Carbodithioic acid esters of fluoxetine, a novel class of dual-function spermicides

Article abstract of DOI:10.1016/j.ejmech.2007.10.024

Carbodithioic acid esters of fluoxetine have been prepared by replacing the methylamino function in aminopropane chain with carbodithioic acid ester group and by adding various S-2-hydroxypropyl ester of dialkyl carbodithioic acid at 3-methylamino group. Some of these compounds showed spermicidal, antifungal and anti-Trichomonas activities. The study revealed that incorporation of carbodithioic acid residue directly into fluoxetine structure leads to compounds with better antifungal and anti-Trichomonas activities, and N-methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]carbodithioic acid S-(2-pyrrolidino-ethyl) ester (14) has shown better profile than both fluoxetine and nonoxynol-9. Further lead optimization may yield a potent dual-function spermicide.

Full text of DOI:10.1016/j.ejmech.2007.10.024

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 2247e2256
http://www.elsevier.com/locate/ejmech
Short communication
Carbodithioic acid esters of fluoxetine, a novel
class of dual-function spermicides*
b
S.T.V.S. Kiran Kumar a, Lalit Kumar a, Vishnu L. Sharma a, , Ashish Jain ,
*
Rajeev K. Jain b, Jagdamba P. Maikhuri b, Manish Kumar c, Praveen K. Shukla c, Gopal Gupta b
a Division of Medicinal and Process Chemistry, Central Drug Research Institute, Lucknow-226001, Uttar Pradesh, India
b Division of Endocrinology, Central Drug Research Institute, Lucknow-226001, Uttar Pradesh, India
c Division of Fermentation Technology, Central Drug Research Institute, Lucknow-226001, Uttar Pradesh, India
Received 8 October 2007; received in revised form 19 October 2007; accepted 19 October 2007
Available online 25 October 2007
Abstract
Carbodithioic acid esters of fluoxetine have been prepared by replacing the methylamino function in aminopropane chain with carbodithioic
acid ester group and by adding various S-2-hydroxypropyl ester of dialkyl carbodithioic acid at 3-methylamino group. Some of these compounds
showed spermicidal, antifungal and anti-Trichomonas activities. The study revealed that incorporation of carbodithioic acid residue directly into
fluoxetine structure leads to compounds with better antifungal and anti-Trichomonas activities, and N-methyl-[3-phenyl-3-(4-trifluoromethyl-
phenoxy)-propyl]carbodithioic acid S-(2-pyrrolidino-ethyl) ester (14) has shown better profile than both fluoxetine and nonoxynol-9. Further
lead optimization may yield a potent dual-function spermicide.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Carbodithioic acid esters; Fluoxetine derivatives; Spermicidals and anti-Trichomonas
1. Introduction
[7], some very common STDs like trichomoniasis significantly
increase vulnerability to HIV [8]. Therefore, developing user-
controlled, non-detergent, topical vaginal spermicides that can
provide protection against pregnancy as well as some very
common sexually transmitted pathogens has become an urgent
global priority [1]. Such agents can effectively alleviate the
global crisis of unwanted pregnancies and AIDS [9]. Efforts
are underway to develop such novel, dually active agents
[10e13].
During our ongoing efforts to develop novel dual-function
spermicides, we reported that fluoxetine showed spermicidal
as well as anti-Trichomonas activities [14], and the anti-Can-
dida activity of imidazole analogues of fluoxetine has already
been demonstrated [15]. Thus modifications in fluoxetine
structure (I; Fig. 1) may lead to compounds having spermi-
cidal as well as anti-STI activities. Here in this communication
the synthesis and biological activity of carbodithioic acid es-
ters of fluoxetine are being reported. Carbodithioic acid group
(II; Fig. 1) is a valuable pharmacophore that induces diverse
The acquired immune deficiency syndrome (AIDS) appears
to thrive in the presence of overpopulation [1], poverty and
other sexually transmitted diseases (STDs) [2,3]. In spite of
the firm resistance of healthy human vagina to HIV infection
[4], w5 million new patients are added annually to w40 mil-
lion living with HIV, half of which are women [5]. This indi-
cates, (a), high prevalence of HIV in heterosexual contacts and
(b), increase in number of women with compromised vaginal
integrity induced by vaginally applied chemical products and/
or STD pathogens. While nonoxynol-9 (N-9), the most widely
used vaginal spermicide, has been shown to increase the risk
of HIV transmission [6] due to its surfactant-type of action
*
C.D.R.I. communication no. 7344.
* Corresponding author. Tel.: þ91 522 2612411x4320; fax: þ91 522
2623405.
E-mail address: vlscdri1@rediffmail.com (V.L. Sharma).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.10.024

2248
S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
CH3
R1
S
S
NH
HCl
N
C
R3
R2
O
Dithiocarbamate group
II
Fluoxetine.HCl
I
F3C
CH3
N
S
R
S
O
III
F3C
R = alkyl, arylalkyl, dialkylaminoethyl
CH3
N
OH
R1
N
CH3
N
OH
S
S
S
S
R2
O
N
O
R1
R2
V
IV
F3C
F3C
NR1R2= dialkylamino, arylalkylamino, cyclicamino NR1R2= dialkylamino, arylalkylamino, cyclicamino
Fig. 1.
biological activities when incorporated in a particular struc-
ture. Very significantly, dialkylaminocarbothioic acid esters
have been shown to have non-detergent type of action as sper-
micide [16] at a test concentration of 0.002%, and a number of
alkyl/aryl esters of diethylamino carbodithioic acid have been
synthesized and evaluated for spermicidal activity [17]. 1-
Dialkylamino carbodithioic acid sodium/potassium salts and
their esters exhibited antibacterial and antifungal activities
[18e21]. Pyrrolidinecarbodithioic acid [22] has been shown
to produce antioxidant-induced changes in AP-1 transcription
complex thereby selectively suppressing the human papillo-
mavirus transcription while its sodium salt enhanced the im-
munostimulatory effect [23] of interleukin-12 and exhibited
antiviral activity [24] on human rhinovirus.
These observations prompted us to introduce carbodithioic
acid group at 3-amino terminus of fluoxetine structure and thus
S-substituted alkyl esters of fluoxetine carbodithioic acid (III;
Fig. 1) were synthesized. Since propranolol [25] has been
found to be a potent inhibitor of sperm motility and one of
the pharmacophore present in propranolol is 1-[3-dialkylami-
nopropan-2-ol], therefore, it was considered worthwhile to
prepare a series of S-[3-dialkylamino propan-2-ol] ester of flu-
oxetine carbodithioic acid (IV; Fig. 1). In another modifica-
tion, fluoxetine was introduced as dialkylamine in
propanolamino group, which was introduced as side chain in
carbodithioic acid esters of different dialkylamines (V;
Fig. 1). All the synthesized compounds were evaluated for
spermicidal and antifungal activities. The compounds, which
showed spermicidal activity, were also tested for anti-Tricho-
monas activity. Nonoxynol-9 was used as reference standard
[14] for biological evaluations.
2. Chemistry
2.1. N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-carbodithioic acid S-(substituted-alkyl) esters
(10e16; Scheme 1)
The free base of the compound N-methyl-[3-phenyl-3-(4-
trifluoromethyl-phenoxy)-propyl]-amine hydrochloride salt
was obtained by reaction with sodium bicarbonate and the
free base (1) was taken into ethyl acetate and reacted with car-
bon disulphide in the presence of aqueous NaOH to form
sodium salt of N-methyl-[3-phenyl-3-(4-trifluoromethyl-phe-
noxy)-propyl]-amino carbodithioic acid (2). The formed so-
dium salt was characterized by spectral data and used in
further reaction with chloro derivatives (3e9) to get the final
products N-methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-carbodithioic acid S-(substituted-alkyl) esters (10e16;
Scheme 1).
2.2. N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-carbodithioic acid 3-dialkylamino-2-hydroxy-
propyl esters (30e35; Scheme 1)
N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
carbodithioic acid 3-dialkylamino-2-hydroxy-propyl esters
(30e35) were synthesized by reaction of N-methyl-[3-
phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-carbodithioic
acid sodium salt (2) with epoxy compounds (24e29) obtained
from reaction of dialkylamines (17e22) with epichlorohydrin
(23) in the presence of triethylamine.

S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
2249
CH3
S
CH3
N
NH + CS2 + NaOH
S- Na+
O
O
2
1
F3C
F3C
R1
R1
O
Cl
R
O
HN
N
+
Cl
3-9
R2
17-22
R2
24-29
23
S
S
CH3
N
S
S
CH3
N
R
N
R2
O
O
R1
OH
10-16
30-35
F3C
F3C
No.
30:
NR1R2
N
No.
33:
NR1R2
N
No.
R
No.
14:
R
N
N
Cl
10:
11:
N
O
34:
35:
N
N
31:
32:
O
15:
16:
N
N
N
12:
13:
N
N
Scheme 1.
2.3. Dialkylamino carbodithioic acid 2-hydroxy-3-
{methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino}-propyl esters (43e48; Scheme 2)
3. Results and discussion
Twenty compounds (2, 10e16, 30e35, 43e48) were eval-
uated in vitro for their spermicidal and antifungal activities.
Twelve compounds (2, 10e14, 16, 30, 33e35, 48) showed
spermicidal activity at concentrations ranging from 0.05e
1.0%. Eleven compounds (10, 12e14, 16, 30, 33e35, 44,
48) exhibited antifungal activity at concentrations ranging
from 1.56e50 mg/ml. Ten compounds (10, 12e14, 16, 30,
33e35, 48) showed both spermicidal and antifungal activities.
These compounds were also evaluated for anti-Trichomonas
activity. Seven compounds (12e14, 16, 30, 35, 48) showed
anti-Trichomonas activity at 7e52 mg/ml concentrations.
Fluoxetine and N-9 showed spermicidal MEC of 0.05%. The
N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
amine (1) on reaction with epichlorohydrin (23) in the presence
of triethylamine gave the corresponding epoxy compound N-
methyl-oxiranylmethyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amine (36). This epoxy compound 36 was reacted with
sodiumsaltsof dialkylaminocarbodithioic acid (37e42) synthe-
sized by reaction of carbon disulfide and amine, to give the final
products dialkylamino carbodithioic acid 2-hydroxy-3-{methyl-
[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-propyl
esters (43e48; Scheme 2).
O
O
CH3
CH3
N
NH + Cl
O
O
23
36
1
F3C
F3C
R1
R2
R1
R2
S
NaOH + CS2 + HN
N
CH3 OH
+Na -S
N
S
S
37-42
O
N
R2
R1
43-48
F3C
No.
43:
NR1R2
No.
46:
47:
48:
NR1R2
N
N
N
N
N
O
44:
45
N
N
Scheme 2.

2250
S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
Table 1
Biological activity of the compounds
Compound no.
Spermicidal
MEC (%)
Antifungal MIC (mg/ml)
Anti-Trichomonas MIC
(mg/ml) (mean ꢀ SE)
1
2
3
4
5
6
2
10
1.0
1.0
1.0
1.0
1.0
0.05
e
1.0
0.5
e
e
25
50
e
50
50
3.12
e
e
e
e
e
96 ꢀ 5.1
>200
>200
50
e
50
50
6.25
e
25
e
12.5
6.25
25
e
6.25
50
e
12.5
e
6.25
12.5
12.5
e
6.25
25
e
50
e
25
6.25
12.5
e
12.5
50
50
e
25
50
25
e
25
e
50
50
3.12
e
1.56
50
e
11
12
52 ꢀ 2.55
24 ꢀ 1.87
14 ꢀ 0.61
NS
13
14
15
16
3.12
e
1.56
e
13.5 ꢀ 0.61
6.95 ꢀ 0.34
NS
30
31
e
e
32
33
e
e
50
e
e
e
e
e
50
25
25
25
e
50
50
50
50
e
NS
>200
>200
0.5
0.5
0.5
e
34
35
e
e
50
e
25
e
25
e
12 ꢀ 0.94
NS
NS
43
44
e
e
e
25
e
12.5
e
e
50
e
45
46
e
e
25
e
e
NS
NS
e
e
e
e
e
e
47
48
e
e
e
e
e
e
e
NS
1.0
0.05
0.05
e
e
12.5
25
e
e
25
50
e
e
e
6.68 ꢀ 0.33
28 ꢀ 1.22
23 ꢀ 1.24
0.54 ꢀ 0.03
Fluoxetine
Nonoxynol-9
Metronidazole
50
e
e
50
e
e
e
50
50
e
e
e
e
e
1. Candida albicans, 2. Cryptococcus neoformans, 3. Sporothrix schenckii, 4. Trichophyton mentagrophytes, 5. Aspergillus fumigatus, 6. Candida parapsilosis
(ATCC-22019); MEC ¼ minimum effective concentration; MIC ¼ minimum inhibitory concentration; NS ¼ not screened; (e) ¼ inactive.
antifungal and anti-Trichomonas MIC of fluoxetine were 25e
50 and 28 mg/ml, while that of N-9 were 50 (only 1 strain) and
23 mg/ml, respectively. (Table 1). Metronidazole exhibited
anti-Trichomonas activity at 0.54 mg/ml.
In S-(3-substituted amino-2-hydroxy-propyl) esters of flu-
oxetine carbodithioic acid (30e35), four compounds (30,
33e35) retained all the three activities, whereas two com-
pounds (31, 32) were inactive in spermicidal and moderately
active in antifungal evaluation. The pyrrolidino (30) and N-
methyl piperazino (35) compounds were most active as their
anti-Trichomonas activity was enhanced approximately 4 and
2.5-folds over fluoxetine, but their spermicidal activity was de-
creased and antifungal activity was comparable. Morpholino
(31) and piperidino (32) compounds showed moderate activity
in antifungal tests and were inactive in spermicidal evaluations.
Azepino (33) and diethylamino (34) compounds showed spermi-
cidal and antifungal activities almost comparable to pyrrolidino
compound (30) but failed to show any activity in anti-Trichomo-
nas evaluation. The activity profile of compounds 30, 32 and 33
suggests that increasing the methylene group in amino ring results
in reduction or complete loss of activities. The presence of oxy-
gen (31) in the cyclic amino ring resulted in reduction/loss of
activities whereas acyclic amine residue (34) resulted in loss
of anti-Trichomonas activity though mild spermicidal and anti-
fungal activities were retained.
The objective of this study was to evaluate the effect of
introduction of carbodithioic acid moiety into fluoxetine
structure on spermicidal, antifungal and anti-Trichomonas
activities (Table 1). While carbodithioic acid sodium salt
(2) of fluoxetine showed spermicidal (MEC: 1%), antifungal
(MIC: 25 mg/ml, one strain) and anti-Trichomonas activities
(MIC: 96 mg/ml), it was less effective as compared to fluox-
etine$HCl (MEC: spermicidal 0.05%, antifungal 25e50 mg/
ml, anti-Trichomonas 28 mg/ml). Among the carbodithioic
acid S-substituted alkyl esters of fluoxetine (10e16), five
compounds (10, 12e14, 16) showed very good to moderate
activities. The 2-substituted aminoethyl derivatives (12e14,
16) were most active but 2-morpholino analogue (15) was in-
active. The replacement of amino group by chloride (10) or
a change in alkyl chain i.e., benzyl derivative (11) resulted
in either decrease or complete loss of activities. The 2-pyrro-
lidinoethyl analogue (14) showed much better activity profile
than nonoxynol-9 and fluoxetine while spermicidal activity
was retained at the same level (0.05%), antifungal and anti-
Trichomonas activities were markedly improved i.e., 8-fold
to 16-fold increase against two strains of Candida with a 2-
fold increase in anti-Trichomonas activity. The piperidino
ethyl derivative (16) exhibited similar activities except that
there was decrease in spermicidal activity (1%). In dimethy-
lamino (12) and diethylamino (13) derivatives the three activ-
ities were retained.
Among compounds utilizing fluoxetine as an amine (43e48)
only one compound (48) with N-methylpiperazine residue has
shown weak spermicidal activity while others are inactive.
This suggests that the carbodithioic acid residue must be directly
attached to the fluoxetine structure for spermicidal activity. On
theotherhand, compound(48)exhibitedgoodanti-Trichomonas
activity along with moderate antifungal activity.
The most active compound (14) was tested for anti-
Candida activity against seven more Candida strains and

S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
2251
Table 2
Activity of compound 14 against Candida strains
Compound no.
Anti-Candida activity (mg/ml)
1
2
3
4
5
6
7
8
9
14
Fluconazole
6.25
0.5
3.125
0.5
6.25
2.0
6.25
1.0
6.25
4.0
3.125
1.0
6.25
1.0
6.25
0.25
6.25
0.25
1. Candida albicans, 2. Candida albicans MTCC 183, 3. Candida albicans MTCC 1346, 4. Candida albicans ATCC 10231, 5. Candida kuisei ATCC 6258, 6.
Candida parapsilosis ATCC 22019, 7. Candida albicans ATCC 10453, 8. Candida albicans ATCC 6019, 9. Candida albicans ATCC 66027.
results are given in Table 2. The compound showed very good
anti-Candida activity at 3.12e6.25 mg/ml concentrations.
ethyl acetate, aqueous sodium bicarbonate (10%, 1.5 equiv)
was added dropwise with stirring in an ice bath. The reaction
mixture was brought to room temperature and stirred till it be-
came clear. The ethyl acetate layer was separated, washed and
dried over sodium sulphate. Sodium sulphate was filtered off
and ethyl acetate was concentrated under reduced pressure in ro-
tavapor to get the free base. The free base (1, 0.1 mol) was dis-
solved in ethyl acetate and cooled in an ice bath with stirring.
NaOH (0.15 mol, 30%) was added dropwise followed by CS2
(0.12 mol) and kept stirring for 3 h. Later the reaction mixture
was brought to room temperature and stirring continued for an-
other 3 h. The ethyl acetate was concentrated under reduced
pressure in rotavapor and dried by evaporating few times with
acetone. The residue obtained was taken into hexane and cooled.
The separated white solid was filtered and dried in vacuum
desiccator.
4. Conclusion
The study demonstrated that incorporation of carbodithioic
acid residue directly into fluoxetine structure leads to com-
pounds with better antifungal and anti-Trichomonas activity
and N-methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-pro-
pyl]-carbodithioic acid S-(2-pyrrolidino-ethyl) ester (14) has
shown better profile than both fluoxetine and nonoxynol-9.
Further lead optimization may result into a potent dual-func-
tion spermicide. On the other hand, nonoxynol-9 has been pro-
posed for an additive therapy in metronidazole-resistant cases
of vaginal trichomoniasis [26]. However, nonoxynol-9 use is
associated with surfactant-type of cytotoxicity that may in-
crease susceptibility to HIVand STD infections, and therefore,
the non-surfactant structures 14, 16, 30, 35 and 48 (with more
potent anti-Trichomonas activity) may serve as safer options in
such cases.
Yield: 90%, mp 94 ꢂC. Anal. Calcd for C18H17F3NNaOS2.
Found: C, 53.29; H, 4.53; N, 3.29. Required: C, 53.06; H,
4.21; N, 3.44. IR (KBr, cmꢁ1): 2940.7, 2834.1, 1598.9,
1
1481.3, 1249.2, 1111.0, 966.0. H NMR (200 MHz, CDCl3):
d 2.01e2.50 (m, 2H, CH2CHOR), 3.20 (s, 3H, NeCH3),
3.98e4.32 (m, 2H, NeCH2), 5.23e5.25 (m, 1H, CHOR),
6.62 (d, 2H, J ¼ 8.0 Hz, ArH ortho to O), 7.00e7.08 (m,
7H, ArH of Ph, ortho to CF3).
5. Experimental section
5.1. Chemistry
Melting points were determined in open capillary tubes on an
electrically heated block and are uncorrected. IR spectra (nmax in
cmꢁ1) of the compounds were recorded on PerkineElmer’s
FTIR 8201 PC spectrophotometer. 1H NMR and 13C NMR spec-
tra were recorded on Bruker DRX-200 FT spectrometer in deu-
terated solvents with TMS as internal reference (chemical shifts
in d parts per million, J in hertz). Mass spectra were recorded on
Jeol/SX-102/DA-6000 FABMS spectrometer. Elemental analy-
ses were performed on Carlo Erba EA-1108 micro analyzer.
All compounds were analyzed for C, H, N and the results
obtained were within ꢀ0.4% of calculated values. Thin layer
chromatography was performed on precoated alumina plastic
plates (Aldrich). Anhydrous sodium sulphate was used as drying
agent. All chemicals and solvents are procured from Sigmae
Aldrich/Merck India Ltd. 1-Oxiranylmethyl-dialkylamines
(24e29) [27] and 1-dialkylamino carbodithioic acid sodium
salts (37e42) [17] were prepared by known procedures.
5.1.2. Synthesis of N-methyl-3-phenyl-3-[4-(trifluoromethyl)-
phenoxy]-propylamine carbodithioic acid esters (10e16)
N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-propyl-
amine carbodithioic acid sodium salt (2, 0.1 mol) was taken
into methanol and stirred at room temperature to which chloro
derivatives (3e9, 0.12 mol) were added. The reaction mixture
was further stirred at room temperature for 12 h (as monitored
by TLC). The methanol was concentrated under reduced pres-
sure in rotavapor and the residue was taken into ethyl acetate.
The ethyl acetate layer was washed and dried over sodium sul-
phate. Sodium sulphate was filtered off and ethyl acetate was
concentrated under reduced pressure in rotavapor. The com-
pounds were further purified by column chromatography
with ethyl acetate/hexane (1:3) mixture.
5.1.2.1. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-chloro-ethyl] ester
(10). Yield: 60%, oil. Anal. Calcd for C20H21ClF3NOS2. Found:
C, 53.49; H, 4.58; N, 3.07. Required: C, 53.62; H, 4.73; N, 3.13. IR
(neat, cmꢁ1): 3021.5, 2928.4, 1609.2, 1440.3, 1323.7, 1251.5,
5.1.1. Synthesis of N-methyl-3-phenyl-3-[4-(trifluoromethyl)-
phenoxy]-propylamine carbodithioic acid sodium salt (2)
To a pre-cooled mixture of N-methyl-3-phenyl-3-[4-(trifluor-
omethyl)-phenoxy]-propylamine hydrochloride (1, 0.3 mol) in
1
1111.6, 770.7. H NMR (200 MHz, CDCl3): d 2.09e2.15 (m,
2H, CH2CHOR), 2.92 (s, 3H, NeCH3), 3.12 (t, 2H, J ¼ 3.5 Hz,

2252
S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
SeCH2), 3.33e3.38 (m, 2H, NeCH2), 3.43 (t, 2H, J ¼ 7.1 Hz,
CH2eCl), 5.08e5.14 (m, 1H, CHOR), 6.81 (d, 2H,
J ¼ 8.5 Hz, ArH ortho to O), 7.25 (s, 5H, ArH of Ph), 7.36 (d,
2H, J ¼ 8.3 Hz, ArH ortho to CF3). MS (FAB): m/z 448
(Mþ þ 1), 401, 352, 327, 232, 207, 117.
pyrrolidine), 2.79e2.86 (m, 2H, NeCH2), 3.32e3.48 (m,
5H, NeCH3, SeCH2), 4.00e4.17 (m, 2H, NeCH2), 5.27e
5.30 (m, 1H, CHOR), 6.89 (d, 2H, J ¼ 8.7 Hz, ArH ortho
to O), 7.32 (s, 5H, ArH of Ph), 7.43 (d, 2H, J ¼ 8.0 Hz,
ArH ortho to CF3). MS (FAB): m/z 483 (Mþ þ 1), 412,
352, 248, 147, 117.
5.1.2.2. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-benzyl] ester (11). Yield:
95%, oil. Anal. Calcd for C25H24F3NOS2. Found: C, 62.93; H,
5.07; N, 3.26. Required: C, 63.14; H, 5.09; N, 2.95. IR (neat,
cmꢁ1): 3020.8, 2985.4, 1657.3, 1614.9, 1489.8, 1326.8,
5.1.2.6. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-morpholino-ethyl] ester
(15). Yield: 92%, oil. Anal. Calcd for C24H29F3N2O2S2.
Found: C, 57.67; H, 5.94; N, 5.98. Required: C, 57.81; H,
5.86; N, 5.62. IR (neat, cmꢁ1): 3017.1, 2931.7, 1615.5,
1487.9, 1325.6, 1218.1, 1118.3, 1066.4, 760.4. 1H NMR
(200 MHz, CDCl3): d 2.19e2.33 (m, 2H, CH2CHOR),
2.51e2.59 (m, 4H, 2 ꢃ N-CH2 of morpholine), 2.72e2.75
(m, 2H, NeCH2), 3.32e3.48 (m, 5H, NeCH3, SeCH2),
3.68e3.70 (m, 4H, 2 ꢃ OeCH2 of morpholine), 3.96e4.25
(m, 2H, NeCH2), 5.19e5.24 (m, 1H, CHOR), 6.86 (d, 2H,
J ¼ 8.3 Hz, ArH ortho to O), 7.32 (s, 5H, ArH of Ph), 7.43
(d, 2H, J ¼ 8.6 Hz, ArH ortho to CF3). MS (FAB): m/z 499
(Mþ þ 1), 412, 352, 248, 205, 113.
1
1216.8, 1119.2, 1068.0, 764.6. H NMR (200 MHz, CDCl3):
d 2.12e2.32 (m, 2H, CH2CHOR), 3.29e3.48 (m, 3H, Ne
CH3), 4.10e4.32 (m, 2H, NeCH2), 4.45 (s, 2H, SeCH2Ph),
5.19e5.31 (m, 1H, CHOR), 6.73e6.91 (m, 2H, ArH meta to
CF3), 7.24e7.37 (m, 10H, ArH of Ph ꢃ 2), 7.39e7.43 (m,
2H, ArH ortho to CF3). MS (FAB): m/z 476 (Mþ þ 1), 352,
314, 277, 248, 117, 91.
5.1.2.3. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-dimethyl amino-ethyl]
ester (12). Yield: 77%, oil. Anal. Calcd for C22H27F3N2OS2.
Found: C, 57.69; H, 5.69; N, 6.31. Required: C, 57.87; H,
5.96; N, 6.14. IR (neat, cmꢁ1): 3021.7, 2931.2, 1620.2,
1488.7, 1326.4, 1217.4, 1118.6, 1065.7, 761.0. 1H NMR
(200 MHz, CDCl3): d 2.29e2.34 (m, 8H, 2 ꢃ NeCH3,
CH2CHOR), 2.41e2.65 (m, 2H, NeCH2), 3.32e3.47 (m,
6H, NeCH3, SeCH2, NeCH2), 4.20e4.41 (m, 1H, Ne
CH2), 5.18e5.29 (m, 1H, CHOR), 6.89 (d, 2H, J ¼ 8.5 Hz,
ArH ortho to O), 7.32 (s, 5H, ArH of Ph), 7.43 (d, 2H,
J ¼ 8.3 Hz, ArH ortho to CF3). MS (FAB): m/z 457
(Mþ þ 1), 412, 391, 352, 307, 248, 117.
5.1.2.7. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-piperidino-ethyl] ester
(16). Yield: 75%, oil. Anal. Calcd for C25H31F3N2OS2.
Found: C, 60.13; H, 6.17; N, 5.98. Required: C, 60.46; H,
6.29; N, 5.64. IR (neat, cmꢁ1): 2933.8, 2855.4, 1614.5,
1384.2, 1324.2, 1248.8, 1116.4, 1062.0, 756.4. 1H NMR
(200 MHz, CDCl3): d 1.56e1.64 (m, 6H, 3 ꢃ CH2 of piperi-
dine), 2.30e2.33 (m, 2H, CH2CHOR), 2.44e2.46 (m, 6H,
2 ꢃ NeCH2 of piperidine and NeCH2), 3.31e3.48 (m, 5H,
NeCH3, SeCH2), 4.16e4.22 (m, 2H, NeCH2), 5.19e5.45
(m, 1H, CHOR), 6.89 (d, 2H, J ¼ 8.5 Hz, ArH ortho to O),
7.32 (s, 5H, ArH of Ph), 7.43 (d, 2H, J ¼ 8.6 Hz, ArH ortho
to CF3). MS (FAB): m/z 497 (Mþ þ 1), 412, 352, 248, 112.
5.1.2.4. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-diethyl amino-ethyl] ester
(13). Yield: 85%, oil. Anal. Calcd for C24H31F3N2OS2.
Found: C, 59.29; H, 6.28; N, 5.96. Required: C, 59.48; H,
6.45; N, 5.78. IR (neat, cmꢁ1): 3019.4, 2971.9, 2929.8,
1616.4, 1487.9, 1326.4, 1248.0, 1118.2, 1067.6, 759.4. 1H
NMR (200 MHz, CDCl3): d 1.22 (t, 6H, J ¼ 7.0 Hz, 2 ꢃ CH3
of ethyl), 2.21e2.31 (m, 2H, CH2CHOR), 2.56e2.66 (m,
6H, 3 ꢃ NeCH2 of ethyl), 3.30e3.48 (m, 6H, NeCH3, Se
CH2, NeCH2), 4.15e4.20 (m, 1H, NeCH2), 5.20e5.28 (m,
1H, CHOR), 6.89 (d, 2H, J ¼ 8.4 Hz, ArH ortho to O), 7.32
(s, 5H, ArH of Ph), 7.43 (d, 2H, J ¼ 8.3 Hz, ArH ortho to
CF3). MS (FAB): m/z 485 (Mþ þ 1), 469, 412, 307, 248,
205, 117.
5.1.3. Synthesis of N-methyl-[3-phenyl-3-(4-trifluoromethyl-
phenoxy)-propyl]-amino carbodithioic acid 3-
(dialkylamino)-2-hydroxy-propyl esters (30e35)
1-Oxiranylmethyl-dialkylamines (24e29, 0.01 mol) was
dissolved in methanol and N-methyl-3-phenyl-3-[4-(trifluoro-
methyl)-phenoxy]-propylamine carbodithioic acid sodium
salt (2, 0.01 mol) was added at room temperature with stir-
ring and the stirring was continued for 12 h until the reac-
tion was over (as monitored by TLC). The methanol was
evaporated under reduced pressure in rotavapor and the res-
idue was taken into ethyl acetate. The ethyl acetate layer
was washed and dried over sodium sulphate. Sodium sul-
phate was filtered off and ethyl acetate was evaporated un-
der reduced pressure in rotavapor to get the oily compound.
The oily compounds were further purified by column chro-
matography using ethyl acetate/hexane (1:3) mixture as
eluent.
5.1.2.5. N-Methyl-3-phenyl-3-[4-(trifluoromethyl)-phenoxy]-
propylamine carbodithioic acid S-[2-pyrrolidino-ethyl] ester
(14). Yield: 85%, oil. Anal. Calcd for C24H29F3N2OS2.
Found: C, 59.58; H, 5.97; N, 5.67. Required: C, 59.73; H,
6.06; N, 5.80. IR (neat, cmꢁ1): 3021.5, 2934.0, 1605.3,
1
1398.7, 1216.3, 1116.7, 1065.4, 760.7. H NMR (200 MHz,
CDCl3): d 1.79 (s, 4H, 2 ꢃ CH2 of pyrrolidine), 2.30e2.33
5.1.3.1. N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-pro-
pyl]-amino carbodithioic acid 3-(pyrrolidino)-2-hydroxy-propyl
ester (30). Yield: 72%, oil. Anal. Calcd for C25H31F3N2O2S2.
(m, 2H, CH2CHOR), 2.58 (s, 4H, 2 ꢃ NeCH2 of

S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
2253
Found: C, 58.39; H, 6.02; N, 5.58. Required: C, 58.57; H, 6.10; N,
5.46. IR (neat, cmꢁ1): 3399, 3012, 2931, 2369, 1615, 1326, 1248,
1
1116, 766. H NMR (200 MHz, CDCl3): d 1.65e1.77 (m, 4H,
Ph), 7.36 (d, 2H, J ¼ 8.0 Hz, ArH ortho to CF3). MS (FAB):
m/z 541 (Mþ þ 1), 507, 442, 255, 156, 138, 112.
CH2 ꢃ 2-pyrrolidine), 2.09e2.21 (m, 4H, NeCH2, CH2
CHOR), 2.55e2.65 (m, 4H, NeCH2 ꢃ 2-pyrrolidine), 3.19e
3.27 (m, 3H, NeCH3), 3.31e3.41 (m, 2H, NeCH2), 3.91e4.02
(m, 1H, CHOH), 4.03e4.18 (m, 2H, SeCH2), 5.16 (t, 1H
J ¼ 7.6 Hz, CHOR), 6.82 (d, 2H, J ¼ 8.3 Hz, ArH meta to
CF3), 7.19e7.25 (m, 5H, ArH oh Ph), 7.36 (d, 2H, J ¼ 8.3 Hz,
ArH ortho to CF3). MS (FAB): m/z 513 (Mþ þ 1), 442, 310,
248, 232, 205, 160, 110.
5.1.3.5.
N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino carbodithioic acid 3-(diethyl amino)-2-hy-
droxy-propyl ester (34). Yield: 71%, oil. Anal. Calcd for
C25H33F3N2O2S2. Found: C, 58.18; H, 6.29; N, 5.29. Re-
quired: C, 58.34; H, 6.29; N, 5.44. IR (neat, cmꢁ1): 3398,
1
3010, 2930, 2366, 1614, 1515, 1327, 1249, 1114, 836. H
NMR (200 MHz, CDCl3): d 2.12e2.32 (m, 6H, CH3 ꢃ 2),
2.44e2.50 (m, 2H, CH2 CHOR), 2.53e2.68 (m, 2H, Ne
CH2), 2.87e3.05 (m, 2H, NeCH2), 3.24e3.54 (m, 7H, Ne
CH3, NeCH2 ꢃ 2), 3.81e3.98 (m, 2H, SeCH2), 4.03e4.45
(m, 1H, CHOH), 5.31e5.36 (m, 1H, CHOR), 6.94 (d, 2H,
J ¼ 8.4 Hz, ArH meta to CF3), 7.26e7.45 (m, 7H, ArH of
Ph, ArH ortho to CF3). MS (FAB): m/z 515 (Mþ þ 1), 442,
352, 248, 232, 205.
5.1.3.2. N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino carbodithioic acid 3-(morpholino)-2-hydroxy-
propyl ester (31). Yield: 79%, oil. Anal. Calcd for
C25H31F3N2O3S2. Found: C, 56.65; H, 5.79; N, 5.52. Re-
quired: C, 56.80; H, 5.91; N, 5.30. IR (neat, cmꢁ1): 3403,
1
3010, 2924, 2372, 1616, 1491, 1327, 1218, 1116, 769. H
NMR (200 MHz, CDCl3): d 2.31e2.55 (m, 6H, 2 ꢃ NeCH2
morpholine, CH2 CHOR), 2.60e2.65 (m, 2H, NeCH2), 3.31
(s, 3H, NeCH3), 3.49e3.59 (m, 2H, NeCH2), 3.68e3.70
(m, 4H, OeCH2 morpholine), 3.95e3.98 (m, 2H, SeCH2),
4.10e4.13 (m, 1H, CHOH), 5.19e5.32 (m, 1H, CHOR),
6.89 (d, 2H, J ¼ 8.5 Hz, ArH meta to CF3), 7.22e7.32 (m,
5H, ArH of Ph), 7.43 (d, 2H, J ¼ 8.6 Hz, ArH ortho to CF3).
MS (FAB): m/z 529 (Mþ þ 1), 453, 442, 248, 232, 147, 117,
100.
5.1.3.6. N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino carbodithioic acid 3-(4-methyl-piperazino)-2-
hydroxy-propyl ester (35). Yield: 68%, oil. Anal. Calcd for
C26H34F3N3O2S2. Found: C, 57.42; H, 6.21; N, 7.89. Re-
quired: C, 57.65; H, 6.33; N, 7.76. IR (neat, cmꢁ1): 3399,
1
3029, 2929, 2374, 1615, 1326, 1249, 1113, 767. H NMR
(200 MHz, CDCl3): d 1.97e2.23 (m, 7H, NeCH3 piperazine,
NeCH2, CH2CHOR), 2.30e2.54 (m, 4H, NeCH2 piperazine),
2.84e2.98 (m, 4H, NeCH2 piperazine), 3.28 (s, 3H, NeCH3),
3.41e3.50 (m, 4H, NeCH2, SeCH2), 3.74e4.10 (m, 1H,
CHOH), 5.13e5.17 (m, 1H, CHOR), 6.82 (d, 2H,
J ¼ 8.5 Hz, ArH meta to CF3), 7.19e7.25 (m, 5H, ArH of
Ph), 7.35 (d, 2H, J ¼ 6.9 Hz, ArH ortho to CF3). MS (FAB):
m/z 542 (Mþ þ 1), 543 (Mþ þ 2), 442, 322, 251, 232, 218,
175, 117.
5.1.3.3.
N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino carbodithioic acid 3-(piperidino)-2-hydroxy-
propyl ester (32). Yield: 73%, oil. Anal. Calcd for
C26H33F3N2O2S2. Found: C, 59.05; H, 6.15; N, 5.55. Re-
quired: C, 59.29; H, 6.32; N, 5.32. IR (neat, cmꢁ1): 3428,
2922, 2833, 2381, 1652, 1616, 1325, 1249, 1114, 1066, 837.
1H NMR (200 MHz, CDCl3): d 0.75e0.80 (m, 2H, CH2 of pi-
peridine),
1.18e1.91
(m,
6H,
CH2 ꢃ 2-piperidine,
5.1.4. Synthesis of methyl-oxiranylmethyl-[3-phenyl-3-
(4-trifluoromethyl-phenoxy)-propyl]-amine (36)
CH2CHOR), 2.06e2.51 (m, 6H, NeCH2, NeCH2 ꢃ 2-piperi-
dine), 2.82e2.91 (m, 3H, NeCH3), 3.20e3.24 (m, 2H, Se
CH2), 3.41e3.45 (m, 2H, NeCH2), 4.08e4.19 (m, 1H,
CHOH), 5.07 (t, 1H, J ¼ 7.8 Hz, CHOR), 6.89 (d, 2H,
J ¼ 5.5 Hz, ArH ortho to O), 7.32e7.39 (m, 5H, ArH oh
Ph), 7.42 (d, 2H, J ¼ 8.3 Hz, ArH ortho to CF3). MS (FAB):
m/z 527 (Mþ þ 1), 451, 232, 175, 117, 98.
To a pre-cooled mixture of N-methyl-3-phenyl-3-[4-(trifluor-
omethyl)-phenoxy]-propylamine hydrochloride (1, 0.3 mol) in
ethyl acetate, aqueous sodium bicarbonate (10%, 1.5 equiv)
was added dropwise with stirring in an ice bath. The reaction
mixture was brought to room temperature and stirred until it be-
came clear. The ethyl acetate layer was separated, washed and
dried over sodium sulphate. Sodium sulphate was filtered off
and ethyl acetate was concentrated under reduced pressure in
rotavapor to get the free base. The free base (0.1 mol) was dis-
solved in methanol cooled in an ice bath and triethylamine
(0.015 mol) was added. Epichlorohydrin (0.012 mol) was added
dropwise to the reaction mixture and stirring was continued in
and ice bath for 3 h until the reaction was completed (as mon-
itored by TLC). The methanol was evaporated under reduced
pressure in rotavapor and the residue was taken into ethyl ace-
tate. The solid triethylamine hydrochloride was filtered and the
ethyl acetate layer was washed and dried over sodium sulphate.
Sodium sulphate was filtered and ethyl acetate was concentrated
under reduced pressure in rotavapor. The formed compound
was used as it is without further purification.
5.1.3.4.
N-Methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-
propyl]-amino carbodithioic acid 3-(azepino)-2-hydroxy-pro-
pyl ester (33). Yield: 72%, oil. Anal. Calcd for
C27H35F3N2O2S2. Found: C, 59.79; H, 6.38; N, 5.02. Re-
quired: C, 59.98; H, 6.52; N, 5.18. IR (neat, cmꢁ1): 3428,
1
2927, 2855, 2373, 1617, 1326, 1249, 1115, 758. H NMR
(200 MHz, CDCl3): d 1.18 (s, 4H, CH2 ꢃ 2-azepine), 1.51e
1.62 (m, 4H, CH2 ꢃ 2-azepine), 2.10e2.26 (m, 2H,
CH2CHOR), 2.60e2.71 (m, 6H, NeCH2, NeCH2 ꢃ 2-aze-
pine), 3.16e3.27 (m, 3H, NeCH3), 3.41e3.67 (m, 2H, Ne
CH2), 3.84e3.92 (m, 2H, SeCH2), 4.09e4.21 (m, 1H,
CHOH), 5.16 (t, 1H, J ¼ 7.8 Hz, CHOR), 6.82 (d, 2H,
J ¼ 8.0 Hz, ArH ortho to O), 7.19e7.25 (m, 5H, ArH oh

2254
S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
5.1.5. Synthesis of dialkylamino carbodithioic acid
2-hydroxy-3-{methyl-[3-phenyl-3-(4-trifluoromethyl-
phenoxy)-propyl]-amino}-propyl esters (43e48)
(s, 3H, NeCH3), 2.47 (t, 2H, J ¼ 8.0 Hz, NeCH2), 2.61 (d,
2H, J ¼ 8.0 Hz, NeCH2CHOH), 3.31e3.37 (quintet, 1H,
CHOH), 3.63e3.66 (m, 1H, SeCH2), 3.67e3.81 (m, 3H, Ne
CH2 piperidine, SeCH2), 3.94e3.96 (m, 2H, NeCH2 piperi-
dine), 5.32e5.19 (m, 1H, CHOR), 6.88 (d, 2H, J ¼ 10.0 Hz,
ArH meta to CF3), 7.29e7.36 (m, 5H, ArH of Ph), 7.41 (d,
2H, J ¼ 10.0 Hz, ArH ortho to CF3). MS (FAB): m/z 527
(Mþ þ 1), 348, 322, 216, 128, 100.
Methyl-oxiranylmethyl-[3-phenyl-3-(4-trifluoromethyl-
phenoxy)-propyl]-amine (36, 0.01 mol) was dissolved in
methanol and 1-dialkylamino carbodithioic acid sodium salts
(37e42, 0.01 mol) were added at room temperature with stir-
ring. The stirring was continued for 6 h till the reaction was
over (as monitored by TLC). The methanol was evaporated
under reduced pressure in rotavapor and the residue was taken
into ethyl acetate. The ethyl acetate layer was washed and
dried over sodium sulphate. Sodium sulphate was filtered off
and ethyl acetate was evaporated under reduced pressure in
rotavapor to get the oily compound. The compounds were fur-
ther purified by column chromatography using ethyl acetate/
hexane (1:3) mixture as eluent.
5.1.5.4. Azepine-1-carbodithioic acid 2-hydroxy-3-{methyl-[3-
phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-propyl ester
(46). Yield: 91%, oil. Anal. Calcd for C27H35F3N2O2S2. Found:
C, 59.69; H, 6.31; N, 5.32. Required: C, 59.98; H, 6.52; N, 5.18.
IR (neat, cmꢁ1): 3436.5, 3029.5, 2936.2, 2373.9, 1630.3, 1489.9,
1
1326.4, 1217.7, 1117.4, 760.8. H NMR (200 MHz, CDCl3):
d 1.57e1.6 (m, 4H, 2 ꢃ CH2 of azepine), 1.78e1.92 (m, 4H,
2 ꢃ CH2 of azepine), 2.08e2.21 (m, 2H, CH2CHOR), 2.29
(s, 3H, NeCH3), 2.45e2.48 (m, 2H, NeCH2), 2.58e2.64 (m,
2H, NeCH2CHOH), 3.31e3.38 (m, 1H, SeCH2), 3.61e3.64
(m, 1H, SeCH2), 3.89e3.96 (m, 3H, CHOH, NeCH2 of aze-
pine), 4.14e4.22 (m, 2H, NeCH2 of azepine), 5.21e5.27 (m,
1H, CHOR), 6.89 (d, 2H, J ¼ 8.3 Hz, ArH ortho to O), 7.32 (s,
5H, ArH of Ph), 7.41 (d, 2H, J ¼ 8.5 Hz, ArH ortho to CF3).
MS (FAB): m/z 541 (Mþ þ 1), 507, 348, 322, 232, 142, 100.
5.1.5.1. Pyrrolidine-1-carbodithioic acid 2-hydroxy-3-{methyl-
[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-propyl
ester (43). Yield: 89%, oil. Anal. Calcd for C25H31F3N2O2S2.
Found: C, 58.82; H, 6.36; N, 5.28. Required: C, 58.57; H,
6.10; N, 5.46. IR (neat, cmꢁ1): 3019.5, 2975.4, 1614.5,
1515.7, 1436.2, 1327.0, 1217.6, 1119.2, 1063.5, 762.4. 1H
NMR (200 MHz, CDCl3): d 1.93e2.10 (m, 6H, 2 ꢃ CH2 of pyr-
rolidine, CH2CHOR), 2.29 (s, 3H, NeCH3), 2.47 (t, 2H,
J ¼ 5.1 Hz, NeCH2), 2.61 (d, 2H, J ¼ 6.7 Hz, NeCH2CHOH),
3.02e3.41 (m, 1H, CHOH), 3.62e3.69 (m, 4H, 2 ꢃ NeCH2 of
pyrrolidine), 3.89e3.95 (m, 2H, SeCH2), 5.25e5.27 (m, 1H,
CHOR), 6.89 (d, 2H, J ¼ 8.5 Hz, ArH ortho to O), 7.32 (s,
5H, ArH of Ph), 7.41 (d, 2H, J ¼ 8.4 Hz, ArH ortho to CF3).
MS (FAB): m/z 513 (Mþ þ 1), 479, 348, 322, 251, 204, 114.
5.1.5.5. Benzyl methyl-amino-1-carbodithioic acid 2-hydroxy-3-
{methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-
propyl ester (47). Yield: 66%, oil. Anal. Calcd for
C29H33F3N2O2S2. Found: C, 61.73; H, 5.79; N, 5.12. Required:
C, 61.90; H, 5.91; N, 4.98. IR (neat, cmꢁ1): 3405.7, 3031.4,
2932.5, 2372.7, 1615.4, 1480.0, 1386.0, 1324.9, 1251.1,
1
1165.4, 1114.5, 761.5. H NMR (200 MHz, CDCl3): d 2.01
5.1.5.2. Morpholine-1-carbodithioic acid 2-hydroxy-3-
{methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-
amino}-propyl ester (44). Yield: 63%, oil. Anal. Calcd for
C25H31F3N2O3S2. Found: C, 56.58; H, 5.79; N, 5.57. Re-
quired: C, 56.80; H, 5.91; N, 5.30. IR (neat, cmꢁ1): 3434,
(t, 2H, J ¼ 7.3 Hz, CH2CHOR), 2.12e2.20 (m, 3H, NeCH3),
2.31 (s, 3H, NeCH3), 2.49 (d, 2H, J ¼ 8.4 Hz, NeCH2CHOH),
2.60 (t, 2H, J ¼ 6.2 Hz, NeCH2), 3.18e3.29 (m, 2H, SeCH2),
3.34e3.46 (m, 1H, CHOH), 3.73e3.74 (m, 1H, CH2 of benzyl),
3.87e3.42 (m, 1H, CH2 of benzyl), 5.23e5.29 (m, 1H, CHOR),
6.89 (d, 2H, J ¼ 8.6 Hz, ArH ortho to O), 7.25e7.32 (m, 10H,
ArH of Ph), 7.41 (d, 2H, J ¼ 8.2 Hz, ArH ortho to CF3). MS
(FAB): m/z 563 (Mþ þ 1), 529, 364, 348, 322, 251, 218, 117.
1
3024, 2928, 1637, 1460, 1327, 1218, 1165, 1116, 763. H
NMR (200 MHz, CDCl3): d 2.16e2.23 (m, 2H, CH2CHOR),
2.38 (s, 3H, NeCH3), 2.56 (t, 2H, J ¼ 5.0 Hz, NeCH2),
2.67e2.76 (m, 2H, NeCH2), 3.31 (t, 1H, J ¼ 5.0 Hz,
CHOH), 3.53e3.55 (m, 1H, SeCH2), 3.65e3.75 (m, 4H,
NeCH2 morpholine), 3.93e4.32 (m, 5H, OeCH2 morpho-
line, SeCH2), 5.26 (t, 1H, J ¼ 3.0 Hz, CHOR), 6.89 (d,
2H, J ¼ 5.6 Hz, ArH meta to CF3), 7.30e7.33 (m, 5H, Ph),
7.42 (d, 2H, J ¼ 5.6 Hz, ArH ortho to CF3). MS (FAB): m/
z 528 (Mþ), 402, 366, 322, 220, 130.
5.1.5.6. 4-Methyl-piperazine-1-carbodithioic acid 2-hydroxy-3-
{methyl-[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-
propyl ester (48). Yield: 71%, oil. Anal. Calcd for
C26H34F3N3O2S2. Found: C, 57.58; H, 6.25; N, 7.95. Required:
C, 57.65; H, 6.33; N, 7.76. IR (neat, cmꢁ1): 3422.9, 2941.3,
2851.2, 2375.0, 1615.0, 1425.5, 1324.9, 1247.0, 1116.4,
1066.5, 758.4. 1H NMR (200 MHz, CDCl3): d 1.74e2.07
(m, 2H, CH2CHOR), 2.28 (s, 3H, NeCH3), 2.32 (s, 3H,
NeCH3), 2.45e2.48 (m, 4H, 2 ꢃ NeCH2 of piperazine),
2.58e2.61 (m, 2H, NeCH2), 3.30e3.36 (m, 1H, CHOH),
3.40e3.60 (m, 2H, NeCH2CHOH), 3.62e3.71 (m, 2H, Ne
CH2 of piperazine), 3.92e3.96 (m, 2H, NeCH2 of piperazine),
4.27e4.38 (m, 2H, SeCH2), 5.23e5.26 (m, 1H, CHOR), 6.88
(d, 2H, J ¼ 10.0 Hz, ArH ortho to O), 7.32 (s, 5H, ArH
of Ph), 7.41 (d, 2H, J ¼ 10.0 Hz, ArH ortho to CF3). MS
5.1.5.3. Piperidine-1-carbodithioic acid 2-hydroxy-3-{methyl-
[3-phenyl-3-(4-trifluoromethyl-phenoxy)-propyl]-amino}-propyl
ester (45). Yield: 87%, oil. Anal. Calcd for C26H33F3N2O2S2.
Found: C, 59.11; H, 6.16; N, 5.55. Required: C, 59.29; H,
6.32; N, 5.32. IR (neat, cmꢁ1): 3431.8, 2937.9, 2857.5,
2369.0, 1615.2, 1428.8, 1325.3, 1246.8, 1116.3, 1066.8,
760.7. 1H NMR (200 MHz, CDCl3): d 1.58e1.71 (m, 6H,
CH2 ꢃ 3 of piperidine), 2.03e2.20 (m, 2H, CH2CHOR), 2.30

S.T.V.S. Kiran Kumar et al. / European Journal of Medicinal Chemistry 43 (2008) 2247e2256
2255
(FAB): m/z 542 (Mþ þ 1), 508, 366, 322, 251, 218, 175,
Micro titer plates were incubated at 35 ꢂC. MICs were re-
corded after 48 h of incubation.
143, 117.
Acknowledgement
5.2. Biology
Authors are thankful to Mrs. Tara Rawat for her technical
assistance. S.T.V.S.K.K. is thankful to Ministry of Health
and Family Welfare, Government of India for grant of research
fellowship. L.K. is thankful to UGC for the research
fellowship.
5.2.1. Spermicidal activity
Minimum effective (spermicidal) concentration (MEC) was
determined by the standard procedure [7]. Briefly, the test
compounds were dissolved in a minimum volume of DMSO
and diluted with physiological saline (0.85% NaCl in distilled
water) to make a 1.0% (10 mg/ml) solution. The solutions
were further diluted serially with saline. A spermicidal test
was performed with each dilution starting from 1.0% until
the minimum effective concentration (MEC) was arrived.
For this purpose 0.05 ml of liquefied human semen was added
to 0.25 ml of test solution and vortexed for 10 s. A drop of the
mixture was immediately placed on a microscope slide, cov-
ered with a cover glass and immediately examined under
a phase contrast microscope in five fields of vision. The re-
sults were scored positive if 100% spermatozoa became im-
motile in 20 s. The MEC was determined in three individual
semen samples from different donors. The minimum concen-
tration of compound capable of killing 100% sperm in w20 s
in ‘‘all’’ the semen samples was denoted as MEC and is re-
corded in Table 1.
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