Efficient synthesis of novel 1,2,4-triazole fused acyclic and 21-28 membered macrocyclic and/or lariat macrocyclic oxaazathia crown compounds with potential antimicrobial activity

Article abstract of DOI:10.1016/j.ejmech.2010.08.046

Versatile simple efficient routes with good to excellent yields towards different functionalized 1,ω-bis(1,2,4-triazoles), 21-28 membered 1,2,4-triazole fused macrocyclic and/or lariat macrocyclic oxaazathia crown Schiff bases and/or amines have been investigated. Antimicrobial screening of some selected compounds revealed different inhibitory effects against Aspergillus fumigatus RCMB 002008 (1), Penicillium italicum RCMB 001018 (1), Syncephalastrum racemosum RCMB 016001 Candida albicans RCMB 005003, Staphylococcus aureus RCMB 106-001 (1), Pseudomonas aeruginosa RCMB 102-002, Bacillus subtilis RCMB 101-001 and Escherichia coli RCMB 103-001.

Full text of DOI:10.1016/j.ejmech.2010.08.046

European Journal of Medicinal Chemistry 45 (2010) 5265e5277
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Efficient synthesis of novel 1,2,4-triazole fused acyclic and 21e28 membered
macrocyclic and/or lariat macrocyclic oxaazathia crown compounds with
potential antimicrobial activity
*
Nasser S.A.M. Khalil
Regional Center for Food and Feed, Agricultural Research Center, 9 El Gamaa St., PO Box 588 Orman, Giza, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Versatile simple efficient routes with good to excellent yields towards different functionalized 1,u-bis
Received 24 April 2010
Received in revised form
19 August 2010
Accepted 21 August 2010
Available online 26 September 2010
(1,2,4-triazoles), 21e28 membered 1,2,4-triazole fused macrocyclic and/or lariat macrocyclic oxaazathia
crown Schiff bases and/or amines have been investigated. Antimicrobial screening of some selected
compounds revealed different inhibitory effects against Aspergillus fumigatus RCMB 002008 (1), Penicil-
lium italicum RCMB 001018 (1), Syncephalastrum racemosum RCMB 016001 Candida albicans RCMB 005003,
Staphylococcus aureus RCMB 106-001 (1), Pseudomonas aeruginosa RCMB 102-002, Bacillus subtilis RCMB
101-001 and Escherichia coli RCMB 103-001.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
1,u-bis(1,2,4-triazoles)
Oxaazathia crown Schiff bases
Oxaazathia crown amines
Antimicrobial activity
1. Introduction
anxiolytic, selectively inhibits central serotonin uptake) and Tri-
azolam (sedative and hypnotic) [18].
1,2,4-Tiazole moiety appears frequently in the structure of various
natural products [1] and the synthesis of compounds incorporating
this moiety has attracted widespread attention of chemists as well as
biologists, mainly due to their diverse biological activities in phar-
maceutical and agrochemical fields [2e18]. A large variety 1,2,4-tia-
zole derivatives possess antibacterial [2,3], antifungal [2,4],
antimycobacterial [5,10], antiviral [6], anti-inflammatory [7], anti-
convulsant [8], antidepressant [9], antitubercular [10], antitumoral
[11], antihypertensive [12], analgesic [13], enzyme inhibitor [14],
hypoglycemic [15], sedative, hypnotic [16], antiparasitic, herbicidal,
insecticidal and plant growth activities [17]. Thus, several potent
drugs possessing triazole nucleushave beenapplied in medicine, like,
Alprazolam (anxiolytic agent, tranquilizer), Anastrozole, Letrozole,
Vorozole (antineoplastics, nonsteroidal competitive aromatase
inhibitors), Estazolam (hypnotic, sedative, tranquilizer), Etoperidone
(antidepressant), Fluconazole, Itraconazole, Terconazole (antifungal
agents), Ribavirin (antiviral agent), Benatradin (diuretic), Rilmazafon
(hypnotic, anxiolytic, used in the case of neurotic insomnia), Nefa-
zodone (antidepressant, 5-HT2 A-antagonist), Rizatriptan (anti-
migraine agent), Trapidil (hypotensive),Trazodone (antidepressant,
Schiff bases are considered as a very important class of organic
compounds which have wide applications in many biological
aspects [19]. Many Schiff bases containing 1,2,4-triaole moiety
exhibit antibacterial, antifungal [20] and antitumoral activities [21].
Metal complexes of some Schiff bases are used as model molecules
for biological oxygen carrier systems [22]. Transition metal
complexes of tetradentate Schiff base ligands find applications as
model analogues of certain metal enzymes [23].
Mixed N,O,S-donorcrowns formaninterestingclass ofcompounds,
which have found use as selective extractants for soft metal cations
[24] and as models for the active sites of some enzymes [25].
Pendant arm macrocycles have also attracted considerable
attention, because of their unique coordination and structural
properties [26] and their roles in bioinorganic chemistry as models
of biomolecules and in modern chemical techniques such as
magnetic resonance imaging [27].
Encouraged by these facts and in continuation of an ongoing
program of research on the synthesis of some biologically active
compounds [28e42] as well as the synthesis of macrocyclic crown
compounds [43] the current work reports the synthesis and anti-
microbial activity of some novel 1,2,4-triazole fused acyclic,
macrocyclic and lariat macrocyclic oxaazathia crown Schiff bases
and crown bis(amines).
* Tel.: þ202 0106571765, þ202 35732280; fax: þ202 35713250.
E-mail address: nasserkhalil_23@hotmail.com.
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.08.046

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N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
2. Results and discussion
Compounds 25e27 when converted into their potassium salts
28e30(Scheme2), followedbyreactionwithallylbromideindryDMF,
afforded the corresponding 1, -bis[4-(2-allyloxybenzylideneamino)-
2.1. Synthesis
u
5-(pyridin-3-yl)-1,2,4-triazol-3-ylsulfanyl]alkanes 34e36. The latter
compounds were alternatively prepared via condensation of
compound 15 with 2-allyloxy-benzaldehyde (31) (obtained from
reaction of the potassium salt 2 with allyl bromide) in refluxing acetic
acid to give the corresponding 4-(2-allyloxybenzylideneamino)-5-
(pyridin-3-yl)-2,4-dihydro-[1,2,4]-triazole-3-thione (32) followed by
its conversion to the potassium salt 33 then reaction with diha-
loalkanes. A third alternative route to prepare compounds 34e36 was
achieved via condensation of compounds 22e24 with 2-allyloxy-
benzaldehyde 31 in refluxing acetic acid.
Compounds 16e24, 28e30 and 34e36 were investigated as
useful precursors for the synthesis of versatile 1,2,4-triazole fused
macrocyclic and lariat macrocyclic oxaazathia crown compounds.
Recently, ring clothing metathesis (RCM) [43] has found increasing
application in the synthesis of macrocyclic compounds. Unfortu-
nately, application of RCM on the dienes 34e36 (Scheme 3), using
The precursors 1,u-bisaldehydes 9e14 (Scheme 1) needed for the
titled synthesis were synthesized starting with salislaldehyde. Thus,
the latter compound was converted into its potassium salt 2, which
was then reacted with the appropriate 1,
3e7/or epichlorohydrin 8 to afford the corresponding 1,
hydes 9e13/or 14. Condensation of 5-pyridin-3-yl-4H-1,2,4-[triazole]-
3-thione (15) with the appropriate 1, -bis(aldehyde) 9e14 gave the
corresponding 1, -bis{[[5-(pyridin-3-yl)-3-thioxo-2,4-dihydro-[1,2,4]
u-bis functionalized alkanes
u-bisalde-
u
u
triazol-4-ylimino]methyl]phenoxy}alkanes 16e21. On the other hand,
reaction of compound 15 with dihaloalkanes in 50% aqueous ethanol
containing sodium hydroxide gave the corresponding 1,u-bis
[4-amino-5-(pyridin-3-yl)-1,2,4-triazol-3-ylsulfanyl]alkanes 22e24
which were condensed with salisylaldehyde to give the corresponding
1,u-bis[4-(2-hydroxybenzylideneamino)-5-(pyridin-3-yl)-1,2,4-tri-
azol-3-ylsulfanyl]alkanes 25e27.
Y
CHO
O
OHC
O
CHO
OK
CHO
OH
z
z
DMF
/ H2O
/
3-7
8
Cl
or
O
Y
2
1
9-14
CHO
OHC
O
H
N
H
N
S
S
O
H
N
N
N
N
N
N
N
N
N
Y
N
N
S
N
9-14
NH2
15
O
O
AcOH
Y
16-21
3-5 Z= Br
6, 7 Z= Ts
3, 9, 16 Y= -
X
KOH/ 50% aq. EtOH
Br
Br
4, 10, 17 Y= CH2
5, 11, 18 Y= (CH2)2
6, 12, 19 Y= (CH2OCH2)
7, 13, 20 Y= (CH2OCH2)2
14, 21 Y= CHOH
O
H
X
X
OH
S
S
S
S
1
N
N
N
N
N
N
N
N
AcOH
N
N
N
N
NH2
H2N
N
N
N
N
N
N
OH
HO
22-24
25-27
22, 25 X= -
23, 26 X= CH2
24, 27 X= (CH2)2
Scheme 1. Versatile efficient synthetic routes towards novel 1,2,4-triazole fused acyclic azathia and/or oxaazathia crown compounds.

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
5267
X
S
S
N
N
N
N
N
N
KOH
N
N
25-27
N
N
MeOH
OK
OK
28-30
15
Br
DMF
O
O
H
H
Br
O
OK
AcOH
X
31
S
2
S
S
N
N
N
N
N
N
H
N
N
N
N
N
N
N
N
N
O
O
O
34-36
O
32
X
Br
Br
MeOH KOH
DMF
H
O
AcOH
N
N
N
SK
N
N
31
O
22-24
28, 34 X= -
33
29, 35 X= CH2
30, 36 X= (CH2)2
Scheme 2. Versatile efficient synthetic routes towards 1,2,4-triazole fused acyclic oxaazathia crown 1,
u
-dienes.
X
(I, 2.5-10 mol%)/DCM or C6H6/ 48 h reflux
S
S
N
N
34-36
N
N
N
N
N
N
RCM
N
N
O
O
PCy3
Ru
Cl
Cl
Ph
37-39
PCy3
Grubbs' catalust (I)
u-dienes 34e36, using Gubbs’ Catalyst (I), failed to afford the expected oxaazathia macrocyclic Schiff bases 37e39.
Scheme 3. Application of RCM on the 1,

5268
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
Grubbs’ catalyst (I), at different molar ratios (2.5e10 mol%), in
different refluxing solvents (CH2Cl2 and benzene), did not afford
the expected macrocyclic Schiff bases 37e39.
Scheme 4 outlines three successful efficient synthetic routes
towards the desired 1,2,4-triazole fused macrocyclic and lariat
macrocyclic oxaazathia crown compounds 42e47. The first route is
conversion of compounds 17 and 18 into their potaasium salts 40
and 41 followed by their reaction with the appropriate dihalo
compounds to give the corresponding macrocyclic Schiff bases 42
and 43, respectively. The second route is reaction of compounds 29
and 30 with the appropriate dihalo compounds to give the corre-
sponding macrocycles 42 and 43, respectively. The third route is
condensation of the 1,u-bis(amines) 22e24 with 1,u-bis(alde-
hydes) 10, 11, 13, 14 to give the corresponding macrocycles 42e47.
17, 18
KOH/MeOH
SK
N
KS
N
N
N
N
N
N
N
N
N
O
O
Y
40, 41
X
DMF
Br
X
Br
S
S
N
N
N
N
N
N
Y
N
N
N
N
10, 11, 13, 14
AcOH
Br
DMF
Br
22-24
29, 30
O
O
42 X= CH2, Y= CH2
43 X, Y= (CH2)2
Y
42-47
44 X= (CH2)2, Y= (CH2OCH2)2
45, 48 X= 0, Y= CHOH
46, 49 X= CH2, Y= CHOH
NaBH4 / MeOH
47, 50 X= (CH2)2, Y= CHOH
X
S
S
N
N
N
N
N
N
NH
HN
N
N
O
O
Y
48-50
Scheme 4. Versatile efficient synthetic routes towards novel 21e28 membered macrocylic and/or lariat macrocyclic crown compounds.

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
5269
Table 1
Antimicrobial Activity of compounds 15, 17e25, 43, 44, 46, 47 and 49 compared to standard antimicrobial agents.
Test Organisms
Compound
Compd 15a
Compd 17a
Compd 18a
Concentration (mg/mL)
1.0
2.5
5.0
1.0
2.5
5.0
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
þ
0
0
0
0
0
þ
0
0
0
0
0
0
þ
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
0
þ
þ
0
þ
þ
þ
þ
þ
0
þ
þ
0
0
þ
0
þ
0
0
þ
þ
þ
0
Escherichia coli
0
0
0
0
Test Organisms
Compd 19a
Compd 20a
Compd 21a
Concentration (mg/mL)
1.0
2.5
5.0
1.0
2.5
5.0
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
þ
0
0
0
0
þ
0
þ
þ
0
0
0
þ
þ
þ
0
0
0
0
þ
0
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
0
0
þ (250)c
þþ (250)c
þ (250)c
0
þþ
þþ
þþ
þ
0
0
0
0
0
þ
þ
0
0
0
0
0
0
0
0
0
þ
þ
þ
þ
þþ (250)c
Escherichia coli
0
0
0
þ
þ (250)c
Test Organisms
Compd 22a
Compd 23a
Compd 24a
Concentration (mg/mL)
1.0
2.5
5.0
1.0
2.5
5.0
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
þ
0
0
0
0
0
þ
0
þ
0
0
0
0
0
0
0
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
þ
0
þ
þ
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
0
0
þ
0
þ
þ
þ
þ
0
0
þ
0
0
þ
0
þ
0
þ
þ
Escherichia coli
0
0
Test Organisms
Compd 25a
Compd 43a
Compd 44a
Concentration (mg/mL)
1.0
2.5
5.0
1.0
2.5
5.0
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
þ
0
0
þ
0
0
0
þ
þ
0
0
þ
0
0
0
0
0
0
0
0
0
0
0
0
0
0
þ
0
þ
0
0
þ
þ
0
0
0
þ (250)c
0
þ
0
0
0
0
0
þ
þ (250)c
þ (250)c
þ (250)c
0
0
þ
þ
0
þ
þ
Escherichia coli
0
þ (250)c
Test Organisms
Compd 46a
Compd 47a
Compd 49a
Concentration (mg/mL)
1.0
2.5
5.0
1.0
2.5
5.0
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
Staphylococcus aureus
Pseudomonas aeruginosa
Bacillus subtilis
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
þ
0
0
0
0
0
þ
0
þ
0
0
0
0
0
0
0
þ
0
0
0
0
0
0
0
0
0
0
0
0
0
þ
þ
þ
0
þ
þ
þ
0
0
0
þ
þþ
þþ
þþ
Escherichia coli
0
0
0
0
Test Organisms
St.b
Concentration (mg/mL)
1.0
2.5
5.0
Aspergillus fumigatus
Penicillium italicum
Syncephalastrum racemosum
Candida albicans
þþ
þþ
þþþ
þþ
þþ
þþþ
þþþ
þþþ
þþ
þþþ
þþþ
þþþ
þþ
Staphylococcus aureus
þþ
þþ
(continued on next page)

5270
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
Table 1 (continued )
Test Organisms
St.b
Concentration (mg/mL)
1.0
2.5
5.0
Pseudomonas aeruginosa
Bacillus subtilis
Escherichia coli
þþ
þþ
þþ
þþþ
þþþ
þþ
þþþ
þþþ
þþ
Note: The test was done using the diffusion agar technique. Inhibition values ¼ 0.1e0.5 cm beyond control ¼ þ; inhibition values ¼ 0.6e1.0 cm beyond control ¼ þþ;
inhibition values ¼ 1.0e1.5 cm beyond control ¼ þþþ; 0 ¼ no inhibition detected.
a
100
m
L of each concentration was tested (5.0, 2.5, 1.0 mg/mL); well diameter ¼ 0.6 cm.
b
c
St. ¼ Reference standard; Chloramphenicol was used as a standard antibacterial agent and Terbinafin was used as a standard antifungal agent.
MIC values are given in brackets MIC (
mg/mL) ¼ minimum inhibitory concentration, i.e., lowest concentration to completely inhibit microbial growth.
Reduction of compounds 45e47 with sodium borohydride in
refluxing methanol proceeded smoothly to give the macrocyclic bis
(amines) 48e50.
active against Penicillium italicum RCMB 001018 (1) and all have
Schiff base and NHC(S)N moieties in their structure. Compounds
21, 46, 47, 49 are all active against Bacillus subtilis RCMB 101-001
and all are characterized by the presence of the CHOH group in the
spacer between the triazole units. Compounds 17, 19 are also
active against Bacillus subtilis RCMB 101-001 and both have two
OCH2CH2 groups in their structure. While compound 22, having
two amino groups, with a short spacer between the triazole units
2.2. Antimicrobial activity
Compounds 15, 17e25, 43, 44, 46, 47 and 49 were evaluated
for their antibacterial and antifungal activities against two Gram-
positive bacterial strains (Bacillus subtilis RCMB 101-001 and
Staphylococcus aureus RCMB 106-001 (1)), two Gram-negative
bacterial strains (Pseudomonas aeruginosa RCMB 102-002 and
Escherichia coli RCMB 103-001), one yeast (Candida albicans RCMB
005003) and three fungal strains (Aspergillus fumigatus RCMB
002008 (1), Penicillium italicum RCMB 001018 (1) and Syncepha-
lastrum racemosum RCMB 016001). The screening results (Table 1)
indicated that all the tested compounds exhibited different
inhibitory effects against different test organisms. Compound 15
(at concentration 5.0 mg/mL) showed an inhibitory effect against
Penicillium italicum RCMB 001018 (1) and Escherichia coli RCMB
103-001. Conversion of this parent triazole into the correspond-
(X
¼
0), is active against Candida albicans RCMB 005003,
compound 24, having the same amino groups, with a longer
spacer between the triazole units (X ¼ (CH2)2), is active against
Syncephalastrum racemosum RCMB 016001. Compound 43, with
Schiff base motif as well as aliphatic methylene groups (X,
Y ¼ (CH2)2) groups in the spacer between triazole units is active
against Staphylococcus aureus RCMB 106-001 (1) and Escherichia
coli RCMB 103-001.
The minimum inhibitory concentrations (MICs) of compounds
21 and 43 were determined and found to be 250 mg/mL.
3. Experimental
3.1. Synthesis
3.1.1. General
All melting points are uncorrected. IR spectra were recorded in
KBr discs using PerkineElmer 1430 spectrometer. 1H and 13C NMR
spectra were measured with a Varian Mercury 300 spectrometer
(300 MHz 1H NMR, 75 MHz 13C NMR). Mass spectra were measured
on Shimadzu GCMS-QP2010 Plus spectrometer (with an EI ioniza-
tion mode and 70 eV electronic voltage) and with LCMS using
Agilent 1100 series LC/MSD (with an API-ES/APCI ionization mode).
Elemental analyses were carried out at the Micro Analytical Center,
Cairo University, Giza, Egypt. TLC was performed on Fluka silica gel
60 F254 aluminum sheets, and products were detected using
254 nm light. Fluka silica gel 60 (70e230 mesh) was used for
column chromatography.
ing
acyclic
1,
u
-bis(triazoles)
17e25/macrocyclic
crown
compounds 43, 44/or lariat macrocycles 46, 47, 49 enhanced the
inhibitory effect against one or more type of the test organisms.
Thus, compared to compound 15, compounds 19, 21, 23 (at
concentrations 2.5e5.0 mg/mL) showed higher inhibitory effect
against Aspergillus fumigatus RCMB 002008 (1), compounds 18,
19e22, 46 (at concentrations 1.0e5.0 mg/mL) showed higher
inhibitory effect against Penicillium italicum RCMB 001018 (1),
compounds 17e19, 21, 23e25, 44, 46 (at concentrations
1e5.0 mg/mL) showed higher inhibitory effect against Synce-
phalastrum racemosum RCMB 016001, compounds 18, 20, 22, 23,
43, 46 (at concentrations 1.0e5.0 mg/mL) showed higher inhib-
itory effect against Candida albicans RCMB 005003, compounds 17,
18, 20, 22, 24, 43, 44, 47 (at concentrations 1.0e5.0 mg/mL)
showed higher inhibitory effect against Staphylococcus aureus
RCMB 106-001 (1), compounds 18, 43, 44 (at concentrations
2.5e5.0 mg/mL) showed higher inhibitory effect against Pseudo-
monas aeruginosa RCMB 102-002, compounds 17, 19, 21, 24, 25,
46, 47, 49 (at concentrations 1e5.0 mg/mL) showed higher
inhibitory effect against Bacillus subtilis RCMB 101-001,
compounds 21, 43, 44 showed higher inhibitory effect against
Escherichia coli RCMB 103-001 (at concentrations 1.0e2.5 mg/mL).
On the other hand, compounds 17, 23, 24, 44, 47, 49 (at
concentration 5.0 mg/mL) exhibited lower inhibitory effect
against Penicillium italicum RCMB 001018 (1), compounds 17e20,
23e25, 46, 47, 49 (at concentration 5.0 mg/mL) exhibited lower
inhibitory effect against Escherichia coli RCMB 103-001, when
compared to compound 15.
3.1.1.1. Synthesis of the K-salts 2, 28e30, 33, 40, 41. A solution of
each of compounds 1, 25e27, 32, 17, 18 (10 mmol) and KOH [0.56 g
(10 mmol) for compounds 2, 32 and 1.12 g (20 mmol) for
compounds 25e27, 17, 18] in methanol (100 mL) was stirred at
room temperature for 10 min. The solvent was then removed in
vacuo and the remaining residue was washed with dry ether
(3 ꢀ 50 mL), collected and dried. It was then used in the next steps
without further purification.
3.1.1.2. Synthesis of 1,u-bis(2-formylphenoxy)alkanes 9e13. General
procedure. The K-salt 2 (30 mmol) was dissolved in dry DMF
(75 mL) and the appropriate dihalide 3e5 (15 mmol)/or bis(tosyl)
derivative 6,7 (15 mmol) was added. The reaction mixture was
heated in water bath at 100 ꢁC for 8e10 h, during which time KCl
The biological screening of the mentioned compounds
revealed some similarity between compounds with comparable
antimicrobial activity. Thus, compounds 18, 19, 20 and 21 are all

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
5271
was precipitated. Ice and water were added and the product was
extracted with DCM (100 mL). The organic extract was washed two
times with 10% aqueous KOH solution (2 ꢀ 100 mL), then water
(3 ꢀ 100 mL) and dried (Na2SO4). After evaporation of DCM under
reduced pressure, compounds 9e11 were recrystallized from
ethanol while compounds 12 and 13 were obtained as oils and used
without further purification.
J ¼ 7.9 Hz, ArH), 6.97 (t, 2H, J ¼ 7.9 Hz, ArH), 7.47 (m, 2H, ArH), 7.71
(dd, 2H, J ¼ 1.6, 7.9 Hz, ArH), 10.37 (s, 2H, CHO). Anal. Calcd for
C17H16O5 (300.3): C, 67.99; H, 5.37. Found: C, 67.83; H, 5.49.
3.1.1.4. Synthesis of 1,u-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihy-
dro-[1,2,4]triazol-4-ylimino]methyl]phenoxy}alkanes 16e21. General
procedure. To a solution of compound 15 (2 mmol) in glacial acetic
acid (100 mL), was added the appropriate bis(aldehyde) 9e14
(1 mmol) and the reaction mixture was heated at reflux tempera-
ture for 2 h. The excess AcOH was evaporated to be about 20 mL and
the reaction mixture was left to cool. The product was collected by
filtration, washed several times with methanol, dried and recrys-
tallized from DMF/MeOH.
3.1.1.2.1. 1,2-Bis(2-formylphenoxy)ethane (9). Yield 1.82 g (45%);
colorless crystals, mp 128e130 ꢁC. IR: 3076, 3004, 2934, 2872,1668,
1600, 1490, 1442, 1390, 1253, 1191, 1160, 1099, 1063, 949, 865, 832,
760, 661. 1H NMR (CDCl3):
d 4.46 (s, 4H, OCH2CH2O), 7.00 (dd, 4H,
J ¼ 1.8, 7.9 Hz, ArH), 7.49 (dt, 2H, J ¼ 1.8, 7.9 Hz, ArH), 7.74 (dd, 2H,
J ¼ 1.8, 7.9 Hz, ArH), 10.35 (s, 2H, CHO). Anal. Calcd for C16H14O4
(270.3): C, 71.10; H, 5.22. Found: C, 70.98; H, 5.24.
3.1.1.4.1. 1,2-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}ethane (16). Yield 99.3 mg
(16%); pale crystals, mp 295e297 ꢁC (dec.). IR: 3424, 3229, 3099,
3068, 3017, 2964, 2927, 2900, 2819, 2756, 1598, 1536, 1489, 1453,
1417, 1360, 1254, 1160, 1109, 1047, 1026, 965, 932, 887, 810, 755, 698,
3.1.1.2.2. 1,3-Bis(2-formylphenoxy)propane (10). Yield 3.33
g
(78%); colorless crystals, mp 99e100 ꢁC. IR: 3073, 3040, 3014, 2966,
2931, 2870, 2764, 1685, 1599, 1485, 1457, 1391, 1287, 1240, 1190,
1162, 1103, 1053, 1022, 953, 842, 818, 760, 654, 606, 533, 496, 438.
1H NMR (CDCl3):
d
2.42 (quint, 2H, J ¼ 6.0 Hz, OCH2CH2), 4.32 (t, 4H,
641, 615, 589, 507, 470. 1H NMR (DMSO-d6):
d 4.53 (s, 4H, OCH2
-
J ¼ 6.0 Hz, OCH2CH2), 7.01 (d, 2H, J ¼ 8.1 Hz, ArH), 7.03 (t, 2H,
J ¼ 8.1 Hz, ArH), 7.54 (dt, 2H, J ¼ 1.8, 8.1 Hz, ArH), 7.82 (dd, 2H,
J ¼ 1.8, 8.1 Hz, ArH), 10.49 (s, 2H, CHO). Anal. Calcd for C17H16O4
(284.3): C, 71.82; H, 5.67. Found: C, 71.66; H, 5.51.
CH2O), 7.03 (t, 2H, J ¼ 7.6 Hz, ArH), 7.29 (d, 2H, J ¼ 7.6 Hz, ArH), 7.51
(ddd, 2H, JH-5 pyrid eH-2 pyrid.
.
¼ 0.9 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz,
JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.), 7.54 (dd, 2H, J ¼ 1.2, 7.6 Hz,
ArH), 7.82 (dd, 2H, J ¼ 1.2, 7.6 Hz, ArH), 8.18 (td, 2H, JH-4 pyrid.eH-6
pyrid. ¼1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,
H-4 pyrid.), 8.68 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5
3.1.1.2.3. 1,4-Bis(2-formylphenoxy)butane (11). Yield 3.04
g
(68%); colorless crystals, mp 146e148 ꢁC. IR: 3108, 3076, 3047,
2950, 2877, 2758, 1680, 1651, 1599, 1488, 1458, 1387, 1288, 1239,
1193, 1168, 1104, 1058, 1042, 1002, 950, 868, 842, 810, 757, 654, 603,
¼ 4.8 Hz, H-6 pyrid.), 8.98 (dd, 2H, JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz,
pyrid.
JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.),10.17 (s, 2H, CH]N),14.13 (s,
2H, D2O exchangeable NH). Anal. Calcd for C30H24N10O2S2 (620.7):
C, 58.05; H, 3.90; N, 22.57; S, 10.33. Found: C, 58.19; H, 4.09; N,
22.44; S, 10.29.
524, 440. 1H NMR (CDCl3):
d
2.09 (quint, 4H, J ¼ 2.7 Hz, OCH2CH2),
4.18 (t, 4H, J ¼ 2.7 Hz, OCH2CH2), 6.98 (d, 2H, J ¼ 8.2 Hz, ArH), 7.02 (t,
2H, J ¼ 8.2 Hz, ArH), 7.53 (dt, 2H, J ¼ 1.8, 8.2 Hz, ArH), 7.81 (dd, 2H,
J ¼ 1.8, 8.2 Hz, ArH), 10.49 (s, 2H, CHO). Anal. Calcd for C18H18O4
(298.3): C, 72.47; H, 6.08. Found: C, 72.52; H, 6.12.
3.1.1.4.2. 1,3-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}propane
(17). Yield
3.1.1.2.4. 1,5-Bis(2-formylphenoxy)-3-oxapentane
(12). Yield
399.9 mg (63%); pale crystals, mp 298e300 ꢁC. IR: 3449, 3077,
3046, 3014, 2922, 2884, 2744, 1598, 1534, 1486, 1455, 1418, 1395,
1361, 1294, 1259, 1200, 1160, 1109, 1050, 1027, 993, 966, 887, 855,
809, 753, 698, 644, 617, 585, 536, 504, 467. 1H NMR (DMSO-d6):
3.30 g (70%); colorless oil. IR: 3081, 2872, 2765, 1958, 1685, 1599,
1484, 1454, 1395, 1287, 1244, 1133, 1051, 928, 834, 759, 656, 440. 1H
NMR (CDCl3):
d
3.95 (t, 4H, J ¼ 4.6 Hz, OCH2CH2O), 4.23 (t, 4H,
J ¼ 4.6 Hz, OCH2CH2O), 6.95 (d, 2H, J ¼ 8.0 Hz, ArH), 7.00 (t, 2H,
J ¼ 8.0 Hz, ArH), 7.48 (dt, 2H, J ¼ 2.0, 8.0 Hz, ArH), 7.77 (dd, 2H,
J ¼ 2.0, 8.0 Hz, ArH), 10.45 (s, 2H, CHO). Anal. Calcd for C18H18O5
(314.3): C, 68.78; H, 5.77. Found: C, 68.69; H, 5.88.
d
2.25 (quint, 2H, J ¼ 5.8 Hz, OCH2CH2), 4.38 (t, 4H, J ¼ 5.8,
OCH2CH2), 7.05 (t, 2H, J ¼ 7.6 Hz, ArH), 7.21 (d, 2H, J ¼ 8.4 Hz, ArH),
7.54 (m, 4H, ArH, H-5 pyrid.), 7.86 (dd, 2H, J ¼ 1.5, 7.8 Hz, ArH),
8.23 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.69 (dd, 2H, JH-6 pyrid.eH-4
3.1.1.2.5. 1,8-Bis(2-formylphenoxy)-3,6-dioxaoctane (13). Yield
5.27 g (98%); colorless oil. IR: 3075, 2872, 1958, 1685, 1599, 1484,
1456, 1395, 1287, 1244, 1191, 1124,1052, 929, 834, 761, 657, 606, 531,
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.01 (dd, 2H,
pyrid.
JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.),
10.28 (s, 2H, CH]N), 14.28 (s, 2H, D2O exchangeable NH). Anal.
Calcd for C31H26N10O2S2 (634.7): C, 58.66; H, 4.13; N, 22.07; S, 10.10.
Found: C, 58.54; H, 4.09; N, 21.99; S, 10.21.
441. 1H NMR (CDCl3):
d 3.71 (s, 4H, OCH2CH2O), 3.87 (t, 4H,
J ¼ 4.6 Hz, OCH2CH2O), 4.21 (t, 4H, J ¼ 4.6 Hz, OCH2CH2O), 6.97 (m,
4H, ArH), 7.48 (dt, 2H, J ¼ 1.8, 7.5 Hz, ArH), 7.77 (dd, 2H, J ¼ 1.8,
7.5 Hz, ArH), 10.47 (s, 2H, CHO). Anal. Calcd for C20H22O6 (358.4): C,
67.03; H, 6.19. Found: C, 66.94; H, 6.06.
3.1.1.4.3. 1,4-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}butane
(18). Yield
506.1 mg (78%); pale crystals, mp 301e303 ꢁC (dec.). IR: 3423, 3070,
3038, 2928, 2875, 2827, 2675, 1598, 1516, 1486, 1453, 1418, 1355,
1291, 1254, 1193, 1161, 1131, 1106, 1041, 961, 921, 874, 808, 757, 700,
3.1.1.3. 1,3-Bis(2-formylphenoxy)-2-propanol (14). Potassium salt 2
(100 mmol) was dissolved in boiling water (100 mL). The solution
was cooled to 50 ꢁC, epichlorohydrin (50 mmol) was added drop
wise with stirring over a period of 3 h. The reaction mixture was
stirred at 50 ꢁC for an additional 4 h, cooled to room temperature
and acidified with conc. HCl. The formed product was extracted
with chloroform (150 mL) and washed with KOH solution (100 mL,
0.1 M) then water (3 ꢀ 100 mL). The organic layer was dried
(anhydrous Na2SO4), the solvent was evaporated under reduced
pressure and the formed residue was recrystallized from benzene.
The resulting colorless crystals were collected by filtration and
dried in a vacuum desiccator over P4O10. Yield 12.76 g (85%), mp
114 ꢁC. IR: 3470, 3106, 2941, 2877, 2839, 2759, 1679, 1599, 1486,
646, 582, 528, 488, 419. 1H NMR (DMSO-d6):
d 2.01 (s, 4H,
OCH2CH2), 4.18 (s, 4H, OCH2CH2), 7.03 (t, 2H, J ¼ 7.8 Hz, ArH), 7.18 (d,
2H, J ¼ 7.8 Hz, ArH), 7.53 (dt, 2H, J ¼ 1.5, 7.8, ArH), 7.57 (dd, 2H,
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.),
7.86 (dd, 2H, J ¼ 1.5, 7.8 Hz, ArH), 8.24 (td, 2H, JH-4
pyrid.eH-6
¼1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,
pyrid.
H-4 pyrid.), 8.71 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5
¼ 4.8 Hz, H-6 pyrid.), 9.02 (d, 2H, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-
pyrid.
2 pyrid.), 10.32 (s, 2H, CH]N), 14.24 (br, 2H, D2O exchangeable NH).
Anal. Calcd for C32H28N10O2S2 (648.8): C, 59.24; H, 4.35; N, 21.59; S,
9.88. Found: C, 59.31; H, 4.29; N, 21.47; S, 9.76.
1274, 1163, 1031, 844, 756, 662. 1H NMR (CDCl3):
d
2.11 (s, 1H, D2O
3.1.1.4.4. 1,5-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}-3-oxapentane (19). Yield
372.3 mg (56%); pale crystals, mp 189e190 (resolidify at 204 ꢁC and
exchangeable OH), 4.258 (d, 2H, J ¼ 5.7 Hz, OCH2), 4.263 (d, 2H,
J ¼ 4.8 Hz, OCH2), 4.49 (quint, 1H, J ¼ 5.1 Hz, CHOH), 6.96 (d, 2H,

5272
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
melt again at 307e308 ꢁC). IR: 3417, 3071, 3033, 2924, 2873, 2733,
1598, 1548, 1487, 1450, 1417, 1354, 1291, 1254, 1193, 1162, 1131, 1111,
1046, 959, 923, 875, 810, 755, 700, 648, 584, 524, 484. 1H NMR
8.37 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.70 (dd, 2H, JH-6 pyrid.eH-4
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.16 (dd, 2H,
pyrid.
(CDCl3):
d
4.04 (t, 4H, J ¼ 4.5 Hz, OCH2CH2O), 4.25 (t, 4H, J ¼ 4.5 Hz,
JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.).
Anal. Calcd for C16H16N10S2 (412.5): C, 46.59; H, 3.91; N, 33.96; S,
15.55. Found: C, 46.49; H, 4.00; N, 33.89; S, 15.52.
3.1.1.5.2. 1,3-Bis[4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-
ylsulfanyl]propane (23). Yield 1.09 g (51%); colorless crystals, mp
230e232 ꢁC. IR: 3305, 3177, 3083, 2953, 2919, 1629, 1592, 1567,
1506, 1479, 1450, 1414, 1393, 1354, 1326, 1279, 1186, 1125, 1100,
1016, 967, 874, 813, 738, 704, 619, 593, 497, 437. 1H NMR
OCH2CH2O), 6.98 (t, 2H, J ¼ 7.8 Hz, ArH), 7.02 (d, 2H, J ¼ 7.8 Hz, ArH),
7.42 (m, 4H, ArH, H-5 pyrid.), 7.94 (dd, 2H, J ¼ 1.5, 7.8 Hz, ArH), 8.26
(td, 2H, JH-4
¼ 1.8 Hz, JH-4
¼ 2.1 Hz,
pyrid.eH-6 pyrid.
pyrid.eH-2 pyrid.
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.73 (dd, 2H, JH-6 pyrid.eH-4
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.25 (d, 2H,
pyrid.
JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, H-2 pyrid.), 10.49 (s, 2H, CH]N), 12.73
(br, 2H, D2O exchangeable NH). Anal. Calcd for C32H28N10O3S2
(664.8): C, 57.82; H, 4.25; N, 21.07; S, 9.65. Found: C, 57.76; H, 4.36;
N, 20.98; S, 9.62.
(DMSO-d6):
d
2.17 (quint, 2H, J ¼ 6.9 Hz, SCH2CH2), 3.34 (t, 4H,
J ¼ 6.9 Hz, SCH2), 6.19 (s, 4H, D2O exchangeable NH2), 7.55 (ddd, 2H,
JH-5 pyrid.eH-2 pyrid. ¼ 0.9 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4
3.1.1.4.5. 1,8-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}-3,6-dioxaoctane
(20). Yield 439.5 mg (62%); pale crystals, mp 191e193 (resolidify at
204 ꢁC and melt again at 263e265 ꢁC). IR: 3447, 3078, 3039, 2924,
2872, 2729,1597,1487,1451,1418,1353,1296,1253,1193,1164,1105,
1046, 957, 922, 875, 813, 755, 699, 637, 584, 524, 478. 1H NMR
¼ 8.1 Hz, H-5 pyrid.), 8.36 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz,
pyrid.
JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.),
8.68 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz,
H-6 pyrid.), 9.15 (dd, 2H, JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, JH-2 pyrid.eH-4
¼ 2.1 Hz, H-2 pyrid.). Anal. Calcd for C17H18N10S2 (426.5): C,
pyrid.
(CDCl3):
d
3.77 (s, 4H, OCH2CH2O), 3.90 (t, 4H, J ¼ 4.5 Hz, ArOCH2
47.87; H, 4.25; N, 32.84; S, 15.03. Found: C, 47.84; H, 4.29; N, 32.97;
S, 15.12.
-
CH2O), 4.22 (t, 4H, J ¼ 4.5 Hz, OCH2CH2O), 6.97 (t, 2H, J ¼ 7.8 Hz,
ArH), 7.00 (d, 2H, J ¼ 7.8 Hz, ArH), 7.43 (m, 4H, ArH, H-5 pyrid.), 7.99
(dd, 2H, J ¼ 1.5, 7.8 Hz, ArH), 8.24 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼1.8 Hz,
JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.),
8.70 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz,
H-6 pyrid.), 9.22 (d, 2H, JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, H-2 pyrid.),
10.50 (s, 2H, CH]N), 11.46 (br, 2H, D2O exchangeable NH). Anal.
Calcd for C34H32N10O4S2 (708.8): C, 57.61; H, 4.55; N, 19.76; S, 9.05.
Found: C, 57.55; H, 4.62; N, 19.61; S, 9.11.
3.1.1.5.3. 1,4-Bis[4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-
ylsulfanyl]butane (24). Yield 1.52 g (69%); colorless crystals, mp
218e220 ꢁC. IR: 3343, 3172, 2948, 1628, 1582, 1566, 1479, 1450,
1393, 1355, 1313, 1273, 1204, 1130, 1054, 966, 814, 780, 731, 700,
599, 450. 1H NMR (DMSO-d6):
d
1.89 (quint, 4H, J ¼ 5.7 Hz,
SCH2CH2), 3.23 (t, 4H, J ¼ 5.7 Hz, SCH2CH2), 6.16 (s, 4H, D2O
exchangeable NH2), 7.55 (ddd, 2H, JH-5
¼ 0.9 Hz,
pyrid.eH-2 pyrid.
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.),
8.34 (qd, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.67 (dd, 2H, JH-6 pyrid.eH-4
3.1.1.4.6. 1,3-Bis{[[5-(pyridin-3-yl)-3-thioxo-2H-3,4-dihydro-
[1,2,4]triazol-4-ylimino]methyl]phenoxy}propan-2-ol
(21). Yield
292.8 mg (45%); pale crystals, mp 188e190 (resolidify at 204 ꢁC
and melt again at 294e296 ꢁC). IR: 3381, 3072, 3039, 2927, 2882,
2736, 1598, 1548, 1489, 1450, 1417, 1354, 1291, 1250, 1162, 1108,
1028, 962, 875, 812, 754, 701, 647, 588, 524, 492. 1H NMR (CDCl3):
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.13 (dd, 2H,
pyrid.
JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.).
Anal. Calcd for C18H20N10S2 (440.6): C, 49.07; H, 4.58; N, 31.79; S,
14.56. Found: C, 49.14; H, 4.61; N, 31.69; S, 14.43.
d
3.47 (s, 1H, D2O exchangeable CHOH), 4.36 (d, 2H, J ¼ 5.4 Hz,
OCH2), 4.50 (d, 2H, J ¼ 5.1 Hz, OCH2), 5.54 (quint, 1H, J ¼ 5.1 Hz,
CHOH), 7.02 (t, 2H, J ¼ 7.5 Hz, ArH), 7.04 (d, 2H, J ¼ 7.5 Hz, ArH),
7.45 (m, 4H, ArH, H-5 pyrid.), 7.91 (td, 2H, J ¼ 1.8, 7.5 Hz, ArH), 8.24
3.1.1.6. Synthesis of 1,u-bis[4-(2-hydroxybenzylideneamino)-5-(pyr-
idin-3-yl)-4H-1,2,4-triazol-3-ylsulfanyl]alkanes (25e27). General
procedure. To a solution of each of compounds 22e24 (1 mmol) in
glacial acetic acid (75 mL) was added salicylaldehyde (1) (0.21 mL,
2 mmol). The reaction mixture was heated at reflux temperature for
3 h. The excess solvent was then evaporated to a small volume
(about 10 mL) and the reaction mixture was allowed to cool to room
temperature. The formed product was collected by filtration,
washed with water (3 ꢀ 50 mL), followed by MeOH (2 ꢀ 10 mL) and
recrystallized from acetic acid to give colorless crystals of
compounds 25e27.
(td, 2H, JH-4
JH-4
¼ 1.8 Hz, JH-4
¼ 2.1 Hz,
pyrid.eH-6 pyrid.
pyrid.eH-2 pyrid.
¼ 8.1 Hz, H-4 pyrid.), 8.72 (dd, 2H, JH-6
pyrid.eH-5 pyrid.
¼ 1.8 Hz, JH-6
¼ 4.8 Hz, H-6 pyrid.),
pyrid.eH-4 pyrid.
pyrid.eH-5 pyrid.
9.24 (dd, 2H, JH-2 pyrid.eH-5 pyrid. ¼ 0.9 Hz, JH-2 pyrid.eH-4 pyrid. ¼ 2.1-
Hz, H-2 pyrid.), 10.52 (s, 2H, CH]N), 13.28 (br, 2H, D2O
exchangeable NH). Anal. Calcd for C31H26N10O3S2 (650.7): C, 57.22;
H, 4.03; N, 21.52; S, 9.85. Found: C, 57.31; H, 4.12; N, 21.37; S, 9.76.
3.1.1.5. Synthesis of 1,
u
-bis[4-amino-5-(pyridin-3-yl)-4H-1,2,4-tri-
3.1.1.6.1. 1,2-Bis[4-(2-hydroxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]ethane (25). Yield 571 mg (92%);
colorless crystals, mp 244e246 ꢁC. IR: 3440 (br), 2929, 1604, 1450,
azol-3-ylsulfanyl]alkanes (22e24). General procedure. To a solution
of compound 15 (1.93 g, 10 mmol) in aqueous alcoholic NaOH
solution [prepared by dissolving NaOH (0.40 g, 10 mmol) in 100 mL
50% aqueous EtOH] was added the appropriate dihalo compound
(5 mmol) and the reaction mixture was heated at reflux tempera-
ture for 1e3 h, after which time the product is precipitated. The
reaction mixture was allowed to cool and the product was collected
by filtration, washed with 10% aqueous NaOH solution (2 ꢀ 50 mL),
water (3 ꢀ 100 mL) and MeOH (2 ꢀ 10 mL), dried and recrystallized
from DMF.
1267,1032, 970, 816, 756, 702, 596.1H NMR (DMSO-d6):
d
3.59 (s, 4H,
SCH2CH2), 6.89 (t, 2H, J ¼ 7.8 Hz, ArH), 6.96 (d, 2H, J ¼ 8.4 Hz, ArH),
7.45 (m, 2H, ArH), 7.53 (ddd, 2H, JH-5
¼ 0.9 Hz,
pyrid.eH-2 pyrid.
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.),
7.76 (dd, 2H, J ¼ 1.5, 7.8 Hz, ArH), 8.18 (td, 2H, JH-4
pyrid.eH-6
pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,
H-4 pyrid.), 8.67 (d, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 4.8 Hz, JH-6 pyrid.eH-5
¼ 4.8 Hz, H-6 pyrid.), 8.96 (s, 2H, CH]N), 8.99 (s, 2H, H-2
pyrid.
3.1.1.5.1. 1,2-Bis[4-amino-5-(pyridin-3-yl)-4H-1,2,4-triazol-3-
ylsulfanyl]ethane (22). Yield 1.24 g (60%); colorless crystals, mp
230e232 ꢁC. IR: 3308, 3180, 2922, 1629, 1593, 1569, 1480, 1451,
1414, 1394, 1327, 1280, 1253, 1188, 1126, 1019, 968, 813, 703, 620,
pyrid.), 10.57 (s, 2H, D2O exchangeable OH). Anal. Calcd for
C30H24N10O2S2 (620.7): C, 58.05; H, 3.90; N, 22.57; S, 10.33. Found: C,
57.97; H, 3.88; N, 22.63; S, 10.27.
3.1.1.6.2. 1,3-Bis[4-(2-hydroxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]propane (26). Yield 603 mg (95%);
colorless crystals, mp 198 ꢁC. IR: 3420, 3059, 2922, 2852, 2714, 1654,
1602, 1571, 1456, 1347, 1307, 1259, 1186, 1154, 1120, 1097, 1027, 969,
595, 439. 1H NMR (DMSO-d6):
d 3.59 (s, 4H, SCH2CH2S), 6.21 (s, 4H,
D2O exchangeable NH2), 7.57 (ddd, 2H, JH-5 pyrid.eH-2 pyrid. ¼ 0.9 Hz,
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.),

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
5273
887, 840, 811, 755, 701, 623, 590, 552, 475. 1H NMR (CDCl3):
d
2.34
5 pyrid.), 8.26 (td, 1H, JH-4
¼ 1.5 Hz, JH-4
pyrid.eH-6 pyrid.
pyrid.eH-2
(quint, 2H, J ¼ 6.9 Hz, SCH2CH2), 3.45 (t, 4H, J ¼ 6.9 Hz, SCH2CH2), 6.99
¼ 1.8 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 7.8 Hz, H-4 pyrid.), 8.71 (dd, 1H,
pyrid.
(t, 2H, J ¼ 7.5 Hz, ArH), 7.05 (d, 2H, J ¼ 8.4 Hz, ArH), 7.42 (m, 6H, ArH, H-
JH-6 pyrid.eH-4 pyrid. ¼ 1.5 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.),
9.03 (s, 1H, H-2 pyrid.), 10.32 (s, 1H, CH]N), 14.30 (s, 1H, D2O
exchangeable NH). Anal. Calcd for C17H15N5OS (337.4): C, 60.52; H,
4.48; N, 20.76; S, 9.50. Found: C, 60.42; H, 4.39; N, 20.61; S, 9.41.
5 pyrid.), 8.11 (td, 2H, JH-4
pyrid. ¼ 1.8 Hz, JH-4
pyrid.eH-6
pyrid.eH-2
¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.65 (dd, 2H,
pyrid.
JH-6 pyrid.eH-4 pyrid. ¼1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz,H-6pyrid.), 8.78
(s, 2H, CH]N), 9.04 (d, 2H, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.),
10.18 (br s, 2H, D2O exchangeable OH). Anal. Calcd for C31H26N10O2S2
(634.7): C, 58.66; H, 4.13; N, 22.07; S,10.10. Found: C, 58.59; H, 4.17; N,
21.98; S, 10.01.
3.1.1.9. 1,u-Bis[4-(2-allyloxybenzylideneamino)-5-(pyridin-3-yl)-4H-
1,2,4-triazol-3-ylsulfanyl]alkanes (34e36). General procedur-
es. Procedure A. To a solution of each of the K-salts 28e30
(1.0 mmol) in dry DMF (2.5 mL) was added allyl bromide (0.17 mL,
2.01 mmol). The reaction mixture was then heated at reflux
temperature for 5 min during which time KCl was separated. The
mixture was then cooled, diluted with water (50 mL) and the
precipitate was collected by filtration, washed with cold water
(3 ꢀ 50 mL) and dried at room temperature. The product was
purified by column chromatography over silica gel using MeOH/
CHCl3 as an eluent.
Procedure B. The K-salt 33 (375.5 mg, 1.0 mmol) was dissolved in
dry DMF (2.5 mL) and to the formed solution was added the
appropriate dihalo compound (0.5 mmol). The reaction mixture
was then worked up as in procedure A.
Procedure C. To a solution of the appropriate bis(amines) 22e24
(1.0 mmol) in AcOH (40 mL) was added a solution of 2-allyloxy-
benzaldehyde (31) (324.4 mg, 2.0 mmol) in AcOH (10 mL). The
reaction mixture was heated at reflux temperature for 2 h. The
solvent was then evaporated and the remaining residue was puri-
fied by column chromatography over silica gel using MeOH/CHCl3
as an eluent.
3.1.1.6.3. 1,4-Bis[4-(2-hydroxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]butane (27). Yield 623 mg (96%);
colorless crystals, mp 252e253 ꢁC (dec.). IR: 3053, 2930, 2855,
2710, 1602, 1573, 1457, 1375, 1348, 1307, 1261, 1188, 1155, 1121, 1096,
1026, 968, 914, 887, 838, 811, 756, 702, 621, 590, 551, 527, 479. 1H
NMR (DMSO-d6):
d
1.85 (quint, 4H, J ¼ 6.6 Hz, SCH2CH2), 3.28 (t, 4H,
J ¼ 6.6 Hz, SCH2), 6.97 (t, 2H, J ¼ 8.1 Hz, ArH), 6.99 (d, 2H, J ¼ 8.1 Hz,
ArH), 7.46 (m, 2H, ArH), 7.46 (ddd, 2H, JH-5 pyrid.eH-2 pyrid. ¼ 0.9 Hz,
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, H-5 pyrid.),
7.85 (m, 2H, ArH), 8.23 (td, 2H, JH-4
pyrid. ¼ 1.8 Hz,
pyrid.eH-6
JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.),
8.66 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz,
H-6 pyrid.), 8.99 (s, 2H, CH]N), 9.01 (s, 2H, H-2 pyrid.), 10.56 (s, 2H,
D2O exchangeable OH). Anal. Calcd for C32H28N10O2S2 (648.8): C,
59.24; H, 4.35; N, 21.59; S, 9.88. Found: C, 59.19; H, 4.31; N, 21.63; S,
9.69.
3.1.1.7. 2-Allyloxy-benzaldehyde (31). A mixture of salicylaldehyde
(5 mL, 47.7 mmol), allyl bromide (3.7 mL, 43.7 mmol) and anhy-
drous K2CO3 (7.22 g, 52.2 mmol) in dry acetone (100 mL) was
heated at reflux temperature for 9 h. The solid precipitate was
filtered off and the solvent was evaporated in vacuo. The remaining
oil was dissolved in DCM (150 mL), washed with 10% aqueos KOH
solution (2 ꢀ 150 mL) then water (3 ꢀ 150 mL), dried over anhy-
drous Na2SO4 and the solvent was then removed in vacuo and the
remaining oil was purified by column chromatography over silica
gel using EtOAc/pet ether (bp 40e60 ꢁC) as an eluent to give 7.09 g
(100%; based on allyl bromide) of colorless oil. Rf ¼ 0.96 [EtOAc/pet
ether (bp 40e60 ꢁC) 3:2]. IR: 3080, 3040, 3018, 2991, 2923, 2867,
2765, 1688, 1599, 1486, 1456, 1422, 1396, 1363, 1289, 1240, 1192,
1162, 1105, 1068, 1045, 997, 932, 840, 812, 759, 658, 586, 531, 504,
3.1.1.9.1. 1,2-Bis[4-(2-allyloxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]ethane (34). Yield 476.5 (68%,
procedure A), 504.6 mg (72%, procedure B), 203.2 mg (29%, proce-
dure C), colorless crystals, mp 180e182 ꢁC. Rf ¼ 0.72 (MeOH/CHCl3
1:9). IR: 3039, 2924, 2868, 1742, 1649, 1614, 1595, 1572, 1485, 1454,
1436, 1423, 1362, 1346, 1328, 1292, 1252, 1194, 1165, 1141, 1117, 1093,
1018, 997, 971, 930, 881, 831, 816, 757, 729, 716, 680, 649, 628, 611,
595, 529, 485. 1H NMR (CDCl3):
d 3.77 (s, 4H, SCH2CH2S), 4.57 (td, 4H,
J ¼ 1.5, 5.2 Hz, CH2CH]), 5.26 (Qd, 2H, J ¼ 1.5, 10.5 Hz, CH2]), 5.34
(Qd, 2H, J ¼ 1.5, 17.2 Hz, CH2]), 5.96 (m, 2H, J ¼ 1.5, 5.2, 10.5,17.2 Hz,
CH]), 6.93 (d, 2H, J ¼ 7.9 Hz, ArH), 7.01 (t, 2H, J ¼ 7.9 Hz, ArH), 7.36
(dd, 2H, JH-5
¼ 8.1 Hz, JH-5
¼ 4.8 Hz,
pyrid.eH-4 pyrid.
pyrid.eH-6 pyrid.
466, 441. 1H NMR (CDCl3):
d
4.63 (td, 2H, J ¼ 1.5, 5.1 Hz, CH2CH]),
H-5 pyrid.), 7.48 (m, 2H, J ¼ 1.8, 7.9 Hz, ArH), 8.01 (dd, 2H, J ¼ 1.8,
7.9 Hz, ArH), 8.26 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2
5.31 (dd, 1H, J ¼ 1.5, 10.5 Hz, CH2]), 5.43 (dd, 1H, J ¼ 1.6, 17.2 Hz,
CH2]), 6.05 (m, 1H, CH]), 6.95 (d, 1H, J ¼ 7.8 Hz, ArH), 6.99 (t, 1H,
J ¼ 7.8 Hz, ArH), 7.50 (dt,1H, J ¼ 1.8, 7.8 Hz, ArH), 7.81 (dd,1H, J ¼ 1.8,
7.8 Hz, ArH), 10.51 (s, 1H, CHO). Anal. Calcd for C10H10O2 (162.2): C,
74.06; H, 6.21. Found: C, 74.12; H, 6.36.
¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.62 (br d, 2H,
pyrid.
JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.02 (s, 2H, CH]N), 9.18 (br s,
2H, H-2 pyrid.). Anal. Calcd for C36H32N10O2S2 (700.8): C,
61.70; H, 4.60; N, 19.99; S, 9.15. Found: C, 61.68; H, 4.53; N, 20.12; S,
8.98.
3.1.1.8. 4-(2-allyloxybenzylideneamino)-5-(pyridin-3-yl)-2,4-dihy-
dro-[1,2,4]-triazole-3-thione (32). To a solution of compound 15
(1.93 g,10 mmol) in glacial acetic acid (75 mL) was added 2-allyloxy-
benzaldehyde (31) (1.62 g, 10 mmol). The reaction mixture was
heated at reflux temperature for 3 h. The excess AcOH was evapo-
rated to a small volume (about 10 mL) and the reaction mixture was
allowed to cool to room temperature. The formed product was
collected by filtration, washed with water (3 ꢀ 100 mL) followed by
MeOH (3 ꢀ 10 mL) and recrystallized from AcOH/MeOH to give
yellow crystals of compound 32. Yield 3.07 g (91%). IR: 3448, 3105,
3071, 3022, 2862, 2820, 2700, 1597, 1548, 1515, 1483, 1447, 1415,
1353,1331,1297,1260,1189,1163,1125,1024, 990, 962, 912, 876, 812,
3.1.1.9.2. 1,3-Bis[4-(2-allyloxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]propane (35). Yield 493.3 (69%,
procedure A), 521.9 mg (73%, procedure B), 536.2 mg (75%, procedure
C), colorless crystals, mp 144e146 ꢁC. Rf ¼ 0.69 (MeOH/CHCl3 1:9). IR:
3075, 3002, 2924, 1937, 1645, 1595, 1573, 1486, 1441, 1424, 1413, 1369,
1347, 1325, 1293, 1253, 1190, 1163, 1104, 1044, 1016, 994, 965, 940, 916,
884, 850, 832, 804, 750, 707, 679, 664, 638, 617, 585, 529, 511, 484. 1H
NMR (CDCl3):
d
2.30 (quint, 2H, J ¼ 7.0 Hz, SCH2CH2), 3.39 (t, 4H,
J¼ 7.0 Hz, SCH2CH2), 4.55 (td, 4H, J¼ 1.5, 5.2 Hz, CH2CH]), 5.23 (dd, 2H,
J¼ 1.5, 10.5 Hz, CH2]), 5.32 (dd, 2H, J¼ 1.5, 17.2 Hz, CH2]), 5.93 (m, 2H,
J ¼ 1.5, 5.2,10.5,17.2 Hz, CH]), 6.90 (d, 2H, J ¼ 7.9 Hz, ArH), 6.98 (t, 2H,
J ¼ 7.9 Hz, ArH), 7.32 (dd, 2H, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6
751, 698, 647, 630, 585, 524, 491, 468.1H NMR (DMSO-d6):
d
4.70 (td,
¼ 4.8Hz, H-5 pyrid.), 7.44 (dt, 2H, J¼ 1.4, 7.9 Hz, ArH), 8.00 (dd, 2H,
pyrid.
2H, J ¼ 1.5, 4.5 Hz, CH2CH]), 5.27 (td,1H, J ¼ 1.5,10.8 Hz, CH2]), 5.52
(td, 1H, J ¼ 1.5, 17.3 Hz, CH2]), 6.05 (m, 1H, CH]), 7.08 (t, 1H,
J ¼8.1 Hz, ArH), 7.19 (d,1H, J ¼ 8.1 Hz, ArH), 7.57(t,1H, J ¼8.1 Hz, ArH),
7.58 (d,1H, J ¼ 8.1 Hz, ArH), 7.91 (d,1H, JH-5 pyrid.eH-4 pyrid. ¼ 7.8 Hz, H-
J¼ 1.4, 7.9 Hz, ArH), 8.24 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼1.8 Hz, JH-4 pyrid.eH-2
¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.58 (dd, 2H,
pyrid.
JH-6 pyrid.eH-4 pyrid. ¼1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.01
(s, 2H, CH]N), 9.15 (d, 2H, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.). Anal.

5274
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
Calcd for C37H34N10O2S2 (714.9): C, 62.17; H, 4.79; N, 19.59; S, 8.97.
Found: C, 62.02; H, 4.85; N, 19.63; S, 8.89.
GCMS: m/z (relative intensity); 578 [M e (O2 þ S2), 9%], 577 (22%), 551
(20%), 516 (30%), 415 (18%), 368 (5%), 354 (7%), 335 (5%), 313 (23%), 307
(5%), 264 (23%), 239 (22%), 236 (6%), 219 (6%),185 (7.5%),162 (11%),149
(23%),135 (21%),121 (26%),105 (89%), 85 (46%), 77 (87%), 57 (100%), 55
(84%), 50 (7%). Anal. Calcd for C34H30N10O2S2 (674.8): C, 60.52; H, 4.48;
N, 20.76; S, 9.50. Found: C, 60.44; H, 4.52; N, 20.83; S, 9.49.
3.1.1.9.3. 1,4-Bis[4-(2-allyloxybenzylideneamino)-5-(pyridin-3-
yl)-4H-1,2,4-triazol-3-ylsulfanyl]butane (36). Yield 510.2 mg (70%,
procedure A), 539.4 mg (74%, procedure B), 328 mg (45%, procedure
C), colorless crystals, mp 155e157 ꢁC. Rf ¼ 0.73 (MeOH/CHCl3 1:9).
IR: 2922, 2869, 1596, 1569, 1479, 1452, 1434, 1376, 1350, 1296, 1242,
1186, 1159, 1103, 1046, 996, 966, 939, 910, 883, 817, 767, 753, 701,
3.1.1.10.2. 3,24-Di(pyridin-3-yl)-12,13,14,29,30,31-hexahydro-
15H,32H-bis[1,2,4]triazolo[4,3-f:3,4-n]dibenzo[b,r]
668, 621, 584, 479. 1H NMR (CDCl3):
d
1.97 (quint, 4H, J ¼ 6.3 Hz,
[1,20,5,6,15,16,8,13]dioxatetrazadithiacyclotetracosine
(43). Yield
SCH2CH2), 3.32 (t, 4H, J ¼ 6.3 Hz, SCH2CH2), 4.60 (td, 4H, J ¼ 1.3,
5.1 Hz, CH2CH]), 5.29 (dd, 2H, J ¼ 1.3, 10.5 Hz, CH2]), 5.38 (dd, 2H,
J ¼ 1.3, 17.2 Hz, CH2]), 5.99 (m, 2H, J ¼ 1.3, 5.1, 10.5, 17.2 Hz, CH]),
6.95 (d, 2H, J ¼ 7.8 Hz, ArH), 7.05 (t, 2H, J ¼ 7.8 Hz, ArH), 7.38 (dd, 2H,
JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.),
7.50 (dt, 2H, J ¼ 1.7, 7.8 Hz, ArH), 8.06 (dd, 2H, J ¼ 1.7, 7.8 Hz, ArH),
8.31 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.64 (br d, 2H, JH-6 pyrid.eH-5
527.2 mg (75%, A), 555.3 mg (79%, B), 569.3 mg (81%, C), colorless
crystals, mp 226e228 ꢁC. Rf ¼ 0.20 (MeOH/CHCl3 0.5:9.5). IR: 3070,
2944, 2858, 1596,1571, 1477,1454,1434,1410,1376,1349, 1298,1252,
1191,1163,1105,1044,1023, 986, 965, 882, 813, 758, 703, 669, 636, 618,
582, 484.1H NMR (CDCl3):
d
2.04 (quint, 4H, J ¼ 5.8 Hz, SCH2CH2), 2.11
(quint, 4H, J ¼ 5.7 Hz, OCH2CH2), 3.43 (t, 4H, J ¼ 5.8 Hz, SCH2CH2), 4.16
(t, 4H, J ¼ 5.7 Hz, OCH2CH2), 6.99 (d, 2H, J ¼ 7.9 Hz, ArH), 7.05 (t, 2H,
J ¼ 7.9 Hz, ArH),7.48 (dd, 2H, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6
¼ 4.8 Hz, H-6 pyrid.), 9.05 (s, 2H, CH]N), 9.21 (br s, 2H, H-2
¼ 4.8 Hz, H-5 pyrid.), 7.53 (dt, 2H, J ¼ 1.5, 7.9 Hz, ArH), 8.08 (dd,
pyrid.
pyrid.
pyrid.). Anal. Calcd for C38H36N10O2S2 (728.9): C, 62.62; H, 4.98; N,
19.22; S, 8.80. Found: C, 62.54; H, 5.02; N, 19.09; S, 8.77.
2H, J ¼ 1.5, 7.9 Hz, ArH), 8.47 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz,
JH-4 pyrid.eH-2 pyrid. ¼ 2.1Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,H-4pyrid.), 8.67
(dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6
pyrid.), 9.21 (s, 2H, CH]N), 9.28(d, 2H, JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2
pyrid.). LCMS: m/z ¼ 703 (M þ 1). GCMS: m/z (relative intensity); 579
[M e (O2 þ S2 þ C2H4) þ 1, 4%], 578 [M e (O2 þ S2 þ C2H4), 10%], 577
[Me (O2 þS2 þ C2H4)e 1, 22%], 551(22%), 415(4%), 367(5%),339(9%),
313 (26%), 264 (24%), 239 (24%), 236 (7%), 213 (5%),185 (6%),171 (7%),
158 (7%),149 (17%),129 (17%),121 (24%), 98 (45%), 97 (52%), 83 (63%),
55 (100%), 51 (7%). Anal. Calcd for C36H34N10O2S2 (702.9): C, 61.52; H,
4.88; N, 19.93; S, 9.12. Found: C, 61.56; H, 4.75; N, 20.09; S, 8.97.
3.1.1.10.3. 3,28-Di(pyridin-3-yl)-12,13,15,16,18,33,34,35-octahy-
dro-19H,36H-bis[1,2,4]triazolo[4,3-f:3,4-n]dibenzo[b,r]
3.1.1.10. Synthesis of the macrocyclic Schiff bases 42e47. General
procedures. Procedure A. To a solution of each of the K-salts 40 and
41 (1.0 mmol) in dry DMF (2.5 mL) was added the appropriate 1,u-
dihaloalkane (1.0 mmol). After heating the reaction mixture at
reflux temperature for 5 min (during which time KCl was sepa-
rated), it was cooled, diluted with water (20 mL) and the precipitate
was collected by filtration, washed with cold water (3 ꢀ 50 mL),
dried at room temperature and the remaining residue was purified
by column chromatography over silica gel using MeOH/CHCl3 as an
eluent and recrystallized from MeOH.
Procedure B. Each of the K-salts 29 and 30 (1.0 mmol) was dis-
solved in dry DMF (2.5 mL) and to the formed solution was added
[1,20,23,26,5,6,15,16,8,13]tetraoxatetrazadithiacycloocatacosine
(44). Yield 442.5 mg (58%, C), colorless crystals, mp 200e202 ꢁC.
the appropriate 1,
u
-dihaloalkane (1.0 mmol). The reaction mixture
1H NMR (CDCl3):
d
2.13 (quint, 4H, J ¼ 6.3 Hz, SCH2CH2), 3.43 (t, 4H,
was then worked up as described in procedure A.
J ¼ 6.3 Hz, SCH2CH2), 3.78 (s, 4H, OCH2CH2O), 3.90 (t, 4H,
J ¼ 4.5 Hz, ArOCH2CH2O), 4.22 (t, 4H, J ¼ 4.5 Hz, OCH2CH2O) 6.96
(d, 2H, J ¼ 7.8 Hz, ArH), 7.07 (t, 2H, J ¼ 7.8 Hz, ArH), 7.43 (dd, 2H,
JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.),
7.51 (dt, 2H, J ¼ 1.7, 7.8 Hz, ArH), 8.05 (dd, 2H, J ¼ 1.7, 7.8 Hz, ArH),
8.39 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.67 (dd, 2H, JH-6 pyrid.eH-4
Procedure C. A solution of each of the appropriate 1,u-bis(alde-
hydes) 10, 11, 13, 14 (1 mmol) in AcOH (10 mL) was added to
a solution of the appropriate 1, -bis(amine) 22e24 (1 mmol) in
u
AcOH (90 mL). The reaction mixture was heated at reflux temper-
ature for 3 h. The excess AcOH was evaporated to a small volume
(ca. 10 mL) and the reaction mixture was allowed to cool to room
temperature. The formed product was collected by filtration,
washed successively with water (3 ꢀ 100 mL) and MeOH
(2 ꢀ 20 mL) then dried at room temperature. Compounds 42, 43
were purified as described in procedure A, compound 44 was
recrystallized from AcOH/MeOH, Compounds 45e47 were recrys-
tallized from CHCl3/pet ether (bp 40e60 ꢁC).
3.1.1.10.1. 3,23-Di(pyridin-3-yl)-12,13,28,29-tetrahydro-14H,30H-
bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,q][1,19,5,6,14,15,8,12]dioxate-
trazadithiacyclodocosine (42). Yield 499.3 mg (74%, B), 587.1 mg (87%,
C) colorless crystals, mp 238e240 ꢁC. Rf ¼ 0.22 (MeOH/CHCl3 0.5:9.5).
IR: 3057, 2924, 2876, 2361, 1597, 1436, 1404, 1369, 1349, 1255, 1157,
1099,1033,1000, 959, 876, 821, 751, 699, 617, 582, 485.1HNMR(CDCl3):
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.17 (s, 2H,
pyrid.
CH]N), 9.26 (d, 2H JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-2 pyrid.). Anal.
Calcd for C38H38N10O4S2 (762.9): C, 59.83; H, 5.02; N, 18.36; S, 8.41.
Found: C, 59.77; H, 5.07; N, 18.34; S, 8.43
3.1.1.10.4. 13-Hydroxy-3,23-di(pyridin-3-yl)-12,13,28-trihydro-
14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-l]dibenzo[b,p][1,18,5,6,13,14,8,11]
dioxatetrazadithiacyclohenicosine (45). Yield 541.4 mg (80%, C);
colorless crystals, mp 291e293 ꢁC (resolidify after melting and melt
again at >350 ꢁC). IR: 3390 (br), 3071, 2930, 2876, 1599, 1572, 1484,
1452, 1376, 1351, 1324, 1293, 1255, 1191, 1163, 1106, 1026, 967, 886,
813, 758, 704, 619, 587, 476. 1H NMR (CDCl3):
d 2.02 (s, 1H, D2O
exchangeable OH), 3.47 (s, 4H, SCH2CH2S), 4.27 (d, 2H, J ¼ 5.4 Hz,
ArOCH2), 4.31 (m, 1H, CHOH), 4.40 (d, 2H, J ¼ 5.4 Hz, ArOCH2), 7.04
(d, 2H, J ¼ 7.7 Hz, ArH), 7.09 (t, 2H, J ¼ 7.7 Hz, ArH), 7.37 (dd, 2H, JH-5
d
2.50 (quint, 2H, J ¼ 6.3 Hz, SCH2CH2), 2.52 (quint, 2H, J ¼ 7.2 Hz,
OCH2CH2), 3.56 (t, 4H, J ¼ 6.3 Hz, SCH2CH2), 4.30 (t, 4H, J ¼ 7.2 Hz,
OCH2CH2), 7.00 (dd, 2H, J ¼ 1.5, 7.7 Hz, ArH), 7.09 (t, 2H, J ¼ 7.7 Hz, ArH),
7.47 (ddd, 2H, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz,
JH-5 pyrid.eH-2 pyrid. ¼ 0.9 Hz, H-5 pyrid.), 7.53 (m, 2H, J ¼ 1.5, 7.7 Hz, ArH),
8.03 (dd, 2H, J¼1.5, 7.7 Hz, ArH), 8.43 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼1.8 Hz,
JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.69
(dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6
¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.), 7.53
pyrid.eH-4 pyrid.
(dt, 2H, J ¼ 1.4, 7.7 Hz, ArH), 7.97 (dd, 2H, J ¼ 1.4, 7.7 Hz, ArH), 8.29
(td, 2H, JH-4
¼ 1.8 Hz, JH-4
¼ 2.1 Hz,
pyrid.eH-6 pyrid.
pyrid.eH-2 pyrid.
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.63 (dd, 2H, JH-6 pyrid.eH-4
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.20 (s, 2H,
pyrid.
CH]N), 9.24 (s, 2H, H-2 pyrid.). Anal. Calcd for C33H28N10O3S2
(676.8): C, 58.57; H, 4.17; N, 20.70; S, 9.48. Found: C, 58.49; H, 4.09;
N, 20.62; S, 9.57.
pyrid.), 9.29 (dd, 2H, JH-2
¼ 2.1 Hz, JH-2
pyrid.eH-4 pyrid.
pyrid.eH-5
d26.58,
¼ 0.9Hz,H-2pyrid.), 9.30(s,2H, CH]N).13CNMR(CDCl3):
pyrid.
29.62, 32.55, 65.18,112.52,120.39,121.82,123.60,127.43,134.79,136.15,
3.1.1.10.5. 13-Hydroxy-3,23-di(pyridin-3-yl)-12,13,28,29-tetrahy-
dro-14H,30H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,q]
146.46,148.39,149.95,150.72,158.73,159.33. LCMS: m/z¼ 675 (M þ 1).

N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
5275
[1,19,5,6,14,15,8,12]dioxatetrazadithiacyclodocosine
(46). Yield
¼1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,
pyrid.
594.1 mg (86%, C); colorless crystals, mp 281e282 ꢁC (resolidify
after melting and melt again at >350 ꢁC). IR: 3380, 3071, 2913,
2878, 1599, 1572, 1485, 1452, 1377, 1350, 1325, 1293, 1254, 1190,
1162, 1105, 1026, 966, 888, 813, 757, 704, 618, 586, 476. 1H NMR
H-4 pyrid.), 8.66 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz, JH-6 pyrid.eH-5
¼ 4.8 Hz, H-6 pyrid.), 9.09 (d, 2H JH-2 pyrid.eH-4 pyrid. ¼ 2.1 Hz, H-
pyrid.
2 pyrid.). Anal. Calcd for C33H32N10O3S2 (680.8): C, 58.22; H, 4.74; N,
20.57; S, 9.42. Found: C, 58.23; H, 4.62; N, 20.56; S, 9.39.
3.1.1.11.2. 13-Hydroxy-3,23-di(pyridin-3-yl)-5,6,12,13,20,21,28,29-
octahydro-14H,30H-bis[1,2,4]triazolo[4,3-f:3,4-m]dibenzo[b,q]
(CDCl3): d 2.03 (s, 1H, D2O exchangeable OH), 2.16 (s, 2H, SCH2CH2),
3.47 (s, 4H, SCH2CH2), 4.29 (d, 4H, J ¼ 5.4 Hz, ArOCH2), 4.70 (q, 1H
J ¼ 5.1 CHOH), 7.02 (d, 2H, J ¼ 7.8 Hz, ArH), 7.09 (t, 2H, J ¼ 7.8 Hz,
[1,19,5,6,14,15,8,12]dioxatetrazadithiacyclodocosine
(49). Yield
ArH), 7.40 (dd, 2H, JH-5
¼ 8.1 Hz, JH-5
149.3 mg (93%); colorless crystals, mp 274e276 ꢁC (dec.). IR: 3221,
3067, 2927, 2872, 1599, 1530, 1493, 1451, 1292, 1244, 1192, 1162,
1121, 1029, 963, 898, 813, 754, 704, 664, 625, 532. 1H NMR (CDCl3):
pyrid.eH-4 pyrid.
pyrid.eH-6
¼ 4.8 Hz, H-5 pyrid.), 7.53 (dt, 2H, J ¼ 1.4, 7.7 Hz, ArH), 7.92 (dd,
pyrid.
2H, J ¼ 1.4, 7.7 Hz, ArH), 8.35 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz,
JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.),
8.64 (d, 2H, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.23 (s, 2H, CH]
N), 9.31 (s, 2H, H-2 pyrid.). Anal. Calcd for C34H30N10O3S2 (690.8): C,
59.12; H, 4.38; N, 20.28; S, 9.28. Found: C, 59.00; H, 4.47; N, 20.32; S,
9.19.
d
2.25 (quint, 2H, J ¼ 6.4 Hz, SCH2CH2), 3.38 (t, 4H, J ¼ 6.4 Hz,
SCH2CH2), 3.90 (s,1H, D2O exchangeable OH), 4.00 (d, 4H, J ¼ 5.5 Hz,
ArCH2), 4.07 (dd, 4H, J ¼ 6.3, 11.4 Hz, ArOCH2), 4.61 (quint, 1H
J ¼ 5.1 Hz, CHOH), 6.08 (t, 2H, J ¼ 5.5 Hz, D2O exchangeable NH),
6.73 (d, 2H, J ¼ 7.7 Hz, ArH), 6.74 (t, 2H, J ¼ 7.7 Hz, ArH), 6.99 (dd, 2H,
J ¼ 1.4, 7.7 Hz, ArH), 7.13 (dt, 2H, J ¼ 1.4, 7.7 Hz, ArH), 7.20 (dd, 2H,
JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.),
8.18 (td, 2H, JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz,
JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz, H-4 pyrid.), 8.50 (dd, 2H, JH-6 pyrid.eH-4
3.1.1.10.6. 13-Hydroxy-3,23-di(pyridin-3-yl)-12,13,28,29,30-pen-
tahydro-14H,31H-bis-[1,2,4]triazolo[4,3-f:3,4-n]dibenzo[b,r]
[1,20,5,6,15,16,8,13]dioxatetrazadithiacyclotricosine
606.1 mg (86%, C); colorless crystals, mp 286e287 ꢁC (resolidify
after melting and melt again at >350 ꢁC). IR: 3403, 3105, 3040,
2929, 2867, 1599, 1569, 1486, 1439, 1410, 1377, 1352, 1299, 1552,
1189, 1160, 1106, 1044, 1006, 966, 894, 814, 764, 704, 670, 628, 618,
(47). Yield
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.16 (d, 2H,
pyrid.
JH-2
¼
2.1 Hz, H-2 pyrid.). Anal. Calcd for
C34H34N10O3S2 (694.8): C, 58.77; H, 4.93; N, 20.16; S, 9.23. Found: C,
58.66; H, 4.81; N, 19.99; S, 9.21.
pyrid.eH-4 pyrid.
578, 483. 1H NMR (DMSO-d6):
d
1.92 (quint, 2H, J ¼ 5.2 Hz,
SCH2CH2), 3.26 (t, 4H, J ¼ 5.2 Hz, SCH2CH2), 4.16 (dd, 2H, J ¼ 7.2,
9.0 Hz, ArOCH2), 4.29 (br s, 1H, CHOH), 4.31 (d, 2H, J ¼ 9.0 Hz,
ArOCH2), 5.45 (d, 1H, J ¼ 4.2 Hz, D2O, exchangeable OH), 7.14 (t, 2H,
J ¼ 7.8 Hz, ArH), 7.24 (d, 2H, J ¼ 7.8 Hz, ArH), 7.58 (tdd, 2H,
JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, JH-5 pyrid.eH-2
3.1.1.11.3. 13-Hydroxy-3,23-di(pyridin-3-yl)-
5,6,12,13,20,21,28,29,30-nonahydro-14H,31H-bis[1,2,4]triazolo[4,3-
f:3,4-n]dibenzo[b,r][1,20,5,6,15,16,8,13]dioxatetrazadithiacyclo-
tricosine (50). Yield 127.2 mg (78%); colorless crystals, mp
271e273 ꢁC (dec.). IR: 3220, 3066, 2925, 2855, 1599, 1493, 1452,
1417, 1378, 1290, 1245, 1191, 1162, 1120, 1045, 963, 895, 834, 812,
¼ 0.9 Hz, H-5 pyrid.), 7.64 (tt, 2H, J ¼ 0.8, 7.8 Hz, ArH), 7.98 (dd,
pyrid.
2H, J ¼ 1.2, 7.8 Hz, ArH), 7.20 (dd, 2H, JH-5 pyrid.eH-4 pyrid. ¼ 8.1 Hz,
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.), 8.29 (m, 2H, JH-4 pyrid.eH-6
753, 704, 624, 600, 479, 434. 1H NMR (CDCl3):
d 1.95 (quint, 4H,
J ¼ 4.6 Hz, SCH2CH2), 3.21 (t, 4H, J ¼ 4.6 Hz, SCH2CH2), 4.08 (s, 1H,
D2O exchangeable OH), 4.11 (d, 4H, J ¼ 5.8, ArCH2), 4.23 (dd, 4H,
J ¼ 4.6, 10.6 Hz, ArOCH2), 4.52 (quint, 1H, J ¼ 5.5 Hz, CHOH), 6.23 (t,
2H, J ¼ 5.8 Hz, D2O exchangeable NH), 6.77 (d, 2H, J ¼ 7.8 Hz, ArH),
6.80 (dt, 2H, J ¼ 1.3, 7.8 Hz, ArH), 6.98 (dd, 2H, J ¼ 1.3, 7.8 Hz, ArH),
¼1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5 pyrid. ¼ 8.1 Hz,
pyrid.
H-4 pyrid.), 8.69 (ddd, 2H, JH-6 pyrid.eH-2 pyrid. ¼ 0.9 Hz, JH-6 pyrid.eH-4
¼ 1.8 Hz, JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.08 (dd, 2H,
pyrid.
JH-2
¼ JH-2
¼ 0.9 Hz, JH-2
pyrid.eH-5 pyrid.
pyrid.eH-6 pyrid.
pyrid.eH-4
¼ 1.8 Hz, H-2 pyrid.), 9.42 (s, 2H, CH]N). Anal. Calcd for
7.17 (dt, 2H, J ¼ 1.3, 7.8 Hz, ArH), 7.52 (dd, 2H, JH-5
pyrid.
pyrid.eH-4
C35H32N10O3S2 (704.8): C, 59.64; H, 4.58; N, 19.87; S, 9.10. Found: C,
59.69; H, 4.48; N, 19.82; S, 9.04.
¼ 8.1 Hz, JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.), 8.56 (td, 2H,
pyrid.
JH-4 pyrid.eH-6 pyrid. ¼ 1.8 Hz, JH-4 pyrid.eH-2 pyrid. ¼ 2.1 Hz, JH-4 pyrid.eH-5
¼ 8.1 Hz, H-4 pyrid.), 8.63 (dd, 2H, JH-6 pyrid.eH-4 pyrid. ¼ 1.8 Hz,
pyrid.
3.1.1.11. General procedure for the synthesis of macrocyclic amines
48e50. To a stirred boiling solution of each of 45e47 (0.23 mmol)
in methanol (10 mL) was added sodium borohydride (0.20 g,
5.29 mmol) in incremental amounts over a period of 15 min. After
the effervescence had stopped, the reaction mixture was heated at
reflux temperature for 1 h. The solvent was then removed in vacuo
and the remaining residue was extracted into DCM (50 mL). The
extract was washed with water (2 ꢀ 50 mL), dried (Na2SO4),
reduced by rotary evaporator (to ca. 10 mL) and pet ether (bp
40e60 ꢁC) (10 mL) was added. The solid obtained upon cooling was
collected by filtration and recrystallized from DCM/pet ether (bp
40e60 ꢁC) to give colorless crystals of 48e50.
JH-6 pyrid.eH-5 pyrid. ¼ 4.8 Hz, H-6 pyrid.), 9.46 (d, 2H, JH-2 pyrid.eH-4
¼ 2.1 Hz, H-2 pyrid.). Anal. Calcd for C35H36N10O3S2 (708.9): C,
pyrid.
59.30; H, 5.12; N, 19.76; S, 9.05. Found: C, 59.23; H, 5.01; N, 19.68; S,
9.00.
3.2. Antimicrobial activity
Antimicrobial screening of compounds 15, 17e25, 43, 44, 46, 47
and 49 was carried out using the diffusion agar technique [44]. The
test organisms were obtained from the culture of the Regional
Center for Mycology and Biotechnology, Faculty of Science, Al-
Azhar University, Cairo, Egypt. Compounds, 15, 17e25, 43, 44, 46,
47, 49 and standard antimicrobial agents (chloramphenicol and
terbinafin were used as standard antibacterial and antifungal
agents, respectively) were dissolved in DMF (5.0 mg/mL). Further
dilutions of the compounds and standard drugs were prepared at
the required quantities of 5.0, 2.5 and 1.0 mg/mL concentrations. All
the compounds were tested for their in vitro growth inhibitory
activity against two Gram-positive bacteria (Bacillus subtilis RCMB
101-001 and Staphylococcus aureus RCMB 106-001 (1)), two Gram-
negative bacteria (Pseudomonas aeruginosa RCMB 102-002 and
Escherichia coli RCMB 103-001), one yeast (Candida albicans RCMB
005003) and three fungal strains (Aspergillus fumigatus RCMB
002008 (1), Penicillium italicum RCMB 001018 (1) and Syncepha-
lastrum racemosum RCMB 016001). The minimum inhibitory
3.1.1.11.1. 13-Hydroxy-3,23-di(pyridin-3-yl)-5,6,12,13,20,21,28-
heptahydro-14H,29H-bis[1,2,4]triazolo[4,3-f:3,4-l]dibenzo[b,p]
[1,18,5,6,13,14,8,11]dioxatetrazadithiacyclohenicosine
(48). Yield
150.3 mg (96%); colorless crystals, mp 278e280 ꢁC (dec.). IR: 3228,
3065, 2927, 2872, 1598, 1548, 1493, 1452, 1417, 1293, 1244, 1191,
1163, 1121, 1029, 961, 894, 813, 754, 703, 627, 525, 488. 1H NMR
(DMSO-d6): d 3.39 (s, 4H, SCH2CH2S), 3.91 (s, 1H, D2O exchangeable
OH), 3.93 (d, 4H, J ¼ 4.6 Hz, ArCH2), 4.02 (dd, 4H, J ¼ 6.0, 10.2 Hz,
ArOCH2), 4.52 (quint, 1H J ¼ 5.1 Hz, CHOH), 6.61 (t, 2H, J ¼ 4.6 Hz,
D2O exchangeable NH), 6.73 (d, 2H, J ¼ 7.7 Hz, ArH), 6.75 (t, 2H,
J ¼ 7.7 Hz, ArH), 6.98 (dd, 2H, J ¼ 1.4, 7.7 Hz, ArH), 7.23 (dt, 2H,
J ¼ 1.4, 7.7 Hz, ArH), 7.52 (dd, 2H, JH-5
¼ 8.1 Hz,
pyrid.eH-4 pyrid.
JH-5 pyrid.eH-6 pyrid. ¼ 4.8 Hz, H-5 pyrid.), 8.29 (td, 2H, JH-4 pyrid.eH-6

5276
N.S.A.M. Khalil / European Journal of Medicinal Chemistry 45 (2010) 5265e5277
pyridinoyl)-4-aroylthiosemicarbazide derivatives, Gaodeng Xuexiao Huaxue
Xuebao 10 (1989) 471;
Chem. Abstr. 112 (1990) 158149w;
(d) W. Rudnicka, H. Foks, M. Janowiec, Z. Zwolska-Kwiek, Pyrazine derivatives.
XXI. Synthesis and tuberculostatic activity of 4-aryl-1-pyrazinoylth-
iosemicarbazides and of the products of their cyclization to the derivatives of
1,2,4-triazol-3-thione, Acta Pol. Pharm. 43 (1986) 523;
concentrations (MICs) of compounds 21 and 43 were determined
via further twofold serial dilutions to prepare the required quan-
tities of 1000, 500, 250, 125, 62.50, 31.25, 15.63, 7.81, 3.91, 1.95, 0.98,
0.49
mg/mL concentrations. The antimicrobial activities were
expressed as the diameter of the inhibition zones (Table 1).
Chem. Abstr. 108 (1988) 131695b;
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derivatives thereof with isocyanates and isothiocyanates, Acta Pol. Pharm. 35
(1978) 135;
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