Synthesis, antibacterial and QSAR evaluation of 5-oxo and 5-thio derivatives of 1,4-disubstituted tetrazoles

Article abstract of DOI:10.1016/j.bmcl.2015.04.070

Abstract A series of 1,4-disubstituted tetrazol-5-ones 3a, 5, 7, 12, 13 and 1,4-disubstituted tetrazol-5-thiones 3b, 9, 10 was synthesized and fully characterized by IR, MS, ¹H NMR and ¹³C NMR. The series was evaluated for in vitro antibacterial activity against four Gram negative (Escherichia coli, Proteus mirabilis, Klebsiella pneumonia, and Pseudomonas aeruginosa) and three Gram positive (Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis) bacteria. The zone of inhibition was measured using the well-diffusion assay, and in vitro minimum inhibitory concentration (MIC) was determined by microbroth dilution assay. MIC values indicate that compounds exhibited a varied range (0.2-37 μg/mL) of antibacterial activity against the tested bacterial strains. Statistically significant QSAR models were developed by the simple linear regression analysis for the correlation of MIC with computed descriptors. The concluded cross validated regression factors are 0.953 and 0.986 for E. coli, and S. aureus, respectively.

Full text of DOI:10.1016/j.bmcl.2015.04.070

Accepted Manuscript
Synthesis, antibacterial and QSAR evaluation of 5-oxo and 5-thio derivatives
of 1,4-disubstituted tetrazoles
Rami Y. Morjan, Nisreen H. El-Attar, Omar S. Abu- Teim, Maschke Ulrich,
Adel M. Awadallah, Ahmed M. Mkadmh, Abdelrauof A. Elmanama, James
Raftery, Fakhr M. Abu-Awwad, Zyad J. Yaseen, Ammar F. Elqidrea, John M.
Gardiner
PII:
S0960-894X(15)00402-3
DOI:
http://dx.doi.org/10.1016/j.bmcl.2015.04.070
BMCL 22653
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 March 2015
19 April 2015
20 April 2015
Please cite this article as: Morjan, R.Y., El-Attar, N.H., Abu- Teim, O.S., Ulrich, M., Awadallah, A.M., Mkadmh,
A.M., Elmanama, A.A., Raftery, J., Abu-Awwad, F.M., Yaseen, Z.J., Elqidrea, A.F., Gardiner, J.M., Synthesis,
antibacterial and QSAR evaluation of 5-oxo and 5-thio derivatives of 1,4-disubstituted tetrazoles, Bioorganic &
Medicinal Chemistry Letters (2015), doi: http://dx.doi.org/10.1016/j.bmcl.2015.04.070
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Synthesis, antibacterial, and QSAR evaluation of 5-
oxo and 5-thio derivatives of 1,4-disubstituted
tetrazoles
Rami Y. Morjan, Nisreen H. El-Attar, Omar S. Abu-Teim, Maschke Ulrich, Adel M. Awadallah, Ahmed M.
Mkadmh, Abdelrauof A. Elmanama, James Raftery, Fakhr M. Abu-Awwad, Zyad J. Yaseen, Ammar F. Elqidra,
and John M. Gardiner*
S. aureus inhibitors at 0.19-5.3 µg / mL
N
Inactive
N
N
N
N
CO2H
N
N
O
X=O
X=S
O
N
2
OH
Ph
N
N
N
N
Ph
Ph
N
N
Ph
N
N
O
O
S
X
Ph
H
N
N
N
N
N
N
N
N
H
S
N
N
N
N
N
OR
N
Ph
Ph
N
S
N
Ph
S
CO2Et
O
S. aureus inhibitor 5.3 µg / mL; E. coli 15.9 µg / mL
R = H, Ac, Bn

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.els evier.com
Synthesis, antibacterial and QSAR evaluation of 5-oxo and 5-thio derivatives of
1,4-disubstituted tetrazoles
Rami Y. Morjana, Nisreen H. El-Attarb, Omar S. Abu- Teimb, Maschke Ulrichc, Adel M. Awadallaha, Ahmed M.
Mkadmhd, Abdelrauof A. Elmanamae, James Rafteryf, Fakhr M. Abu-Awwada, Zyad J. Yaseena, Ammar F.
Elqidreacand John M. Gardinerg,∗
aChemistry Department, Faculty of Science, Islamic University of Gaza, PO Box 108, Gaza Strip, Palestine.
bChemistry Department, Faculty of Science, Al-Azhar University, P. O. Box 1277, Gaza, Palestine.
cUMET, UMR CNRS N°8207, Université Lille 1 - Sciences et Technologies, 59655 Villeneuve d'Ascq Cedex, France.
dChemistry Department, Faculty of Applied Science, Alaqsa University, PO Box 4051, Gaza, Palestine.
eMedical Laboratory Sciences Department, Faculty of Health Science, Islamic University of Gaza, P.O. Box 108, Gaza Strip, Palestine.
fSchool of Chemistry, The University of Manchester, Brunswick Street, Manchester, M13 9PL, United Kingdom.
gManchester Institute of Biotechnology, School of Chemistry and EPS, The University of Manchester, Manchester M1 7DN, United Kingdom.
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
Accepted
Available online
A series of 1,4-disubstituted tetrazol-5-ones 3a, 5, 7, 12, 13 1,4-disubstituted tetrazol-5-thiones
3b, 9, 10 was synthesized and fully characterized by IR, MS, 1H NMR and 13C NMR. The series
was evaluated for in vitro antibacterial activity against four Gram negative (Escherichia coli,
Proteus mirabilis, Klebsiella pneumonia, and Pseudomonas aeruginosa) and three Gram
positive (Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis) bacteria. The
zone of inhibition was measured using the well-diffusion assay, and in vitro minimum inhibitory
concentration (MIC) was determined by microbroth dilution assay. MIC values indicate that
compounds exhibited a varied range (0.2–37ꢀµg/mL) of antibacterial activity against the tested
bacterial strains. Statistically significant QSAR models were developed by the simple linear
regression analysis for the correlation of MIC with computed descriptors. The concluded cross
validated regression factors are 0.953 and 0.986 for E. coli, and S. aureus respectively.
Keywords:
Tetrazole
Tetrazolones
Tetrazolethiones
Antibacterial
QSAR
2009 Elsevier Ltd. All rights reserved.
Microbial infections have been of recent concern due to the
increasing emergence of multidrug-resistant strains, intractable
tetrazoles possess hypotensive[14], antimicrobial[15], antiviral[16]
antiallergic[17], cytostatic[18], antifungal activity[19]. The tetrazole
ring is also an isostere of carboxyl[20-21], amide[22], imidazole[23]
,
pathogenic microorganisms and newly arising pathogens[1–4]
.
,
Various synthetic and semi-synthetic antimicrobial agents have
been discovered and extensively used in the clinic to treat various
community, environment and hospital-acquired microbial
infections[5-6]. There is a continuous demand to find drugs that
have effects on Gram-positive and Gram-negative, as well as
multidrug-resistant bacteria[7-8]. However, and despite significant
progress in this field; there are still some unresolved problems for
development of new clinical drugs, including narrow
benzimidazole[24] and carbazole groups[25] in designing various
new types of drug molecules. Dozens of highly effective drugs
whose active pharmaceutical ingredients contain the tetrazole
ring are reported and approved by FDA. Examples are Losartan,
Valsartan, Irbesartan, Flomoxef and Cefonicid[26-30]. Various
methodologies for preparing compounds with a tetrazole ring
system have been developed, among the most important are those
based on cycloaddition reaction of azides with cyanide or
isonitriles[31-33]. Tetrazolones and tetrazolethiones have also
received considerable attention in the last few years. Many
pesticides[34] and herbicides[35], and drugs have been patented for
the treatment of central nervous system disorders,[36] HIV,[37]
sexual dysfunction,[38] asthma, [39] diabetes, [40] and also a number
[9]
antimicrobial spectrum, adverse effects and high toxicity .
The discovery and development of structurally-novel
antimicrobial agents with good pharmacological profile and
excellent activity towards resistant strains are highly desirable[10–
11]. Tetrazoles have received attention in recent years due to
widespread applications notably in the field of medicinal
of antiviral[41]
,
antibacterial[42] antimicrobial[43]
agents have been reported containing one of
, and anti-
[44]
inflammatory
[12-13]. Many
c—he—mis—try due to their privileged biological activity
∗ Corresponding author. Tel.: +44-161-306-4530; e-mail: gardiner@manchester.ac.uk

these ring systems. In a local study conducted at Al-shifa
hospital`s burn unit it was shown that Pseudomonas isolates were
resistant to most of antimicrobials used except for piperacillin-
tazobactam. The incidence of methicillin-resistant Staphylococci
according to the oxacillin sensitivity test was 60% in patient
samples, 77.8% in health care worker samples and 90% in
environmental samples[45]. This indicates the necessity for new
active compounds that could supercede old inactive
antimicrobials.
tetrazoles 1a and 1b, respectively, which then undergo direct
alkylation at N4 of the tetrazole ring of 1a. In the case of 1b the
alkylation occurs at S rather than at N as a result of thione/thiol
tautomerism leading to the formation of 6.
We obtained crystals of N-benzyl derivative 5 and obtained an X-
ray crystal structure[50]. The crystal structure of compound 5 has a
space point group P 21/n with a unit cell dimensions 8.0027(8)
Å, 13.0948(11) Å, 12.0557 Å and cell angles 90.00, 105.462(7),
and 90.00 for α, β and γ, respectively (Figure 1). The crystal
packing diagram and full details of the crystal structure are
shown in (Figure S1, Supplementary Data)
Quantitative structure activity relationship (QSAR) is an
important method employed for the prediction of biological
activity of compounds and in finding quantitative correlations
between the molecular structures and their biological activities
[46]
.
Herein, we describe the synthesis, antimicrobial activity and
QSAR investigations for a series of novel 1,4-disubstituted
tetrazol-5-one-5-thione.
The starting materials, 1,4-dihydro-1-hydroxymethyl-4-phenyl
tetrazol-5-one 2a and its thione counterpart 2b, were synthesized
according to the reported procedures.[47] These were intended to
be substrates for the synthesis of a range of O-alkylated and O-
acylated derivatives for biological evaluation.
Figure 1. X-ray structure of 5
Following from the outcomes of acylation and benzylation
reactions, we evaluated reactions of 2 with a bis-alkylating agent.
The reaction of 2a and 2b with one equivalent of 1,6-
dibromohexane afforded the bis-tetrazole dimeric compounds 7
and 8 in 11% and 10% yield, respectively. The yields were
significantly increased when two equivalents of 1a and 1b were
reacted with one equivalent of the dibromohexane as this
produced 7 and 8 in 70% and 68% respectively (Scheme 3).
Compound 8 was also previously reported via reaction of two
equivalents of 1,6-dibromohexane with 5-mercapto-1-
phenyltetrazole[55]. The outcomes from 2a and 2b are attributed
again to the in situ deformylation to generate 1a and 1b followed
by direct reaction with 1,6-dibromohexane to form 7 and 8,
however, this does not appear to be as effective as direct N-
alkylations for the dimerizations.
Initial work involved targeting acylation and benzylations.
Reaction of either 2a or 2b with acetic anhydride in pyridine
afforded the novel compounds 3a and 3b in 51% and 40% yield,
respectively (Scheme 1).
O
O
N
N
N
N
N
N
O
OH
N
37% HCOH
N
N
N
N
NH
O
O
60 °C
0 °C
pyridine,
r.t/24h
X
X
X
1a: X= O
1b: X= S
2a: X= O
2b: X= S
3a: X= O 51%
3b: X= S 40%
Scheme 1: Reaction of 2a and 2b with acetic anhydride.
By contrast, reaction of 2a or 2b with benzyl bromide using
KOH and 18-crown-6 as phase transfer catalyst in DMSO, at
room temperature, afforded compounds 5 and 6 in 33% and 56%
yield respectively, instead of the expected products 4a and 4b
(Scheme 2).
Br(CH2)6Br (1 eq.)
N
18-crown-6,
KOH, DMSO
N
OH
N
N
11%
N
O
O
N
N
O
2a
N
N
N
N
Br(CH2)6Br (2 eq.)
N
N
N
7
18-crown-6,
KOH, DMSO
N
N
N
NH
O
N
N
N
N
OH PhCH2Br
18-crown-6
N
N
70%
O
1a
X
4a: X= O
4b: X= S
X
KOH, DMSO
– HCOH
Br(CH2)6Br (1 eq.)
2a: X= O
2b: X= S
N
18-crown-6,
KOH, DMSO
N
OH
N
N
N
N
N
N
N
N
11%
N
N
N
S
H
N
N
N
NH
2b
S
N
S
O
X
N
N
N
N
Br(CH2)6Br (2 eq.)
N
S
6 56%
1a: X= O
1b: X= S
5 33%
N
N
N
18-crown-6,
KOH, DMSO
N
NH
8
Scheme 2: Reaction of tetrazolinone 2a and 2b with benzyl bromide.
68%
S
1b
The synthesis of compound 5 was previously reported via direct
Scheme 3: Synthesis of dimers 7 and 8.
[48]
reaction of the parent tetrazole 1a with benzyl bromide
and
Alkylation at S following in situ loss of formaldehyde from 2b
was also observed using ethyl 2-chloroacetate as the electrophile,
thereby giving rise to the known[56] compound 9 as the only
product (Scheme 4).
compound 6 has been prepared directly via thiol alkylation at
sulfur[49]. The formation of compounds 5 and 6 in the reactions of
Scheme 2 is believed to arise via in situ loss of formaldehyde
(HCOH) from the starting materials 2a and 2b to form the NH

N
N
concentration (MIC) using microbroth dilution assay. Each
compound was serially diluted in fixed volumes containing
standardized bacterial suspension (standardization was made by
comparing growth to 0.5 McFarland turbidity standards). A
positive growth control was included for each plate.
Cl
CO2Et
N
N
S
CO2Et
N
N
9
42%
OH
N
N
O
O
O
O
S
Table 1: Zone of inhibition in mm for compounds testeda
Zone of inhibition in mm
N
N
OH
2b
O
N
N
O
Gram-positive bacteria Gram-negative bacteria
S
Compound
50%
S. a
12
18
38
32
9
10
0
0
0
0
9
24
0
S.s
B. s
14
16
33
30
14
12
0
0
0
0
13
12
12
9
E.c K. p P. m P.a
10
1a
1b
2a
2b
3a
3b
5
6
7
8
9
11
10
14
30
31
0
9
8
22
19
0
0
0
11
24
23
0
Scheme 4: Reactions of 2b with ethyl 2-chloroacetate or succinic anhydride.
12
42
42
10
0
0
0
0
0
13
19
0
0
0
19
34
26
11
15
7
Similarly to acylation (cf. Scheme 1), reaction of 2b with
succinic anhydride afforded the expected compound 10 in 50%
yield. No evidence of any by-product formation as a result of
losing formaldehyde was observed. In order to avoid the in situ
formation of compounds 1a and 1b and to be able to extend the
linkage at N4 of the tetrazol-5-one/thione rings, we employed a
different starting material, namely the homologous hydroxyethyl-
bearing 11. The reaction of 11 with acetic anhydride afforded the
acylation product 12 in 60% yield, but the key difference was
that O-alkylations now proceeded without the N-alkylation seen
with 2a. The reaction of 11 with benzyl bromide under phase
transfer catalyst conditions afforded compound 13 in 47%
(Scheme 5).
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
14
11
12
15
20
0
17
0
0
0
10
11
12
13
11
11
12
0
16
13
0
0
0
0
0
a S. a Staphylococcus aureus, S.s Streptococcus spp., B.s Bacillus subtilis, E.c
Escherichia coli, K.p, Klebsiella pneumonia P.m, Proteus mirabilis, P.a
Pseudomonas aeruginosa.
Scheme 5: Reaction of 11 with acetic anhydride and benzyl bromide
With this series of six new tetrazoles along with the known
compounds prepared, we undertook evaluation of their
antibacterial effects. The well-diffusion assay methodology
was employed to screen DMSO solutions of 1,4-disubstituted
tetrazol-5-ones 3a, 5, 7, 12, 13 and 1,4-disubstituted tetrazol-5-
Microtiter plates were incubated for 24 hours at 37 ºC. Growth
inhibition was detected by adding 20 µl of 0.5% aqueous 2,3,5-
triphenyltetrazolium chloride (TTC), supplied by Merck. MIC
was defined as the lowest concentration of inoculum that
inhibited visible growth, as indicated by TTC color change (red
to colorless)[59].
[57]
Table 2. The MIC results of compounds that exhibited antibacterial activity
(µg / mL)
Compound
E. coli
1.5432
1.7672
1.76
S. aureus
1.5432
1.7637
0.19
1.76
2.66
4.62
5.29
1.37
5.29
1a
1b
2a
2b
3a
3b
9
10
11
12
0.58
13.88
13.88
15.87
1.37
8.00
37.03
thiones 3b, 9, 10, and the starting materials 1a, 1b, 2a and 2b for
antimicrobial activity. Four Gram negative (Escherichia coli,
Proteus mirabilis, Klebsiella pneumonia, and Pseudomonas
aeruginosa) and three Gram positive isolates (Staphylococcus
aureus, Enterococcus faecalis, and Bacillus subtilis) obtained
from Al-Shifa Hospital Microbiology laboratory were used as
test organisms. All compounds either in powder or oil forms
were weighed (range from 45 to 250 mg) and dissolved in
DMSO. The volume of DMSO used ranged from 750 to 2000 µl.
In short, 6 holes were punched on each of three Muller Hinton
agar plates that were inoculated with standardized bacterial
suspension [58]. 100 µl of each of the tested compound solutions
were carefully dispensed in the corresponding hole. Plates were
set for 30 minutes at the refrigerator temperature and then
incubated for 24 hours at 37 ºC. The zone of inhibition in mm
for the tested compounds is provided in Table 1.
37.03
Compounds 1a, 1b, 2a, 2b, 3a, 3b and 9-12 were evaluated for
their antibacterial activity against Gram positive (Staphylococcus
aureus) and Gram negative (Escherichia coli) bacteria to
determine the MIC. These compounds showed antibacterial
activities by the microbroth dilution assay and the MIC results
are summarized in Table 2. Zones of inhibition around the ten
compounds (1a, 1b, 2a, 2b, 3a, 3b, 9-12) by the microbroth
dilution method are shown in (Figure S2, Supplementary
Data). Reduction of 2,3,5-triphenyltetrazolium chloride giving a
red color was used as an indicator of bacterial growth in MIC
determination (Figure S3, Supplementary Data).
A
notable broad-spectrum effect of some of the tested
All compounds that showed measurable antibacterial activity
were further tested to determine their minimum inhibitory
compounds was evident, especially, for compounds 2a, 2b, and

10, whilst 3a, 10 and 11 all showed activity against 4 of the panel
of microrganisms. In addition, the effects on P. aeruginosa of 2a,
2b, and 10 are particularly promising. MIC values indicate that
the ten compounds reported in Table 2 exhibited a varied range
(0.2–37ꢀµg/mL) of antibacterial activity. The MIC values of
compounds 2a and 2b showed the maximum inhibition activity
(0.19 and 0.59ꢀmg/mL respectively). Further studies to determine
lethal dose, safety and mechanism of action of these compounds
will be our priority with the results reported here showing that
readily-accessible 1,4-differentially-substituted tetrazoles – the
chemistry herein illustrating the capacity for further structural
diversification - offer a promising scaffold for new antibacterial
discovery.
Figure 2b
Figure 2. Correlations between experimental and calculated MIC
values (2a): Escherichia coli (2b): Staphylococcus aureus.
Acknowledgments
Computational and QSAR Work
The authors would like to thank the French Government for the
financial support of this project through Al Maqdisi l2Fl program
The molecular geometries of the structures listed in Table 2 were
fully optimized at B3LYP/6-31G(d) level of theory using
Gaussian 2003 for windows (G03W) without any applied
molecular symmetry constraint[60,61]. The optimized structures
were properly attributed to their local minima with no imaginary
frequencies, followed by QSAR calculations at the same level of
Supplementary Material
Supplementary data (representative experimental procedures,
characterization data, and copies of spectra, and images of
assays) associated with this article can be found, in the online
version, at http://….
theory using CODESSA software (version 2.10)[62]
.
In QSAR procedures, 300 physicochemical descriptors were
computed for each of the optimized structures. Employing a
heuristic method for the whole dataset, the validated descriptors
are then ranked according to their correlation coefficients.
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