Synthesis, antimicrobial evaluation and QSAR studies of novel piperidin-4-yl-5-spiro-thiadiazoline derivatives

Article abstract of DOI:10.1016/j.bmcl.2010.10.002

In an attempt to find a new class of antimicrobial agents, a series of new 1,3,4-thiadiazolines were synthesized from 2,6-diarylpiperidin-4-ones, via the corresponding 4′-phenylthiosemicarbazones. All the synthesized compounds (23-39) were virtually screened against bacterial (Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi) and fungal strains (Candida albicans, Rhizopus sp, Aspergillus niger and Aspergillus flavus) by serial dilution method. QSAR study indicated that the increase in weakly polar component of solvent accessible surface area will favour antibacterial activity while increase in polarizability and decrease in ionisation potential and hydrogen bond donor will favour antifungal activity.

Full text of DOI:10.1016/j.bmcl.2010.10.002

Bioorganic & Medicinal Chemistry Letters 20 (2010) 6909–6914
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antimicrobial evaluation and QSAR studies of novel
piperidin-4-yl-5-spiro-thiadiazoline derivatives
Seeman Umamatheswari a,b, Bhaskar Balaji b, Muthiah Ramanathan b, Senthamaraikannan Kabilan a,
⇑
a Department of Chemistry, Annamalai University, Annamalainagar 608 002, India
b Department of Pharmacology, PSG College of Pharmacy, Coimbatore 641 004, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In an attempt to find a new class of antimicrobial agents, a series of new 1,3,4-thiadiazolines were
synthesized from 2,6-diarylpiperidin-4-ones, via the corresponding 40-phenylthiosemicarbazones. All
the synthesized compounds (23–39) were virtually screened against bacterial (Staphylococcus aureus,
Escherichia coli, Pseudomonas aeruginosa and Salmonella typhi) and fungal strains (Candida albicans,
Rhizopus sp, Aspergillus niger and Aspergillus flavus) by serial dilution method. QSAR study indicated that
the increase in weakly polar component of solvent accessible surface area will favour antibacterial
activity while increase in polarizability and decrease in ionisation potential and hydrogen bond donor
will favour antifungal activity.
Received 16 August 2010
Revised 30 September 2010
Accepted 1 October 2010
Available online 8 October 2010
Keywords:
2,6-Diarylpiperidin-4-one
Thiadiazoline
Antimicrobial activity
QSAR
Ó 2010 Elsevier Ltd. All rights reserved.
Since resistance of pathogenic bacteria towards available anti-
biotics is rapidly becoming a major worldwide problem, the design
of new compounds to deal with resistant bacteria has become one
of the most important areas of antibacterial research today. Hence,
the development of newer antimicrobial agents is essential to
overcome the rapidly developing drug resistance and side effects.1
In recent years, there has been a growing interest pertaining to
the synthesis of bioactive compounds in the field of organic
chemistry. Among the family of heterocyclic compounds, nitrogen
containing heterocycles especially piperidin-4-ones gain consider-
able importance owing to their varied biological properties such as
antiviral, antitumour,2 analgesic,3 local anaesthetic,4,5 antimicro-
bial, bactericidal, fungicidal, herbicidal, insecticidal, antihistaminic,
anti-inflammatory, anticancer, CNS stimulant and depressant
activities.6–8 The skeletal ring of piperidine nucleus can also be
often found in the molecular framework of many synthetic and
natural medicaments.9 1,3,4-Thiadiazole nucleus constitutes the
active part of several biologically active compounds, including
antibacterial,10–13 antifungal,12,13 antitubercular,14–16 and analge-
sic17 agents.
synthetic routes for achieving the biologically challenging hetero-
cyclic systems,18 has induced us to synthesize a class of molecules
having piperidinyl-thiadiazolines and to evaluate their antimicro-
bial activity. The role of structural features is determined from
QSAR studies.
As illustrated in Scheme 1, piperidin-4-yl-5-spiro-thiadiazolines
(23–39) were synthesized. Conversion of ketone into 40-phenylthi-
osemicarbazones are primarily depends upon the substitution of
active methylene carbons. The C-3, C-5 unsubstituted and C-3
substituted ketones yield the corresponding 40-phenylthiosemicar-
bazone, respectively, within 3–6 h, depending on the nature and
size of the substituent. But ketones with methyl substitution at C-
3 and C-5 take more than 72 h for the conversion. Thiosemicarba-
zones undergo cyclisation reaction with freshly distilled acetic
anhydride to yield the desired product 23–39 as shown in Scheme
1. Under acetylating condition, thiosemicarbazones 12–22 with
acetic anhydride in 2:1 ratio refluxed for 12–48 h yields 4-acetyl-
2-(N-phenylamino)-5-spiro-(N-acetyl-2,6-diarylpiperidin-4-yl)-4,
5-dihydro-[1,3,4]thiadiazoles (23–33) whereas in equal mol ratio
(1:1) of thiosemicarbazones and acetic anhydrides refluxed
for 12–15 h exclusively yields 4-acetyl-2-(N-phenylamino)-5-
Furthermore, synthesis of novel chemical entities, which are
still in resemblance with bioactive molecules by virtue of the pres-
ence of some critical structural features, is an essential component
of the search for new leads in drug designing programs. Hence, a
careful perusal of literature on antimicrobial agents and our con-
tinued interest in the development of simpler and more convenient
spiro-(2,6-diarylpiperidin-4-yl)-4,5-dihydro-[1,3,4]
thiadiazoles
(34–39). All the synthesized compounds 23–39 were characterised
by MS, IR, 1H, and 13C NMR spectroscopy and single crystal X-ray
diffraction studies.
In compounds 23–33, due to the presence of acetyl moiety at
the piperidine ring nitrogen site, the coupling constant values are
changed abnormally from their parent piperidones whose confor-
mations have been well established by using their coupling
⇑
Corresponding author.
E-mail address: drskabilan08@gmail.com (S. Kabilan).
0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2010.10.002

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S. Umamatheswari et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6909–6914
O
O
R2
R1
R2
R1
(a)
O
O
+
N
H
H
H
R
R
1-11
CH3COONH4
R
R
(b)
S
N
N
H
NH
N
CH3
H
N
2
S
34N
R2
R1
(c)
O
1
5
R2
R1
4
5
6
3
2
N
H
12-22
1
N
R
R
R
H3C
23-33
Compounds
O
R
(d)
R
R1
R2
1
2
3
4
5
6
7
8
9
12 23 34
13 24 35
14 25 36 Cl
15 26 37 Br
16 27 38 CH3
17 28 39 OCH3
18 29
19 30
20 31
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
N
CH3
H
N
3
2
H
Cl
Br
CH3
CH3 CH3
CH3 CH3
CH3 CH3
CH3 CH3
O
S 1
N
4
5
R2
R1
4
5
6
3
2
10 21 32
11 22 33
1
OCH3 CH3 CH3
N
H
34-39
R
R
Scheme 1. Schematic representation showing synthesis of compounds 23–39. Reagent and conditions: (a) EtOH/warm; (b) 40-phenylthiosemicarbazide, H+/MeOH, reflux,
3–72 h; (c) compounds 12–22 and Ac2O (1:2), reflux, 12–48 h, 90 °C; (d) compounds 12–17 and Ac2O (1:2), reflux, 12–15 h, 90 °C.
constants.19 Hence, the observed vicinal coupling constants
total puckering amplitude, QT = 0.7385 (4) Å and h = 93.80 (3)°.
The decrease in the N1–C28 bond length [1.352 (3) Å] when com-
pared to C1–N1 [1.484 (3) Å] and C5–N1 (1.479 (3) Å) lengths indi-
cates the effective conjugation between lone pair of nitrogen with
carbonyl group. The torsion angles C1–N1–C28–C29 of 173.3(2)°
and C5–N1–C28–O1 of ꢁ6.1 (3)° confirms the coplanar of
N–COCH3 group. The sum of the bond angles around N3 atom
[359.3 (15)°] indicates the sp2 hybridization. The torsion angles
C27–C26–N2–N3 [ꢁ7.7 (3)°] and C27–C26–N2–C3 [ꢁ178.0 (2)°]
indicate that atoms C27 and C26 lie in the plane of the five-mem-
bered ring (N2/N3/C19/S1/C3). The torsion angles C20–N6–C19–S1
[ꢁ170.02 (15)°], N3–C19–N6–S1 [8.1(19)°] and N6–C19–N3–N2
[ꢁ178.14 (18)°] also indicate that the substituted moiety at C18
lie in the plane of the ring to which it is attached. The ORTEP dia-
gram of compound 28 is depicted in Figure 2.
3
3J2,3 ꢀ 8.0 Hz and J5,6 ꢀ 7.0 Hz suggest that compounds 23–33
are not in chair form. If it adopts a normal chair conformation with
equatorial orientation of all substituents, the observed coupling
3
3
constants J2a,3a and J5a,6a should be around 10.5 Hz. Moreover,
the coupling constants are not favourable for boat conformation
also. If it exists in a rigid boat form, the vicinal coupling constants
should be about 4 Hz. Hence, the abnormal vicinal coupling con-
stants indicate that piperidone ring adopts asymmetric non-chair
conformation (see Supplementary data for more details) which is
further confirmed from single crystal X-ray diffraction studies.
Of the synthesized compounds 23–33, compounds 25 and 28
were suitable for single crystal XRD study. The ORTEP diagram of
compound 25 is depicted in Figure 1. Analysis of torsion angles,
asymmetry parameters and least-squares plane calculation20
shows that the piperidine ring adopts a twist boat conformation
with the puckering parameters and the smallest displacement
asymmetry parameters21 being q2 = 0.7369 Å and q3 = ꢁ0.0490 Å,
In the case of compounds 34–39 the vicinal coupling constant
values are similar to parent piperidones19 which reveals that the
piperidine ring in compounds 34–39 exist in chair conformation

S. Umamatheswari et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6909–6914
6911
Figure 1. ORTEP diagram of compound 25.
Figure 2. ORTEP diagram of compound 28.
with equatorial orientation of aryl groups at C-2, C-6 and methyl
H
group at C-3. Moreover the position of chemical shifts of com-
pounds 34–39 suggests that the N–COCH3 group of thiadiazoline
moiety is oriented at equatorial disposition of C-4 carbon of six-
membered heterocyclic ring akin to our earlier report22 (Fig. 3)
(see Supplementary data).
N
S1
2
H
3 N
H
5
4
5
6
4
N
2
N 1
R1
3
R
CH3
The synthesized compounds were tested against bacterial strains
viz., Staphylococcus aureus (ATCC-25825), Bacillus subtilis (ATCC-
451), Salmonella typhi (ATCC-24915), Escherichia coli (ATCC-25835)
and Klebsiella pneumonia (ATCC-15490) and fungal strains viz. Cryp-
tococcus neoformans (ATCC-3312), Candida albicans (ATCC-3122),
Rhizopus sp. (ATCC-2915), Aspergillus niger (ATCC-598) and Aspergil-
lus flavus (ATCC-485) using the literature precedent.23 Ciprofloxacin
and Amphotericin B were used as standard for bacteria and fungal
strains, respectively.
H
H
O
R
Figure 3. Conformation of compounds 34–39.
The compounds with methyl substitution at C-3 and C-5 of
piperidine showed remarkable increase in antimicrobial activity
than the unsubstituted and methyl substitution at C-3 of piperi-
dine ring. A close analysis of the screening results reveals that
the halogen substitution at para -position of phenyl ring at C-2
and C-6 piperidine ring increased antimicrobial activity. It is to
be noted that the presence of N-acetyl group in the piperidine ring
shows improved antibacterial and antifungal activity, while, the
replacement of methyl or methoxy group in place of halogens
shows decrease in antimicrobial activity.

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S. Umamatheswari et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6909–6914
S. aureus
E. coli
r2 = 0.83
r2 = 0.83
5.5
5
5.5
5
4.5
4
4.5
4
3.5
3.5
3.5
3.5
4
4.5
5
5.5
4
4.5
5
5.5
Predicted -log MIC
Observed -log MIC
P. aeruginosa
S. typhi
r2 = 0.79
r2 = 0.84
5.5
5.5
5
5
4.5
4
4.5
4
3.5
3.5
3.5
4
4.5
5
5.5
3.5
4
4.5
5
5.5
Observed -log MIC
Observed -log MIC
Rhizopus sp
C. albicans
r2 = 0.84
r2 = 0.84
5.5
5
5.5
5
4.5
4
4.5
4
3.5
3.5
3.5
4
4.5
5
5.5
3.5
4
4.5
5
5.5
Observed -log MIC
Observed -log MIC
r2 = 0.81
A. niger
A. flavus
r2 = 0.80
5
4.5
4
4.8
4.6
4.4
4.2
4
3.8
3.5
3.5
3.8
4
4.2
4.4
4.6
4.8
4
4.5
5
Observed -log MIC
Observed -log MIC
Figure 4. Comparison of observed and predicted activities of the compounds in the training set.
The quantitative structure–activity relationship (QSAR) analysis
was undertaken to establish the relationship between antimicro-
bial activity of the synthesized compounds and their molecular
descriptors. Structures of the synthesized compounds were
sketched and cleaned up in Maestro.24 The structures were pro-
cessed using LigPrep25 and minimized using MacroModel26 with
OPLS-2005 force field. Molecular descriptors were generated by
QikProp27 for each of the minimized compound reflecting Monte
Carlo simulation studies.28 The ‘forward stepping’ method was
used to build QSAR equations in Strike29 programme between
pMIC activity of the synthesized compounds and their molecular
descriptors. Combinations of descriptors were selected for analysis
based on low interrelationship limit <0.50.30 Based on structural
variation and biological activity, compounds were divided into a
training set of 13 compounds (75% of the dataset) and a test set
of 4 compounds (25% of the dataset). Multiple linear regression
method was used to identify the statistically important QSAR mod-
el on the basis of squared correlation coefficient (r2), standard devi-
ation (S.D), Fisher’s value (F), Q (r/S.D) value and t-value for the
training set. Robustness of the derived models were verified by
using three different types of validation viz. (i) Leave one out
(LOO) internal validation or cross-validation (q2), (ii) external val-
idation by predicting the activity of test set (four compounds)
and (iii) randomization test.31 Local Correlation Integral Outlier
(LOCI) detection methodology by Strike was used to remove the
outlier which uses a density-based approach to identify outliers
within the data set.29
The experimental and predicted values of pMIC of training and
test set compounds are given in Supplementary data. The final sta-
tistically valid QSAR models detailing statistical qualities and
descriptors are tabulated in Tables 1 and 2, respectively. The
graphs of predicted pMIC versus experimental pMIC for the train-
ing and test sets are depicted in Figures 4 and 5, respectively.
Eqs. 1–4 indicate the predominance of Weakly Polar component
of Solvent accessible surface Area (WPSA) in describing the activity
against all the bacterial strains taken in the present study. WPSA
descriptor pertains to the surface area for all halogens, sulfur and
phosphorous atoms, and correlates positively with the antibacte-
rial activity. This justifies the increased antibacterial activity of
the compounds substituted with halogens. From Eqs. 2 and 3 it
can be stated that polarizability and PISA negatively correlates
with pMIC of E. coli and P. aeruginosa, respectively. Descriptor PISA

S. Umamatheswari et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6909–6914
S. aureus
E. coli
6913
r2 = 0.85
r2 = 0.77
5
4.8
4.6
4.4
4.2
4
5
4.8
4.6
4.4
4.2
4
3.8
3.6
3.8
3.6
3.6
3.6
3.6
3.8
3.8
3.8
4
4.2
4.4
4.6
4.8
5
3.6
3.6
3.6
3.8
4
4.2
4.4
4.6
4.6
4.6
4.8
5
Observed -log MIC
Observed -log MIC
P. aeruginosa
S. typhi
r2 = 0.79
r2 = 0.88
5
4.8
4.6
4.4
4.2
4
5
4.8
4.6
4.4
4.2
4
3.8
3.6
3.8
3.6
4
4.2
4.4
4.6
4.8
5
4.1
Observed -log MIC
Observed -log MIC
C. albicans
Rhizopus sp.
r2 = 0.84
r2 = 0.82
5
4.8
4.6
4.4
4.2
4
5
4.8
4.6
4.4
4.2
4
3.8
3.6
3.8
3.6
4
4.2
4.4
4.6
4.8
5
3.8
4
4.2
4.4
4.8
5
Observed -log MIC
Observed -log MIC
A. niger
A. flavus
r2 = 0.80
r2 = 0.88
5
4.8
4.6
4.4
4.2
4
4.8
4.6
4.4
4.2
4
3.8
3.6
3.8
3.6
3.8
4
4.2
4.4
4.6
4.8
5
3.8
4
4.2
4.4
4.6
4.8
Observed -log MIC
Observed -log MIC
Figure 5. Comparison of observed and predicted activities of the compounds in the test set.
Table 1
QSAR statistics of modelled equations
r2pred
Organism
n
r2
R
S.D.
Q
q2
F value
P value
Randomized r2
S. aureus
E. coli
P. aeruginosa
S. typhi
C. albicans
Rhizopus sp.
A. niger
13
12
13
12
12
12
12
12
0.83
0.83
0.84
0.79
0.84
0.84
0.81
0.80
0.91
0.91
0.92
0.89
0.92
0.92
0.90
0.89
0.17
0.23
0.17
0.18
0.16
0.15
0.15
0.13
5.352
3.957
5.411
4.944
5.750
6.133
6.000
6.846
0.76
0.72
0.71
0.66
0.79
0.71
0.69
0.74
53.5 (1,11)
21.6 (2, 9)
25.3 (2,10)
17.3 (2,9)
53.4 (1,10)
23.8 (2,9)
19.5 (2,9)
42.1 (1,10)
1.514eꢁ05
3.690eꢁ04
1.218eꢁ04
8.298eꢁ04
2.573eꢁ05
2.531eꢁ04
5.347eꢁ04
6.989eꢁ05
0.074
0.183
0.138
0.184
0.085
0.178
0.167
0.081
0.77
0.85
0.88
0.79
0.82
0.84
0.80
0.88
A. flavus
quantifies the
p
component of solvent accessible surface area, that
antibacterial activity against S. typhi. FOSA represents the aliphatic
portion of the solvent-accessible surface area that is composed of
saturated carbons and the attached hydrogen.32 This explains the
increased biological activity of the compounds having methyl or
methoxy substitutions. However t-value (Table 2) indicates that
the halogens (WPSA) are more significant in increasing the biolog-
ical activity when compared to methyl or methoxy substitutions
(FOSA) which is in accordance with the experimental results.
is, it reflects hydrophobicity of the molecule due to aromatic re-
gion. As PISA is negatively correlated with pMIC, any substitution
which decreases aromatic hydrophobicity of the molecule will fa-
vour the antibacterial activity against P. aeruginosa. This is also evi-
dent from the experimental results that compound 23 showed high
PISA value and less activity against P. aeruginosa. In Eq. 4, descrip-
tor hydrophobic surface area (FOSA) correlates positively with the

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S. Umamatheswari et al. / Bioorg. Med. Chem. Lett. 20 (2010) 6909–6914
Table 2
graphic data for compounds 25 (CCDC No. 697341) and 28 (CCDC
No. 686014) can be obtained free of charge from www.ccdc.cam.a-
c.uk/conts/retrieving.html.
Best multiple linear regression model and t-values
Variable
Coefficient
S.E
t-value
Eq. 1 for S. aureus
Intercept
WPSA
Acknowledgements
3.997
0.061
65.495
7.314
4.759eꢁ03
6.507eꢁ04
This research work has been supported by Council of Scientific
and Industrial Research, New Delhi. The authors would like to
acknowledge NMR research centre, IISc-Bangalore and Department
of Chemistry, IIT-Madras, for recording NMR and single crystal XRD
respectively. B.B. and M.R. acknowledge the Department of Science
and Technology, SERC division, New Delhi for the financial assis-
tance towards QSAR programme.
Eq. 2 for E. coli
Intercept
WPSA
ꢁ6.482
1.984
3.267
1.306
5.394
1.286eꢁ03
ꢁ2.008eꢁ01
9.851eꢁ04
3.723eꢁ02
Polarizability
Eq. 3 for P. aeruginosa
Intercept
PISA
5.615
3.220eꢁ01
7.169eꢁ04
6.605eꢁ04
17.435
4.511
4.069
ꢁ3.234eꢁ03
WPSA
2.688eꢁ03
Eq. 4 for S. typhi
Intercept
FOSA
1.582eꢁ01
7.135eꢁ04
8.377eꢁ04
23.383
2.973
5.872
References and notes
3.699
2.121eꢁ03
4.919eꢁ03
1. (a) Projan, S. J.; Shlaes, D. M. Clin. Microbiol. Infect. 2004, 10, 18; (b) Fidler, D. F.
Emerg. Infect. Dis. 1998, 4, 169; (c) Oren, I.; Temiz, O.; Yalcin, I.; Sener, E.;
Altanlar, N. Eur. J. Pharm. Sci. 1998, 7, 153; (d) Hong, C. Y. J. Farmaco 2001, 56,
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Schiaffella, F.; Fringuelli, R. Bioorg. Med. Chem. 2002, 10, 3415; (f) Hatya, S.
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9. Daly, J. W. In The Alkaloids; Cordell, G. A., Ed.; Academic press: Sandiego, CA,
1998; p 141.
WPSA
Eq. 5 for C. albicans
Intercept
Polarizability
ꢁ4.236
1.186
3.572
7.309
1.608eꢁ01
2.200eꢁ02
Eq. 6 for Rhizopus sp.
Intercept
HB donor
3.078
4.234eꢁ01
9.380eꢁ02
8.405eꢁ02
7.271
6.112
4.719
ꢁ5.734eꢁ01
Log P
3.966eꢁ01
Eq. 7 for A. niger
Intercept
Volume
1.717
1.014
1.693
3.167
4.596
2.157eꢁ03
ꢁ4.274eꢁ01
6.809eꢁ04
9.299eꢁ02
HB donor
Eq. 8 for A. flavus
Intercept
IP
40.912
ꢁ5.276
6.906
7.112
6.489
8.130eꢁ01
´
10. Modzelewska-Banachiewicz, B.; Banachiewicz, J.; Chodkowska, A.; Jagiello-Wo
In Eq. 5, polarizability has positive correlation with the anti-
fungal activity against C. albicans. Polarizability is related to size
and hydrophobicity of the compound. Sharma et al. observed that
increasing the polarizability of the compounds with bulkier substi-
tution increased the antifungal activity.33 Hydrogen bond (HB) do-
nor negatively correlates with the antifungal activity of the
compounds against Rhizopus sp. and A. niger (Eqs. 6 and 7). In addi-
tion, Eq. 6 indicates that lipophilicity can increase the antifungal
activity of the synthesized compounds against Rhizopus sp. This
may be due to the increased facilitation of the permeability of
the molecules through the fungal cell membrane.34 Compound
26 had high lipophilicity value (6.126) and exhibits better activity
against Rhizopus sp. From the Eq. 7 it can be stated that high molec-
ular volume favours the antifungal activity against A. niger which is
also evident from the experimental data. Further, a decrease in ion-
isation potential favours the antifungal activity against A. flavus
(Eq. 8). Ionisation potential highly correlates with WPSA (see Sup-
plementary data for more details) which implies that decrease in
halogens is favourable for antifungal activity against A. flavus. As
per the obtained Eq. 8, the compounds which are substituted with
methyl or methoxy groups showed better antifungal activity
against A. flavus.
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Detailed methodology of QSAR, complete experimental details
and conformation studies are given. Supplementary crystallo-