Synthesis of halogen derivatives of benzo[h]chromene and benzo[a]anthracene with promising antimicrobial activities.

Article abstract of DOI:10.1016/S0014-827X(02)01263-6

The synthesis of novel 7-(4-halophenyl)-8,9-dihydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene derivatives has been reported. The key intermediate 3-amino-9-chloro-1-(4-halophenyl)-1H-benzo[h]chromene-2-carbonitrile (3) was obtained by treating 4-halobenzylidenmalononitriles (1a-c) and ethyl 4-halobenzylidenmalonates (1d-f) with 4-chloro-1-naphthol (2) in ethanolic piperidine solution. Antimicrobial activity was shown for most of the synthesized compounds.

Full text of DOI:10.1016/S0014-827X(02)01263-6

Il Farmaco 57 (2002) 715Á722
/
www.elsevier.com/locate/farmac
Synthesis of halogen derivatives of benzo[h]chromene and
benzo[a]anthracene with promising antimicrobial activities
Mostafa M. Khafagy, Ashraf H.F. Abd El-Wahab, Fathy A. Eid, Ahmed M. El-
Agrody *
Chemistry Department, Faculty of science, Al-Azhar University, Nasr City 11884, Cairo, Egypt
Received 24 September 2001; accepted 10 March 2002
Abstract
The synthesis of novel 7-(4-halophenyl)-8,9-dihydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene derivatives has been reported.
The key intermediate 3-amino-9-chloro-1-(4-halophenyl)-1H-benzo[h]chromene-2-carbonitrile (3) was obtained by treating 4-
halobenzylidenmalononitriles (1aÁ
piperidine solution. Antimicrobial activity was shown for most of the synthesized compounds. # 2002 Editions scientifiques et
me´dicales Elsevier SAS. All rights reserved.
/
c) and ethyl 4-halobenzylidenmalonates (1dÁf) with 4-chloro-1-naphthol (2) in ethanolic
/
´
Keywords: 4-Halobenzylidenmalononitriles; Ethyl 4-halobenzylidenmalonates; 4-Chloro-1-naphthol; Benzo[h]chromenes; Benzo[a]anthracenes;
Antimicrobial activity
1. Introduction
2. Chemistry
In continuation of our previous work [1Á
Chromenes and fused chromenes are biologically
/
3,15Á17] on
/
interesting compounds with antimicrobial activities [1Á
/
the synthesis of fused chromenes using enaminonitriles,
we report here the synthesis of a variety of new
heterocyclic compounds. Thus condensation of various
3], inhibitors of influenza virus sialidases [4,5], DNA
stand-breaking activity and mutagenicity [6], antiviral
agent [7], antiproliferation agent [8], sex pheromone [9],
antitumor [10] and central nervous system (CNS)
activity [11].
substituted benzylidenmalononitriles (1aÁ/c) and ethyl
benzylidenmalonates (1dÁf) with 4-chloro-1-naphthol
/
(2) in ethanolic piperidine afforded 1:1 adducts (Scheme
1).
1
On the basis of H NMR and UV data, structure 4
Benzylidenmalononitriles and ethyl benzylidenmalo-
nates are versatile reagents for construction of hetero-
cyclic system [12Á14]. They are prone to react with a
/
was excluded [15Á
basis of 1H NMR spectra, which showed 1-H at d 4.97Á
5.00 ppm 3aÁf. The UV spectrum of 3aÁf revealed a
weak shoulder [16Á20] characteristic for 1H-chromene
at lmax (CHCl3) 275 nm (log o 2.70Á2.86), respectively.
Interaction of 3-amino-9-chloro-1-(4-halophenyl)-
1H-benzo[h]chromene-2-carbonitrile (3aÁc) with acetic
anhydride for 30 min. afforded the N-acetyl derivative
(5aÁc), while heating of 3aÁc with acetic anhydride for 6
/
19]. Structure 3 was established on the
variety of compounds containing acidic hydrogen atoms
to provide Michael adducts as intermediate, which
undergo spontaneous cyclization to b-enaminonitriles
/
/
/
/
and b-enaminocarboxylic esters, respectively [15Á
/19].
/
The present study is part of our program aimed at
developing new approaches for the synthesis of fused
heterocyclic systems. We report here the synthesis of
benzo[h]chromene derivatives and their utility as buil-
ding blocks in the synthesis of novel fused chromenes
aiming at the evaluation of their antimicrobial activity.
/
/
/
h afforded 5-chloro-10-methyl-7-(4-halophenyl)-8,9-di-
hydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene-8-one
(6aÁ
/
c) (Scheme 1). Structure 5aÁc was established on
/
the basis of IR which showed the presence of CN (2214,
2219, 2222 cmꢀ1) and CO of acetyl (1705, 1712, 1728
* Corresponding author
E-mail address: elagrody_am@yahoo.com (A.M. El-Agrody).
´
0014-827X/02/$ - see front matter # 2002 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
PII: S 0 0 1 4 - 8 2 7 X ( 0 2 ) 0 1 2 6 3 - 6

716
M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á722
/
cmꢀ1), respectively, while for 6aÁ
and the presence of CO of amide (1659, 1658, 1659
cmꢀ1), respectively. 1H NMR spectra for 5aÁ
c revealed
the presence of signal at d 2.55, 2.66, 2.71 ppm (3H, s,
COCH3) and 10.14, 10.35, 10.40 ppm (1H, br, NH),
while for 6a, c showed d 2.51, 2.52 (3H, s, 10-CH3) and
12.60, 12.63 ppm (1H, br, NH; exchangable). Structures
/
c the absence of CN
Condensation of 3aÁc with benzaldehyde or 4-meth-
oxybenzaldehyde in dioxan-piperidine solution under
reflux afforded the corresponding 3-arylmethylene-
/
/
amino derivatives (7aÁ
methyleneamino-9-chloro-1-(4-halophenyl)-1H-benzo-
[h]chromene-2-carbonitriles (7aÁc) were treated with
/f) (Scheme 1). When 3-aryl-
/
hydrazine or phenylhydrazine in absolute ethanol under
stirring at room temperature or under reflux, an
addition product 8 formed, from which elimination of
benzaldehyde hydrazon/4-methoxybenzaldehyde hy-
drazone and benzaldehyde phenylhydrazone/4-methox-
ybenzaldehyde phenylhydrazone, respectively, gave the
6aÁ/c were also supported by an independent synthesis
of the same products from 3dÁ/f and acetonitrile in
the presence of HCl gas [21] (m.p. and mixed m.p.)
(Scheme 1).
Scheme 1.

M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á
/722
717
Scheme 2.
b-enaminonitriles 3aÁ
derivatives (9) (Scheme 1). Structures 5Á
lished by spectral data and analogy with our previous
work [1Á3,15Á17].
Treatment of 3aÁ
anhydride at reflux gave the corresponding 3-ethoxy-
methyleneamino derivatives (10aÁc) (Scheme 2). Hydra-
zinolysis of 10aÁc in ethanol at room temperature under
stirring afforded the anthracene derivatives (11aÁc)
(Scheme 2). Reaction of 10aÁc with methylamine in
methanol at room temperature yielded the anthracene
derivatives (12aÁc) (Scheme 2). Ammonolysis of (10aÁc)
in methanol at room temperature for 1 h gave the open-
chain products (13aÁc), while ammonolysis of (10a) in
/
c [16,22] instead of the anthracene
cene (14a) (Scheme 2). Structure 14a was established by
an independent synthesis of the same product from 3a
and formamide under reflux (m.p. and mixed m.p.). Also
/
7 were estab-
/
/
cyclization of 13a in dioxanÁ
afforded 14a (m.p. and mixed m.p.) (Scheme 2).
Structures 13aÁc were established on the basis of IR
/piperidine under reflux
/
c with triethyl orthoformate in acetic
/
/
which showed the presence of CN (2206, 2206, 2199
cmꢀ1) and NH2 at (3464, 3155; 3464, 3348, 3155; 3395,
3163 cmꢀ1) respectively, while for 14a the absence of CN
and the presence of NH2 at (3294, 3148 cmꢀ1). 1H NMR
spectrum for 13c revealed the presence of signal at d 8.30
/
/
/
/
/
(1H, s, NÄ
/
CH) and d 7.21 ppm (2H, br, NH2), while for
14a showed d 8.33 (1H, s, 10-H) and d 6.78 ppm (2H, br,
NH2). The mass spectrum of 13c exhibited a molecular
/
ion peak m/z 377 (Mꢁ, 43%) and 379 (Mꢁꢁ
2, 14.5%)
together with a base peak at m/z 282 (100%).
/
dioxan solution for 2 h afforded 8-amino-5-chloro-7-(4-
chlorophenyl)-7H-12-oxa-9,11-diaza-benzo[a]anthra-

718
M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á722
/
3. Experimental
formed was collected by filtration and recrystallized
from a suitable solvent to give 3-amino-9-chloro-1-(4-
M.p.s are uncorrected and were determined on a
Stuart Scientific Co. Ltd. m.p.s apparatus. IR spectra
nmax KBr, cmꢀ1 were recorded on a FT IR/5300
halophenyl)-1H-benzo[h]chromene-2-carbonitriles (3aÁ
c) and ethyl 3-amino-9-chloro-1-(4-halophenyl)-1H-
benzo-[h]chromene-2-carboxylates (3dÁf) (Table 1).
/
/
spectrometer. UV spectra were measured on a PerkinÁ
/
1
Elmer Lambda-3B UVÁVisible spectrophotometer; H
/
3.2. 3-Acetylamino-9-chloro-1-(4-halophenyl)-1H-
benzo[h]chromene-2-carbonitrile (5aÁc)
NMR spectra d (ppm) on Varian Gemini (200 MHz)
spectrometer and mass spectra on a Shimadzu GC-MS-
QP 1000 EX spectrometer. Elemental analyses were
/
A solution of 3aÁc (0.01 mol) in Ac2O (20 ml) was
heated under reflux for 30 min. The solid product
formed was filtered, washed with cooled EtOH, dried
/
determined on a PerkinÁ
/
Elmer 240 C microanalyser and
0.2% of the
the results for C, H, N were within 9
/
calculated values. Characteristics of the prepared com-
pounds are given in (Table 1) and spectral data are
shown in (Table 2).
and recrystallized from suitable solvent to give 5aÁc
(Table 1).
/
3.3. 5-Chloro-10-methyl-7-(4-halophenyl)-8,9-dihydro-
3.1. Reaction of 1aÁf with 4-chloro-1-naphthol (2)
/
7H-12-oxa-9,11-diaza-benzo[a]anthracene-8-one(6aÁ
/
c)
3.1.1. General procedure
A solution of 1aÁf (0.01 mol) in EtOH (30 ml) was
treated with 4-chloro-1-naphthol (2) (0.01 mol) and
piperidine (0.5 ml). The reaction mixture was heated
until complete precipitation (reaction times: 15 min for
3.3.1. Method (a)
A solution of 3aÁ
heated under reflux for 6 h. The solid product formed
/
/
c (0.01 mol) in Ac2O (20 ml) was
was filtered, washed with cooled EtOH, dried and
c (Table
1).
recrystallized from suitable solvent to give 6aÁ
/
1aÁ
/
c; 120 min for 1dÁf). The solid product which
/
Table 1
Analytical data for the synthesized compounds
Comp.
Solvent
Colour
Yield (%)
M.p. (8C)
Molecular formula
3a
3b
Benzene
Benzene
Benzene
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Dioxan
Dioxan
Dioxan
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Dioxan
Dioxan
Dioxan
Dioxan
Colourless
Colourless
Yellow
89
90
88
73
76
78
80
81
82
78
80
79
86
82
81
79
83
86
72
76
79
82
85
84
83
80
81
79
78
80
78
224
226
246
170
162
184
220
224
232
315
325
ꢀ325
270
262
280
260
265
272
185
176
168
218
216
204
245
249
260
275
266
272
214
C
20H12Cl2N2O
C20H12BrClN2O
20H12ClFN2O
C22H17Cl2NO
C22H17BrClNO3
3c
3d
C
Colourless
Colourless
Yellow
3e
3f
5a
C22H17ClFNO3
C22H14Cl2N2O2
C22H14BrClN2O2
C22H14ClFN2O2
C22H14Cl2N2O2
C22H14BrClN2O2
C22H14ClFN2O2
C27H16Cl2N2O
Pale yellow
Pale yellow
Pale yellow
Colourless
Colourless
Colourless
Yellow
5b
5c
6a
6b
6c
7a
7b
7c
Yellow
Yellow
C
27H16BrClN2O
C27H16ClFN2O
C28H18Cl2N2O2
7d
7e
Yellow
Yellow
Yellow
C28H18BrClN2O2
C28H18ClFN2O2
C23H16Cl2N2O2
C23H16BrClN2O2
C23H16ClFN2O2
C21H14Cl2N4O
7f
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
Colourless
C21H14BrClN4O
C
21H14ClFN4O
C22H15Cl2N3O
C22H15BrClN3O
C22H15ClFN3O
C
21H13Cl2N3O
C21H13BrClN3O
C21H13ClFN3O
C21H13Cl2N3O

M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á
/722
719
Table 2
Spectral data for the synthesized compounds
Comp.
IR (KBr) cmꢀ1
1H NMR (d ppm) (in DMSO-d6)
3a
3472, 3333, 3194 (NH2); 3040, 2940, 2900 (CH stretching); 2191 4.98 (1H, s, 1-H); 7.30Á
(CN)
/
8.36 (11H, m, ArÃHꢁNH2)
8.37 (11H, m, ArÃHꢁNH2)
8.32 (11H, m, ArÃHꢁNH2)
3b
3c
3464, 3325, 3194 (NH2); 3050, 2945, 2950 (CH stretching); 2191 4.90 (1H, s, 1-H); 7.28Á
/
(CN)
3464, 3325, 3194 (NH2); 3060, 2930 (CH stretching); 2191 (CN) 4.97 (1H, s, 1-H); 7.13Á
/
a
3d
3387, 3287 (NH2); 3078, 2978, 2901 (CH stretching); 1674 (CO) 1.18 (3H, t, CH3, Jꢂ7.2 Hz); 4.12 (2H, q, CH2, Jꢂ7.2 Hz); 4.99 (1H, s,
1-H); 6.49 (2H, br, NH2); 7.20Á8.26 (9H, m, ArÃH)
3485, 3325 (NH2); 3026, 2980, 2936, 2891 (CH stretching); 1684 1.19 (3H, t, CH3, Jꢂ7.2 Hz); 4.12 (2H, q, CH2, Jꢂ7.2 Hz); 4.98 (1H, s,
(CO) 1-H); 6.49 (2H, br, NH2); 7.20Á8.26 (9H, m, ArÃH)
3387, 3287 (NH2); 3078, 2978, 2908 (CH stretching); 1674 (CO) 1.18 (3H, t, CH3, Jꢂ7.2 Hz); 4.11 (2H, q, CH2, Jꢂ7.2 Hz); 5.00 (1H, s,
1-H); 6.48 (2H, br, NH2); 6.88Á8.26 (9H, m, ArÃH)
3256 (NH); 3000, 2940 (CH stretching); 2214 (CN); 1705 (CO) 2.55 (3H, s, COCH3); 4.76 (1H, s, 1-H); 6.91Á
(1H, br, NH, exchangeable)
/
a
3e
/
a
3f
/
a
5a
/
8.11 (9H, m, ArÃH); 10.14
8.56 (9H, m, ArÃH); 10.35
8.57 (9H, m, ArÃH); 10.40
a
5b
3280 (NH); 3010, 2960 (CH stretching); 2219 (CN); 1712 (CO) 2.66 (3H, s, COCH3); 5.30 (1H, s, 1-H); 7.12Á
/
(1H, br, NH, exchangeable)
a
5c
3340 (NH); 3040, 2930 (CH stretching); 2222 (CN); 1728 (CO) 2.71 (3H, s, COCH3); 5.37 (1H, s, 1-H); 7.10Á
/
(1H, br, NH, exchangeable)
6a
3260 (NH); 3009, 2855, 2786, 2708 (CH stretching); 1659 (CO) 2.51(3H, s, CH3); 5.32 (1H, s, 7-H); 7.33Á
/
8.37 (9H, m, ArÃH); 12.60
(1H, br, NH, exchangeable)
6b
6c
3240 (NH); 3010, 2862, 2790, 2720 (CH stretching); 1658 (CO)
3200 (NH); 3010, 2862, 2793, 2708 (CH stretching); 1659 (CO) 2.52 (3H, s, CH3); 5.31 (1H, s, 7-H); 7.04Á
(1H, br, NH, exchangeable)
/
8.37 (9H, m, ArÃH); 12.63
7a
7c
3020, 2960, 2920 (CH stretching); 2214 (CN), 1605 (CÄN)
3060, 2950, 2900 (CH stretching); 2214 (CN); 1597 (CÄN)
3050, 3000, 2900, 2805 (CH stretching); 2212 (CN); 1641
(CÄN)
a
5.05 (1H, s, 1-H); 7.12Á
3.91 (3H, s, OCH3); 5.00 (1H, s, 1-H); 6.99Á
(1H, s, NÄCH)
/
8.35 (14H, m, ArÃH); 9.16 (1H, s, NÄCH)
7e
/
8.34 (13H, m, ArÃH); 9.06
a
10a
3060, 3015, 2986, 2957, 2900 (CH stretching); 2206 (CN); 1620 1.43 (3H, t, CH3, Jꢂ7.2 Hz); 4.50 (2H, q, CH2, Jꢂ7.2 Hz); 4.91 (1H, s,
(CÄN)
3065, 2971, 2955, 2915 (CH stretching); 2206 (CN); 1620
1-H); 7.07Á
1.43 (3H, t, CH3, Jꢂ7.2 Hz); 4.50 (2H, q, CH2, Jꢂ7.2 Hz); 4.92 (1H, s,
1-H); 7.08Á8.25 (9H, m, ArÃH) 8.59 (1H, s, NÄCH)
1.43 (3H, t, CH3, Jꢂ7.2 Hz); 4.50 (2H, q, CH2, Jꢂ7.2 Hz); 4.91 (1H, s,
1-H); 6.99Á8.23 (9H, m, ArÃH); 8.59 (1H, s, NÄCH)
5.39 (1H, s, 7-H); 5.72 (2H, br, NH2, exchangeable); 6.78 (1H, br, NH,
exchangeable); 7.30Á836 (10H, m, ArÃHꢁ10-H)
5.37 (1H, s, 7-H); 5.71 (2H, br, NH2, exchangeable); 6.79 (1H, br, NH,
exchangeable); 7.36Á8.36 (10H, m, ArÃHꢁ10-H)
5.38 (1H, s, 7-H); 5.72 (2H, br, NH2, exchangeable); 6.72 (1H, s, br, NH,
exchangeable); 7.06Á8.36 (10H, m, ArÃHꢁ10-H)
3.41 (3H, s, NÃCH3); 4.94 (1H, s, 7-H); 7.16Á
H); 7.83 (1H, br, NH)
/
8.24 (9H, m, ArÃH); 8.59 (1H, s, NÄCH)
a
10b
(CÄN)
3050, 2992, 2973, 2870 (CH stretching); 2206 (CN); 1620
/
a
10c
(CÄN)
/
11a
11b
11c
3340, 3294 (NH2); 3148 (NH); 1659 (CÄN)
/
3350, 2394 (NH2); 3194 (NH); 1660 (CÄN)
3335, 3249 (NH2); 3140 (NH); 1659 (CÄN)
3333 (NH); 2950, 2855 (CH stretching); 1650 (CÄN)
/
/
a
12a
/
9.46 (10H, m, ArÃHꢁ10-
a
12b
12c
3348 (NH); 3000, 2955 (CH stretching); 1655 (CÄN)
3341 (NH); 2993, 2940, 2870 (CH stretching); 1660 (CÄN)
a
3.43 (3H, s, NÃCH3); 4.98 (1H, s, 7-H); 6.96Á
/
8.48 (10H, m, ArÃHꢁ10-
H); 7.48 (1H, br, NH)
13a
13b
3464, 3155 (NH2); 2206 (CN); 1674 (CÄN)
3464, 3348, 3155 (NH2); 2206 (CN); 1674 (CÄN)
3395, 3163 (NH2); 2199 (CN); 1674 (CÄN)
a
13c
4.56 (1H, s, 1-H); 6.67Á
NH2)
5.36 (1H, s,7-H); 6.78 (2H, br, NH2, exchangeable); 7.32Á
ArÃH); 8.33 (1H, s, 10-H)
/
8.30 (10H, m, ArÃHꢁNÄCH); 7.21 (2H, br,
14a
3294, 3148 (NH2); 1659 (CÄN)
/
8.32 (9H, m,
a
1H NMR in CDCl3.
3.3.2. Method (b)
A stream of dry HCl gas was passed through a
3.4. 3-Arylmethyleneamino-9-chloro-1-(4-halophenyl)-
1H-benzo[h]chromene-2-carbonitrile (7aÁf)
/
mixture of 3dÁ
/
f (0.01 mol) and MeCN (30 ml) for 4Á6 h.
/
The reaction mixture was poured into ice-water and
basified with 10% ammonium hydroxide solution to give
3.4.1. General procedure
A mixture of 3aÁc (0.01 mol), benzaldehyde or 4-
methoxybenzaldehyde (0.01 mol), dioxan (20 ml) and
/
6aÁ
/
c (m.p. and mixed m.p.) yield (60Á68%).
/

720
M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á722
/
piperidine (0.5 ml) was refluxed for 4 h. The solid
product, which formed, was collected by filtration and
3.7. 9-Amino-5-chloro-8-imino-7-(4-halophenyl)-8,9-
dihydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene
recrystallized from suitable solvent to give 7aÁ
/f (Table
(11aÁ
/
c)
1).
A solution of 10aÁ
/
c (0.01 mol) and hydrazine hydrate
(99%, 5 ml) in EtOH (50 ml) was stirred at room
temperature for 45 min. The solid product, which
formed, was collected by filtration and recrystallized
3.5. Reaction of 7aÁc with hydrazine derivatives
/
from suitable solvent to give 11aÁc (Table 1).
/
A mixture of 7aÁ
phenyl hydrazine (0.01 mol) in EtOH was stirring at
room temperature or reflux for 2 h to give 3aÁc (m.p.
and mixed m.p.) yield (75Á80%).
/
c (0.01 mol), hydrazine hydrate or
/
3.8. 5-Chloro-8-imino-9-methyl-7-(4-halophenyl)-8,9-
dihydro-7H-12-oxa-9,11-diaza-benzo[a]anthracene
/
(12aÁ
/
c)
Compound 12aÁ
mol) and MeNH2 (0.01 mol) according to the procedure
described for 11 (Table 1).
/
c was prepared from 10aÁc (0.01
/
3.6. 9-Chloro-3-ethoxymethyleneamino-1-(4-halo-
phenyl)-1H-benzo[h]chromene-2-carbonitrile (10aÁ
/
c)
A mixture of b-enaminonitrile 3aÁ
/
c (0.01 mol),
triethyl orthoformate (0.01 mol) and Ac2O (30 ml) was
refluxed for 4 h. The solvent was removed under
reduced pressure and the separated solid was recrystal-
lized from proper solvent to give the ethoxymethylenea-
3.9. 3-Aminomethyleneamino-9-chloro-1-(4-halophenyl)-
1H-benzo[h]chromene-2 carbonitrile (13aÁc)
/
A stream of NH3 gas was passed through 10aÁ
/c (0.01
mino derivatives 10aÁc (Table 1).
/
mol) in MeOH at room temperature for 1 h. The solid
Table 3
Antibacterial activity of the synthesized compounds
Comp.
S. aureus (NCTC-7447)
Bacillus cereus (ATCC-14579)
S. marcescens (IMRU-70)
P. mirabilis (NTCC-289)
3a
3b
19
18
19
20
19
19
20
28
26
22
21
20
21
23
22
20
19
20
22
18
21
21
23
22
25
24
25
24
22
26
15
12
17
19
20
21
21
20
25
19
22
20
22
26
21
18
20
21
22
14
20
23
22
21
22
23
22
22
20
25
19
18
16
18
19
20
26
27
25
27
24
24
20
26
22
20
19
20
22
18
22
21
23
22
28
25
25
23
22
26
15
18
19
20
21
22
25
26
26
26
23
25
22
25
21
18
20
21
22
15
20
22
23
22
27
24
23
23
22
25
3c
3d
3e
3f
5a
5b
5c
6a
6b
6c
7a
7b
7c
7d
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
a
Ampicillin (25 mg)
a
Paper discs manufactured by Bristol-Myers Squibb, Giza, Egypt.

M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á
/722
721
product formed upon cooling was collected to give the
open-chain product 13aÁc (Table 1).
Table 5
Analytical data for the synthesized compounds
/
Comp. Molecular formula Found (required) %
C
H
N
3.10. 8-Amino-5-chloro-7-(4-chlorophenyl)-7H-12-oxa-
9,11-diaza-benzo[a]anthracene (14a)
3a
3b
C
20H12Cl2N2O
65.22 (65.41) 3.19 (3.29) 7.42 (7.62)
58.15 (58.35) 3.63 (3.93) 6.50 (6.80)
71.45 (71.75) 3.41 (3.61) 8.26 (8.36)
63.62 (63.72) 4.03 (4.13) 3.22 (3.52)
57.30 (57.60) 3.53 (3.73) 3.00 (3.05)
66.32 (66.42) 4.10 (4.30) 3.22 (3.52)
64.10 (64.40) 3.38 (3.68) 6.52 (6.82)
57.80 (58.10) 3.12 (3.32) 6.06 (6.16)
66.88 (67.09) 3.53 (3.83) 7.00 (7.11)
64.26 (64.56) 3.34 (3.44) 6.54 (6.84)
58.00 (58.23) 3.00 (3.11) 6.07 (6.17)
67.00 (67.26) 3.29 (3.59) 7.00 (7.13)
70.90 (71.22) 3.34 (3.54) 6.05 (6.15)
64.80 (64.90) 3.02 (3.22) 5.40 (5.60)
73.69 (73.89) 3.37 (3.67) 6.18 (6.38)
69.00 (69.28) 3.53 (3.73) 5.47 (5.77)
63.18 (63.48) 3.12 (3.42) 5.18 (5.28)
71.21 (71.41) 3.55 (3.85) 5.64 (5.94)
65.00 (65.26) 3.50 (3.80) 6.41 (6.61)
59.00 (59.06) 3.34 (3.44) 5.88 (5.98)
67.70 (67.900 3.66 (3.96) 6.78 (6.88)
61.42 (61.62) 3.34 (3.44) 13.38 (13.68)
55.39 (55.59) 3.00 (3.11) 12.14 (12.34)
64.00 (64.21) 3.29 (3.59) 14.07 (14.27)
64.62 (64.72) 3.40 (3.70) 10.09 (10.29)
58.16 (58.36) 3.13 (3.33) 8.92 (9.28)
57.13 (67.43) 3.52 (3.82) 10.42 (10.72)
63.90 (64.01) 3.12 (3.32) 10.45 (10.65)
57.21 (57.51) 2.88 (2.98) 9.27 (9.57)
66.57 (66.77) 3.36 (3.46) 11.00 (11.11)
63.90 (64.01) 3.22 (3.32) 10.35 (10.65)
C20H12BrClN2O
C20H12ClFN2O
C22H17Cl2NO
3c
3d
3.10.1. Method (a)
3e
C22H17BrClNO3
C22H17ClFNO3
3f
5a
A mixture of 3a (0.01 mol) and formamide (0.01 mol)
was reflux for 3 h. The solvent was removed under
vacuum. The solid obtained was recrystallized from
proper solvent to give 14a (Table 1).
C
C
22H14Cl2N2O2
22H14BrClN2O2
5b
5c
C22H14ClFN2O2
C22H14Cl2N2O2
6a
6b
C
C
22H14BrClN2O2
22H14ClFN2O2
6c
7a
C27H16Cl2N2O
C27H16BrClN2O
3.10.2. Method (b)
7b
7c
C
C
27H16ClFN2O
28H18Cl2N2O2
Compound 14a was prepared from 10a (0.01 mol) and
NH3 gas in dioxan solution (2 h, the mixture left in
refrigerator overnight) according to the procedure
described for 13 to give 14a (m.p. and mixed m.p.) yield
(61%).
7d
7e
C28H18BrClN2O2
28H18ClFN2O2
C23H16Cl2N2O2
23H16BrClN2O2
C23H16ClFN2O2
7f
C
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
C
C
C
21H14Cl2N4O
21H14BrClN4O
Table 4
Antifungal activity of the synthesized compounds
C21H14ClFN4O
22H15Cl2N3O
C
Comp.
Aspergillus ochraceus
Penicillium chrysogenum
C22H15BrClN3O
C22H15ClFN3O
Wilhelm (AUCC-230)
Thom (AUCC-530)
3a
3b
12
5
13
8
C
C
21H13Cl2N3O
21H13BrClN3O
3c
3d
15
18
19
19
18
21
20
19
20
18
17
17
19
19
18
19
22
14
17
18
19
20
20
20
18
20
19
22
16
20
21
22
21
22
21
20
21
19
17
20
20
13
18
20
20
12
15
20
20
19
21
22
21
20
19
24
C21H13ClFN3O
21H13Cl2N3O
C
3e
3f
5a
3.10.3. Method (c)
5b
5c
Compound 13a (0.01 mol) was heated under reflux in
dioxan (20 ml) and piperidine (0.5 ml) for 3 h to give 14a
(m.p. and mixed m.p.) yield (58%).
6a
6b
6c
7a
7b
7c
4. Biological screening
7d
10a
10b
10c
11a
11b
11c
12a
12b
12c
13a
13b
13c
14a
Mycostatine
(30 mg)
4.1. Antibacterial activity
The newly synthesized compounds were screened for
their antibacterial activity against four species of
bacteria, gram-positive bacteria namely Staphylococcus
aureus (NCTC- 7447), Bacillus cereus (ATCC-14579)
and gram-negative bacteria Serratia marcescens
(IMRU-70) and Proteus mirabilis (NCTC-289) using
Ampicillin (25 mg) as reference compound [23]. The
tested compounds were dissolved in (DMF) to get a
solution of 1% concentration. Filter paper discs (what-
man No. 3 filter paper, 5 mm diameter) were saturated
with former solution. The saturated filter paper discs
were placed on the nutrient agar (Difco) dishes seeded
aPaper discs manufactured by Bristol-Myers Squibb, Giza, Egypt.

722
M.M. Khafagy et al. / Il Farmaco 57 (2002) 715Á722
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DMF showed no inhibition zone. The results are
illustrated in (Table 3).
/
gawa, DNA strand-breaking activity and mutagenicity of 2,3-
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a
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From the biological assay it was found that com-
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marcescens and P. mirabilis, while compounds 6a and
12c showed high activity against S. marcescens and P.
mirabilis. For antifungal activity, compounds 3f, 5b and
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