 4.79 %. Found: C, 63.76; H,
4.26; N, 4.89 %; IR (KBr, cm–1): 2910 (aliphatic C–H), 1732 (CO), 1387
(SO2N); 1H-NMR (? MHz, DMSO-d6, δ / ppm): 2.4 (3H, s, CH3), 3.2 (2H,
s, C11–H, C12–H), 4.7 (2H, s, C9–H, C10–H), 6.8–7.6 (17H, m, Ar-H).
Compound 8a: Yield: 80 %, 3.48 g; m.p. 257 °C; Calcd. for
C26H21N3O3 (423.46): C, 73.74; H, 5.00; N, 9.92 %. Found: C, 73.64; H,
4.92; N, 9.85 %; IR (KBr, cm–1): 3369, 3200 (2NH), 1727 (2CO), 1660
(CO).
Compound 8b: Yield: 62 %, 2.71 g; m.p. 248 °C; Calcd. for
C27H23N3O3 (437.49): C, 74.12; H, 5.30; N, 9.60 %. Found: C, 74.23; H,
5.43; N, 9.74 %; IR (KBr, cm–1): 3386, 3197 (NH), 2939 (aliphatic C–H),
1717 (2CO), 1658 cm–1 (CO); 1H-NMR (? MHz, DMSO-d6, δ / ppm): 2.4
(3H, s, CH3), 3.2 (2H, s, C11–H, C12–H), 4.7 (2H, s, C9–H, C10–H), 4.8 (1H,
s, NH), 5.4 (2H, s, CH2), 6.8–7.4 (12H, m, Ar–H), 9.4 (1H, s, NH); MS (m/z,
(relative abundance, %)): 437 (M+, 3.2), 259 (1.1), 202 (11.3), 178 (100),
120 (9.5), 91 (33).
Compound 8c: Yield: 75 %, 3.4 g; m.p. 260 °C; Calcd. for
C26H20ClN3O3 (457.91): C, 68.20; H, 4.40; N, 9.18 %. Found: C, 68.27; H,
4.48; N, 9.27 %; IR (KBr, cm–1): 3365, 3210 (2NH), 1725 (2CO), 1658
(CO).
Compound 9a: Yield: 78 %, 0.6 g; m.p. 274 °C; Calcd. for C28H22N2O3
(434.49): C, 77.40; H, 5.10; N, 6.45 %. Found: C, 77.48; H, 5.23; N, 6.53 %;
IR (KBr, cm–1): 2963 (aliphatic C–H), 1737 (2CO), 1732 (CO); MS (m/z,
(relative abundance, %)): 435 (M+, 14.0), 391 (0.9), 347 (2.2), 288 (0.8), 257
(5.3), 243 (2.2), 203 (7.0), 178 (100), 161 (5.3), 105 (22.6), 91 (9.7), 77
(1.3).
Compound 9b: Yield: 70 %, 0.52 g; m.p. 275 °C; Calcd. for
C29H24N2O3 (448.51): C, 77.66; H, 5.39; N, 6.25 %. Found: C, 77.72; H,
5.46; N, 6.33 %; IR (KBr, cm–1): 2867 (aliphatic C–H), 1727 (2CO), 1718
(CO).
Compound 9c: Yield: 80 %, 0.64 g; m.p. 292 °C; Calcd. for
C28H21ClN2O3 (468.93): C, 71.72; H, 4.51; N, 5.97 %. Found: C, 71.69; H,
4.47; N, 5.95 %; IR (KBr, cm–1): 2851 (aliphatic C–H), 1742 (2CO), 1730
(CO); 1H-NMR (? MHz, DMSO-d6, δ / ppm): 3.2 (2H, s, C11–H, C12–H),
4.7 (2H, s, C9–H, C10–H), 5.4 (2H, s, NCH2CO), 6.2 (2H, s, NCH2N), 6.8–
7.6 (12H, m, Ar–H); MS (m/z, (relative abundance, %)): 471 (M++2, 0.12),
469 (M+, 0.4), 291 (0.1), 178 (100), 138 (18.8), 75 (7.1).
Compound 10: Yield: 70 %, 1.22 g; mp 267–268oC (glacial acetic) and
Yield: 80 %, 1.4 g; m.p. 269 °C (THF); Calcd. for C19H16N4O2S (364.42):
C, 62.62; H, 4.43; N, 15.37 %. Found: C, 62.70; H, 4.46; N, 15.42 %; IR
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(KBr, cm–1): 3409, 3248, 3142 (NH, NH2), 1775, 1736 (2CO), 1461, 1111
(CSNH); MS (m/z, (relative abundance, %)): 348 (M+, 1.0), 275 (0.7), 202
(3.2), 178 (100), 101 (9.7), 84 (6.4).
Compound 11: Yield: 84.7 %, 0.503 g; m.p. 197 °C; Calcd. for
C19H15N3O2S (349.41): C, 65.31; H, 4.33; N, 12.03 %. Found: C, 65.38; H,
4.39; N, 12.07 %; IR (KBr, cm–1): 3136, 3111 (2NH), 2937–2866 (OH),
1709 (CO), 1461, 1256 (CSNH); MS (m/z, (relative abundance, %)): 203
(ethenoanthracene, 3.0), 178 (100), 152 (13.0), 81 (11.7), 59 (13.0).
Compound 12: Yield: 85 %, 0.7 g; m.p. 229 °C; Calcd. for
C24H25N3O2S (419.54): C, 68.71; H, 6.01; N, 10.02 %. Found: C, 68.80; H,
6.07; N, 10.06 %; IR (KBr, cm–1): 3172 (NH), 2949–2851 (OH), 1703 (CO);
1H–NMR (? MHz, DMSO-d , δ / ppm): 0.8 (3H, t, CH ), 1.2–1.7 (6H, m,
6
3
3CH2), 3.2 (2H, d, C11–H, C12–H), 3.6 (2H, t, SCH2), 4.7 (2H, d, C9–H,
C10–H), 7.1–7.3 (8H, m, Ar-H), 11.5 (1H, s, NH), 12.3 (1H, s, OH); MS
(m/z, (relative abundance, %)): 420 (M+, 0.6), 375 (1.1), 347 (0.5), 330 (0.6),
241 (1.3), 197 (1.4), 194 (4.7), 178 (100), 97 (3.3), 51 (3.0).
Chemistry
The synthetic procedures adopted to obtain the target compounds are
depicted in Schemes 1–3. Dibenzobarallene,1 and 3-(1,4-dioxo3,4,4e,5,10,10a-hexahydro-1H-5,10-benzeno-benzo[g]phthalazin-2-yl)-3oxo-propiononitrile (2) were prepared according to previously reported
methods.9,10
Reaction of the propionyl nitrile derivative 2 with benzaldehyde or panisaldehyde, in the presence of sodium methoxide afforded the
corresponding acrylonitrile derivatives 3a and b, respectively. The structures
of 3a and b were supported by both their analytical and spectral data. The
1H-NMR spectrum of 3a displayed a singlet signal at δ 7.8 due to the
methine proton of benzylidene. In addition, compound 3b displayed two
singlet signals at δ 3.8 and 7.7 due to OCH3 and methine protons,
respectively. The 13C-NMR spectrum of 3a exhibited signals at 118.3 and
112.4 due to ethylenic carbons; in addition, 3b exhibited, among others,
signals at δ 114, 109 and 55.3 due to ethylenic and OCH3 carbons,
respectively. Furthermore, the reaction of the propionyl nitrile derivative 2
with cyclohexanone or cyclopentanone in a 1:2 molar ratio under Gewald
reaction condition11–13 afforded the products 4a and b, respectively, in low
yields.
Scheme 1
The formulation of 4a and b were based on their mass, IR, 1H- and 13CNMR spectra. The 1H-NMR spectra of 4a and b displayed multiplet signals
at δ 1.4–2.9 and 1.4–3.0 due to methylene and NH protons, respectively. The
13C-NMR spectrum of 4a displayed signals at δ 21.8, 22.1, 23.1, 23.8, 24.5,
24.9, 25.3, 25.7 and 26.9 due to CH2 carbons; signals at 78.5, 139.5, 128.2,
126.6, 125.0 and 194.8, 177.3, 174.6 due to spiro, thiophene and carbonyl
carbons, respectively. The mass spectrum of 4a exhibited the molecular ion
peak at m/z 549, which is in agreement with its molecular formula
C33H31N3O3S, in addition to other fragment ion peaks at m/z 506 and 493,
451, 371, 328, 275 and 259, which are illustrated in the fragmentation
pattern shown in Fig. 2.
Figure 2
Additionally, reaction of adduct 1 with the appropriate acid hydrazide,14
in acetic acid or DMF afforded the interesting phthalazinedione derivatives
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5a–d; an analogous reaction behavior has already been reported.15–18 The
structures of 5a–d were confirmed based on their spectral data. The IR
spectra of 5a–d showed NH bands at 3374–3163 cm–1 and three carbonyl
bands at around 1729 and 1660 cm–1. Moreover, the IR spectra of 5a and d
showed additional bands at 3387 and 1357 cm–1, due to –OH and –SO2N
groups, respectively. Furthermore, the 1H-NMR spectrum of 5a displayed
singlet signals at δ 10.8 and 11.4 due to OH and NH protons, respectively;
also, 5d displayed a singlet signal at δ 10.8 due to the NH proton of the
phthalazine ring. The 13C-NMR spectrum of 5a revealed signals at 173.9
and 177.4 due to three carbonyl carbons. The mass spectrum of 5b gave the
molecular ion peak at m/z 428 and 430 corresponding to [M+] and [M++2],
which are in agreement with its molecular formula C25H17ClN2O3. In
addition to the base, a peak at m/z 178 corresponding to anthracene was also
observed.
Treatment of 5d with acetic anhydride and p-toluene sulfonyl chloride
in the presence of a few drops of TEA yielded the phthalazine derivatives 6
and 7, respectively. The 1H-NMR spectrum of 7 revealed a singlet signal at δ
2.4 due to the CH3 group; analogous behaviors were recorded in the
literature.15,17–20
Scheme 2
Furthermore, condensation of compound 1 with the appropriate Narylamino acetic acid hydrazide,21 in DMF yielded the corresponding
phthalazinediones derivatives 8a–c. The structures of 8a–c were based on
spectral data. Thus, the IR spectra of 8a–c showed 2NH bands at 3386–3365
and 3210–3197 in addition to carbonyl bands at 1725–1717 and 1660–1658
cm–1. The mass spectrum of 8b exhibited a molecular ion peak at m/z 437,
which is in agreement with its molecular formula C27H23N3O3, the base
peak at m/z 178 corresponding to anthracene and a fragment ion peak at m/z
259 due to [M+–anthracene]. The 1H NMR spectrum of 8b displayed singlet
signals at δ 2.4, 4.8, 5.4 and 9.4 due to CH3, NHAr, CH2, NHCO protons,
respectively.
Cyclization of the phthalazinediones 8a-c by reaction with 37 %
formalin in glacial acetic acid was studied with the aim of preparing the
1,2,4-triazine derivatives 9a–c with potential biological activities.22,23 The
structures of 9a–c were based on analytical and spectral data. The IR spectra
of 9a–c showed the absence of NH bands. The 1H-NMR spectrum of 9c
revealed, beside the disappearance of NH signal, the appearance of signals at
δ 5.4 and 6.2 due to CH2CO and NCH2N protons, respectively. The mass
spectrum of 9c exhibited a molecular ion peak at m/z 469 and 471
corresponding to [M+] and [M++2], which is in agreement with its molecular
formula C27H20ClN3O3. The major fragment ion peaks at m/z 291 and 178
were attributed to [M+–anthracene] and anthracene, respectively.
Scheme 3
The remarkable biological importance of 1,2,4-triazole derivatives,24–26
prompted an investigation of the synthesis of some new triazole derivatives
of expected antimicrobial activity. Thus, the adduct 1 was reacted with
thiosemicarbazide in acetic acid or in THF to give 10. The structure of 10
was ascertained through spectral data. Its mass spectrum exhibited the
molecular ion peak [M+] at m/z 348, which is consistent with the molecular
formula C19H15 N3O2S, in addition to other fragment ion peaks at m/z 275
and 178 due to [M+–NCSNH2] and anthracene, respectively. The derivative
10 was then heated with dilute aqueous sodium hydroxide to yield the
DOI:10.2298/JSC091122028K
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corresponding 5-thioxo-2,5-dihydro-1H-[1,2,4]triazole derivative 11, the
structure of which was confirmed by analytical and spectral data.
Scheme 4
The IR spectrum of 11 showed bands at 3136, 3111, 2937–2866, 1709
and 1461, 1256 cm–1 due to 2NH, OH, 3CO and CSNH groups, respectively.
Moreover, the mass spectrum of 11 exhibited the molecular ion peak at m/z
203, corresponding to [M+–(CO2, triazole moiety)]. Subsequent, alkylation
of 11 using n-pentyl bromide and a few drops of TEA furnished the 5pentyl-sulfanyl-2H-[1,2,4]-triazole derivative 12. The spectral data of 12 are
fully in accordance with the proposed structure, particularly the 1H-NMR
spectrum that displayed signals at δ 0.8, 1.2–1.7, 3.6, 11.5 and 12.3 due to
CH3, 3CH2, CH2S, NH and OH protons, respectively. The mass spectrum of
12 added further support to the assigned structure. The molecular ion peak
appeared at m/z 420, the fragmentation pattern proceeded by two different
routes. In one pathway, the consecutive expulsion of CO2 and N2 from [M+]
gave peaks at m/z 375 and 347, respectively. In the other route, the
molecular ion peak underwent fragmentation with the cleavage anthracene
(m/z =178) and another fragment ion at m/z 241. The synchronous loss of
CO2 from the latter species gave a fragment ion peak at m/z 197. The
characteristic fragment ions are shown in the fragmentation pattern given in
Fig. 3.
Figure 3
Pharmacology
Twenty compounds were screened by the agar diffusion technique27 for
their in vitro antibacterial activities against two strains of bacteria Bacillus
thuringiensis and Escherichia coli. The bacteria were maintained on nutrient
agar. DMSO showed no inhibition zones. The agar media were incubated
with different cultures of the tested microorganism. After 24 h of incubation
at 30 °C; the diameter of inhibition zone (mm) was measured (Table I).
Ampicillin and chloramphenicol were purchased from the Egyptian market
and used in a concentration 2 mg ml–1 as references.
TABLE I
The results depicted in Table I revealed that compounds 3a, 3b, 4a, 5b,
5d, 6, 7 and 12 exhibited interestingly high antibacterial activities against the
reference drugs.
Thus, it would appear that the introduction of arylidene,
benzothiophene, sulfonyl, sulfonate or triazole moieties enhances the
antibacterial properties of 3-(1,4-dioxo-3,4,4e,5,10,10a-hexahydro-1H-5,10benzeno-benzo[g]phthalazin-2-yl)-3-oxo-propiononitrile (2) (Fig. 2). By
comparing the results obtained for the antibacterial activity of the
compounds reported in this study with their structures, the following
structure activity relation ships (SARs) were postulated: (i) compounds 3a
and 3b were more potent than compound 2, which may be attributed to the
introduction of the arylidene moiety; (ii) compound 4a was more potent than
compound 2 due to presence of the benzothiophenetriazaepine moiety; (iii)
compounds 5d, 6 and 7 were more potent than compound 2 due to the
replacement of the propiononitrile moiety by an arylsulfonyl moiety; (iv)
compound 7 was more potent than 5d and 6, which may be due to the
presence of two arylsulfonate groups and (v) compound 12 was more potent
than compound 2 which may be attributed to the replacement of the
pyridazinedione moiety with a triazole moiety.
Figure 4
EXPERIMENTAL
DOI:10.2298/JSC091122028K
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All melting points are in degree centigrade and were measured on a Gallenkamp
electric melting point apparatus. Thin layer chromatography, TLC, analysis was
performed on silica gel 60 F254 pre-coated aluminum sheets. The IR spectra were
recorded using the KBr wafer technique on a MATSON 5000 FTIR spectrometer, at the
Faculty of Science, Mansoura University. The 1H-NMR spectra were determined on
either a Varian XL 200 MHz instrument at the Faculty of Science, Cairo University, a
Brucker WP 300 instrument at the Georg-August University Gottingen, Germany or a
Brucker AC 300 instrument at the Eberhard-Karls University, Tubingen, Germany, in
CDCl3 or DMSO solvent using TMS as the internal standard. The 13C-NMR spectra
were determined on a Brucker AC 300 instrument at the Eberhard-Karls University,
Tubingen, Germany, in CDCl3 or DMSO solvent using TMS as the internal standard.
The mass spectra were recorded on a Finnegan MAT 212 instrument and the elemental
analyses (C, H, and N) were performed in the Microanalytical Center of Cairo
University, Egypt.
2-[1,4-Dioxo-3,4,4a,5,10,10a-hexahydro-1H-5,10-benzeno-benzo[g]-phthalazine-2carbonyl]-3-(phenyl or p-methoxyphenyl)-acrylonitriles 3a, b
General procedure
A mixture of 2 (3.57 g; 0.01 mole) and benzaldehyde or p-anisaldehyde (0.011
mole) was added to a solution of sodium methoxide (0.34 g; 0.015 mole) in methanol (20
ml). The reaction mixture was heated until a clear solution was obtained. The reaction
mixture was left overnight. The products were separated and crystallized from ethanol–
benzene to give 3a and b, respectively.
Synthesis of (4H)-1,2,4-triazepin-7-one derivatives (4a, b)
General procedure
To a mixture of 2 (1.07 g; 0.003 mole), cyclohexanone or cyclopentanone (0.006
mole) and sulfur (0.11 g; 0.0035 mole) in ethanol (30 ml) was added morpholine (0.45
ml). The reaction mixture was heated on a water bath at 80–90 oC with stirring for 1 h.
Another portion of morpholine (0.15 ml) was added to the reaction mixture and stirred
for another 3.5 h. The separated products were crystallized from ethanol–benzene to give
4a and b as colorless crystals and a white powder, respectively.
Synthesis of 2-[(2-hydroxybenzoyl) or (4-chlorobenzoyl) or (pyridine-4-carbonyl) or
(benzenesulfonyl)]-2,3,4a,5,10,10a-hexahydro-5,10-benzeno-benzo[g]phthalazine-1,4dione (5a–d)
General procedure
A solution of 1 (2.76 g; 0.01 mole) and the corresponding acid hydrazide
derivatives (0.01 mole) in DMF (20 ml) were refluxed for 3–4 h. The reaction mixture
was poured into a beaker containing ice and then the separated product was crystallized
from a suitable solvent to afford the phthalazine-1,4-diones 5a–d. 5a: white powder, 5b:
crystallization from DMF and separated as colorless needless crystals, 5c: crystallization
from benzene-ethanol and separated as colorless needless crystal, 5d: crystallization
from DMF–methanol.
Synthesis of acetic acid-3-benzene-sulfonyl-4-oxo-3,4,4a,5,10,10a-hexahydro-5,10benzeno-benzo[g]phthalazin-1-yl ester (6)
A mixture of 5d (0.75 g; 0.0017 mole) and a few drops of TEA in (10 ml) acetic
anhydride was warmed for 2 h. The separated product was crystallized from benzene–
ethanol to give 6.
Synthesis
of
toluene-4-sulfonic
acid-3-benzenesulfonyl-4-oxo-3,4,4a,5,10,10ahexahydro-5,10-benzeno-benzo[g]phthalazin-1-yl ester (7):
A mixture of 5d (1.3 g; 0.003 mole) p-toluenesulfonyl chloride (0.66 g; 0.0035
mole) and few drops of TEA in dichloromethane (20 ml) was heated under reflux for 3 h.
The solvent was distilled off and the residue was washed with water and crystallized
from methanol–benzene to give 7;
Synthesis
of
2-[1-oxo-2-{(phenyl)/(p-tolyl)/(p-chlorophenyl)}-amino-ethyl]2,3,4a,5,10,10a-hexahydro-5,10-benzeno-benzo[g]-phthalazine-1,4-dione (8a–c)
General procedure:
A solution of 1 (2.76 g; 0.01 mole) and the appropriate arylaminoacetylhydrazide,
namely anilinoacetylhydrazide, p-toluidinoacetyl hydrazide or p-chloroanilinoacetyl
hydrazide (0.01 mole) in DMF (20 ml) were heated under reflux for 3–4 h. The reaction
mixture was diluted with water. The separated products were filtered and crystallized
from a suitable solvent to give 8a–c. 8a: crystallized from methanol–benzene; white
powder, 8b: crystallized from methanol–benzene; 8c: crystallized from benzene–ethanol;
Synthesis of {2-(phenyl)/ (p-tolyl)/(p-chlorophenyl)}-2,3,5a,6,11,11a-hexahydro-6,11benzeno-benzo[i]-1H-2,4a,12a-triaza-anthracene-4,5,12-trione (9a–c)
DOI:10.2298/JSC091122028K
7
General procedure
A solution of 8a–c (0.0017 mole), formalin 37 % (0.3 ml, 0.0035 mole) and a few
drops of glacial acetic acid in DMF (10 ml) were warmed on a water bath for 2–3 h. The
reaction mixture was diluted with water. The separated product was filtered and
crystallized from a suitable solvent to give 9a–c. 9a: crystallized from benzene; 9b:
crystallized from benzene; colorless crystals; 9c: crystallized from benzene–ethanol;
white powder,
Synthesis
of
2-[1,4-dioxo-3,4,4a,5,10,10a-hexahydro-1H-5,10-benzeno-benzo[g]phthalazin-2-yl]-thiamide (10)
A mixture of 1 (1.38 g; 0.005 mole) and thiosemicarbazide (0.53 g; 0.005 mole) in
glacial acetic acid (20 ml) was heated on a water path at 90 °C for 8 h. The separated
product was crystallized from benzene–ethanol to give 10.
The above procedure was carried out in THF (20 ml) instead of glacial acetic acid.
The reaction mixture was heated under reflux for 2.5 h. The separated product was
crystallized to give 10.
Synthesis of 12-[5-thioxo-2,5-dihydro-1H-[1,2,4]triazol-3-yl]-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid (11)
A solution of 10 (0.6 g; 0.0017 mole) in 1 % sodium hydroxide (100 ml) was
heated on water bath at 95 °C for 2 h. The solution was left to cool and acidified with
dilute hydrochloric acid. The separated product was crystallized from benzene–ethanol to
give 11;
Synthesis of 12-[5-pentylsulfanyl-2H-[1,2,4]triazol-3-yl]-9,10-dihydro-9,10-ethanoanthracene-11-carboxylic acid (12)
A solution of 11 (1.0 g; 0.0028 mole), 1-bromopentane (0.5 g; 0.0032 mole) and a
few drops of TEA in ethane (25 ml) was heated under reflux for 1 h. The reaction
mixture was diluted with water. The separated product was crystallized from ethanol–
benzene to give 12;
In vitro antimicrobial activity
The tested compounds were evaluated by the agar diffusion technique, 27 using a 2
mg ml–1 solution in DMSO. The test organisms were B. thuringiensis as gram-positive
bacteria and E. coli as gram-negative bacteria. A control using DMSO without the test
compound was included for each organism. Ampicillin and chloramphenicol in DMSO
were used as the reference drugs.
CONCLUSION
In conclusion, we reported herein a simple and convenient route for the
synthesis of some new heterocycles based on the phthalazinedione moiety,
which were tested for their antibacterial activity.
Acknowledgements. Dr. S. Bondock and Dr. E. Abd El-Latif, Chemistry
Department, Faculty of Science, Mansoura University, for performing the spectral
measurements, and Dr. A. Mohamadin and Dr. A. El-Morsey, Botany Department,
Faculty of Science, Mansoura University, for the microbiological screening, are greatly
acknowledged.
Извод
Синтеза и антибактеријска активност нових деривата фталазиндиона
ABD EL-GALIL M. KHALIL, MOGED A. BERGHOT и MOSTAFA A. GOUDA*
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt.
Дибензобарелен (1) је коришћен као главни интермедијер у синтези нових 2супституисаних
(1,4-диоксо-3,4,4e,5,10,10a-хексахидро-1H-5,10-бензенобензо[g]фталазина: 2, 5a–d, 8a–c и 10. Кондензацијом 2 са бензалдехидом или
анизалдехидом добијени су нови деривати акрилонитрила 3а и 3б. Деривати тиофена
4а и 4б добијени су Гевалдовом (Gewald) реакцијом 2 са циклохексаноном или
циклопентаноном. Реакцијом 5д са ацетил–хлоридом или пара-толуолсулфонилхлоридом добијени су одговарајући деривати триазина 6 и 7. Циклизацијом деривата
8а–ц са формалдехидом добијени су одговарајући деривати триазина 9а–ц. Отварањем
прстена деривата 10 натријум–хидроксидом добијен је одговарајући дериват 11 који
алкиловањем са бромпентаном даје пентилсулфанил дериват 12. Одабрана једињења су
испитана као антибактеријски агенси
DOI:10.2298/JSC091122028K
8
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8. M. A. Berghot, Arch. Pharmacal. Res. 24 (2001) 263
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12. H. Zhang, G. Yang, J. Chen, Z. Chen, Synlett. (2004) 3055
13. K. Gewald, E. Schinke, H. Boettcher, Chem. Ber. 99 (1966) 94
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(1994) 157621t
16. H. Satoh, M. Tonegawa, K. Kitahara, R. Aoyagi, Tokyo Ika Daigaku Kiyo 5 (1979)
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17. E. Dunkels, S. Hillers, Latvijas PSR Zinatnu Akad. Vestis, 2 (1954) 105; C.A. 49
(1955) 9659h
18. E. Domagalina, I. Kurpiel, J. Mojejko, Roczniki Chem. 38 (1964) 571
19. D. Stefanye, W. L. Howard, J. Org. Chem. 19 (1954) 115
20. H. Śladowska, J. Potoczek, M. Sokowska, G. Rajtar, M. Sieklucka-Dziuba, T. Kocki,
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24. F. Havaldar, A. R. Patil, Eur. J. Chem. 5 (2008) 347
25. G. I. Chipen, D. E. Duka, V. Ya. Grinshtein, Chem. Heterocyclic Comp. 2 (1966) 84
26. O. M. Aboul Wafa, F. A. Berto, Arch. Pharm. (Weinheim) 325 (1992) 123
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DOI:10.2298/JSC091122028K
9
TABLE / I. Inhibition zone (mean diameter of inhibition in mm) as a criterion of the
antibacterial activities of the newly synthesized compounds:
Inhibition Zone in mm
Compound No
2
3a
3b
4a
4b
5a
5b
5c
5d
6
7
8a
8b
8c
9a
9b
9c
10
11
12
Ampicillin
Chloramphenicol
DOI:10.2298/JSC091122028K
Gram positive bacteria
"B. thuringiensis"
22
27
28
21
18
17
32
16
27
26
40
18
16
20
17
18
17
15
16
24
18
23
Gram negative bacteria
"E. coli"
16
20
19
20
17
15
25
17
22
21
22
16
18
17
16
16
16
14
13
22
19
20
10
CONMe2
O
CH3
N
N
O
O
AcHN
N
H
H
N
O
O
O
N
H
N
O
NHAr
HN
O
1
antihypoxic and antipyretic agent, HAV 3C inhibitor,
2
Fig. 1
DOI:10.2298/JSC091122028K
11
O
A
O
O
O
A
m/z= 259
O
N
N
B
H
N H
NB
O
S
m/z= 275
O
m/z= 549
[M+]
-CH2CH2CH3
- anthracene
O
N
N
H
O
N
O
N
N
S
O
m/z= 371
N
O
O
m/z= 506
O
-CH2CH4CH4
N
N
N
O
H
CH
S
H
- anthracene
CH
O
S
m/z= 328
Fig. 2
DOI:10.2298/JSC091122028K
12
H
N
+
H
N
-CO2
N
N
COOH N
N
SCH2(CH2)3CH3
Route B
COOH
H
N
N
m/z = 419 [M+]
m/z = 197
m/z = 241
SCH2(CH2)3CH3
-CO2
H
N
Route A
N
N
SCH2(CH2)3CH3
m/z = 375
N
SCH2(CH2)3CH3
-N2
m/z = 347
Fig. 3
DOI:10.2298/JSC091122028K
13
O
O
N
NH
O
CN
CN
N
NH
O
O
O
CHAr
O
O
2
O
SO2Ph
N
NH
O
5d
S
O
N
N
6
O
4a
3a, Ar= C6H5
3b, Ar= 4-MeOC6H4
O
NH
N
N
SO2Ph
N
N
OCOCH3
SO2Ph
O
S
O
O
7
COOH
CH3
H
N
N
12
N
SCH2(CH2)3CH3
Fig. 4
DOI:10.2298/JSC091122028K
14
O
O
Cage
O
O H
H
2
H2N N C C CN
N
NH
Cage
DMF
O
O
O
1
CN
2
O
ArCHO
S,
n
MeONa
n
O
O
Cage =
NH
N
N
Cage
O
Cage
O
S
n
O
N
NH
CN
CHAr
O
3a, Ar= C6H5
3b, Ar= 4-MeOC6H4
4a, n= 2
4b, n= 1
Scheme 1
DOI:10.2298/JSC091122028K
15
O
O
O
CN
N
NH
Cage
O
+ PhSO2NHNH2
DMF
or AcOH
SO2Ph
N
NH
Cage
O
2
5d
ArCONHNH2
DMF
O
O
N
NH
Cage
ArSO2Cl
Ac2O/ Et3N
Et3N
O
O
Ar
N
N
Cage
O
SO2Ph
OCOCH3
6
5a, Ar= 2-OHC6H4
5b, Ar= 4-ClC6H4
5c, Ar= 4-pyridyl
Cage
N
N
SO2Ph
OSO2Ar
7, Ar= 4-MeC6H4
Cage =
Scheme 2
DOI:10.2298/JSC091122028K
16
O
O
2
+
ArNHCH2CONHNH2
DMF
NHAr
N
NH
Cage
8a, Ar= C6H5
8b, Ar= 4-MeC6H4
8c, Ar= 4-ClC6H4
O
CH2O/ AcOH
O
Cage =
O
N
N
Cage
O
N
Ar
9a, Ar= C6H5
9b, Ar= 4-MeC6H4
9c, Ar= 4-ClC6H4
Scheme 3
DOI:10.2298/JSC091122028K
17
O
2
+
H2NNHCSNH2
AcOH
H
N
N
NH
Cage
O
NH2
S
10
i- 1% NaOH
ii- dil. HCl
COOH
COOH
Cage
n-C5H11Br
H
N
N
12
N
Cage
H
N
EtOH/ Et3N
N
SCH2(CH2)3CH3
11
NH
S
Cage =
Scheme 4
DOI:10.2298/JSC091122028K
18
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