Pharmacology & Pharmacy, 2011, 2, 1-9
doi:10.4236/pp.2011.21001 Published Online January 2011 (http://www.SciRP.org/journal/pp)
1
Symmetrical Acyclic Aryl Aldazines with
Antibacterial and Antifungal Activity
Vanya B. Kurteva,1,* Svilen P. Simeonov,1 Margarita Stoilova-Disheva2
1Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Sciences, Sofia, Bulgaria; 2Institute of Micro-
biology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Received October 19th, 2010; revised November 8th, 2010; accepted November 15th, 2010.
ABSTRACT
A series of 22 symmetrical acyclic aromatic aldazines were obtained and their qualitative an timicrobial activities were
evaluated against 10 bacterial and 3 fungal species. The results demonstrated that the bi- and polycyclic aromatics
studied are remarkably more active than benzaldazines. The latter possess antibacterial activities only, which were
dramatically redu ced by the introduction of substituen ts. The tests showed that the activities ar e strongly dependent on
the type and position of the substituents and that the effects on antibacterial and antifungal activities are the opposite.
2-Naphtaldazine was significantly more active than its position isomer 1-naphthaldazine against Saccharomyces cere-
visiae and Penicillium chrysogenum, whereas both compounds possess commensurable activities towards Candida
tropicalis and the bacterial strains. From the other side, the presence of 4-hydroxy substituent in 1-naphthaldazine re-
duced the antibacterial and increased the antifungal activities, while the influence of 2-hydroxy group led to reversed
results.
Keywords: Symmetrical Acyclic Aryl Aldazines, Synthesi s , Antibacterial Activity, Antifungal Activity
1. Introduction
Azines are a class of organic compounds containing
R1R2C = N_N = CR3R4 fragment. Depending on the na-
ture of the substituents R, they are divided in several
sub-groups: 1) symmetrical (R1R2 = R3R4) and unsym-
metrical (R1R2 ≠ R3R4); 2) aldazines (R1 = R3 = H), ketaz-
ines (R1R2R3R4 ≠ H) and mixed azines (R1 = H, R2R3R4 ≠
H); 3) aromatic and aliphatic; 4) cyclic and acyclic. Nu-
merous examples are well-known ever since 19th century
but only a limited number of synthetic pathways are ap-
plied for their preparation. The classical scheme for the
construction of acyclic aldazines is based on a reaction of
aldehydes with hydrazine [1,2]. Despite the high toxicity
of the latter, the protocol is very fast, simple and efficient
and is still widely exploited. Semicarbazide has been also
applied as a reagent in a two-step procedure involving
thermolysis of the intermediately formed semicarbazones
at high temperature [3,4]. Recently, the transformation
has achieved as an environmentally benign solvent-free
procedure under microwave irradiation [5,6].
Compounds possessing azine moiety are still the order
of the day due to the broad spectrum of biological active-
ity profiles displayed. Ketazines, mixed azines, and cy-
clic compounds have exhibited antitumor [7-12], anti-

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 2
bacterial [13-20], anti-inflammatory [21], antimalarial
dyes [22], anticonvulsant [23,24], insect growth regula-
tors [25] and many other activities. Contrary, acyclic
aldazines are much less studied. Unsymmetrical aldazi-
nes have shown antitumor [26], antibacterial [27,28], and
antioxidant [29] activity. Symmetrical 4-bromo benzal-
dazine has evaluated as anticonvulsant agent but shown
very low activity [30]. Similar monosubstituted benzal-
dazines have been tested as allosteric modulators [31]
and has found that 2-fluoro and 3-fluoro compounds
possessed positive activity, while 4-fluoro, 3-chloro, 3-
and 4-methoxy, and 3-hydroxy analogues were not active.
Recently, a series of unsymmetrical and two examples of
symmetrical 3-indolyl aldazines have been studied and
have found to exhibit antioxidant [29] and antibacterial
[28] activity. The latter presents, to the best of our
knowledge, the only record in the literature on the
evaluation of antibacterial and antifungal activity of
symmetrical aryl aldazines.
In this paper, we report on a synthesis, characterization
and qualitative antibacterial and antifungal activity
evaluation of a series of 22 symmetrical acyclic aryl al-
dazines.
2. Results and Discussion
2.1. Chemistry
The titled symmetrical aldazines were obtained by the
classical protocol from aldehydes and hydrazine sulphate
in ethanol, as shown on Scheme 1. Aromatic aldehydes
with varied ring size and type and position of the sub-
stituents were chosen in an attempt to study the influence
of different factors on the activity. The syntheses of al-
dazines 20-22 were carried out in ethanol/dimethylfor-
mamide instead of pure ethanol due to the limited solu-
bility of the starting aldehydes. The compounds 1-16 and
18-22 were isolated in high to excellent yields (Table 1)
after a very simple work-up. The E,E-configuration of
the products was assumed on the bases of the previously
confirmed by X-ray analysis stereochemistry of a similar
symmetrical aryl aldazine sample [6].
The naphthaldazine 17 possessing a non-conjugated
side-chain was obtained in moderate yield from 15 by
Mannich reaction (Scheme 2, Table 1). As it was found
that 17 is less active than the corresponding unsubstituted
compound 15, other examples were not synthesized.
All known aldazines, 1-11, 13-16, 18, 19, 21, and 22,
were characterized by a comparison of the melting points
with the literature data (Table 1) and by their NMR
spectra, given in the experimental section. The structures
of the new members, 12, 17 and 20, were additionally
confirmed by electrospray ionization mass spectrometry.
2.2. Pharmacology
The in vitro antibacterial and antifungal activities of the
synthesized compounds against a series of species were
determined qualitatively by the agar cup test according to
the European Pharmacopoeia [48]. Shortly, suspensions
of the test microorganisms were inoculated into sterile
melted nutrient agar media and poured into Petri dishes.
The bacterial strains were grown in nutrient agar (Serva,
Germany) for 24 h at 37˚C while the yeast and fungal
strains were incubated in yeast peptone dextrose agar
(YEPD) and in potato dextrose agar (PDA), respectively
for 72 h at 28˚C. Six per dish wells, each 8 mm in di-
ameter, were prepared. Fifty microliter of each sample in
dimethylsulfoxide (25 mg/ml or 12.5 mg/ml) was added
to the appropriate well. For pre-diffision the Petri dishes
were placed at 4˚C for 2 h. The antimicrobial activity
was estimated by the diameter of inhibitory zones (mm)
in the agar layer. Control experiments were carried out
with the pure solvent.
Scheme 1. Synthesis of symmetrical aryl aldazines 1-16 and 18-22.
Scheme 2. Synthesis of symmetri c al aryl naphthalda zine 17.

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 3
Table 1. Synthesis and physical data of symmetrical aryl aldazines 1-22.
Azine Ar group Yield, % m.p., ˚C (lit.) Rf-value, (MP)a
1 Ph 90 91.5-92 (92 [32]) 0.63 (A)
2 4-OH-C6H4 88 258-259 (268 [33]) 0.36 (B)
3 3-OH-C6H4 94 205.5-206 (205 [34]) 0.51 (B)
4 2-OH-C6H4 96 210-211 (213-214 [3]) 0.85 (B)
5 3-OMe-2-OH-C6H3 98 192-193 (196 [35]) 0.47 (A)
6 4-NMe2-C6H4 87 254.5-255 (250-253 [33]) 0.59 (A)
7 4-Cl-C6H4 93 210-211 (213 [36]) 0.71 (A)
8 3-Cl-C6H4 93 142-143 (141 [37]) 0.75 (A)
9 2-Cl-C6H4 89 143.5-144 (143.5 [38]) 0.77 (A)
10 2,6-Cl2-C6H3 87 152.5-153 (153 [39]) 0.76 (A)
11 2,4-Cl2-C6H3 95 218-219 (213 [40]) 0.83 (A)
12 2-Cl-4-F-C6H3 97 193.5-194 0.80 (A)
13 3-F-C6H4 91 134-135 (132 [41]) 0.72 (A)
14 1-naphthyl 96 156-156.5 (156 [42]) 0.74 (A)
15 4-OH-1-naphthyl 84 235-236 (236 [43]) 0.58 (B)
16 2-OH-1-naphthyl 89 290-293 (>290 [44]) 0.86 (B)
17 4-OH-3-R-1-naphthylb 35 232-232.5 0.28 (C)
18 2-naphthyl 93 232-232.5 (232 [45]) 0.71 (A)
19 4-Ph-C6H4 64 243.5-244 (230-245 [46]) 0.68 (A)
20 2-fluoryl 97 260-261 0.71 (A)
21 9-phenanthryl 82 232-232.5 (244 [47]) 0.70 (A)
22 1-pyrenyl 94 299 (299 [39]) 0.81 (A)
aMobile phase (MP), A: CH2Cl2, B: CH2Cl2:MeOH 90:10, C: EtOAc:Et3N 100:1; bDepicted on Scheme 2.
2.2.1. Anti bacterial Activity
The antibacterial activities of aldazines 1-22 were evalu-
ated against the Gram (+) strains Bacillus subtilis ATCC
6633, Bacillus idosus B241, Bacillus megaterium NRRL
1353895, Bacillus mycoides DSMZ 274, Bacillus cereus
ATCC 11778, Acinetobacter johnstonii ATCC 17909,
Staphylococcus aureus NRRL B 313, Sarcina lutea
ATCC 9341, and Micrococcus luteus ATCC 9631, and
the Gram (-) strain Escherichia coli ATCC 8739. Strep-
tomycin and Gentamycin were used as standard drugs.
The antibacterial screening demonstrated that half of
the tested products, listed on Table 2, are active against
all strains. Inside the benzaldazine series 1-13, the un-
substituted compound 1 exhibited good activities, while
the introduction of substituents in the phenyl ring led to
loss of activity in general. The only exceptions were
4-hydroxy compound 2 and 2-chloro-4-fluoro derivative
12, both possessing lower activity than 1. The compare-
son with their non-active position analogues, 2 vs 3-5 and
12 vs 13, could be an indication that hydroxyl group and
fluorine atom at para-position slightly reduce the activity
of the unsubstituted azine 1, while their effect if ortho- or
meta-positioned is significant. Contrary, the introduction
of a hydroxyl group in 1-naphthaldazine 14 led to better
inhibition against the most part of the Gram (+)-bacteria
of the ortho-substituted compound, 14 vs 16, and com-
mensurable or reduced activities of para-hydroxy prod-
uct, 14 vs 15. The incorporation of a side-chain in 17,

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 4
Table 2. Aldazines with antibacte rial activity; zone of inhibitiona in mm.
Azine Bacillus
subtilis Bacillus idosus Bacillus megat. Bacillus mycoides Bacillus cereus Acinetob. johnst. Staph. aureus Sarcina lutea Microc. luteus E. coli
1b 20 21 20 16 17 24 18 20 19 30
2b 10 18 17 15 26 17 17 17 16 20
12b - 15 14 16 17 - 12 14 15 25
14b 19 18 20 11 22 18 21 23 21 24
15b 13 19 12 18 16 16 14 14 14 25
16c 17 26 24 19 25 27 15 25 22 25
17c 11 12 11 10 12 11 12 11 12 12
18c 20 23 21 16 20 25 22 25 23 30
19c 15 19 20 15 19 17 17 18 20 37
20c 22 25 25 14 22 26 23 20 25 23
22c 15 19 14 15 19 13 12 18 21 33
Ref 1b,e 35 30 30 35 30 30 32 27 30 35
Ref 2d,f 30 35 36 32 29 39 35 34 38 31
aDMSO solutions with different concentrations; indicated for each compound: b25 mg/ml; c12.5 mg/ml; d20 mg/ml; eStreptomycin; fGentamycin.
where the hydroxyl proton is strongly hydrogen-bonded -
with piperidine nitrogen, resulted in an additional reduc-
tion of the activity, 15 vs 17.
2.2.2. An ti fungal Ac ti vi ty
The antifungal activity of compounds 1-22 were exam-
ined against the yeast strains Candida tropicalis ATCC
20336 and Saccharomyces cerevisiae ATCC 9763, and
the fungal strain Penicillium chrysogenum CECT 2802.
Fluconazole and Itraconazole were used as standard
drugs.
The qualitative experiments showed that only four
products, three naphthaldazines (14, 15 and 18) and a
fluorenealdazine, listed on Table 3, exhibit significant
antifungal activities. The rest of the aldazines gave
commensurable zones of inhibition of maximum 10-12
mm. A comparison between the active compounds (Ta-
ble 3) shows that inside the naphthaldazine series,
2-naphtal- dazine 18 is remarkably more active than its
position isomer 1-naphthaldazine 14 against Saccharo-
myces cer- evisiae and Penicillium chrysogenum, while
both com- pounds possess the same activity towards
Candida tropicalis. From the other side, the position of
the hydroxy substituent in 1-naphthaldazine displayed a
reversed effect in respect to antibacterial tests. The pres
ence of a 4-hydroxyl substituent, 14 vs 15, led to slight
increase of the activity towards the yeast strains tested
and reduced activity against the fungal strain, while
2-hydroxy derivative 16 was not active in general.
Table 3. Aldazines with antifungal activity; zone of inhibit-
tiona in mm.
Compound Candida
tropicalis Saccharomyces cerevisiae Penicillium chrysogenum
14b 20 18 18
15b 24 25 15
18c 20 30 35
20c 21 23 20
Fluconazolb 35 - -
Itraconazolec- 30 -
aDMSO solutions with different concentrations; indicated for each com-
pound: b25 mg/ml; c12.5 mg/ml.
3. Conclusions
A series of 19 known and 3 new symmetrical acyclic
aromatic aldazines were obtained. Their qualitative an-
timicrobial activities were evaluated against 10 bacterial
and 3 fungal species. Eleven compounds exhibited good
to moderate antibacterial activities, while only four bi-
cyclic azines possessed significant antifungal activities. It
was observed that the introduction of substituents in the
phenyl ring led to loss of antibacterial activity in general,
whereas none of the compounds showed significant anti-
fungal activity. The position isomers 1-naphthaldazine
and 2-naphthaldazine exhibited commensurable antibac-

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 5
terial activities, while 2-naphtaldazine was significantly
more active against Saccharomyces cerevisiae and Peni-
cillium chrysogenum. The introduction of a hydroxyl
group in 1-naphthaldazine led to better inhibition against
the most part of the Gram (+)-bacteria of the ortho-sub-
stituted compound and similar or reduced activities of
para-hydroxy product. Contrary, the presence of a
4-hydroxy group led to slight increase of the activity to-
wards the yeast strains tested and reduced activity against
the fungal strain, whereas 2-hydroxy derivative was not
active in general.
4. Experimental
4.1. General
All reagents were purchased from Aldrich, Merck and
Fluka and were used without any further purification.
Fluka silica gel/TLC-cards 60778 with fluorescent indi-
cator 254 nm were used for TLC chromatography and
Rf-values determination. The high performance flash
chromatography (HPFC) purifications were carried out
on a Biotage HorizonTM system (Charlottesville, Vir-
ginia, USA) on silica gel. The melting points were de-
termined in capillary tubes on SRS MPA100 OptiMelt
(Sunnyvale, CA, USA) automated melting point system.
The NMR spectra were recorded on a Bruker Avance
DRX 250 and Bruker Avance II+ 600 (where indicated)
spectrometers (Rheinstetten, Germany); the chemical
shifts were quoted in ppm in δ-values against tetrame-
thylsilane (TMS) as an internal standard and the coupling
constants were calculated in Hz. The chemical shifts are
given with different decimals according to the accuracy
(fid resolution) of the corresponding experiments. The
assignment of the signals was achieved on the bases of
the cross-peaks in the 2D experiments (COSY, NOESY,
HSQC, HMBC). For simplicity, the carbon bearing the
azine moiety is designated as C-1 in all products except
18, 20 and 21, where the nomenclature of the corre-
sponding fused carbocycles is followed. The aldazines 11
and 19-22 are not enough soluble to record carbon spec-
tra at room temperature in a reasonable time-scale. The
ESI mass-spectra were recorded on a DFS High Resolu-
tion Magnetic Sector MS, Thermo Scientific (Waltham,
MA, USA).
The reaction yields, melting points, and Rf-values of
the products are listed on Table 1.
4.2. Preparation of Aldazines 1-16 and 18-22
To a solution of aldehyde (10 mmol) in EtOH (20 ml)
and DMF (5 ml, only for the preparation of 20-22) hy-
drazine hydrate (5 mmol) and then a drop of conc. H2SO4
were added and the mixture was stirred at room tem-
perature for 1 h. The residue formed was filtered off,
washed with water and then with EtOH and was dried in
air.
1,2-Dibenzylidenehydrazine (1). NMR (CDCl3): 1H
7.436 (m, 6H, CH-3, CH-4 and CH-5), 7.837 (dd, 4H, J
2.0, 7.8, CH-2 and CH-6), 8.661 (s, 2H, CH = N); 13C
128.83 (CH-2 and CH-6), 129.39 (CH-3 and CH-5),
131.83 (CH-4), 134.27 (Cquat-1), 161.89 (CH = N).
1,2-Bis(4-hydroxybenzylidene)hydrazine (2). NMR
(CDCl3:DMSO-d6 2:1): 1H 6.79 (d, 4H, J 8.6, CH-3 and
CH-5), 7.58 (d, 4H, J 8.6, CH-2 and CH-6), 8.45 (s, 2H,
CH = N), 9.69 (bs, 2H, OH, exchangeable signal); 13C
115.52 (CH-3 and CH-5), 125.09 (Cquat-1), 129.70 (CH-2
and CH-6), 159.85 (Cquat-4), 160.52 (CH = N).
1,2-Bis(3-hydroxybenzylidene)hydrazine (3). NMR
(CDCl3:DMSO-d6 5:1): 1H 6.86 (m, 2H, CH-5), 7.17 (m,
4H, CH-2 and CH-6), 7.24 (dd, 2H, J 1.2, 2.7, CH-2),
8.45 (s, 2H, CH = N), 9.16 (bs, 2H, OH, exchangeable
signal); 13C 114.20 (CH-2), 118.26 (CH-4), 119.49
(CH-6), 129.23 (CH-5), 134.70 (Cquat-1), 157.25 (Cquat-3),
161.15 (CH = N).
1,2-Bis(2-hydroxybenzylidene)hydrazine (4). NMR
(CDCl3:CF3COOH 3:1): 1H 7.18 (m, 4H, CH-3 and
CH-5), 7.57 (dd, 2H, J 1.6, 8.0, CH-6), 7.69 (ddd, 2H, J
1.6, 7.3, 8.7, CH-4), 8.98 (s, 2H, CH = N), 11.69 (bs, OH,
overlapped with COOH of CF3COOH); 13C 114.23
(Cquat-1), 118.03 (CH-3 or CH-5), 122.69 (CH-3 or
CH-5), 136.06 (CH-4 or CH-6), 139.94 (CH-4 or CH-6),
160.49 (Cquat-2), 164.58 (CH = N); NMR (DMSO-d6): 1H
6.96 (m, 4H, CH-3 and CH-5), 7.40 (ddd, 2H, J 1.8, 7.2,
8.3, CH-4), 7.69 (dd, 2H, J 1.9, 8.3, CH-6), 9.00 (s, 2H,
CH = N), 11.11 (bs, OH, exchangeable signal).
1,2-Bis(2-hydroxy-3-methoxybenzylidene)hydrazine (5).
NMR (CDCl3): 1H 3.93 (s, 6H, OCH3), 6.96 (m, 6H, CH),
8.70 (s, 2H, CH=N), 11.57 (bs, 2H, OH, exchangeable);
13C 56.16 (OCH3), 115.03 (CH-4), 117.29 (Cquat-1),
119.40 (CH-5), 124.01 (CH-6), 148.30 (Cquat), 149.63
(Cquat), 164.80 (CH = N); NMR (DMSO-d6): 1H 3.83 (s,
6H, OCH3), 6.91 (t, 2H, J 7.9, CH-5), 7.13 (dd, 2H, J 1.4,
8.1, CH-4), 7.29 (dd, 2H, J 1.4, 7.9, CH-6), 8.98 (s, 2H,
CH = N), 10.87 (s, 2H, OH); NMR (DMSO-d6): 1H 3.833
(s, 6H, OCH3), 6.910 (t, 2H, CH-5), 7.127 (dd, 2H, J46
1.4, J45 8.1, CH-4), 7.288 (dd, 2H, J46 1.4, J56 7.9, CH-6),
8.985 (s, 2H, CH = N), 10.869 (s, 2H, OH).
1,2-Bis(4-dimethylaminobenzylidene)hydra zin e (6). NMR
(CDCl3): 1H 3.034 (s, 12H, NCH3), 6.717 (d, 4H, J 8.9,
CH-3 and CH-5), 7.699 (d, 4H, J 8.9, CH-2 and CH-6),
8.574 (s, 2H, CH=N); 13C 40.16 (NCH3), 111.67 (CH-3
and CH-5), 128.18 (Cquat-1), 129.85 (CH-2 and CH-6),
152.07 (Cquat-4), 160.77 (CH = N).
1,2-Bis(4-chlorobenzylidene)hydraz ine (7). NMR (CDCl3):
1H 7.46 (ddd, 4H, J 1.8, 2.3, 8.4, CH-3 and CH-5), 7.81
(ddd, 4H, J 1.8, 2.3, 8.4, CH-2 and CH-6), 8.60 (s, 2H,
CH = N); 13C 129.15 (CH-2 and CH-6), 129.74 (CH-3

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 6
and CH-5 of Ar), 132.50 (Cquat-1), 137.34 (Cquat-4),
161.01 (CH = N).
1,2-Bis(3-chlorobenzylidene)hydraz ine (8). NMR (CDCl3):
1H 7.46 (m, 4H, CH-4 and CH-5), 7.72 (dt, 2H, J 1.6, 7.2,
CH-6), 7.88 (dd, 2H, J 1.6, 1.8, CH-2), 8.59 (s, 2H, CH =
N); 13C 126.99 (CH-2 or CH-6), 128.14 (CH-2 or CH-6),
130.06 (CH-4 or CH-5), 131.29 (CH-4 or CH-5), 135.00
(Cquat-1 or Cquat-3), 135.74 (Cquat-1 or Cquat-3), 161.06
(CH = N).
1,2-Bis(2-chl orobe nzyli dene) hyd razin e (9). NMR (CDCl3:
DMSO-d6 1:3): 1H 7.43 (m, 2H, CH), 7.51 (m, 4H, CH),
8.16 (m, 2H, CH), 8.97 (s, 2H, CH = N); 13C 127.21
(CH-5 or CH-6), 127.90 (CH-5 or CH-6), 129.82 (CH-3),
130.47 (Cquat-1), 132.59 (CH-4), 134.68 (Cquat-2), 160.52
(CH = N).
1,2-Bis(2,6-dichlorobenzylidene)hydrazine (10). NMR
(CDCl3): 1H 7.28 (dd, 2H, J 7.0, 9.0, CH-4), 7.411 (d, 2H,
J 7.0, CH-3 or CH-5, overlapped signals), 7.413 (d, 2H, J
9.0, CH-3 or CH-5, overlapped signals), 8.82 (s, 2H, CH =
N); 13C 128.94 (CH-3 and CH-5), 130.26 (Cquat-1),
130.96 (CH-4), 135.52 (Cquat-2 and Cquat-6), 157.47 (CH =
N).
1,2-Bis(2,4-dichlorobenzylidene)hydrazine (11). NMR
(CDCl3:DMSO-d6:CF3COOH 3:1:0.05): 1H 7.23 (dd, 2H,
J 2.0, 8.6, CH-5), 7.36 (d, 2H, J 2.0, CH-3), 8.04 (d, 2H,
J 8.6, CH-6), 8.84 (s, 2H, CH = N).
1,2-Bis(2-chloro-4-fluoroben zylidene)hydrazine (12).
NMR (CDCl3): 1H 7.08 (dddd, 2H, J5,CH = N 0.6, J3,5 2.5,
J5,F 7.8, J5,6 8.7, CH-5), 7.19 (dd, 2H, J3,5 2.5, J5,F 8.4,
CH-3), 8.24 (dd, 2H, J6,F 6.3, J5,6 8.8, CH-6), 9.01 (d, 2H,
J5,CH = N 0.6, CH = N); 13C 114.92 (d, J5,F 21.7, CH-5),
117.34 (d, J3,F 24.9, CH-3), 127.89 (d, J1,F 3.6, Cquat-1),
129.94 (d, J6,F 9.2, CH-6), 136.79 (d, J2,F 10.5, Cquat-2),
158.10 (CH = N), 164.16 (d, J4,F 255.9, Cquat-4); MS
(ESI+) m/z 313 (M+), C14H8Cl2F2N2.
1,2-Bis(3-fluorobenzylidene)hydrazine (13). NMR (CDCl3):
1H 7.20 (dddd, 2H, J4,6 1.1, J4,2 2.6, J4,5 8.3, J4,F 9.3,
CH-4), 7.46 (ddd, 2H, J5,6 6.8, J4,5 8.3, J5,F 13.7, CH-5),
7.57 (dt, 2H, J4,6 1.1, J2,6 1.4, J5,6 6.8, CH-6), 7.61 (dd, 2H,
J2,6 1.4, J2,4 2.6, J2,F 9.2, CH-2), 8.61 (d, 2H, JCH = N,F 1.1,
CH = N); 13C 114.55 (d, J2,F 22.5, CH-2), 118.31 (d, J4,F
21.6, CH-4), 124.86 (d, J6,F 2.9, CH-6), 130.37 (d, J5,F 8.1,
CH-5), 136.24 (d, J1,F 7.6, Cquat-1), 161.16 (d, JCH = N,F 3.1,
CH = N), 163.02 (d, J3,F 246.9, Cquat-3).
1,2-Bis(naphthalen-1-ylmethylene)hydrazi ne (14). NMR
(600 MHz, DMSO-d6): 1H 7.661 (ddd, 2H, J79 1.1, J78 6.8,
J67 8.0, CH-7), 7.691 (dd, 2H, J23 7.3, J34 8.1, CH-3),
7.725 (ddd, 2H, J68 1.3, J78 6.8, J89 8.4, CH-8), 8.076 (d,
2H, J67 8.0, CH-6), 8.147 (d, 2H, J34 8.1, CH-4), 8.194
(dd, 2H, J24 0.7, J23 7.3, CH-2), 9.212 (d, 2H, J89 8.4,
CH-9), 9.459 (s, 2H, CH=N); 13C 125.09 (CH-9), 125.56
(CH-3), 126.46 (CH-7), 127.62 (CH-8), 128.79 (CH-6),
129.17 (Cquat-5), 130.42 (CH-2), 130.63 (Cquat-10),
131.96 (CH-4), 133.55 (Cquat-1), 162.02 (CH=N).
1,2-Bis((4-hydroxynaphthalen-1-yl)methylene)hydrazi
ne (15). NMR (DMSO-d6): 1H 7.03 (d, 2H, J 8.0, CH-3),
7.58 (ddd, 2H, J 1.1, 6.8, 8.2, CH-8), 7.70 (ddd, 2H, J 1.5,
6.8, 8.4, CH-7), 7. 97 (d, 2H, J 8.2, CH-2), 8.30 (dd, 2H,
J 1.1, 8.2, CH-9), 9.25 (s, 2H, CH = N), 9.30 (d, 2H, J 8.4,
CH-6), 10.96 (bs, OH); 13C 108.54 (CH-3), 120.87
(Cquat-1), 123.11 (CH-9), 125.25 (Cquat-5), 125.64 (CH-6),
125.82 (CH-8), 128.33 (CH-7), 132.67 (Cquat-10), 133.38
(CH-2), 157.16 (Cquat-4), 162.00 (CH = N).
1,2-Bis((2-hydroxynaphthalen-1-yl)methylene)hydrazi
ne (16). NMR (CDCl3:CF3COOH 3:1): 1H 7.30 (d, 2H, J
9.0, CH-3), 7.50 (dd, 2H, J 7.1, 8.1, CH-7), 7.68 (ddd,
2H, J 1.2, 7.1, 8.5, CH-6), 7.81 (d, 2H, J 8.1, CH-8), 8.07
(d, 2H, J 9.0, CH-4), 8.23 (d, 2H, J 8.5, CH-5), 9.70 (s,
2H, CH = N), 11.08 (bs, OH, overlapped with COOH of
CF3COOH); 13C 106.43 (Cquat-1), 118.08 (CH), 120.11
(CH), 126.13 (CH), 128.98 (Cquat), 130.27 (CH), 130.69
(CH), 132.79 (Cquat), 141.76 (CH), 157.90 (CH = N),
163.29 (Cquat-2).
1,2-Bis(naphthalen-2-ylmethylene)hydrazi ne (18). NMR
(600 MHz, DMSO-d6, 70˚C): 1H 7.634 (m, 4H, CH-7 and
CH-8), 8.012 (d, 2H, J67 7.2, CH-6), 8.054 (m, 4H, CH-4
and CH-9), 8.162 (dd, 2H, J13 1.3, J34 8.5, CH-3), 8.395
(s, 2H, CH-1), 8.938 (s, 2H, CH = N); 13C 123.99 (CH-3),
127.31 (CH-6), 128.10 (CH-7), 128.29 (CH-8), 129.00
(CH-9), 129.08 (CH-4), 131.04 (CH-1), 132.15 (Cquat-5),
133.33 (Cquat-10), 134.93 (Cquat-2), 161.48 (CH = N).
1,2-Bis(biphenyl-4-ylmethylene)hydrazine (19). NMR
(CDCl3:DMSO-d6:CF3COOH 1:1:0.1): 1H 7.33 (m, 6H,
CH), 7.54 (dt, 4H, J 1.5, 7.0, CH), 7.60 (dt, 4H, J 1.7, 8.4,
CH), 7.82 (dt, 4H, J 1.7, 8.4, CH), 8.59 (s, 2H, CH = N).
1,2-Bis((9H-fluoren-2-yl)methylene)hydr azine (20). NMR
(600 MHz, DMSO-d6, 70˚C): 1H 4.035 (s, 4H, CH2),
7.391 (td, 2H, J 1.2, 7.3, CH-7), 7.440 (td, 2H, J 1.0, 7.3,
CH-6), 7.647 (dt, 2H, J 0.9, 7.3, CH-8), 7.928 (dd, 2H, J
0.9, 7.9, CH-3), 7.974 (dd, 2H, J 1.0, 7.3, CH-5), 8.021
(d, 2H, J 7.9, CH-4), 8.126 (s, 2H, CH-1), 8.782 (s, 2H,
CH = N); MS (ESI+) m/z 385 (M+), C28H20N2.
1,2-Bis(phenanthren-9-ylmeth y len e)hydra zi ne (21). NMR
(DMSO-d6): 1H 7.82 (m, 4H, CH), 8.17 (d, 2H, J 7.4,
CH), 8.57 (s, 2H, CH-10), 8.93 (d, 2H, J 7.7, CH), 8.99
(m, 2H, CH), 9.38 (m, 2H, CH), 9.50 (s, 2H, CH = N).
1,2-Bis(pyren-1-ylmethylene)hydrazine (22). NMR (600
MHz, DMSO-d6): 1H 8.076 (t, 2H, J 7.6, CH-7), 8.161
(m, 4H, CH), 8.245 (m, 4H, CH), 8.291 (m, 4H, CH),
8.396 (d, 2H, J 8.1, CH), 8.708 (d, 2H, J 9.4, CH), 8.782
(s, 2H, CH = N).
4.3. Preparation of
1,2-bis((4-hydroxy-3-(morpholinomethyl)
naphthalen-1-yl)methylene)hydrazine (17)
To a solution of 15 (1 mmol) in benzene (20 ml) mor-

Symmetrical Acyclic Aryl Aldazines with Antibacterial and Antifungal Activity 7
pholine (2.1 mmol), paraformaldehyde (2.2 mmol), and
p-toluenesulfonic acid (10 mg) were added and the mix-
ture was refluxed with stirring for 4 h. The products were
partitioned between aq. K2CO3 and CH2Cl2. The organic
layer was washed with water, dried over Na2SO4, evapo-
rated to dryness, and purified by HPFC on silica gel;
mobile phase with a gradient of polarity from hex-
ane:EtOAc:Et3N 50:50:0.5 to EtOAc:Et3N 100:1; NMR
(DMSO-d6:CF3COOH 5:1): 1H 3.264 (bm, 4H, CH2-N
morpholine), 3.387 (bm, 4H, CH2-N morpholine), 3.706
(bm, 4H, CH2-O morpholine), 3.922 (bm, 4H, CH2-O
morpholine), 4.583 (s, 4H, Ar- CH2-N), 7.604 (ddd, 2H, J
1.1, 6.9, 8.4, CH-7 or CH-8), 7.703 (ddd, 2H, J 1.3, 6.9,
8.5, CH-7 or CH-8), 8.121 (s, 2H, CH-2), 8.467 (dd, 2H,
J 1.1, 8.5, CH-6 or CH-9), 9.132 (dd, 2H, J 1.2, 8.4,
CH-6 or CH-9), 9.273 (s, 2H, CH = N), 9.928 (bs, 2H,
OH, exchangeable signal); 13C 52.04 (CH2-N mor-
pholine), 55.76 (Ar-CH2-N), 64.06 (CH2-O morpholine),
110.83 (Cquat), 121.96 (Cquat), 124.25 (CH), 125.80 (CH),
126.20 (Cquat), 126.70 (CH), 129.51 (CH), 133.69 (Cquat),
135.59 (CH), 157.46 (Cquat-4), 161.50 (CH = N); MS
(ESI+) m/z 539 (M+), C32H34N4O4.
5. Acknowledgements
The financial support by the National Research Fund of
Bulgaria, Projects TK-X-1716 and UNA-17/2005, is
gratefully acknowledged.
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