Synthesis and antibacterial activity of N-(5-benzylthio-1,3,4-thiadiazol-2- yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl)piperazinyl quinolone derivatives

Article abstract of DOI:10.1016/j.bmcl.2005.07.016

A series of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl- 1,3,4-thiadiazol-2-yl) derivatives of piperazinyl quinolones was synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative microorganisms. Some of these derivatives exhibit high activity against Gram-positive bacteria; Staphylococcus aureus and Staphylococcus epidermidis, comparable or more potent than their parent N-piperazinyl quinolones norfloxacin and ciprofloxacin as reference drugs. The SAR of this series indicates that both the structure of the benzyl unit and the S or SO₂ linker dramatically impact antibacterial activity.

Full text of DOI:10.1016/j.bmcl.2005.07.016

Bioorganic & Medicinal Chemistry Letters 15 (2005) 4488–4492
Synthesis and antibacterial activity
of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and
N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl)piperazinyl
quinolone derivatives
c
b
b
Alireza Foroumadi,a,b, Saeed Emami, Abdolreza Hassanzadeh, Majid Rajaee,
*
Kazem Sokhanvar,b Mohammad Hassan Moshafib and Abbas Shafieea
aFaculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran
bFaculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
cDepartment of Medicinal Chemistry, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran
Received 30 April 2005; revised 30 June 2005; accepted 7 July 2005
Available online 18 August 2005
Abstract—A series of N-(5-benzylthio-1,3,4-thiadiazol-2-yl) and N-(5-benzylsulfonyl-1,3,4-thiadiazol-2-yl) derivatives of piperazinyl
quinolones was synthesized and evaluated for antibacterial activity against Gram-positive and Gram-negative microorganisms.
Some of these derivatives exhibit high activity against Gram-positive bacteria; Staphylococcus aureus and Staphylococcus epidermi-
dis, comparable or more potent than their parent N-piperazinyl quinolones norfloxacin and ciprofloxacin as reference drugs. The
SAR of this series indicates that both the structure of the benzyl unit and the S or SO2 linker dramatically impact antibacterial
activity.
Ó 2005 Elsevier Ltd. All rights reserved.
Quinolones have become a major class of antibacterial
agents, which are under extensive clinical development.
They have an attraction because of their extremely po-
tent activity, rapid bactericidal effects, and low incidence
of resistance development.1 The main disadvantage of
the quinolones is their limited activity against Gram-
positive pathogens (because of their intrinsically low
activity against these species) and methicillin-resistant
Staphylococcus aureus (MRSA) (because of the develop-
ment of resistance).2 In addition, quinolones can cause
certain adverse effects, such as CNS effects, phototoxic-
ity, tendonitis, hypoglycemia, and serious cardiac
dysrhythmias.3,4 Thus, despite many advances in the
fluoroquinolone field, there exists continuous need for
novel quinolones with better activity profile, pharmaco-
kinetics, and tolerability, to overcome the limitations of
existing drugs.
Most of the quinolone antibacterial research has been
focused on the functionality at C-7 position since the
introduction of norfloxacin 1 and ciprofloxacin 2 (Figs.
1 and 2). Moreover, C-7 substituent is the most adapt-
able site for chemical change and is an area that deter-
mines potency and target preference. This area also
controls the pharmacokinetic properties of the drugs,
with a basic nitrogen.5–7 A five- or six-membered ring
is the most commonly found substitution at position
C-7, for example, gemifloxacin and trovafloxacin, have
an aminopyrrolidine substituent at C-7.8,9 Piperazine
substitution at C-7 position has resulted in a wide range
of clinically useful fluoroquinolone antibacterial agents
namely norfloxacin, ciprofloxacin, perfloxacin, pefloxa-
C5
O
COOH
F
C7
N
Keywords: Quinolone; 1,3,4-Thiadiazole; Antibacterial activity.
*
C8
N1
Corresponding author. Tel.: +98 2166406757; fax: +98 2166461178;
e-mail: aforoumadi@yahoo.com
Figure 1. Quinolone core with main substitution sites.
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.07.016

A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4488–4492
4489
O
O
COOH
F
COOH
F
N
N
N
N
R
R1
N
N
R
N
S
HN
S
(O)n
3, 4
1, Norfloxacin; R= ethyl
2, Ciprofloxacin; R= cyclopropyl
R= ethyl, cyclopropyl
R1= H, NO2
n= 0, 2
Figure 2.
cin, ofloxacin, amifloxacin, fleroxacin, lomefloxacin,
sparfloxacin, difloxacin, enoxacin, enrofloxacin, levo-
floxacin, marbofloxacin, and orbifloxacin.8,9 Fluoro-
quinolones with 7-piperazinyl moiety have been
reported to possess potent antibacterial activity.10–17
According to the inhibition mechanisms of the quino-
lones, proposed by Shen et al.7,18–20 the site near the
C-7 substituent is regarded as the drug–enzyme interac-
tion domain. In addition, Klopman et al. also concluded
that the cell permeability is dominantly controlled by C-
7 substituent.21 These facts motivate our concern to C-7
substituent of quinolone. The piperazine moiety of 7-
piperazinyl quinolones possess enough structural flexi-
bility to allow product optimization. In the preceding
papers, we described a number of N-substituted piperaz-
inyl quinolones by introducing a specific substituents in
the piperazine unit of 7-piperazinyl quinolones.22–29
ent study we have aimed to achieve a better antimicrobi-
al profile at lower concentration, by preparing N-
substituted piperazinyl quinolones 3 and 4 carrying ben-
zylthio- and benzylsulfonyl-1,3,4- thiadiazole derivatives
(Fig. 2).
Our synthetic pathway to intermediates 7a–d and 8a–d,
and target compounds 3a–h and 4a–h is presented in
Schemes 1 and 2. The 2-amino-5-(benzylthio)-1,3,4-thi-
adiazole derivatives 6 was obtained from commercially
available 5-amino-1,3,4-thiadiazol-2-thiol 5. Thus, treat-
ment of 5 with benzylbromide derivatives in presence of
NaOH in 80% ethanol at room temperature afforded
S-benzyl intermediates 6.34 Diazotization of amine 6
with NaNO2 in hydrochloric acid in the presence of cop-
per powder gave the chlorothiadiazoles 7.34,35 Sulfones 8
were prepared by usual procedure from sulfides 7, using
an excess of 30% H2O2 in CH3COOH at 60 °C.34 Reac-
tion of compounds 7a–d with 1 or 2 in DMF in the pres-
ence of NaHCO3 at 130 °C gave compounds 3a–h.29
As 2,5-disubstituted-1,3,4-thiadiazole derivatives are
reported to show antibacterial activity,30–33 in the pres-
R1
R1
N N
N N
N N
b
a
Cl
S
NH2
S
NH2
HS
S
S
S
5
7a-d
6a-d
R1= H, 2-NO2, 3-NO2, 4-NO2
C
R1
O
S
N N
S
Cl
O
8a-d
Scheme 1. Synthesis of intermediates 7 and 8. Reagents and conditions: (a) appropriate benzyl halide, NaOH, EtOH 80%, rt, 12 h; (b) NaNO2, HCl,
Cu, 0 °C, 1 h, then rt, 2 h; (c) H2O2 30% (excess), AcOH, 60 °C, 30–40 min.
O
O
COOH
F
R1
COOH
F
N
N
a or b
N
N
R
N
R
N
N
S
S
HN
(O)n
1 or 2
3a–h and 4a–h
Scheme 2. Synthesis of compounds 3a–h and 4a–h. Reagents and conditions: (a) compounds 7a–d, NaHCO3, DMF, 130 °C; (b) compounds 8a–d,
DMF, NaHCO3, DMF, 90 °C.

4490
A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4488–4492
Similarly, the reaction of compounds 8a–d with 1 or 2 at
90 °C gave the corresponding compounds 4a–h.
Compound 3h was found to exhibit the most potent
in vitro antibacterial activity against Gram-positive
bacteria, with MIC of 0.5, 0.03, and 0.5 lg/mL against
S. aureus, S. epidermidis, and B. subtilis, respectively.
Compounds 3a–h and 4a–h were tested in vitro by con-
ventional agar-dilution method36 against Gram-positive
(Staphylococcus aureus ATCC 6538p, Staphylococcus
epidermidis ATCC 12228 and Bacillus subtilis PTCC
1023) and Gram-negative (Escherichia coli ATCC
8739, Klebsiella pneumoniae ATCC 10031, and Pseudo-
monas aeruginosa ATCC 9027). The minimum inhibito-
ry concentration (MIC) values were determined by
comparison to parent quinolones, norfloxacin 1 and cip-
rofloxacin 2 as reference drugs.
Generally, most compounds showed moderate activity
(MIC = 1–16 lg/mL) against Gram-negative bacteria,
with an exception of antibacterial activity against P.
aeruginosa. All compounds showed poor or no activity
against P. aeruginosa. In fact, Compounds 3h and 4f
were the most potent against all Gram-negative bacte-
ria, with an MIC value of 1–32 lg/mL.
The following SAR trends have been observed. In
general, benzylthio- or benzylsulfonyl-1,3,4-thiadiazole
groups are well tolerated in terms of Gram-positive
activity, as exemplified by the potency of ciprofloxacin
analogs 3e–h (MIC range of 0.5–2 and 0.03–1 lg/mL
for S. aureus and S. epidermidis, respectively). In many
cases, the compounds had superior activity to their
parent quinolones. As is evident from the data, higher
susceptibilities (lower MICs) were observed with
Gram-positive and poorer susceptibilities, with Gram-
negative bacteria. Thus, introduction of 1,3,4-thiadiaz-
ole carrying benzylthio derivatives at the N-4 position
of piperazine ring changes the antibacterial potency
profile of piperazinyl quinolones.
The MIC values in Table 1 indicate that most com-
pounds showed significant activity (MIC = 0.03–4 lg/
mL) against Gram-positive bacteria and moderate to
poor activity (MIC = 1–64 lg/mL) against Gram-nega-
tive pathogens.
Table 1 reveals that compounds 3g and 3h followed by
4g are superior in inhibiting the growth of S. aureus
(MIC = 0.5–1 lg/mL). However, compounds 3b–f and
4f are statistically equivalent in antibacterial activity
and better than the remaining tested compounds. Anti-
bacterial screening of compounds 3a–h and 4a–h against
S. epidermidis reveals that compounds 3b–d, 3f–h and
4f–h show
a
comparable or better activity
(MIC = 0.03–0.5 lg/mL) with respect to the reference
drugs (MIC = 0.25–0.5 lg/mL). Indeed, compounds 3h
and 4f were the most active compounds against S. epide-
rmidis, their activities were found to be 8- to 16-fold
more than reference drugs. Most compounds had
respectable in vitro activity against B. subtilis, but were
less active than reference drugs.
The effect of positional substitution was primarily inves-
tigated by preparing all three possible nitro regioisomers
on benzyl moiety. It was seen that introduction of a ni-
tro group in ciprofloxacin derivatives (R = cyclopropyl)
improved the potency against all tested pathogens, but
in norfloxacin derivatives (R = ethyl) improved the
potency only against Staphylococci. In some cases, the
Table 1. Antibacterial activities of compounds 3a–h and 4a–h against selected strains (MICs in lg/mL)
O
COOH
F
N
N
R1
N
N
R
N
S
S
(O)n
Compound
R
R1
n
S. aureus
S. epidermidis
B. subtilis
K. pneumoniae
P. aeruginosa
E. coli
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
4f
4g
4h
1
Ethyl
Ethyl
H
0
0
0
0
0
0
0
0
2
2
2
2
2
2
2
2
16
4
2
0.5
0.25
0.5
1
8
8
16
32
>64
>64
>64
>64
>64
64
16
16
2-NO2
3-NO2
4-NO2
H
Ethyl
Ethyl
2
8
16
64
16
32
4
2
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
Ethyl
2
4
32
16
16
2
2-NO2
3-NO2
4-NO2
H
2
0.06
0.06
0.03
16
4
0.5
0.5
64
>64
>64
64
16
4
4
2
64
32
2
0.5
8
2
1
>64
64
>64
>64
>64
>64
>64
32
>64
32
Ethyl
Ethyl
Ethyl
2-NO2
3-NO2
4-NO2
H
>64
64
16
64
32
4
>64
>64
>64
4
>64
>64
>64
1
8
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
(Norfloxacin)
(Ciprofloxacin)
4
2-NO2
3-NO2
4-NO2
0.03
0.05
2
1
1
8
16
64
64
8
8
1
>64
2
>64
0.25
0.06
1
0.5
0.5
0.25
0.06
0.015
0.25
0.06
2
0.5

A. Foroumadi et al. / Bioorg. Med. Chem. Lett. 15 (2005) 4488–4492
4491
effect of nitro group was relatively similar for para,
meta, and ortho position. Nevertheless, the effect of ni-
tro-substitution and its position dependent on the other
substituents seems to have different influence on the
antibacterial activity against various bacterial strains.
Comparison between MIC values of thio analogs 3a–h
and sulfones 4a–h revealed that S,S-dioxidation of thio
compounds caused a diminution in antibacterial activity
against most bacterial species. Sulfonyl analogs of nor-
floxacin 4a–d were at best only weakly active as antibac-
terial as measured by MICs.
pend on the balance between drug influx through porin
channels, drug transport across the cytoplasmic mem-
brane, and efflux of drug out of the cytoplasm and the
cell.38 The physicochemical properties of quinolones
(e.g., relative hydrophobicity, charge or molecular mass)
are important for penetration into bacterial cell and
have a different role in Gram-negative and Gram-posi-
tive bacteria. Increasing molecular mass and bulkiness
of substituent at C-7 position hinder penetration of
quinolones into Gram-negative organisms through the
porin channels, although hydrophobic molecules appear
to enter via the lipopolysaccharide or across the lipid
bilayer.39–41 Gram-positive bacteria do not possess an
outer membrane, and so lack outer membrane proteins
and lipopolysaccharide. Accumulation by Gram-posi-
tive bacteria (e.g., S. aureus) is thought to take place
by simple diffusion across the cytoplasmic mem-
brane.42,43 Accordingly, we suggest that compounds like
thiadiazolyl quinolones (3 and 4), which have high
molecular mass and bulky substituent at C-7 position,
are accumulated in the Gram-positive bacteria more
favorably than ciprofloxacin and norfloxacin. More-
over, ciprofloxacin and norfloxacin are zwitterionic
quinolones, but their structural modification to yield
the corresponding thiadiazole derivatives produces com-
pounds with different ionizable groups in the biological
pH range. This charge difference is suggested to account
for the better uptake into Gram-positive bacteria, for
the thiadiazolyl quinolones 3 and 4.
The results of MIC tests against both Gram-positive and
Gram-negative bacteria revealed that ciprofloxacin
derivatives (R = cyclopropyl) were usually more potent
than norfloxacin derivatives (R = ethyl) especially
against Gram-positive pathogens.
In the nitrobenzylthio-1,3,4-thiadiazole series 3b–h com-
parison with the corresponding nitrophenyl-1,3,4-thi-
adiazole derivatives29 brought to the fore that
incorporation of methylthio linkage between phenyl
and thiadiazole in many cases exerted an excellent posi-
tive effect: for example, compound 3g was more active
than nitrophenyl-1,3,4-thiadiazole analog against all of
the tested strains.
In light of the above structure–activity relationships, it
can be suggested that 1,3,4-thiadiazole bearing a certain
pendent group is well tolerated at N-4 position of piper-
azine ring. Methylthio linker is necessary for activity
and nitro-substituent on benzyl moiety enhances anti-
bacterial potency especially against Gram-positive bac-
teria. Moreover, the effects on antibacterial activity
correlate with the inherent activity of the parent
quinolone.
In conclusion, we have identified a series of N-substitut-
ed piperazinyl quinolones 3 and 4 in which the N-4
hydrogen of piperazinyl group of norfloxacin and cipro-
floxacin replaced with various nitrobenzylthio- and
nitrobenzylsulfonyl-1,3,4-thiadiazolyl moieties with
in vitro microbiological activity against Gram-positive
organisms comparable or higher than respective parent
quinolones, ciprofloxacin, and norfloxacin. The SAR
of this series indicates that both the structure of the ben-
zyl unit and the S or SO2 linker dramatically impact
antibacterial activity.
Previously, we reported that novel nitroaryl- and nitro-
heteroaryl-1,3,4-thiadiazolyl quinolones differing from
ciprofloxacin or norfloxacin solely by the linkage of var-
ious nitroaryl- and nitroheteroaryl-1,3,4-thiadiazolyl
groups to the piperazinyl residue at C-7 of the parent
drug have particularly high in vitro activity against
Gram-positive cocci such as S. aureus. Similarly, our
new series of compounds exhibit high activity against
Gram-positive and marginal activity against Gram-neg-
ative bacteria.
Acknowledgment
This work was supported by a grant from Research
Council of Kerman University of Medical Sciences, Ker-
man, Iran.
Although the nature of the C-7 substituent is known to
influence quinolone activity in bacteria,5–7 we identify
addition of the 1,3,4-thiadiazole group as a particular
chemical modification that allows manipulation of selec-
tivity and potency. In exploring possible causes of this
alteration of potency, it was noted that our title com-
pounds 3 and 4 could be viewed as hybrid drugs incor-
porating a quinolone and a functionalized thiadiazole
moiety that, in itself, shows some antibacterial activi-
ty.30–33 Conversely, two general factors that contribute
to antibacterial potency of quinolones are the kinetics
of drug uptake and the ability to inhibit gyrase or topo-
isomerase IV.37 The mechanism by which quinolones en-
ter the bacterial cell is complicated and not entirely
understood. Intracellular quinolone concentrations de-
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