Synthesis and antimicrobial studies of novel 2,4-diaryl-3-azabicyclo[3.3.1] nonan-9-one 4′-phenylthiosemicarbazones

Article abstract of DOI:10.3109/14756366.2010.525508

New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones (compounds 9-16) was obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones. The synthesized compounds have been characterized by their elemental, anal

Full text of DOI:10.3109/14756366.2010.525508

Journal of Enzyme Inhibition and Medicinal Chemistry, 2011; 26(3): 430–439
© 2011 Informa UK, Ltd.
ISSN 1475-6366 print/ISSN 1475-6374 online
DOI: 10.3109/14756366.2010.525508
ORIGINAL ARTICLE
Synthesis and antimicrobial studies of novel 2,4-diaryl-3-
azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones
Seeman Umamatheswari, and Senthamaraikannan Kabilan
Department of Chemistry, Annamalai University, Annamalai Nagar - 608 002, Tamilnadu India
Abstract
New series of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones (compounds 9–16) was
obtained from the corresponding 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ones. The synthesized compounds have
been characterized by their elemental, analytical, and spectral studies. Besides, these reported compounds were
screened for their antibacterial and antifungal activities against a spectrum of microbial organisms. These studies
proved that against bacteria, compounds 10 and 11 against Bacillus subtilis, compound 13 against Salmonella typhi,
show maximum inhibition potency at low concentration (6.25 μg/mL), whereas against fungal, compounds 11, 13,
and 16 against Candida albicans and compounds 12 and 13 against Cryptococcus neoformans, showed beneficial
antifungal activity at minimum concentration (6.25 μg/mL).
Keywords: Azabicyclo[3.3.1]nonan-9-ones, thiosemicarbazones, antibacterial activity, antifungal activity
Introduction
JeyaramanandAvila[16]havereviewedtheimportance
Microbial infections are associated with rates of
attributable morbidity and mortality [1]. e resis-
tance of common pathogens to standard antibiotic
therapies is rapidly becoming a major public health
problem throughout the world. e incidence of
multidrug-resistant Gram-positive and Gram-negative
bacteria is increasing and the infections caused by
them are becoming problematic now-a-days [2]. ere
is an urgent need for the discovery of new compounds
endowed with antimicrobial activity.
Many compounds with a thiosemicarbazone moiety
exhibitsignificantbiologicalproperties[3]becausethiourea
unit (NHCSNH) can easily form chelation with metal ions
likeiron,zinc,magnesium,andsoon.iosemicarbazones
are a class of small molecules that have been evaluated
against Plasmodium falciparum, Trypanosoma brucei, and
Trypanosoma cruzi for various diseases. e effectiveness
of thiosemicarbazone analogues in treating these diseases
is reported due to their activity against cysteine protei-
nases including rhodesain [4–10]. Moreover compounds
with a thiosemicarbazones structure are known to possess
tranquilizing, muscle relaxing, psychoanaleptic, hypnotic,
ulcerogenic, antidepressant, antibacterial, antifungal,
analgesic, and anti-inflammatory properties [11–15].
of bicyclic compounds as intermediates in the synthesis
of a several physiologically active compounds. Similarly,
Lijinsky and Taylor [17] have found that the presence of
substituents at both the α-positions to that of “N” in pipe-
ridin-4-one is important to exert marked biological prop-
erties. In addition, several interesting investigations have
been made through piperidine-based heterocyclic com-
pounds and exhibited numerous biological properties
such as antibacterial, antifungal, antitumor, antiarrhyth-
mic, antithrombic, calcium antagonist, hypotensive, and
neuroleptic activities [18,19]. An essential component of
the search for new leads in drug-designing program is the
synthesisofmoleculesthatarenovelandresembleknown
biologically active molecule by virtue of the presence of
some pharmacophoric groups. Certain small heterocy-
clic molecules act as highly functionalized scaffolds and
are known pharmacophores of a number of biologically
active and useful molecules. Apart from the biological
importance, these bridged bicyclic compounds exhibit
twin-chair, chair-boat, or twin-boat conformations pos-
sessing interesting stereochemistry. In connection with
our earlier work and as part of our ongoing research
programme [20–25], we have planned to design a system
that combines both bioactive azabicyclo[3.3.1]nonane
Address for Correspondence: Kabilan Senthamaraikannan, Annamalai University, Chidambaram, India. E-mail: drskabilan08@gmail.com
(Received 09 April 2010; revised 26 August 2010; accepted 17 September 2010)
430

Synthesis and antimicrobial studies 431
and thiosemicarbazone components together to give a
compact structure like title compounds.
AMX 500MHz spectrometer in CDCl3. For compounds
1–7 (except compound 5), GCMS were recorded on GC
model: Varian GC-MS-Saturn 2200 ermo, capillary col-
umn VF5MS (5% phenyl–95% methyl polysiloxane), 30 m
length, 0.25mm internal diameter, 0.25 µm film thickness,
temperature of column range from 50ºC to 280ºC (10ºC/
min), and injector temperature 250ºC. For compounds
9–16, ES-HRMS was recorded on QTof-Mico YA 263
instrument except compounds 11 and 13.
By employing the literature precedent of Baliah and
Jeyaraman[27],alltheparent2,4-diaryl-3-azabicyclo[3.3.1]
nonan-9-ones (compounds 1–8) were prepared by the
condensation of appropriate ketones, aldehydes, and
ammonium acetate in 1:2:1 ratio using ethanol as solvent.
Experimental
Microbiology
Materials. e 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
antifungal strains, viz., Cryptococcus neoformans
(ATCC-3312), Candida albicans (ATCC-3122), Rhizopus
oryzae (ATCC-9363), Aspergillus niger (ATCC-598), and
Aspergillus flavus (ATCC-485) are procured from National
Chemical Laboratory, Pune, India.
2,4-Diphenyl-3-azabicyclo[3.3.1]nonan-9-one (compound 1)
IR (cm−1): 3317 (N–H stretching), 3057, 3026, 2926, 2857,
2794 (C–H stretching), 1708 (C=O stretching), 1598 (C=C
stretching-Ph). 1H NMR (δ ppm): 7.54–7.30, (m, 10H, aryl
protons); 4.39 (d, 2H, J=2.40 Hz, H-2a and H-4a); 2.89 (m,
1H, H-7a); 2.47 (br s, 1H, H-1, H-5); 1.93 (dd, 1H, J=5.86,
1.46 Hz, H-8e); 1.90 (dd, 1H, J=5.88, 1.48 Hz, H-6e); 1.87
(br s, 1H NH); 1.74–1.64 (m, 2H, H-6a and H-8a); 1.38
(quin, 1H, H-7e). 13C NMR (δ ppm): 217.58 (C-9), 141.37
(C-2′ and C-4′), 128.61(C-2″ and C-4″), 127.62 (C-2″″ and
C-4″″), 126.96 (C-2′″ and C-4′″); 64.81 (C-2 and C-4); 54.05
(C-1 and C-5); 29.14 (C-6 and C-8); 21.21 (C-7). GCMS:
m/z=292.22 (M+1).
In vitro antibacterial and antifungal activity
e in vitro activities of the compounds were tested in
Sabourauds dextrose broth (SDB; Hi-media, Mumbai,
India) for fungi and in Nutrient broth (NB, Hi-media) for
bacteria by the 2-fold serial dilution method [26]. e test
compoundsweredissolvedindimethylsulphoxide(DMSO)
to obtain 1mg/mL stock solutions. Seeded broth (broth
containing microbial spores) was prepared in NB from
24-h-old bacterial cultures on nutrient agar (Hi-media) at
37°C 1°C, whereas fungal spores from 24-h to 7-day-old
SabouraudsagarslantculturesweresuspendedinSDB.e
colony-forming units (cfu) of the seeded broth were deter-
mined by plate count technique and adjusted with the help
of McFarland standards in the range of 104–105 cfu per mL.
e final inoculum size was 105 cfu/mL for antibacterial
assay and 1.1–1.5×102 cfu/mL for antifungal assay. Testing
was performed at pH 6.5 0.2 for bacteria and pH 5.6 0.2
for fungi. Exactly 0.2mL of the solution of test compound
was added to 1.8mL of seeded broth to form the first dilu-
tion. One millilitre of the first dilution solution was diluted
with a further 1mL of the seeded broth to give the second
dilution and so on till six such dilutions were obtained. A
set of assay tubes containing only seeded broth was kept as
control and likewise solvent controls were also run simul-
taneously. e tubes were incubated in biological oxygen
demand (BOD) incubators at 37°C 1°C for bacteria and
28°C 1°C for fungi. e minimum inhibitory concentra-
tions (MICs) were recorded by visual observations after
24h (for bacteria) and 72–96h (for fungi except C. albicans)
of incubation. Ciprofloxacin and amphotericin B were used
as standards for bacterial and fungal studies, respectively.
2,4-Bis(4-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 2)
IR (cm−1): 3318 (N–H stretching); 3071, 2970, 2921, 2852
(C–H stretching); 1707 (C=O stretching); 1603 (C=C
1
stretching-Ph). H NMR (δ ppm): 7.10–7.51 (m, 8H, aro-
matic protons); 4.40 (d, 2H, J=2.20 Hz, H-2a and H-4a);
2.83 (m, 1H, H-7a), 2.44 (br s, 2H, H-1 and H-5), 1.92 (d,
1H, J=5.48 Hz, H-8e), 1.88 (d, 2H, J=5.48 Hz, H-6e and
NH); 1.76–1.67 (m, 2H, H-6a and H-8a); 1.41 (quin, 1H,
H-7e). 13C NMR (δ ppm): 216.90 (C-9); 163.46, 161.01
(C-2″″ and C-4″″), 136.94, 136.92 (C-2′ and C-4′), 128.49,
128.41 (C-2″ and C-4″), 115.61, 115.40 (C-2′″ and C-4′″);
64.17 (C-2, C-4); 53.95 (C-1, C-5); 28.97 (C-6, C-8); 21.15
(C-7). GCMS m/z=328.17 (M+1).
2,4-Bis(3-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 3)
IR (cm−1): 3315 (N–H stretching); 3073, 2978, 2930, 2910,
2852, 2815 (C–H stretching); 1712 (C=O stretching); 1614,
1589 (C=C stretching-Ph). 1H NMR (δ ppm): 7.40–7.02 (m,
8H, aryl protons); 4.42 (d, 2H, J=1.60 Hz, H-2a and H-4a);
2.80 (m, 1H, H-7a); 2.49 (br s, 2H, H-1, H-5); 1.94 (d, 2H,
J=4.80 Hz, H-8e, NH); 1.90 (d, 1H, J=5.20 Hz, H-6e); 1.78–
1.68 (m, 2H, H-6a and H-8a), 1.42 (quin, 1H, H-7e). 13C NMR
(δ ppm): 216.48 (C-9); 164.40, 161.95 (fluoro bearing C-2′″,
C-4′″); 143.88, 143.82 (C-2′, C-4′), 130.31, 130.23 (C-2′″,
C-4′″); 122.58, 122.56 (C-2″, C-4″), 114.75, 114.54, 114.04,
113.82 (C-4″″); 64.19 (C-2 and C-4); 53.78 (C-1 and C-5);
29.14 (C-6 and C-8); 21.17 (C-7). GCMS m/z=327.42 (M+).
Chemistry
in-layer chromatography (TLC) was carried out to mon-
itor the course of the reaction and purity of the product.
e melting points were recorded in open capillaries and
are uncorrected. IR spectra were recorded in KBr (pellet
forms)onAVATAR-330FT-IRspectrophotometer(ermo
Nicolet)andonlynoteworthyabsorptionlevels(reciprocal
centimetres) are listed. 1H NMR spectra were recorded at
500MHz on BRUKER AMX 500MHz spectrophotometer
using CDCl3 as solvent and TMS as internal standard. 13
NMR spectra were recorded at 125.76MHz on BRUKER
C
© 2011 Informa UK, Ltd.

432 S. Umamatheswari and S. Kabilan
2,4-Bis(4-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 4)
C-2″″ and C-4″″); 54.24 (C-1 and C-5); 29.05 (C-6 and
C-8); 21.22 (C-7). GCMS m/z = 351.38 (M+).
IR (cm−1): 3314 (N–H stretching); 3063, 2921, 2852, 2800
(C–H stretching); 1709 (C=O stretching); 1590 (C=C
2,4-Bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 8)
1
stretching-Ph). H NMR (δ ppm): 7.48–7.38 (m, 8H, aro-
IR (cm−1): 3310 (N–H stretching); 3073, 2933, 2930, 2826
(C–H stretching); 1708 (C=O stretching); 1609, 1583 (C=C
matic protons); 4.39 (d, 2H, J=2.20 Hz, H-2a and H-4a);
2.80 (m, 1H, H-7a); 2.44 (br s, 2H, H-1 and H-5); 1.90 (d,
1H, J=4.76 Hz, H-8e); 1.87 (d, 2H, J=4.76 Hz, H-6e and
NH); 1.76–1.66 (m, 2H, H-6a and H-8a); 1.40 (quin, 1H,
H-7e). 13C NMR (δ ppm): 216.64 (C-9); 139.63 (C-2′, C-4′);
133.43 (C-2″″ and C-4″″); 128.88 (C-2″ and C-4″); 128.28
(C-2′″ C-4′″); 64.17 (C-2, C-4); 53.77 (C-1, C-5); 29.00 (C-6,
C-8); 21.14 (C-7). GCMS m/z=359.13 (M+); m/z=361 (M+2
isotopic peak).
1
stretching-Ph). H NMR (δ ppm): 7.31–6.84 (m, 8H, aro-
matic protons); 4.37 (d, J= 2.20 Hz, H-2a, H-4a), 3.84 (s,
6H, OCH3 at C-2′″ and C-4′″); 2.86 (m, H-7a); 2.48 (br
s, H-1, H-5); 1.97 (dd, J= 5.68, 1.48 Hz, H-8e); 1.93 (dd,
J = 4.76, 1.48 Hz, H-6e); 1.90 (s, NH), 1.75–1.65 (m, H-6a,
H-8a); 1.38 (quin, H-7e). 13C NMR (δ ppm): 217.55 (C-9);
159.83 (methoxy bearing C-2′″ and C-4′″); 143.03 (C-2′
and C-4′); 129.61(C-2′″ and C-4′″), 119.27, 112.97(C-2″
and C-4″), 114.6 (C-2″″ and C-4″″); 64.65 (C-2 and C-4);
55.29 (OCH3 at C-2′″ and C-4′″); 54.03 (C-1 and C-5);
29.23 (C-6 and C-8); 21.18 (C-7).
2,4-Bis(2-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 5)
IR (cm−1): 3305 (N–H stretching); 3063, 2973, 2931, 2905,
2852, 2821 (C–H stretching); 1706 (C=O stretching); 1589,
1
General method for synthesis of N′-(2,4-diaryl-3-
azabicyclo[3.3.1]nonan-9-ylidine)bezenecarbothiohydrazides
(compounds 9–16)
1567 (C=C stretching-Ph. H NMR (δ ppm): 4.85 (d, 2H,
J= 2.40 Hz, H-2a, H-4a); 2.88 (m, 1H, H-7a); 2.77 (br s,
2H, H-1, H-5); 1.90 (d, 1H, J= 4.80 Hz, H-8e); 1.87 (dd, 1H,
J= 4.80, 1.60 Hz, H-6e); 1.81–1.71 (m, 2H, H-6a, H-8a);
1.66 (br s, 1H, NH); 1.41 (quin, 1H, H-7e); 8.05–7.27 (m,
8H, aromatic protons). 13C NMR (δ ppm): 216.34 (C-9);
138.17 (C-2′ and C-4′), 132.69 (chloro bearing C-2″ and
C-4″); 130.17 (C-2″ and C-4″); 128.78 (C-2″″ and C-4″″);
128.90, 126.92 (other aromatic carbons); 61.01 (C-2 and
C-4); 49.67 (C-1 and C-5); 29.65 (C-6 and C-8); 20.93
(C-7).
A mixture of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one
(0.01 mol) and 4′-phenylthiosemicarbazide (0.01 mol) in
ethanolic chloroform (1:1 mixture, 50 mL) was refluxed
for 4 h in acidic medium. After cooling, the solid product
was filtered and washed with excess of water and recrys-
tallized from methanol. e recrystallized product fur-
ther purified by column chromatography n-hexane:ethyl
acetate (4:1) as eluent to get pure thiosemicarbazones.
N′-(2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ylidine)
bezenecarbothiohydrazides (compound 9)
2,4-Bis(4-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 6)
IR (cm−1): 3352, 3282, 3258 (N–H stretching); 3058,
3039, 2964, 2912 (C–H stretching); 1616 (C=N stretch-
IR (cm−1): 3315 (N–H stretching); 3024, 2939, 2859 (C–H
stretching); 1714 (C=O stretching); 1599, 1564 (C=C
stretching-Ph). 1H NMR (δ ppm): 7.43–7.21 (m, 8H,
aromatic protons); 4.37 (d, J= 2.20 Hz, H-2a, H-4a); 2.89
(m, H-7a), 2.44 (br s, H-1, H-5); 2.36 (s, CH3 at C-2″″ and
C-4″″); 1.95 (dd, J= 5.86, 1.46 Hz, H-8e); 1.92 (dd, J= 5.32,
1.64 Hz, H-6e, NH); 1.75–1.65 (m, H-6a, H-8a); 1.37 (quin,
H-7e). 13C NMR (δ ppm): 217.99 (C-9); 138.46 (C-2′ and
C-4′); 137.22 (C-2″″ and C-4″″); 129.29, 126.90 (other aro-
matic carbons); 64.71 (C-2, C-4); 54.21 (C-1, C-5); 29.18
(C-6, C-8); 21.27 (C-7); 21.22 (CH3 at C-2″″ and C-4″″).
GCMS m/z= 320.21(M+1).
1
ing). H NMR (δ ppm): 9.21 (s, 1H, NHCS); 8.43 (s, 1H,
CSNHPh); 7.61–7.23 (m, 15H, aryl protons); 4.41 (d,
J = 2.0 Hz, 1H, H-2a); 4.29 (d, J= 2.0 Hz, 1H, H-4a); 3.11
(s, 1H, H-5); 2.83 (m, 1H, H-7a); 2.48 (s, 1H, H-1); 1.79
(dd, 3H, J = 5.88, 1.48 Hz, H-6e, H-8e and NH); 1.46 (m,
3H, H-6a, H-8a and H-7e). 13C NMR (δ ppm): 172.19
(C=S); 169.68 (C=N); 142.67 (C-2′); 142.39 (C-4′); 138.46
(C-4a); 128.42 (C-4b), 128.39 (C-4c), 127.61, 127.51
(C-2″ and C-4″); 127.31, 127.14 (C-2″″ and C-6″″);
126.89 (C-2′″ and C-6′″); 123.67 (C-4d); 65.01 (C-2);
63.98 (C-4); 45.01 (C-1); 36.34 (C-5); 29.08 (C-8); 25.98
(C-6); 20.51 (C-7). HRMS (ES): m/z = 441.1119 (M+H).
2,4-Bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
(compound 7)
IR (cm−1): 3307 (N–H stretching); 3005, 2968, 2933, 2831
(C–H stretching); 1705 (C=O stretching); 1610, 1584 (C=C
stretching-Ph). 1H NMR (δ ppm): 7.46–6.93 (m, 8H, aro-
matic protons); 4.34 (d, 2H, J = 2.56 Hz, H-2a and H-4a);
3.28 (s, 6H, OCH3 at C-2″″ and C-4″″); 2.88 (m, 1H, H-7a);
2.41 (br s, 2H, H-1 and H-5); 1.96 (d, 1H, J = 4.40 Hz,
H-8e); 1.92 (d, 1H, J = 4.76 Hz, H-6e); 1.87 (br s, 1H, NH);
N′-(2,4-Bis(4-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-
ylidine)bezenecarbothiohydrazides (compound 10)
IR (cm−1): 3352, 3261, 3158 (N–H stretching); 3059, 2960,
2936, 2892, 2856, 2798 (C–H stretching); 1638 (C=N stretch-
1
ing). H NMR (δ ppm): 9.21 (s, 1H, NHCS); 8.43 (s, 1H,
NHPh); 7.27–7.56 (m, 13 H, aryl protons); 7.11 (q, 4H, pro-
tons meta to fluorine atom); 4.36 (d, J=2.5 Hz, 1H, H-2a);
4.22 (d, J=1.88 Hz 1H, H-4a); 2.96 (s, 1H, H-5); 2.51 (s, 1H,
H-1); 2.80 (m, 1H, H-7a); 1.81 (m, 3H, H-6e, H-8e and NH);
1.36–1.55 (m, 3H, H-6a and H-8a and H-7e). 13C NMR (δ
ppm): 176.12 (C=S); 167.05 (C=N); 163.89, 161.65 (C-2″″
1.74–1.64 (m, 2H, H-6a, H-8a); 1.38 (quin, 2H, H-7e). 13
C
NMR (δ ppm): 217.88 (C-9); 158.98 (C-2″″ and C-4″″),
136.51(C-2′ and C-4′), 132.27(C-2″ and C-4″), 113.89
(C-2′″ and C-4′″); 64.36 (C-2 and C-4); 55.29 (OCH3 at
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis and antimicrobial studies 433
stretching). 1H NMR (δ ppm): 9.90 (s, 1H, NHCS); 8.47 (s,
1H, CSNHPh); 7.01–7.44 (m, 13H, aryl protons); 4.38 (d,
J= 2.5 Hz, 1H, H-2a); 4.23 (d, J= 2.0 Hz, 1H, H-4a); 2.91 (s,
1H, H-5); 2.47 (s, 1H, H-1); 2.79 (m, 1H, H-7a); 2.31, (s,
6H, CH3 at C-2″″ and C-4″″); 1.86 (dd, 3H, H-6e, H-8e and
NH); 1.38–1.52 (m, 2H, H-6a and H-8a), 1.41 (quintet,
1H, H-7e). 13C NMR (δ ppm): 168.42 (C=S); 157.73 (C=N);
138.10, 137.23(C-2′andC-4′);139.06(C-4a);136.90(C-2″″
and C-4″″), 129.38 (C-4b), 129.05 (C-4c), 127.19 (C-2″
and C-6″), 126.76(C-2′″ and C-6′″), 125.12 (C-4d) (other
aryl carbons); 65.43 (C-2); 63.91 (C-4); 46.57 (C-1); 39.32
(C-5); 29.47 (C-8); 28.14 (C-6); 21.29 (C-7); 21.09 (CH3 at
C-2″″ and C-4″″); HRMS (ES): m/z = 469.1983 (M+H).
and C-4″″); 138.07, 136.28 (C-2′ and C-4′); 139.06 (C-4a);
128.62 (C-4b), 128.38 (C-4c), 128.24, 127.88 (C-2″and C-6″),
127.67 (C-4d), 115.61, 115.11 (C-2′″ and C-6′″); 64.88 (C-2);
63.44 (C-4); 46.56 (C-1); 35.12 (C-5); 29.91 (C-8); 26.87
(C-6); 25.42 (C-7). HRMS (ES): m/z=477.2324 (M+H).
N′-(2,4-Bis(3-fluorophenyl)-3-azabicyclo[3.3.1]nonan-9-
ylidine)bezenecarbothiohydrazides (compound 11)
IR (cm−1): 3397, 3251, 3142 (N–H stretching); 3068, 2989,
1
2946, 2866 (C–H stretching); 1639 (C=N stretching). H
NMR (δ ppm): 9.21 (s, 1H, NHCS); 8.62 (s, 1H, CSNHPh);
6.96–7.44 (m, 13H, protons ortho and meta to the fluorine
atom); 4.43 (d, J=2.5 Hz, 1H, H-2a); 4.24 (d, J=2.5 Hz, 1H,
H-4a); 2.94 (s, 1H, H-5); 2.72 (m, 1H, H-7a); 2.54 (s, 1H,
H-1); 1.80 (b s, 3H, H-6e, H-8e and NH); 1.39–1.57 (m, 2H,
H-6a and H-8a); 1.44 (quintet, 1H, H-7e). 13C NMR (δppm):
169.98 (C=S); 161.79 (C=N); 164.35, 161.56 (C-2′″ and
C-4′″); 144.13 (C-2′); 143.76 (C-4′); 138.27 (C-4a); 130.96,
122.76, 122.41, 121.76, 114.74, 114.63, 114.20, 113.93,
113.69 (other aryl carbons); 64.16 (C-2); 63.22 (C-4); 46.24
(C-1); 39.15 (C-5); 28.67 (C-8); 27.57 (C-6); 21.41 (C-7).
N′-(2,4-Bis(4-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-
ylidine)bezenecarbothiohydrazides (compound 15)
IR (cm−1): 3335, 3238, 3186 (N–H stretching); 3012, 2998,
2947, 3286, 2849 (C–H stretching); 1629 (C=N stretch-
1
ing). H NMR (δ ppm): 9.86 (s, 1H, NHCS); 8.88 (s, 1H,
CSNHPh); 6.93–7.47 (m, 13H, aryl protons); 4.31 (d, J=2.5
Hz, 1H, H-2a); 4.21 (s, 1H, H-4a); 3.82 (d, 6H, OCH3 at C-2″″
and C-4″″); 2.81 (s, 1H, H-5); 2.78 (m, 1H, H-7a); 2.45 (s, 1H,
H-1); 1.90 (dd, 3H, H-6e, H-8e and NH); 1.45 (m, 3H, H-6a
andH-8aandH-7e). 13CNMR(δppm):167.19(C=S);158.56,
159.01 (C-2″″ and C-4″″); 156.32 (C=N); 138.06 (C-4a);
134.12, 133.31 (C-4′ and C-2′); 129.91(C-4b); 127.81(C-4c);
127.56 (C-2″ and C-6″); 126.11 (C-4d); 113.92, 113.80 (C-2′″
and C-6′″); 65.01(C-2); 63.36 (C-4); 55.01 (OCH3 at C-2″and
C-4″″); 46.43 (C-1); 39.12 (C-5); 29.06 (C-8); 27.31 (C-6);
22.13 (C-7). HRMS (ES): m/z=501.2298 (M+H).
N′-(2,4-Bis(4-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-
ylidine)bezenecarbothiohydrazides (compound 12)
IR (cm−1): 3379, 3245 (N–H stretching); 3056, 2997, 2948,
1
2892, 2735 (C–H stretching); 1641 (C=N stretching). H
NMR (δ ppm): 9.91(s, 1H, NHCS); 8.91 (s, 1H, CSNHPh);
7.01–7.50 (13H, aromatic protons); 4.39 (d, J =2.5 Hz, 1H,
H-2a); 4.21 (d, J= 2.0 Hz, 1H, H-4a); 2.85 (s, 1H, H-5); 2.49
(s, 1H, H-1); 2.78 (m, 1H, H-7a); 1.84 (dd, 3H, H-6e, H-8e
and NH); 1.40–155 (m, 2H, H-6a and H-8a); 1.45 (quintet,
1H, H-7e). 13CNMR (δ ppm): 169.46 (C=S); 159.99 (C=N);
140.28 (C-2′); 138.27 (C-4′); 138.96 (C-4a); 133.68, 133.35
(C-2″″ and C-4″″) 128.93 (C-4b); 128.75 (C-4c); 128.43,
128.19 (C-2″ and C-6″) 127.96 (C-4d); 126.23 (C-2′″
and C-6′″); 64.87 (C-2); 63.42 (C-4); 46.41 (C-1); 39.13
(C-5); 28.53 (C-8); 27.32 (C-6); 21.34 (C-7). HRMS (ES):
m/z = 509.1408 (M+H); m/z= 510.1392 (M+2).
2,4-Bis(3-methoxyphenyl)-3-azabicyclo[3.3.1]nonan-9-one
4′-phenylthiosemicarbazones (compound 16)
IR (cm−1): 3359, 3278, 3143 (N–H stretching); 3043, 3021,
2968, 2943, 2879, 2874, 2768 (C–H stretching); 1612 (C=N
1
stretching). H NMR (δ ppm): 9.81 (s, 1H, NHCS); 8.83 (s,
1H, CSNHPh); 6.81–7.43; (m, 13H, aryl protons). 4.36 (d,
1H, H-2a); 4.23 (d, 1H, H-4a); 3.78 (s, 6H, OCH3 at C-2′″ and
C-4′″); 2.83 (m, 1H, H-7a); 2.94 (s, 1H, H-5); 2.49 (s, 1H, H-1);
1.82 (dd, 3H, H-6e, H-8e and NH); 1.43–1.54 (m, 2H, H-6a,
H-8a and H-7e). 13C NMR (δ ppm): 168.14 (C=S); 159.13,
159.07 (C-2′″ and C-4′″); 156.09 (C=N); 143.32, 142.98 (C-2′
and C-4′); 138.90 (C-4a); 129.48 (C-4b), 129.05 (C-4c),
126.25 (C-4d), 125.97, 119.23, 119.06, 113.34, 112.98 (other
aryl carbons); 65.09 (C-2); 63.41 (C-4); 55.21 (OCH3 at C-2′″
and C-4′″); 46.39 (C-1); 39.35 (C-5); 28.76 (C-8); 27.47 (C-6);
21.25 (C-7); HRMS (ES): m/z=500.9981 (M+H).
N′-(2,4-Bis(2-chlorophenyl)-3-azabicyclo[3.3.1]nonan-9-
ylidine)bezenecarbothiohydrazides (compound 13)
IR (cm−1): 3386, 3247, 3143 (N–H stretching); 3042, 2976,
2967, 2946, 2883 (C–H stretching); 1629 (C=N stretching).
1H NMR (δppm): 9.87 (s, 1H, NHCS); 8.29 (s, 1H, CSNHPh);
8.01 (t, 2H, protons ortho to chlorine atom); 7.11–7.42 (m,
11H, otherarylprotons);4.72(d, J=2.5Hz, 1H, H-2a);4.62(d,
J=2.0 Hz 1H, H-4a); 3.18 (d, J=2.0 Hz, 1H, H-5); 2.79 (m,
2H, H-1 and H-7a); 1.79 (dd, 3H, H-6e, H-8e and NH); 1.61
(m, 2H, H-6a and H-8a); 1.39 (quintet, 1H, H-7e). 13C NMR
(δ ppm): 169.34 (C=S); 159.15 (C=N); 138.65 (C-2′); 138.03
(C-4′); 139.01 (C-4a); 133.01, 130.10 (chloro bearing C-2″
and C-6″); 128.95, 128.56, 127.43, 126.19, 126.59, 125.01,
121.43 (other aryl carbons); 62.43 (C-2); 60.58 (C-4); 42.19
(C-1); 35.03 (C-5); 29.18 (C-8); 27.20 (C-6); 21.32 (C-7).
Results and discussion
Chemistry
eparentbicyclicketones(2,4-diaryl-3-azabicyclo[3.3.1]
nonan-9-ones) were prepared according to the literature
precedentbyBaliahandJeyaraman[27]. eketonesupon
treatment with 4′-phenylthiosemicarbazide in the pres-
ence of few drops of mineral acid afforded two different
products, viz., 2,4-Diaryl-3-azabicyclo[3.3.1]nonan-9-one
thiosemicarbazones (9–16) and arylthiosemicarbazones
2,4-Bis(4-methylphenyl)-3-azabicyclo[3.3.1]nonan-9-one
4′-phenylthiosemicarbazones (compound 14)
IR (cm−1): 3392, 3256, 3141 (N–H stretching); 3068, 2992,
2972, 2932, 2888, 2797 (C–H stretching); 1642 (C=N
© 2011 Informa UK, Ltd.

434 S. Umamatheswari and S. Kabilan
(9a–16a) (Scheme 1). e formation of by-product
(arylthiosemicarbazones) is due to poor mass balance
while using mineral acids (HCl or H2SO4) as catalyst in
the condensation of high molecular parent ketones with
thiosemicarbazide. e cleavages of the products were
studied by retro mannich mechanism followed by con-
densation reaction. Further, no more by-products were
found to be formed after workup. e analytical data of
the compounds 1–16 are given in Table 1.
In order to investigate the spectral assignments of
reported compounds 9–16, compound 9 is taken as the
representative compound. e IR spectra of compound
9 show a collective absorption bands appeared in the
region 3352–3258 cm−1, which is assigned to NH stretch-
ing frequency, and C=N stretching frequency appeared
as strong and intense bands at 1616 cm−1, respectively.
For the representative compound 9, H,H-COSY,
NOESY, and HSQC were recorded to assign all the signals
unambiguously, and to establish the stereochemistry.
e H,HCOSY/NOESY and HSQC correlations are repro-
duced in Tables 2 and 3.
D2O exchange NMR, the multiplet centred at 1.79 ppm
corresponding to three protons is reduced to two pro-
tons, because of D2O exchange, which indicates that the
NH proton resonance also overlapped the multiplet.
ere are two broad singlets at 3.11 (1H) and 2.48 (1H)
ppm with the half-width W1/2 of 11.40 and 11.38 Hz, respec-
tively. e broad singlet nature and half-width values
suggest that they are due to the bridgehead protons H-1
and H-5. Further, the observed weak correlation between
3.11 and 2.48ppm strongly implies that the correlation
is due to long-range coupling between the bridgehead
protons because of the “W” arrangement of those protons
(Figure 1).
e difference between H-1 and H-5, that is, Δδ, is
0.63 ppm whereas in the corresponding bicyclic ketone,
the bridgehead protons H-1 and H-5 appear together
at 2.47 ppm (2H) as a broad singlet with a W1/2 of 11.46
Hz. Because of nonbonding interaction between the
N–N(2′) and C(5)-H bonds (Figure 2), the H-5 proton
is deshielded, the deshielding magnitude is quite large
(0.64 ppm). But there is no change in another bridgehead
proton H-1, except for slight deshielding of 0.01 ppm. e
positions, appearance, spectral width, and correlations
strongly suggest that the signals at 3.11 and 2.48 ppm are
due to the bridgehead protons H-5 (syn α) and H-1 (anti
α). ough the bridgehead protons appear as two sepa-
rate signals, both are broad singlets and their half-widths
are also similar to that of its parent ketone 1. Hence,
this suggests that the thiosemicarbazone derivative also
adopts the twin-chair conformation.
Assignment of proton chemical shifts and
stereochemistry
In compound 9, two broad singlets at 8.43 ppm (1H) and
9.21 ppm (1H) are due to NH protons of thiosemicarba-
zone moiety, which are disappeared in the D2O exchange
NMR spectrum. Of the two singlets, the upfield signal at
8.43 has NOE with the proton signal at 3.11 ppm (H-5);
hence, the broad singlet at 8.43 assigned to NH proton at
2′ of thiosemicarbazone moiety. Consequently, the broad
singlet at 9.21 ppm unequivocally assigned to the NH pro-
ton at 4′ of thiosemicarbazone moiety. According to the
e signals at 4.41 (d, J=2.0 Hz) and 4.33ppm (d, J=2.0
Hz) are due to benzylic protons and they only have corre-
lations with the bridgehead protons H-1 and H-5; hence,
O
O
R
R
R1
R2
R1
R2
(a)
N
H
R
O
+
O
R
R1
R2
R1
R2
H
H
1–8
CH3COONH4
(b)
S
N
H
H
N
H
N
N
N
H
+
N
R
R
S
R
R2
R1
R2
R1
R2
N
H
R1
9–16
Scheme 1. Reagent and conditions: (a) EtOH/warm, room temperature, 2–10 days and (b) MeOH-CHCl3, H2NNHCSNHPh/H+, reflux,
90–100°C 4h.
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis and antimicrobial studies 435
we can unambiguously assign the signals to H-2 and H-4.
Further, they have close proximity (NOE) with each other,
hence indicating their orientation as axial. Except for axial
orientation of the protons at C-2 and C-4, there is other-
wise no possibility of NOE between them in the chair
conformation. As a consequence of the observed NOE,
we can conclude that the orientation of the phenyl groups
on the same carbons should be equatorial. Moreover,
1,3-diequatorial orientation of the bulkier substituents is
more favourable in the chair conformation. Further, the
observed strong NOE of the ortho protons with H-7a/H-
8e/H-6e also supports the equatorial orientation of the
phenyl groups and the twin-chair conformation.
usually observed that the chemical shift difference of
protons in the cyclohexane chair conformation is positive
(Δδeq,ax = δeq − δax, is ′0.3ppm), owing to the leading hyper-
conjugation of the C–C single bond [28]. e multiplets
with average difference of 0.33ppm suggest that they are
due to C-6 and C-8 protons. Further, the assignments and
chair conformation of the cyclohexane part are confirmed
by their NOE (Figure 3). Moreover, the observed NOE
between the multiplet at 2.83ppm and the aryl protons
supports attribution of the multiplet to H-7a (endocyclic
proton, which is spatially very close to the ortho protons).
Of the five set of aromatic signals, the double doublet
centred at 7.46 ppm (2H) coupled with the doublet at 7.59
(2H) and triplet at 7.21 ppm (1H). is observation sug-
gests that the signals at 7.59, 7.46, and 7.21 ppm are due
to the phenyl protons of thiosemicarbazone moiety 4b,
4c, and 4d, respectively. e remaining two sets of aryl
signals, a multiplet centred at 7.36 (4H) and at 7.27(6H)
ppm, and the multiplet at 7.36 ppm, have NOE with
H-1/H-2a/H-7a/H-8e of the protons. Hence, the multip-
let at 7.36 ppm is assigned to ortho protons (H-2″/H-4″).
Consequently, the multiplet at 7.27 ppm is due to H-2′″/
H-4′″, H-2″″/H-4″″ protons.
In addition to the “W” correlation, both H-1 and H-5
have correlations with the doublet at 1.79ppm (3H, due
to overlapped NH) and multiplet at 1.46 (3H) ppm. It is
Table 1. Analytical data for compounds 1–16.
Melting point
Entry
R
H
H
H
H
R1
H
H
F
R2
H
F
Yield (%)
(°C)
Mass (M+1)+
1
2
3
4
49
47
43
48
185–186 292.22
198–199 328.17
192–193 327.42 (M+)
174–175 359.13 (M+);
361 (M+2)
H
Cl
H
Table 3. Correlations in the HSQC spectrum of compound 9.
5
Cl
H
H
H
H
H
H
H
H
H
H
CH3
OCH3
H
52
59
49
53
78
81
79
76
218
—
Signal (d (ppm))
Correlations in HSQC
6
160–162 320.21
174–175 351.38 (M+)
7.59 (d, 2H, H-4b)
128.42
128.39
7
H
7.46 (dd, 2H, H-4c)
8
OCH3
H
160–161
—
127.61–126.89
127.61–126.89
123.67
7.35–7.39 (m, 4H, H-2″/H-4″)
7.33 (m, 6H, H-2′″/ H-4′″, H-2″″/H-4″″)
7.21 (t, 1H, H-4d)
9
H
168–170 441.1119
202–203 477.2324
10
11
12
H
F
F
H
180–182
—
4.41 (d, 1H, H-2a)
65.01
H
Cl
224–226 509.1408;
510.1392
4.29 (s, 1H, H-4a)
63.98
3.11 (s, 1H, H-5e)
36.34
(M+2)
2.83 (m, 1H, H-7a)
20.51
13
14
15
16
Cl
H
H
H
H
H
H
CH3
OCH3
H
72
89
81
79
198–200
—
2.48 (b s, 1H, H-1e)
45.01
169–170 469.1983
148–150 501.2298
159–161 500.9981
1.79 (dd, 3H, H-6e, H-8e and NH)
1.46 (m, 3H, H-6a, H-8a and H-7e)
9.21 (s, 1H, NHCS)
25.98, 29.08
25.98, 29.08, 20.51
—
H
OCH3
e observed m/z value is within 0.4% from their theoretical
value.
8.43 (s, 1H, CSNHPh)
—
Table 2. Correlations in the H,H-COSY and NOESY spectra of compound 9.
Signal (d (ppm))
Correlations in H,H-COSY
Correlations in NOESY
7.59 (d, 2H, H-4b)
7.46
7.46 (s), 7.21 (s)
7.46 (dd, 2H, H-4c)
7.59, 7.21
7.59 (s), 7.21 (s)
7.29–7.32
7.29–7.32 (s), 4.41 (s), 4.29 (s)
7.35–7.39
7.35–7.39 (m, 4H, H-2″/H-4″)
7.25–7.30 (m, 6H, H-2′″/ H-4′″, H-2″″/H-4″″)
7.21 (t, 1H, H-4d)
7.35–7.39
7.46
2.48
7.59, 7.46
4.41 (d, 1H, H-2a)
7.35–7.39 (s), 4.29, 2.48 (s), 1.79 (w)
7.35–7.39 (s), 4.41, 3.11 (s), 1.79 (w)
7.35–7.39 (s), 4.29 (s), 1.79, 1.46
7.35–7.39 (w), 1.46
7.35–7.39 (w), 4.41 (s), 1.46 (w)
7.35–7.39, 1.46
4.29 (s, 1H, H-4a)
3.11, 1.46 (w)
3.11 (s, 1H, H-5)
4.29 (s), 2.48 (w) 1.79 (w), 1.46
1.46, 1.79, 1.46
4.41 (s), 1.79, 1.46, 3.11 (w)
3.11, 2.83, 1.46
4.29 (w), 3.11, 2.83, 1.46
—
2.83 (m, 1H, H-7a)
2.48 (b s, 1H, H-1)
1.79 (dd, 3H, H-6e, H-8e and NH)
1.46 (m, 3H, H-6a, H-8a and H-7e)
9.21 (s, 1H, NHCS)
1.79, 2.83
8.43, 3.11
8.43 (s, 1H, CSNHPh)
—
9.21
s, strong correlation; w, weak correlation.
© 2011 Informa UK, Ltd.

436 S. Umamatheswari and S. Kabilan
S
NH
4'
S
NH
3'
N
2'
NH
N
1'
N
9
9
H
H
2
δ+
5
H
H
δ−
1
Ha
Ha
5
Ha
Ph
syn
anti
Ha
6
1
4
8
8
6
He
3
4
He
Ha
Ph
2
N
7
H
3
Ph
He
Ph
N
7
H
Figure 1. Correlations between the protons that are in “W”
arrangements, from the H,H-COSY spectrum of compound 9.
Figure 2. Non-bonded interaction between C–H(5) and N–NH
group.
142.67, and 142.39 ppm are due to the 4′-phenyl, C-2′,
and C-4′ ipso carbons, respectively, and the signals at
169.68 and 172.19 ppm are due to the resonance of C=N
and C=S carbons, respectively. e HSQC correlations
are reproduced in Table 3.
Overall, the chemical shifts, splitting pattern, H,H
correlation, and NOE suggest that the compound is in
twin-chair conformation with equatorial orientation of
the phenyl groups, as depicted in Figure 3. Further, the
twin-chair conformation is evidenced by the W1/2 of H-1
and H-5; these values are in good agreement with the
corresponding ketone and with literature values for the
flattened twin-chair conformation of similar bicycles. If
one of the cycles adopts a boat conformation, the reso-
nances for the bridgehead protons H-1 and H-5 should
be apparent doublets with coupling constants of about 18
Hz [29]. In addition, the observed long-range couplings
between H-2a and H-8a and between H-4a and H-6a are
due to the “W” arrangement of those protons and this is
only possible when the bicycle is in the twin-chair con-
Antimicrobial evaluation
In order to find the effect of potency of inhibitions in com-
pounds9–16byinvitromethod,wemodifieddifferentsub-
stituentsatphenylgroupsin2,4-diaryl-3-azabicyclo[3.3.1]
nonan-9-one4′-phenylthiosemicarbazones.ereported
compounds were tested against bacterial strains, viz.,
S. aureus (ATCC-25825), B. subtilis (ATCC-451), S. typhi
(ATCC-24915), E. coli (ATCC-25835), and K. pneumonia
(ATCC-15490) using the literature precedent by Dhar
et al., [26], and their MIC values are depicted in Table 4.
A glance at the MIC values in Table 4 indicates that
compound9againstS.aureusexhibitminimuminhibition
activity.However,paraormetafluorophenyl-substituted
compound 10 against B. subtilis and S. typhi and com-
pound 11 against B. subtilis exerted significant inhibi-
tion. e compound 10, which was inactive against
K. pneumonia even at maximum concentration (200
μg/mL).
1
formation (Figure 1). Similarly, H NMR signals of other
bicyclic thiosemicarbazones 10–16 are assigned and
summarized in the “Experimental” section.
Assignment of carbon chemical shifts
All the proton-bonded carbon signals of the representa-
tive compound 9 were unambiguously assigned using
HSQC spectrum. In the downfield region, five less intense
signals that appear at 169.68, 172.19, 142.67, 142.39, and
138.46 ppm have no correlation with any proton signals
of the molecule, which indicates that these signals are
due to quaternary carbons. Of the five signals, 138.46,
Surprisingly, replacement of fluorine function by chlo-
rine in compounds 10 and 11 (compounds 12 and 13,
respectively), compound 12 against K. pneumonia, was
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis and antimicrobial studies 437
found to show superior activity than others. However,
compound 12 against S. aureus/E. coli and B. subtilis
shows a reversal in activity, by 8- and 4-fold, respectively,
due to replacement of fluorine by chlorine. Instead of
halogens, methyl or methoxy function substituted com-
pound 14 against E. coli and compound 15 against K.
pneumonia markedly elevated the maximum inhibition
potency at minimum concentration (12.5 μg/mL).
e in vitro antifungal activity of the reported com-
pounds 9–16 were examined with five fungal strains, viz.,
C. albicans (ATCC-3122), R. oryzae (ATCC-9363), C. neo-
formans (ATCC-3312), A. niger (ATCC-598), and A. flavus
(ATCC-485) and amphotericin B was used as standard
drug. e obtained MIC values of the tested compounds
and standard are depicted in Table 5 that indicates all the
testedcompoundsexhibitavariedrange6.25–200μg/mL.
Unsubstituted phenyl groups in compound 9 recorded
minimum to moderate activity (100–200 μg/mL) against
all the tested organisms except A. flavus, which did not
show any inhibition potency even at maximum con-
centration at 200 μg/mL. However, due to introduction
of fluorine atom at the meta or para position of phenyl
groups in compound 9 (compounds 10 and 11) noticed
minimum to moderate inhibition potency against all the
tested fungal organisms with MIC ranging from 6.25 to
100 μg/mL, in which, compound 11 against A. albicans
shows superior inhibition potency at minimum concen-
tration (6.25 μg/mL). Modification of fluorine substituent
by chlorine in compound 10 (compound 12) registered
minimum antifungal activity against all the used strains.
By changing the position of chloro substitution in com-
pound 12 para to ortho (compound 12) 16- and 2-fold
increased activity were noticed against C. albicans and R.
oryzae. Replacement of one proton by methyl analogue in
compound 9 (compound 14), the activity was increased
against all the strains except against A. flavus, which is
inactive even at maximum concentration (200 μg/mL).
Due to modification of methyl analogue by methoxy
group in compound 14, compounds 15 and 16 show
moderate activity against the entire tested fungal strains.
Among the compounds under the antifungal study, com-
pounds 9 and 14 against A. flavus seldom show inhibi-
tion even at maximum concentration (200 μg/mL).
From the close survey of the in vitro antibacterial and
antifungal results against a panel of microbial organisms,
itwasrevealedthattheelectron-withdrawingsubstituents
H
Table 4. Antibacterial activity of compounds 9–16 against
selected bacterial strains (MIC in μg/mL).
4d
H
H
H
4c
4b
4c
4b
Minimum inhibitory concentration (MIC) in
µg/mL
K.
Compound S. aureus B. subtils S. tyhpi
E. coli pneumonia
H
S
4a
4'
9
200
50
100
6.25
6.25
50
200
12.5
100
50
200
—
10
N
H
3'
11
25
100
50
25
100
H
12
100
25
100
25
12.5
2'
13
25
50
6.25
100
50
N
1'
N
14
100
100
50
50
50
12.5
15
100
100
100
200
25
12.5
9
16
200
50
—
25
Ciprofloxacin
25
12.5
—, no inhibition even at maximum concentration 200 µg/mL.
H
H
5
Table 5. Antifungal activity of compounds 9–16 against selected
fungal strains (MIC in μg/mL).
Ha
1
Ha
Ha
H
8
6
Minimum inhibitory concentration (MIC) in
µg/mL
4
2
Ha
He
4'
C.
R.
C.
A.
A.
3
4''
He
2'
Compound
albicans oryzae neoformans niger flavus
H
N
9
200
50
200
50
100
50
200
12.5
—
50
7
H
2''
He
4''
10
11
12
13
14
15
16
2''
Ha
4'''
H
6.25
100
6.25
25
12.5
6.25
6.25
50
50
100
100
25
100
50
2'''
50
4'''
H
4''''
25
50
2'''
100
25
100
25
—
2''''
100
100
25
50
25
6.25
25
50
100
50
25
Figure 3. Twin-chair conformation with equatorial orientation of
the phenyl groups at C-2 and C-4; supported by the NOE observed in
the NOESY spectrum of compound 9. For clarity, the NOE between
the ortho and ring protons is shown by red colour lines.
Amphotericin
-B
25
50
—, no inhibition even at maximum concentration 200 µg/mL.
© 2011 Informa UK, Ltd.

438 S. Umamatheswari and S. Kabilan
900
800
700
600
500
400
300
200
100
0
9
10
11
12
13
14
15
16
S.aureus
B.Subtils
S.tyhpi
E.coli
k.pneumonia
Figure 4. Comparison of potency of compounds 9–16 with ciprofloxacin (as standard) against bacterial strains from serial dilution method.
Scheme 1: Schematic diagram showing the synthesis of 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one 4′-phenylthiosemicarbazones.
450
400
350
300
250
200
150
100
50
0
9
10
11
12
13
14
15
16
C.albicans
Rhizopus sp. C.neoformans
A.niger A.flavus
Figure 5. Comparison of potency of compounds 9–16 with amphotericin B (as standard) against fungal strains from serial dilution
method.
at the ortho/meta/para position of the phenyl groups at
C-2 and C-4 of the 3-azabicyclononane pharmacophore
had remarkable activity against all the tested organisms.
A comparison of potency of the compounds 9–16 is
given in the form of Figures 4 and 5 by employing the
following the equation.
compound 14 against E. coli, compounds 12 and 15
against K. pneumonia were shown to be significant
in their antibacterial potency at 6.25 and 12.5 µg/mL.
Furthermore, their activity was also on a par with the
standard drugs used and for some compounds was even
higher than the activity of the standard drugs. ough
most of the compounds studied exhibited moderate to
significant antibacterial activity, compound 10 (with
o-chlorophenyl group at the C-2 and C-4 positions) was
found to exert a pronounced effect against all the tested
organisms.
Similarly, against the tested fungal strains, compounds
11, 13, and 16 against C. albicans, compounds 11–13
against C. neoformans, compound 10 against A. niger
recorded enhanced activity at 6.25 and 12.5 µg/mL.
However, the activity of compound 11 against all the
tested organisms was found to be superior to the other
compounds and with an even higher activity than the
standard.
MIC(mg/mL)of reference
Potency =
×100
MIC(mg/mL)of tested compound
A close survey of the in vitro antibacterial and antifungal
activity profile of the new 2,4-diaryl-3-azabicyclo[3.3.1]
nonan-9-one 4′-phenylthiosemicarbazones (9–16)
against the tested bacterial and fungal organisms gives
a clear picture about the structure–activity correlations
among compounds 9–16 under study. Compounds with
electron-withdrawing groups (fluoro and chloro) and
electron-donating groups (methyl or methoxy) function
at the aryl groups present at the C-2 and C-4 positions
of the azabicyclo[3.3.1]nonan-9-one moiety exerted a
varied range of biological activities, while the activity was
not significant for compound 9 without any substituent
at the phenyl groups.
Conclusions
A close examination of the in vitro antibacterial and
antifungal activity profile of the differently substi-
tuted novel 2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-one
Among compounds 10–16, compounds 10 and
11 against B. subtilis, compound 13 against S. typhi,
Journal of Enzyme Inhibition and Medicinal Chemistry

Synthesis and antimicrobial studies 439
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Declaration of interest
Authors have no declaration of interest.
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