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Mediterranean Journal of Chemistry 2018, 7(5), 346-358

Synthesis, characterization and in vitro biological screening of

4-hydroxy naphthalen-1-yl, naphtho[1,2-b]furan, benzo[h]chromene
and 5,6-dihydropyridazine derivatives containing sulfonamide
moiety
Mohamed S. A. El-Gaby 1,*, Mohamed I. Hassan 1,*, Modather F. Hussein 1, Ahmed M. Ali 1, Miral A.
Abdelmoaz 2, Mahmoud M. Elaasser 3, Faraghally A. Faraghally 1
1
Department of Chemistry, Faculty of Science, Al-Azhar University at Assiut, Assiut 71524, Egypt
2
Pharmaceutical Organic Chemistry, Faculty Pharmacy, Sinai University, Kantara, Egypt
3
Regional Center for Mycology & Biotechnology, Al-Azhar University, Cairo, Egypt

Abstract: In this study, a series of 4-((4-hydroxynaphthalen-1-yl)diazenyl)benzenesulfonamides have been prepared

by subsequent diazotization of sulfonamide derivatives and coupling with 1-naphthol in alkaline medium. Cyclization
of 4-((4-hydroxynaphthalen-1-yl)diazenyl)benzenesulfonamides with cinnamic acid in the presence of a basic catalyst
afforded the novel naphtho[1,2-b]furans. Also, 4-((4-hydroxynaphthalen-1-yl)diazenyl)benzenesulfonamides can be
cyclized with α‐cyanocinnamonitriles to afford 2-amino-3-cyano-4-phenyl-4H-benzo[h]chromenes. 4-(4-amino-3,5-
dicyano-6-iminopyridazin-1(6H)-yl)benzenesulfonamides were obtained at room temperature by treatment of
2-amino-1,1,3-tricyanopropene with a diazonium salt of sulfonamide derivatives. The structures of newly synthesized
compounds were confirmed by analytical data and spectroscopic techniques. The antimicrobial activity of the obtained
compounds was assessed in vitro by qualitative and quantitative (minimum inhibitory concentration) (MIC) assays.
Keywords: sulfonamide; azobenzene; naphtho[1,2-b]furan; benzo[h]chromene; pyridazine.

Introduction Naphthofuran derivatives have also been reported

to possess diverse biological activities, including anti-
19
Substituted azobenzene have attracted considerable tyrosinase, antioxidant and antibacterial .
attention based on their various physical and chemical Naphtho[1,2-b]furans are very important structural
properties, such as bright colors, good stability, low units found in diverse natural and synthetic products 20.
flammability, and rapid, reversible photo-isomerization They possess a broad spectrum of biological activities
1-4
. Aromatic azo compounds are widely used in the and have been used as precursors for the synthesis of
chemical industry as dyes, pigments 5,6, food additives bioactive materials. Naphtho[1,2-b]furan-4,5-dione
7, indicators 3, radical reaction initiators 8 and (NFD, Fig. 1), a 1,2-furanonaphtho quinone, was
therapeutic agents 9,10. Also, azobenzenes have shown originally isolated from avicennia marina belonging to
promising applications in photo-optical media 11, photo- the family Avicenniaceae and can be synthesized by a
switches 12, photo-mechanical systems 13, micro chemical process. NFD was found to show potent
patterning 14, nonlinear optical media 15, molecular cytotoxicity against human cancer cell lines, including
shuttles 16, nanotubes 17, and in the manufacture of KB (human epidermoid carcinoma, IC50 = 3.05 ± 0.195
protective eye glasses and filters 18. µM), HeLa (human cervical carcinoma,IC50 = 2.85 ±
0.210 µM) and HepG2 (human hepatocellular
carcinoma, IC50 = 3.00 ± 0.040 µM) cell lines 21.

*Corresponding authors: Mohamed S. A. El-Gaby, Mohamed I. Hassan Received October 11, 2018
Email address: [email protected], [email protected] Accepted November 10, 2018
DOI: http://dx.doi.org/10.13171/mjc751912061355msaeg Published December 6, 2018
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 347

Recently, Chen et al. 22 discover, N-(naphtha extensively used drugs for the treatment or conservation
[1,2-b]furan-5-yl) benzene sulfonamides (Fig. 1), as of different illnesses 27. In clinical medicine, they have
novel selective inhibitors of triple-negative breast been used as anticancer 28, antimicrobial 29,
cancer (TNBC). antiobesity 30, carbonic anhydrase 31 and
acetylcholinesterase inhibitor agents for Alzheimer’s
Chromene derivatives are very an important class of
disease 32.
heterocyclic compounds, widely distributed in natural
products. Chromene and its derivatives have also been In view of the above-mentioned benefits and in
recognized as one type of ‘privileged medicinal continuation of our interest in biologically active
scaffolds’ due to their unique pharmacological and compounds 33-37, we report herein the synthesis
biological activities 23. Dong et al. 24,25 designed and of some novel 4-((4-hydroxynaphthalen-1-yl)diazenyl)-
prepared a series of 4-amino-2H-benzo[h]- benzene sulfonamides3a-e, naphtho[1,2-b]-furans
chromen-2-one and 4-amino-7,8,9,10-tetrahydro-2H- 6a-c,benzo[h]chromenes8a,b and 4-(4-amino-3,5-
benzo[h]chromen-2-one derivatives based on the potent dicyano-6-imino-5,6-dihydropyridazin-1(4H)-yl)-
anticancer agents neo-tanshinlactone and its 4-ethyl benzenesulfonamides 13a-e containing a sulfonamido
analogue 26. moiety to evaluate their antimicrobial biological
activity.
Sulfonamides are another important compounds
family for the medicinal industry, and they are now

Figure 1.

Results and Discussion spectra of compounds 3a-e showed the presence of

absorption band at 3357-3448 cm-1 which is
Syntheses and characterizations of the characteristic of the hydroxyl group beside two
compounds absorptions bands for azo and sulfone groups. The
A series of 4-((4-hydroxynaphthalen-1- representative 1HNMR spectrum of compound 3a
yl)diazenyl)benzenesulfonamides 3a-e were (DMSO-d6) shown 7.1, 7.75, 8.35, 8.80 (4d, 4H,
synthesized by coupling of diazonium salt of naphtho-H), 7.47, 7.58 (2m, 2H, naphtho-H), 7.94, 8.24
sulfonamide derivatives 1a-e with 1-naphthol 2 in (2d, 4H, AB-system), 8.10 (s, 2H, NH2 exchangeable
presence of 10% sodium hydroxide (Scheme 1). with D2O), 12.36 (br, 1H, OH exchangeable with D2O).
Diazotization was carried out in the presence of nitrosyl The molecular ion peak of compound 3c was observed
chloride at 0-5 oC. The structure of compounds 3a-e was at m/z 410 (42.83%) corresponding to the molecular
determined by their elemental analysis and spectral data. formula C19H14N4O3S2, and the base peak was found in
Elementary analysis indicated that sulfur was present. the spectrum at m/z 65. The enolic–OH groups of all the
The infrared spectra of all isolated compounds were compounds were chemically detected by the treatment
consistent with the assumed structures. The infrared with a FeCl3 solution, which gives characteristic color.
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 348

Scheme 1. Synthesis of 4-((4-hydroxynaphthalen-1-yl)diazenyl)benzenesulfonamides 3a-e

The reactivity of 4-((4-hydroxynaphthalene- acid 4 in refluxing N,N-dimethylformamide (DMF)

1-yl)diazenyl)benzenesulfonamides 3 towards some containing catalytic amounts of piperidine gave
carbon electrophiles was investigated. Thus, it has been naphtho[1,2-b]furans 6a-c rather than the expected
found that the reaction of 4-((4-hydroxynaphthalen- naphthopyran 5 (Scheme 2).
1-yl)diazenyl)benzenesulfonamides 3a-c with cinnamic

Scheme 2. Synthesis of naphtho[1,2-b]furans 6a-c

Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 349

The structures of compounds 6a-c were established spectrum of compound 6b showed a molecular ion peak
by spectroscopic tools as well as elemental analyses at m/z 469 (12.15%) compatible with molecular formula
data. The infrared spectra of compounds 6a-c indicated C25H19N5O3S. The base peak was found in the spectrum
the absence of the hydroxyl and carbonyl absorption at m/z 55. Also, the mass spectrum of compound 6c
bands. The 1H NMR spectrum of compound 6a showed a molecular ion peak atm/z 510 (7.64%)
(DMSO-d6) 7.25-7.62 (m, 7H, Ph-H and naphtho-H), corresponding to the molecular formula C27H18N4O3S2.
8.20 (s, 1H, furan-H), 8.32, 8.39(2d, 2H, naphtho-H), The molecular ion of compound 6c underwent
8.45, 8.50(2s, 3H, naphtho-H and NH2, exchangeable fragmentation to produce a peak of m/z 57,
with D2O), 7.98, 8.55 (2d, 4H, AB-system). The mass corresponding to the base peak (Scheme 3).

Scheme 3. Fragmentation pattern of naphtho[1,2-b]furan 6c

The formation of 6 from the reaction of 3 with 4 is infrared spectra of compounds 8a, b displayed
assumed to proceed via initial addition naphtholate absorption bands for NH2, C≡N, N=N and SO2
anion (C‐2) in 3 to the activated double bond functions. The mass spectrum of compound 8a showed
in 4 to yield the non-isolable intermediate Michael a molecular ion peak at m/z 481 (1.64%) corresponding
adduct (A) followed by intramolecular cyclization and to the molecular formula C26H19N5O3S. The formation
subsequent decarboxylation to afford the naphthofurans of 8 from the reaction of 3a with 7 is assumed to proceed
6 (Scheme 4). via initial addition of naphtholate anion (C‐2) in 3a to
the activated double bond in 7 to yield the non-isolable
The reaction of compound 3a with α‐ intermediate Michael adduct (B) followed by
cyanocinnamonitriles was investigated. Thus, the intramolecular cyclization through nucleophilic
reaction of compound 3a with α‐cyanocinnamonitriles addition of the hydroxyl group to the cyano group and
7 in refluxing DMF in the presence of piperidine tautomerization 38 to afford benzochromene 8
afforded 2-amino-3-cyano-4-phenyl-4H- (Scheme 5) .
benzo[h]chromenes 8a,b. The structure of 8 was
supported by elemental analysis and spectral data. The
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 350

Scheme 4. Formation of naphtho[1,2-b]furans 6

Scheme 5. 2-amino-3-cyano-4-phenyl-4H-benzo[h]chromenes 8a-b

Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 351

Pyridazine and its derivatives have been extensively salt of sulfonamide derivatives 1a-e at room
investigated because of their important role especially temperature gave 4-(4-amino-3,5-dicyano-6-
in medicinal chemistry, a large variety of biological iminopyridazin-1(6H)-yl)benzenesulfonamide
activities being described: antibacterial, antifungus, derivatives 11a-e, via intramolecular cyclization of 10
antituberculosis, antiviral, anti-inflammatory, through nucleophilic addition of the nitrogen atom to the
anticancer, cardiovascular disorders 39. Thus, treatment cyano group and tautomerization 40 (Scheme 6).
of 2-amino-1,1,3-tricyanopropene 9 with a diazonium

Scheme 6. 4-(4-amino-3,5-dicyano-6-imino-5,6-dihydropyridazin-1(4H)- yl)benzenesulfonamides 11a-e

Antimicrobial activity and minimal inhibition mg/mL using inhibition zone diameter in mm as a
concentration criterion for the antimicrobial activity, and the results
The newly synthesized compounds were evaluated are shown in (Table 1). Based on the results, the newly
for their in-vitro antibacterial activity against synthesized compounds tested displayed variable in-
Staphylococcus aureus, Bacillus subtilis as examples of vitro antimicrobial activities under these screening
Gram-positive bacteria, Proteus vulgarisand conditions. Interestingly, the tested compounds
Escherichia coli as examples of Gram-negative exhibited significant antifungal activities against the
bacteria, using two standard antibiotics, Ampicillin, and filamentous fungus (Aspergillus fumigatus) and
Gentamycin as reference drugs and antifungal potential unicellular yeast (Candida albicans). The highest
against a representative panel of fungal strains i.e. antifungal activity was detected for compound 3b
Aspergillus fumigatus (filamentous fungi), and Candida followed by 3a, 3e, 3d, 3c, respectively. However,
albicans (yeast), using one standard antibiotic, compound 3e exhibited the highest activity against
Amphotericin B as reference drug. The compounds Gram-positive bacteria, Staphylococcus aureus as
were tested for their activity at a concentration of 10 compared with the standard antibiotic, Ampicillin,
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 352

followed by 3b, 3a, 8a and 3d, respectively. On the highly susceptible to compound 3e followed by, 3d, 8a,
other hand, compound 3b exhibited the highest activity 3b, 3a, 6a and 6b as compared with the standard
against Gram-positive bacteria, Bacillus subtilis antibiotic, Gentamycin. The order of activity against
followed by 3a, 3e, 3d and 6a, respectively. Moreover, Escherichia coli was 3e >3b >3a >3d > 6a > 8a >3c >6c
the tested Gram-negative bacteria; Proteus vulgaris was >6b >8b.

Table 1. In-vitro antimicrobial activities of the synthesized compounds tested at 10 mg/mL by well diffusion agar
assay and expressed as inhibition zone diameter (mm) in the form of mean ± standard deviation.
Fungi Gram positive bacteria Gram negative bacteria

C. albicans A. fumigatus S. Aureus B. subtilis Proteus vulgaris E. coli

ATCC RCMB RCMB 010012 NRRL ATCC 13315 ATCC
Compound 10231 002568 B-543 25955
3a 33.5±1.6 29±0.7 20.3±0.5 18.4±0.8 15.8±1.4 21.2±0.4

3b 34.1±1.7 30.7±1.5 21.6±1.3 20.2±0.6 16.1±0.7 22.6±0.8

3c 13±0.7 20.3±1.1 15.8±0.5 8.1±0.2 12.4±0.6 13.1±0.4

3d 14.2±0.6 26±1.2 17.1±0.8 15.4±0.7 17.1±0.8 20.4±1.6

3e 26.1±1.2 27.4±0.8 22.3±1.4 16±0.8 18.9±1.6 23.4±0.9

6a 17.1±0.7 15.7±0.9 16.3±1.1 15.2±1.4 14.7±1.3 17.5±1.2

6b 0 0 13.4±0.9 9.2±0.5 14.5±0.8 10.1±0.7

6c 11.4±0.9 0 13.3±0.8 10.2±0.6 13.5±0.7 11.6±0.5

8a 14.5±1.1 16±0.8 18.2±0.9 14±0.6 16.4±0.8 15.1±1.3

8b 14.6±0.8 12.9±0.3 10.2±0.4 11.5±0.7 10.9±0.4 9.7±0.5

11a 0 0 0 8.6±0.8 0 0

11b 0 0 0 0 0 0

11c 0 0 9.8±0.6 0 0 0

11d 0 0 8.7±0.5 0 0 0

11e 0 0 0 10.2±0.6 0 0

Amphotricin B 25.7±1.3 24.8±1.4 - - - -

Ampicillin - - 27.8±0.6 26.4±0.7 - -

Gentamycin - - - - 25.7±0.9 29.6±1.3

Amphotericin B, ampicillin and gentamycin were used inhibitory concentration as shown in Table 2.
as standard drugs against the tested fungi, Gram- Moreover, compound 3b showed the highest activity
positive and Gram-negative bacteria, respectively. (MIC values ranged from 4.9 to 312.5 µg/ml),
The antimicrobial activities of the synthesized followed by 3a (MIC 4.9-625 µg/ml), 3e (MIC 9.8-625
compounds were also tested to determine the minimum µg/ml), and 3d (MIC 9.8-625 µg/ml).
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 353

Table 2. The antibacterial activities of the synthesized compounds expressed as minimum inhibitory concentration
(µg/ml).
Fungi Gram positive bacteria Gram negative bacteria

C. albicans A. fumigatus S. aureus B. subtilis Proteus E. coli

ATCC RCMB RCMB NRRL B- vulgaris ATCC ATCC
Compound 10231 002568 010012 543 13315 25955
3a 4.9 4.9 39 156 625 39

3b 4.9 4.9 156 156 312.5 39

3c 1250 156 625 5000 1250 625

3d 625 9.8 312.5 625 312.5 156

3e 9.8 9.8 39 625 156 39

6a 312.5 625 625 625 625 312.5

6b NA* NA 625 5000 625 2500

6c 1250 NA 625 2500 625 2500

8a 625 625 312.5 625 625 625

8b 625 1250 2500 1250 2500 2500

Amphotricin B 9.8 2.44 - - - -

Ampicillin - - 1.22 0.6 9.76 9.76

Gentamycin - - 9.76 4.88 0.6 1.22

* NA: No activity

Conclusion Karlsruhe, Germany). 1H spectrum was run at 400 MHz

A series of novel 4-((4-hydroxynaphthalen-1- in deuterated dimethylsulfoxide (DMSO-d6). Chemical
yl)diazenyl) benzenesulfonamides, naphtho[1,2- shifts are expresses in values (ppm) relative to TMS as
b]furans, benzo[h]chromenes and 4-(4-amino-3,5- an internal standard. Mass spectral data were given by a
dicyano-6-imino-5,6-dihydropyridazin-1(4H)- GCMS-QP1000 EX-spectrometer (Shimadzu, Kyoto,
yl)benzenesulfonamides were synthesized to evaluate Japan) at 70 eV. All reagents used were of the Analytical
their antimicrobial biological activity with the hope of grade. Compounds α‐cyanocinnamonitriles 7 41 and 2-
discovering new structure leads serving as antimicrobial amino-1,1,3-tricyanopropene 9 42 have been synthesized
agents. as previously reported.

Experimental General Procedure for Synthesis of 4-((4-

hydroxynaphthalen-1-yl)diazenyl)benzene-
All analyses were done at the Microanalytical sulfonamides 3a-e:
Center, Cairo University, Cairo (Egypt). Melting points
Sulfonamide (0.01 mole) was suspended in water
(uncorrected) were determined in open capillaries on a
(50 ml). Hydrochloric acid (10 ml, 36%) was added
Gallenkamp melting point apparatus (Sanyo
dropwise to this well stirred. The mixture was gradually
Gallenkamp, Southborough, UK). IR spectra (KBr
heated up to 70 °C till clear solution obtained. The
discs) were recorded using a Shimadzu FT-IR 8400S
solution was cooled to 0-5 °C in an ice bath. A solution
spectrophotometer (Shimadzu, Kyoto, Japan), Infrared
of NaNO2 (0.5 mg) in water (5ml) previously cooled
(IR) Spectra were recorded as KBr disks. NMR Spectra
to 0 °C, was then added over a period 5 minutes with
were recorded on a Bruker spectrophotometer (Bruker,
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 354

stirring. 1-naphthol (0.01 mole) was dissolved in 10% aliph.), 1632 (C=C), 1595 (N=N), 1327, 1139 (S=O);
NaOH (10 ml) and then put ice to cool to 5 oC. Then, 1
HNMR (DMSO-d6, ppm): 2.36 (s, 3H, CH3), 6.25 (s,
diazonium salt solution was added occasionally stirring 1H, H-oxazole), 7.25, 7.68, 8.04, 8.12(4d, 4H), 7.51,
very slowly to the 1-naphthol solution. The reaction 7.63 (2m, 2H), 7.88, 7.97(2d, 4H), 11.26 (s, H, NH,
mixture was left to complete for 15 min and occasional exchangeable with D2O), 10.02 (s, 1H, OH,
stirring; then the formed precipitate was filtered and exchangeable with D2O);
dried in air and then recrystallized from proper solvent Anal. Calcd. for C20H16N4O4S: C, 58.81; H, 3.95; N,
to give 3. 13.72; S, 7.85. Found: C, 58.64; H, 3.79; N, 13.54; S,
7.68.
4-((4-hydroxynaphthalen-1-yl)diazenyl)benzene-
sulfonamide 3a. 4-((4-hydroxynaphthalen-1-yl)diazenyl)-N-
(pyrimidin-2-yl)benzenesulfonamide 3e.
Brown crystals (ethanol), Yield:85%, m.p.254-256 °C;
IR(KBr, cm-1): 3357 (OH), 3300, 3249 (NH2),1622 Dark brown crystals (ethanol), Yield:7 8%, m.p. 132-
(C=C), 1594 (N=N), 1356, 1147 (S=O); 134 °C;
1
HNMR (DMSO-d6, ppm): 7.24, 7.72, 7.98, 8.16(4d, IR(KBr, cm-1): 3377 (OH), 3225 (NH), 1625 (C=C),
4H), 7.55, 7.62(2m, 2H), 7.88, 8.26 (2d, 4H), 7.36 (s, 1581 (N=N), 1316, 1155 (S=O);
1
2H, NH2, exchangeable with D2O), 9.45 (s, 1H, OH, HNMR (DMSO-d6, ppm): 6.99, 8.36(m, d,3H, H-
exchangeable with D2O); pyrimidine), 7.23, 7.69, 8.06, 8.15 (4d, 4H), 7.52, 7.60
Anal. Calcd. for C16H13N3O3S: C, 58.70; H, 4.00; N, (2m, 2H), 7.91, 7.98 (2d, 4H), 11.30 (s, H, NH,
12.84; S, 9.80. Found: C, 58.52; H, 3.89; N, 12.58; S, exchangeable with D2O), 9.98 (s, 1H, OH, exchangeable
9.65. with D2O);
Anal. Calcd. for C20H15N5O3S: C, 59.25; H, 3.73; N,
N-carbamimidoyl-4-((4-hydroxynaphthalen-1- 17.27; S, 7.91. Found: C, 58.94; H, 3.64; N, 17.13; S,
yl)diazenyl)benzenesulfonamide 3b. 7.64.
Brown crystals (ethanol), Yield:83%, m.p.246-248 °C;
IR(KBr, cm-1): 3441 (OH), 3329 (NH2), 3272, 3223 General Procedure for Synthesis of naphtho[1,2-
(2NH), 1633 (C=C), 1596 (N=N), 1355, 1165 (S=O); b]furans 6a-c.
1
HNMR (DMSO-d6, ppm): 7.28, 7.72,8.14 (3d, 3H), To a mixture of compound 3 (0.01 mole) and cinnamic
7.49-7.57(2m, 2H), 7.82, 788 (2d, 4H), 6.75 (s, 2H, acid 4 (0.01 mole) in DMF (10 ml), a few drops
NH2, exchangeable with D2O), 7.61, 7.80 (2s, 2H, 2NH, piperidine was added. The reaction mixture was
exchangeable with D2O), 10.03(s, 1H, OH, refluxed for 2 h. After cooling, the precipitate was
exchangeable with D2O); Anal. Calcd. for filtered and recrystallized from proper solvent to give 6.
C17H15N5O3S: C, 55.27; H, 4.09; N, 18.96; S, 8.68.
Found: C, 55.12; H, 3.95; N, 18.76; S, 8.42. 4-((3-phenylnaphtho[1,2-b]furan-5-yl)diazenyl)-
benzenesulfonamide 6a.
4-((4-hydroxynaphthalen-1-yl)diazenyl)-N-(thiazol-2-
yl)benzenesulfonamide 3c. Brown crystals (ethanol), Yield: 79%, m.p.180-182 °C;
IR(KBr, cm-1):3266 (NH2), 1624 (C=C), 1594 (N=N),
Brown crystals (ethanol), Yield: 86%, m.p.202-204 °C; 1316, 1155 (S=O);
IR(KBr, cm-1): 3415 (OH), 3274 (NH), 1627 (C=C), 1
HNMR (DMSO-d6, ppm): 7.28-7.55 (m, d, 5H, Ph-H),
1594 (N=N), 1317, 1138 (S=O); 8.18 (s, 1H, furan-H), 8.32(s, 1H), 8.20, 8.52(2d, 2H),
1
HNMR (DMSO-d6, ppm): 7.30, 7.75, 8.13, 8.15(4d, 7.42, 7.56 (2m, 2H), 7.90, 8.06(2d, 4H), 7.30(s, 2H,
4H), 7.58, 7.71 (2m, 2H), 7.86, 7.92(2d, 4H), 6.73, 7.26 NH2, exchangeable with D2O);
(2d, 2H, H-thiazole), 12.74 (br, H, NH, exchangeable Anal. Calcd. for C24H17N3O3S: C, 67.43; H, 4.01; N,
with D2O), 10.05 (s, 1H, OH, exchangeable with D2O); 11.23; S, 7.50. Found: C, 67.28; H, 3.87; N, 11.14; S,
MS: 410 (M+; 42.83 %), 393 (3.17), 382 (28.92 %), 346 7.38.
(62.87 %), 247 (17.45 %), 219 (4.18 %), 92 (93.25 %),
76(19.77%), 65 (100 %). N-carbamimidoyl-4-((3-phenylnaphtho[1,2-b]furan-
Anal. Calcd. for C19H14N4O3S2: C, 55.60; H, 3.44; N, 5-yl)diazenyl)benzenesulfonamide 6b.
13.65; S, 15.62. Found: C, 55.46; H, 3.28; N, 13.47; S,
Dark brown crystals (ethanol), Yield: 82%, m.p.205-
15,42.
207 °C;
4-((4-hydroxynaphthalen-1-yl)diazenyl)-N-(5- IR(KBr, cm-1): 3440 (NH2), 3328, 3271 (2NH), 1632
methylisoxazol-3-yl)benzenesulfonamide 3d. (C=C), 1595 (N=N), 1307, 1131 (S=O);
1
HNMR (DMSO-d6, ppm): 7.32-7.58 (m, d, 5H, Ph-H),
Brown crystals (ethanol), Yield: 80%, m.p.242-244 °C; 8.17(s, 1H, furan-H), 8.32(s, 1H), 8.17, 8.43 (2d, 2H),
IR(KBr, cm-1): 3448 (OH), 3107 (NH), 2924 (CH- 7.60, 7.67 (2m, 2H), 7.88, 7.96(2d, 4H), 6.74(s, 2H,
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 355

NH2, exchangeable with D2O), 7.75, 8.08(2s, 2H, 2NH, 4-((2-amino-3-cyano-4-(p-tolyl)-4H-benzo[h]-

exchangeable with D2O). chromen-6-yl)diazenyl)benzenesulfonamide 8b.
MS: 469 (M+; 12.15 %), 453 (8.95 %), 426 (10.10 %),
Brown crystals (ethanol), Yield: 87%, m.p.135-137 °C;
398 (6.67 %), 392(6.67%), 362 (14.58 %), 198 (11.76
IR(KBr, cm-1): 3424, 3385 (2NH2), 3034 (CH-arom),
%), 135 (8.31 %), 57 (81.71 %), 55 (100 %).
2870 (CH-aliph), 2186 (CN), 1631 (C=C), 1594 (N=N),
Anal. Calcd. for C25H19N5O3S: C, 63.95; H, 4.08; N,
1358, 1153 (S=O);
10.22; S, 6.83. Found: C, 63.78; H, 3.97; N, 10.10; S, 1
HNMR (DMSO-d6, ppm): 2.35 (s, 3H, CH3), 4.82 (s,
6.65.
1H, 4H-pyran), 7.13, 7.21 (2d, 4H, Ph-CH3), 7.87(s,
4-((3-phenylnaphtho[1,2-b]furan-5-yl)diazenyl)-N- 1H), 8.13, 8.38(2d, 2H), 7.51, 7.54(2m, 2H), 8.15,
(thiazol-2-yl)benzenesulfonamide 6c. 7.81(2d, 4H), 6.89, 7.23 (2s, 4H, 2NH2, exchangeable
with D2O);
Dark brown crystals (ethanol), Yield: 84%, m.p.193- Anal. Calcd. for C27H21N5O3S: C, 65.44; H, 4.27; N,
195°C; 14.13; S, 6.47. Found: C, 65.38; H, 4.09; N, 13.95; S,
IR(KBr, cm-1): 3247 (NH), 1628 (C=C), 1593 (N=N), 6.28.
1311, 1137 (S=O);
1
HNMR (DMSO-d6, ppm): 6.73, 7.19 (2d, 2H, thiazole- General Procedure for Synthesis of 4-(4-amino-3,5-
H), 7.35-7.58 (m, d, 5H, Ph-H), 8.12 (s, 1H, furan-H), dicyano-6-iminopyridazin-1(6H)-yl)benzene-
8.26( s, 1H), 8.14, 8.44 (2d, 2H), 7.43, 7.59 (2m, 2H), sulfonamides 11a-e:
7.93, 8.02 (2d, 4H), 12.64(s, H, NH, exchangeable with
D2O); Sulfonamide (0.01 mole) was suspended in water
MS: 510 (M+; 7.64 %), 494 (4.64 %), 482 (6.39 %), 446 (50 ml). Hydrochloric acid (10 ml, 36%) was added
(4.76 %), 433 (4.14 %), 319 (3.38 %), 267 (3.45 %), 241 drop wise to this well stirred. The mixture was gradually
(7.58 %), 239 (3.29 %), 226 (4.26 %), 209 (4.07 %), 177 heated up to 70 °C till clear solution obtained. The
(4.57 %), 149 (4.76 %), 84 (10.24 %), 58 (27.69), 57 solution was cooled to 0-5 °C in an ice bath. A solution
(100 %), 56 (32.02 %), 52 (7.89 %). Anal. Calcd. for of NaNO2 (0.5 gm) in water (5ml) previously cooled to
C27H18N4O3S2: C, 63.51; H, 3.55; N, 10.97; S, 12.56. 0 °C, was then added over a period 5 minutes with
Found: C, 63.38; H, 3.39; N, 10.75; S, 12.32. stirring. 2-Amino-1,1,3-tricyanopropene 9 (0.01 mole)
was dissolved in ethanol (10 ml) in the presence of
General Procedure for Synthesis of sodium acetate (1 gram) and then put ice to cool to 5 oC.
benzo[h]chromenes 8a,b. Then, diazonium salt solution was added occasionally
stirring very slowly to the 2-Amino-1,1,3-
To a mixture of compound 3 (0.01 mole) and tricyanopropene solution. The reaction mixture was left
α‐cyanocinnamonitrile 7(0.01 mole) in DMF (10 ml), a to complete for 3h and occasional stirring; then the
few drops triethylamine was added. The reaction formed precipitate was filtered and dried in air and then
mixture was refluxed for 1 h. After cooling, the recrystallized from proper solvent to give 11.
precipitate was filtered and recrystallized from proper
solvent to give 8. 4-(4-amino-3,5-dicyano-6-iminopyridazin-1(6H)-
yl)benzenesulfonamide 11a:
4-((2-amino-3-cyano-4-phenyl-4H-benzo[h]chromen-
6-yl)diazenyl)benzenesulfonamide 8a. Yellow crystals (ethanol), Yield: 88%, m.p.158- 160 °C;
IR(KBr, cm-1): 3378, 3312 (2NH2), 3211 (NH), 2219,
Brown crystals (ethanol), Yield: 84%, m.p.90-92 °C; 2199 (2C≡N), 1620 (C=N), 1326, 1159 (S=O);
IR(KBr, cm-1): 3355, 3270 (2NH2), 3054 (CH-arom.), 1
HNMR (DMSO-d6, ppm): 6.65, 7.20 (2br., 4H, 2NH2,
2190 (CN), 1631 (C=C), 1593 (N=N), 1357, 1156 exchangeable with D2O), 7.80, 8.21(2d, 4H, AB-
(S=O); 1HNMR(DMSO-d6, ppm): 4.90 (s, 1H, 4H- system), 9.85(br., 1H, NH, exchangeable with D2O).
pyran), 7.23-7.32 (m, d, 5H, Ph-H), 7.88(s, 1H), 8.12, Anal. Calcd. for C12H9N7O2S: C, 45.71; H, 2.88; N,
8.27(2d, 2H), 7.49, 7.56(2m, 2H), 7.90, 8.25(2d, 4H), 31.10; S, 10.17. Found: C, 45.56; H, 2.64; N, 30.94; S,
6.88, 7.21 (2s, 4H, 2NH2, exchangeable with D2O); 10.04.
MS: 481 (M+; 1.64 %), 465 (1.53%), 455 (1.55%), 452
(25.81%), 401 (2.42%), 404 (4.62%), 373 (12%), 327 4-(4-amino-3,5-dicyano-6-iminopyridazin-1(6H)-yl)-
(8.13%), 297 (100 %), (269 (39.18%), 219 (1.11%), 65 N-carbamimidoylbenzenesulfon amide 11b
(26.78%). Yellow crystals (ethanol), Yield: 82%, m.p.>300 °C;
Anal. Calcd. for C26H19N5O3S: C, 64.85; H, 3.98; N, IR(KBr, cm-1): 3450-3211 (NH+NH2), 2220, 2202
14.54; S, 6.66. Found: C, 64.63; H, 3.74; N, 14.24; S, (2C≡N), 1620 (C=N), 1352, 1138 (S=O);
1
6.39. HNMR (DMSO-d6, ppm): 6.85, 7.10(2br., 4H, 2NH2,
exchangeable with D2O), 7.63, 7.95 (2d, 4H, AB-
Mediterr.J.Chem., 2018, 7(5) M. S. A. El-Gaby et al. 356

system), 7.55, 8.52, 10.10(3br., 3H, 3NH, exchangeable of the test bacteria/fungi were grown in 10 mL of fresh
with D2O). media until they reached a count of approximately 10 8
Anal. Calcd. for C13H11N9O2S:C, 43.69; H, 3.10; N, cells/ml for bacteria or 105 cells/mL for fungi. All the
35.28; S, 8.97. Found: C, 43.46; H, 2.92; N, 35.13; S, newly synthesized compounds were weighed and
8.87. dissolved in dimethyl sulfoxide to prepare extract stock
solution.
4-(4-amino-3,5-dicyano-6-iminopyridazin-1(6H)-yl)-
N-(thiazol-2-yl)benzenesulfon amide 11c One hundred µL of each sample at 5 mg/mL was
added to each well (10 mm diameter holes cut in the agar
Yellow crystals (ethanol), Yield: 85%, m.p.>300 °C; gel). The plates were incubated for 24-48 h at 37 °C (for
IR(KBr, cm-1): 3430 (NH2), 3320, 3214 (2NH), 2216, bacteria and yeast) and 48 h at 28 °C (for filamentous
2201 (2C≡N), 1622 (C=N), 1330, 1147 (S=O); fungi). After incubation, the microorganism's growth
1
HNMR (DMSO-d6, ppm): 6.84, 7.77 (2d, 2H, thiazole), was observed. Ampicillin and Gentamycin were used as
7.70, 7.95 (2d, 4H, AB-system), 6.70 (s, 2H, NH2, standard antibacterial drugs while amphotericin B was
exchangeable with D2O), 9.85, 12.16 (2br., 2H, 2NH, used as a standard antifungal drug. The resulting
exchangeable with D2O). inhibition zone diameters were measured in millimeters
Anal. Calcd. for C15H10N8O2S2 : C, 45.22; H, 2.53; N, and used as a criterion for the antimicrobial activity. If
28.12; S, 16.10. Found: C, 45.22; H, 2.53; N, 28.12; S, an organism is placed on the agar, it will not grow in the
16.10. area around the well if it is susceptible to the chemical.
4-(4-amino-3,5-dicyano-6-iminopyridazin-1(6H)-yl)- This area of no growth around the disc is known as a
N-(5-methylisoxazol-3-yl)benzenesulfonamide 11d: Zone of inhibition. The size of the clear zone is
proportional to the inhibitory action of the compound
Yellow crystals (ethanol), Yield: 80%, m.p.>300 °C; under investigation. Solvent controls (DMSO) were
IR(KBr, cm-1): 3311 (NH2), 3225, 3192 (2NH), 2217, included in every experiment as negative controls.
2199 (2C≡N), 1618 (C=N), 1330, 1159 (S=O); DMSO was used for dissolving the tested compounds
1
HNMR (DMSO-d6, ppm): 2.35 (s, 3H, CH3), 6.15 (s, and showed no inhibition zones, confirming that it does
1H, oxazole-H), 7.72, 8.12(2d, 4H, AB-system), 7.52(s, not influence the growth of the tested microorganisms.
2H, NH2, exchangeable with D2O), 9.76, 11.18(2s, 2H, The active compounds were further investigated to
2NH, exchangeable with D2O); determine their antimicrobial activity expressed
Anal. Calcd. for C16H12N8O3S: C, 48.48; H, 3.05; N, regarding minimum inhibitory concentration (MIC)
28.27; S, 8.09. Found: C, 48.26; H, 2.97; N, 28.12; S, using the modified agar well diffusion method that
7.95. mentioned above. Different concentrations of each
4-(4-amino-3,5-dicyano-6-iminopyridazin-1(6H)-yl)- active compound were tested and compared with
N-(pyrimidin-2-yl)benzenesulfonamide 11e standard drugs. The MIC was then determined as the
lowest concentration inhibiting the growth of the
Yellow crystals (ethanol), Yield: 88%, m.p.>300 °C; organism after 24-48 h 43,45.
IR(KBr, cm-1): 3434 (NH2), 3228, 3213 (2NH), 2216,
2201 (2C≡N), 1621 (C=N), 1339, 1155 (S=O); Conflict of interest
1
HNMR (DMSO-d6, ppm): 6.98, 8.42(m, d, 3H, H-
pyrimidine), 7.68, 8.15 (2d, 4H, AB-system), 7.90(s, The authors declare that they have no conflict of
2H, NH2 exchangeable with D2O), 9.65, 11.26(2s, 2H, interest.
2NH, exchangeable with D2O);
Anal. Calcd. for C16H11N9O2S: C, 48.85; H, 2.82; N, References
32.05; S, 8.15. Found: C, 48.64; H, 2.59; N, 31.97; S,
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