Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as novel Capravirine analogues

Article abstract of DOI:10.1016/j.bmc.2005.04.024

Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-imidazol-2-ylthio) acetamide (3a-c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio] acetate (10), 2-[5-alk

Full text of DOI:10.1016/j.bmc.2005.04.024

Bioorganic & Medicinal Chemistry 13 (2005) 4209–4220
Synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles as
novel Capravirine analogues
Yasser M. Loksha,a Ahmed A. El-Barbary,b Mahmoud A. El-Badawi,b
Claus Nielsenc and Erik B. Pedersena,*
aNucleic Acid Center,ꢀ Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark
bDepartment of Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
cRetrovirus Laboratory, Department of Virology, State Serum Institute, DK-2300 Copenhagen, Denmark
Received 14 December 2004; revised 8 April 2005; accepted 12 April 2005
Available online 17 May 2005
Abstract—Different analogues of Capravirine (AG-1549) or S-1153 were prepared by synthesis of 2-(5-benzyl-4-isopropyl-1-methyl-
2,3-dihydro-1H-imidazol-2-ylthio)acetamide (3a–c), ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-2-ylthio]acetate (10),
2-[5-alkyl-4-substituted 1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamides (12a–f), and 2-[5-benzyl-1-(benzyloxymethyl)-4-iso-
propyl-1H-imidazol-2-ylthio]acetamides (14a–l) from their corresponding amino acids through a sequence of reactions: Dakin–West
reaction, hydrolysis, condensation with thiocyanate derivatives, alkylation with 2-iodoacetamide and ethyl chloroacetate, and
coupling with 4-pyridylmethyl chloride, ethoxymethyl chloride and benzyloxymethyl chloride. All the synthesized compounds
were screened for their activity against HIV-1 (wild type) and some of them (especially Capravirine like structures) were found
active.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
AZT, ddI, or ddC. However, this selectivity together
with the relatively unconserved amino acid sequence in
the drug-binding site has also made most types of NNR-
TIs susceptible to the rapid selection of drug resistant
vira, particularly when administered in monotherapy
either in vitro or in vivo.6,7 All reported NNRTI-resis-
tant mutations occur in residues surrounding the inhib-
itor-binding site on the enzyme.5 A commonly observed
drug-resistant virus contains the single amino acid
mutation Tyr181Cys.8 Additionally, a Lys103Asn muta-
tion appears relatively frequently in vivo giving resis-
tance to many NNRTIs.9 The crystal structures of a
range of NNRTIs, including nevirapine, 1051U91, R-
APA, HEPT, MKC-442, and TNK-651, complexed with
RT5,12–15, show the importance of the interactions of
the aromatic moiety of the inhibitors and the neighbor-
ing residues Tyr181, Tyr188, Phe227, and Trp229. The
significant contribution of Tyr181 to the binding energy
of many NNRTIs is demonstrated by the frequent selec-
tion of an escape mutation at this codon; normally with
a change to cysteine.8 The crystal structures have also
revealed details of the orientation and geometry of the
aromatic interactions between the inhibitors and the
surrounding residues. Comparison of the bound conform-
ations of these NNRTIs showed that the orientation
A major challenge facing medicinal chemistry over the
next few years will be the development of drugs with sig-
nificantly improved resistance profiles for chronic use as
anti-HIV combination therapy. An important compo-
nent of such regimens will be non-nucleoside inhibitors
of HIV-1 reverse transcriptase (NNRTIs). NNRTIs is
a class of structurally diverse aromatic compounds, such
as nevirapine, delavirdine, efavirenz, MKC-442 (emivi-
rine), TIBO, and thiocarboxanilides.1 Structural studies
have revealed that NNRTIs inhibit HIV-1 RT by bind-
˚
ing to an allosteric site, approximately 10 A from the
polymerase active site,2–4 causing a distortion of the cata-
lytic aspartate triad.5 The high selectivity of NNRTIs
for HIV-1 RT over HIV-2 RT and cellular polymerases
contributes to lower cellular toxicity levels than
observed with nucleoside analogues (NRTIs) such as
Keywords: a-Aminoketones; Imidazole-2-thiones; Non-nucleoside
reverse transcriptase inhibitors; Human imminodeficiency virus.
ꢀ A research centre funded by The Danish National Research Foun-
dation for studies on nucleic acid chemical biology.
*
Corresponding author. Tel.: +45 6550 2555; fax: +45 6615 8780;
e-mail: ebp@chem.sdu.dk
0968-0896/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2005.04.024

4210
Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
Figure 1.
of the aromatic groups of many of these inhibitors are
conserved within the binding site.10 An outlier in this
analysis is the rather weak binding inhibitor HEPT,
which has its phenyl ring rotated by 20ꢁ–25ꢁ due to
the loss of interaction with Tyr181.11 A comparative
analysis of complexes of HEPT analogues has suggested
structural features that give conformational changes in
Tyr181 necessary for tight binding in this series.11 Ki-
netic studies of reverse transcriptase that contain the
Tyr181Cys mutation show the rate of dissociation of
the inhibitor from the enzyme increases relative to wild
type.12
Scheme 1.
nine17 with aliphatic acid anhydride (propionic and
isobutyric) and pyridine to afford the a-acylaminoke-
tones (4e,f) in the same manner as described for 4a by
Cleland and Niemann18 and for 4b by Loksha et al.19
Capravirine (formerly known as S-1153 and AG-1549) is
one of the most promising non-nucleoside inhibitors of
HIV-1 reverse transcriptase currently under develop-
ment as a potential anti-AIDS drug, because it has a
favorable profile of resilience to many drug resistance
mutations.13 However, the use of Capravirine has re-
cently been restricted due to vasculitis (an inflammation
of the blood vessels) in animals that received high doses
of Capravirine.14
Hydrolysis of compounds 4e,f with 6 M hydrochloric
acid afforded the a-aminoketone hydrochlorides (5e,f)
in the same procedure previously described by Sheppard
et al.20 for 4a and by Loksha et al.19 for 5b. Treatment of
5e,f with potassium thiocyanate furnished 5-alkyl-4-
(3,5-dimethylbenzyl)-1,3-dihydroimidazole-2-thiones
6e,f (Scheme 2).
The potassium salt of 4-benzyl-5-ethyl-1,3-dihydroimi-
dazole-2-thione (6a) in anhydrous dimethylformamide
was treated with ethyl chloroacetate to afford ethyl
(5-benzyl-4-ethyl-1H-imidazol-2-ylthio)acetate (7). Reflux-
ing compound 7 with aqueous ammonia in ethanol
furnished 2-(5-benzyl-4-ethyl-1H-imidazol-2-ylthio)acet-
amide (8a) in low yield. Coupling compound 7 with
In this article, the synthesis of novel Capravirine
analogues was achieved by synthesis of 2-(aminocarbon-
ylmethylthio)-1H-imidazoles and they were screened for
their biological activity against HIV-1 (Fig. 1).
2. Chemistry
The Dakin–West reaction15,16 was applied on DL-valine
by refluxing it with a mixture of phenylacetic acid
anhydride and pyridine to afford N-(1-isopropyl-2-oxo-
3-phenylpropyl)-2-phenylacetamide, which was not
isolated, but hydrolyzed with 6 M hydrochloric acid to
furnish 3-amino-4-methyl-1-phenylpentan-2-one hydro-
chloride (1). 5-Benzyl-4-isopropyl-1-substituted 1,3-
dihydroimidazole-2-thiones (2a–c) were obtained by
refluxing compound 1 with isothiocyanate derivatives
(methyl, ethyl, and cyclohexyl) in benzene in the pres-
ence of triethylamine followed by refluxing in acetic acid
to convert the thiourea derivatives into the cyclized
imidazoles (2a–c). The potassium salt of each of
compounds 2a–c was treated with 2-iodoacetamide to
afford 2-(5-benzyl-4-isopropyl-1-methyl-2,3-dihydro-1H-
imidazol-2-ylthio)acetamide (3a–c) (Scheme 1).
Compound 6a has been previously prepared by Buller-
well and Lawson21 and compounds 6b–d have been pre-
pared by Loksha et al.19,22 The Dakin–West
reaction15,16 was applied on 3,5-dimethylphenylala-
Scheme 2.

Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
4211
ethoxymethyl chloride in methylene chloride in the pres-
ence of N-ethyldiisopropylamine (EDIA) both afforded
the two possible isomers due to coupling at N-1 and
N-3 of the imidazole ring to furnish ethyl [4-benzyl-1-
(ethoxymethyl)-5-ethyl-1H-imidazol-2-ylthio]acetate (9)
and ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imi-
dazol-2-ylthio]acetate (10) (Scheme 3).
The assignment of structure of compounds 9 and 10 was
confirmed by NOE. Irradiation of NCH2O in com-
pound 9 showed 1.8% NOE in CH3CH2 at C-5 and no
NOE in CH2Ph was detected, while irradiation of the
same group in compound 10 showed no NOE in
CH3CH2 at C-4, but showed 1.7% NOE in CH2Ph.
The potassium salt of each of compounds 6a–f was ob-
tained by stirring the compound in methanolic potas-
sium hydroxide solution. The salt was treated with 2-
iodoacetamide to afford S-alkylated compounds (8a–f).
The two possible tautomers of 8 were obtained as a mix-
ture, which showed doubling of the carbon atoms or line
broadening in the 13C NMR spectra. In some cases,
extensive line broadening caused disappearance of the
lines. Reaction of compounds 8a–f with 4-pyridylmethyl
chloride hydrochloride using sodium hydride afforded
coupling next to the ethyl group (compounds 11a–c)
and next to the benzyl or the cyclohexylmethyl group
(compounds 12a–c, Capravirine analogues) when
R3 was an ethyl group. Only one product (compounds
12d–f) was obtained when R3 was an isopropyl group
due to a larger steric hindrance of the isopropyl group
than for the ethyl group (Scheme 4). Each of the pairs
of compounds 11a–c and 12a–c could not be separated
by column chromatography and they were isolated as
mixture in the ratio of 1:1.2 (11a, 12a), 1:1.2 (11b, 12b)
and 1:1 (11c, 12c). None of the mixtures showed signifi-
cant biological activity against HIV-1 as described later
on and therefore no further attempts were made to
separate the mixtures.
Scheme 4.
methylene chloride in the presence of N-ethyldiisopro-
pylamine (EDIA). Coupling occurred next to the ethyl
group (compounds 13c–f) and next to the benzyl or
the cyclohexylmethyl group (compounds 14a–l). In all
cases when R3 was an isopropyl group, only one product
(compounds 14g–l) was obtained due to the steric hin-
drance of the isopropyl group (Scheme 4).
Alkylation of compounds 8a–f with ethoxymethyl chlo-
ride and benzyloxymethyl chloride was achieved in
The assignment of the structure of compounds 12a–f,
13c–f, and 14a–l was confirmed by NOE. Irradiation
of CH2N in each of compounds 13e,f showed 1.9%,
1.8% NOE, respectively, in CH3CH2 at C-5 and no
NOE was observed in CH2 at C-4 for the same irradia-
tion. Similarly, 2.1%, 2.7%, 1.3%, 1.3%, 2.2%, 1.4%,
1.4%, 1.8%, 1.9% NOE in CH2 at C-5 in compounds
12e,f, 14a,b,e,g,i,j,l, respectively, were detected when
CH2N was irradiated and no NOE was observed for
irradiation of the same group in R3 at C-4.
3. Results of the anti-HIV-1 assay and discussion
The test for activity against HIV-1 was performed in
MT-4 cell cultures infected with wild type HIV-1 (strain
IIIB). Some of the synthesized compounds showed
activity against HIV-1 as shown in Table 1 and the rest
of the compounds are inactive at 100 lM.
Scheme 3.

4212
Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
Table 1. Anti-viral activity of compounds 2–14 against HIV-1 in MT-4
cells
Merck. Microanalyses were carried out at Chemical
Laboratory II at University of Copenhagen, Denmark.
Compound
IC50 (lM)a
CC50 (lM)b
SIc
5.1. 3-Amino-4-methyl-1-phenylpentan-2-one (1)
2b
5.06
32.77
4.46
0.62
4.84
42.17
30.57
0.31
3.75
1.33
2.48
22.85
10.96
0.31
0.15
2.11
4.29
0.03
40.72
>100
>100
38.61
>100
>100
>100
64.04
>100
>100
37.56
>100
>100
>100
29.43
>100
84.32
>100
8
>3
5f
6e
A mixture of DL-valine (3.4 g, 30 mmol), anhyd pyridine
(12 mL, 0.15 mol), and phenylacetic acid anhydride
(38 g, 0.15 mol) was heated in an oil bath at 150 ꢁC for
6 h until carbon dioxide was no longer evolved. The ex-
cess of pyridine, acid anhydride, and the acid formed
were removed under reduced pressure and the residue
was treated with an aqueous satd solution of sodium
bicarbonate (30 mL) to remove the acidic components
and extracted with ether (3 · 50 mL). The combined
ethereal extracts were dried over sodium sulfate (5 g), fil-
tered and evaporated till dryness under vacuo. The resi-
due was treated with 6 M hydrochloric acid (165 mL)
and ethanol (90 mL). The mixture was refluxed for 7 h,
cooled, and the solvents were removed under reduced
pressure. Absolute ethanol (10 mL) was added to the res-
idue and the hydrochloride 1 was precipitated by addi-
tion of ether (50 mL), which was filtered off and dried.
>22.4
62.3
6f
11b + 12b
11c + 12c
12d
>20.7
>2.4
>3.3
12e
12f
206.5
>26.6
>75.2
15.1
14c
14d
14e
14g
>4.4
>9.1
14i
14j
>322.5
196.2
>47.4
19.7
14k
14l
MKC-442
>3333
a 50% Inhibitory concentration required to inhibit HIV-1 (wild type).
b 50% Cytotoxic concentration.
c Selectivity index: ratio CC50/IC50. IC50
1
.
Yield 1.2 g (17%) as a white solid; mp 208–210 ꢁC. H
NMR (DMSO-d6): d 0.89 (d, 3H, J = 6.9 Hz, CH3CH),
1.06 (d, 3H, J = 6.9 Hz, CH3CH), 2.42–2.52 (m, 1H,
(CH3)2CH), 4.02 (CH2Ph), 4.17 (br s, 1H, CH), 7.21–
7.36 (m, 5H, Ph), 8.50 (br s, 3H, NHþ3 ). 13C NMR
(DMSO-d6): d 16.70 (CH3CH), 18.95 (CH3CH), 27.95
[(CH3)2CH], 46.10 (CH2Ph), 62.63 (CH), 126.71,
128.19, 129.79, 133.52 (Carom), 204.15 (CO).
The substituents in the 4- and 5-positions of the imi-
dazole ring were selected from the work of Tanaka
et al.23 and Hopkins et al.24 on uracil derivatives. Sulfur
was introduced to the 2-position in order to have a
resemblance to S-DABO derivatives.25 The activity is in-
creased when ethyl is replaced by an isopropyl at the 4-
position of the imidazole ring as shown when the ethyl
compounds 6e, 12a–c, 14a,c–f are compared with the
corresponding isopropyl compounds 6f, 12d–f, 14g,i–l.
Also, the activity of the compounds was affected by
the group at the 5-position of the imidazole ring in the
order 3,5-Me2Ph > Cy > Ph in compounds 12e,
14i,j > 12f, 14k,l > 12d, 14g,h, respectively. The alk-
oxymethyl substituent at the 1-position of imidazole ring
(compounds 14g,i,k with an ethoxymethyl group and
compounds 14j,l with a benzyloxymethyl group) showed
higher activity than compounds containing 4-pyridyl-
methyl group at the 1-position (compounds 12a–f).
5.2. General procedure for the synthesis of 5-benzyl-4-
isopropyl-1-substituted 1,3-dihydroimidazole-2-thiones
(2a–c)
A mixture of 3-amino-4-methyl-1-phenylpentan-2-one
hydrochloride (1) (0.46 g, 2 mmol), isothiocyanate deriv-
ative (methyl, ethyl, and cyclohexyl) (2 mmol), and tri-
ethylamine (0.28 mL, 2 mmol) in anhyd benzene
(20 mL) was refluxed for 3 h. The solvent was removed
under reduced pressure, then acetic acid (15 mL) was
added to the residual material and the mixture was re-
fluxed for 2 h. The solvent was concentrated to 5 mL,
then water (20 mL) was added and the solid product
formed was filtered off, washed with ether (20 mL),
and dried to afford compounds 2a–c.
4. Conclusion
Although activities were found against HIV-1 for the
novel Capravirine analogues, they were in all cases lower
than the uracil reference compound MKC-442.
5.2.1. 5-Benzyl-4-isopropyl-1-methyl-1,3-dihydroimidazole-
2-thione (2a). Yield 153 mg (30%) as a white solid; mp
133–135 ꢁC. 1H NMR (DMSO-d6): d 1.18 (d, 6H,
J = 7.1 Hz, (CH3)2CH), 30.02 [hept, 1H, J = 7.1 Hz,
(CH3)2CH], 3.19 (s, 3H, CH3N), 3.92 (s, 2H, CH2Ph),
7.11–7.34 (m, 6H, HNH and Ph), 12.07 (s, 1H, NH).
13C NMR (DMSO-d6): d 21.86 [(CH3)2CH], 23.48
[(CH3)2CH], 30.53 (CH3N), 121.72 (C-4), 126.36,
127.77, 128.58, 130.36 (Carom), 138.06 (C-5), 160.14
(C@S). Anal. Calcd for C14H18N2SÆ0.5H2O: C, 65.84;
H, 7.50; N, 10.97. Found: C, 65.84; H, 7.52; N, 11.09.
5. Experimental
NMR spectra were recorded on a Varian Gemini 2000
NMR spectrophotometer at 300 MHz for 1H and
75 MHz for 13C with TMS as an internal standard. EI
mass spectra were recorded on a Finnigan MAT SSQ
710. MALDI spectra were recorded on a 4.7 T Ultima
Fourier transform Mass spectrometer (IonSpec, Irvine,
CA). Melting points were determined in a Buchi melting
¨
point apparatus. The silica gel (0.040–0.063 mm) used
for column chromatography was purchased from
5.2.2. 5-Benzyl-1-ethyl-4-isopropyl-1,3-dihydroimidazole-
2-thione (2b). Yield 240 mg (46%) as a white solid; mp
162–164 ꢁC. 1H NMR (CDCl3):
J = 7.1 Hz, CH3CH2), 1.30 [d, 6H, J = 6.9 Hz,
d
1.09 (t, 3H,

Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
4213
(CH3)2CH], 2.93 [hept, 1H, J = 7.0 Hz, (CH3)2CH],
3.84–3.91 (m, 4H, CH3CH2 and CH2Ph), 7.07–7.32
(m, 5H, Ph), 11.95 (s, 1H, NH). 13C NMR (CDCl3): d
13.71 (CH3CH2), 22.55 [(CH3)2CH], 24.53 [(CH3)2CH],
29.23 (CH2Ph), 39.53 (CH3CH2), 121.29 (C-4), 126.82,
127.69, 128.74, 131.91 (Carom), 137.45 (C-5), 158.18
(C@S). EI-MS: m/z 260 (100%, M+). Anal. Calcd for
C15H20N2SÆ0.25H2O: C, 68.01; H, 7.80; N, 10.57.
Found: C, 67.87; H, 7.57; N, 10.40.
M+), 273 (100%). Anal. Calcd for C17H23N3OSÆ0.5H2O:
C, 62.55; H, 7.41; N, 2.87. Found: C, 62.59; H, 7.16; N,
2.61.
5.3.3. 2-(5-Benzyl-1-cyclohexyl-4-isopropyl-1H-imidazol-
2-ylthio)acetamide (3c). Yield 310 mg (81%) as a white
1
solid; mp 165–167 ꢁC. H NMR (CDCl3): d 1.01–1.27
[m, 11H, (CH3)CH and Hcy], 1.43–2.00 (m, 5H, Hcy),
2.90 [hept, 1H, J = 6.8 Hz, (CH3)2CH], 6.64–3.72 (m,
3H, CH–N and CH2S), 3.94 (s, 2H, CH2Ph), 5.63 (br
s, 1H, HNH), 7.05–7.30 (m, 5H, Ph), 9.37 (br s,
HNH). 13C NMR (CDCl3): d 23.13 [(CH3)2CH], 24.87
[(CH3)2CH], 26.14, 31.25, 56.46 (Ccy), 29.78 (CH2Ph),
36.57 (CH2S), 126.29 (C-4), 126.48, 127.81, 128.53,
138.84 (Carom), 138.53 (C-2), 144.50 (C-5). EI-MS: m/z
371 (51%, M+), 313 (100%). Anal. Calcd for
C21H29N3OSÆ0.6H2O: C, 65.97; H, 7.96; N, 10.99.
Found: C, 65.78; H, 7.66; N, 10.73.
5.2.3. 5-Benzyl-1-cyclohexyl-4-isopropyl-1,3-dihydroimid-
azole-2-thione (2c). Yield 510 mg (79%) as a white solid;
1
mp 130–132 ꢁC. H NMR (DMSO-d6): d 0.89–1.22 [m,
11H, (CH3)2CH and Hcy] 1.48–1.60 (m, 4H, Hcy), 2.92
(br s, 1H, CH–N), 3.07 [hept, 1H, J = 7.2 Hz,
(CH3)2CH], 3.95 (s, 2H, CH2Ph), 7.11–7.36 (m, 5H,
Ph), 11.96 (s, 1H, NH). 13C NMR (DMSO-d6): d
21.77 [(CH3)2CH], 23.51 [(CH3)2CH], 24.53, 25.57,
28.35, 56.03 (Ccy), 28.44 (CH2Ph), 121.55 (C-4),
126.29, 128.39, 138.78 (Carom),127.72 (C-4), 130.93 (C-
5), 159.17 (C@S). EI-MS: 314 (62%, M+), 232 (100%).
Anal. Calcd for C19H26N2SÆ0.5H2O: C, 70.54; H, 8.41;
N, 8.66. Found: C, 70.10; H, 8.41; N, 8.92.
5.4. General procedure for the synthesis of a-acylamino-
ketones (4e,f)
A mixture of DL-3,5-dimethylphenylalanine (5.8 g, 30
mmol), anhydrous pyridine (25 mL) and aliphatic acid
anhydride (propionic or isobutyric) (0.3 mol) was heated
in an oil bath at 150 ꢁC for 12 h until carbon dioxide was
no longer evolved. The excess of pyridine, acid anhydride
and the resulting acid were removed under reduced pres-
sure, the residue was treated with an aqueous satd solu-
tion of sodium bicarbonate (20 mL) to remove the acidic
components and then extracted with ether (3 · 50 mL).
After removal of the solvent from the dried ether extract,
the residue was treated with petroleum ether (60–80 ꢁC)
(50 mL) and left at 5 ꢁC overnight. The solid product
formed was filtered off, washed with petroleum ether
(60–80 ꢁC), dried, and recrystallized from xylene/petro-
leum ether (60–80 ꢁC) to give compounds 4e,f.
5.3. General procedure for the synthesis of 2-(5-benzyl-4-
isopropyl-1-substituted 1H-imidazol-2-ylthio)acetamides
(3a–c)
To a solution of potassium hydroxide (0.056 g, 1 mmol)
in methanol (10 mL), compound 2 (1 mmol) was added
and the mixture was stirred for 0.5 h. 2-Iodoacetamide
(0.186 g, 1 mmol) was added to the reaction mixture
and it was stirred at rt for an additional hour. The sol-
vent was removed under reduced pressure and water
(15 mL) was added to the residual material. The solid
product formed was filtered off and recrystallized from
ethanol/water to give 3a–c.
5.3.1. 2-(5-Benzyl-4-isopropyl-1-methyl-1H-imidazol-2-yl-
thio)acetamide (3a). Yield 230 mg (76%) as a white solid;
mp 148–150 ꢁC. H NMR (DMSO-d6): d 1.36 [d, 6H,
5.4.1. N-[1-(3,5-Dimethylbenzyl)-2-oxobutyl]propion-amide
(4e). Yield 4.1 g (52%) as a white solid; mp 90–92 ꢁC. 1H
NMR (DMSO-d6): d 0.88 (t, 3H, J = 7.2 Hz, CH3CH2),
0.93 (t, 3H, J = 7.8 Hz, CH3CH2), 2.07 (q, 2H,
J = 7.2 Hz, CH2CH3), 2.22 (s, 6H, 2 · CH3), 2.29–2.51
(m, 2H, CH2CH3), 2.66 (dd, 1H, J = 9.4, 13.6 Hz,
HCH–CH), 2.91 (dd, 1H, J = 5.0, 13.9 Hz, HCH–CH),
4.34–4.41 (m, 1H, CH2CHNH), 6.8 (s, 3H, Harom), 8.15
(d, 1H, J = 7.2 Hz, NH). 13C NMR (DMSO-d6): d 7.32
(CH2CH3), 9.72 (CH2CH3), 20.78 (2 · CH3) 28.14
(CH2CH3), 32.20 (CH2CH3), 35.31 (CH2CH), 59.09
(CH), 126.73, 127.62, 136.87, 137.66 (Carom), 172.92
(CONH), 209.76 (COCH). EI-MS: m/z 261 (4%, M+),
148 (100%). Anal. Calcd for C16H23NO2: C, 73.53; H,
8.87; N, 5.36. Found: C, 73.29; H, 8.75; N, 5.36.
1
J = 6.6 Hz, (CH3)2CH], 2.91 [hept, 1H, J = 6.6 Hz,
(CH3)2CH], 3.32 (s, 3H, CH3–N), 3.58 (s, 2H, CH2S),
3.96 (s, 2H, CH2Ph), 7.07–7.31 (m, 6H, HNH and Ph),
7.79 (br s, 1H, HNH). 13C NMR (DMSO-d6): d 23.02
[(CH3)2CH], 25.61 [(CH3)2CH], 28.47 (CH2Ph), 30.69
(CH3–N), 37.29 (CH2S), 125.99 (C-4), 126.10, 127.74,
128.48, 138.87 (Carom), 137.60 (C-2), 144.23 (C-5),
169.82 (C@O); HRMS (MALDI) m/z calcd for
C16H22N3OS+ (MH+) 304.1471, found 304.1478.
5.3.2. 2-(5-Benzyl-1-ethyl-4-isopropyl-1H-imidazol-2-yl-
thio)acetamide (3b). Yield 260 mg (79%) as a white solid;
1
mp 136–138 ꢁC. H NMR (DMSO-d6): d 0.88 (t, 3H,
J = 7.0 Hz, CH3CH2), 1.15 [d, 6H, J = 6.8 Hz,
(CH3)2CH], 2.90 [hept, 1H, J = 6.8 Hz, (CH3)2CH],
3.65 (s, 2H, CH2S), 3.75 (q, 2H, J = 7.0 Hz, CH3CH2),
3.96 (s, 2H, CH2Ph), 7.09–7.32 (m, 6H, HNH and Ph),
7.87 (br s, 1H, HNH). 13C NMR (DMSO-d6): d 15.43
(CH3CH2), 23.06 [(CH3)2CH], 25.59 [(CH3)2CH], 28.36
(CH2Ph), 37.17 (CH2S), 38.59 (CH2–N), 125.02 (C-4),
126.17, 127.82, 128.45, 137.39 (Carom), 139.17 (C-5),
144.31 (C-2), 169.85 (C@O). EI-MS: m/z 317 (43%,
5.4.2. N-[1-(3,5-Dimethylbenzyl)-3-methyl-2-oxobutyl]iso-
butyramide (4f). Yield 1.3 g (15%) as a white solid; mp
115–116 ꢁC. 1H NMR (CDCl3):
d 1.02 (d, 3H,
J = 6.6 Hz, CH3), 1.03 (d, 3H, J = 6.7 Hz, CH3), 1.11
(d, 3H, J = 6.7 Hz, CH3), 1.13 (d, 3H, J = 6.3 Hz,
CH3), 2.27 (s, 6H, 2 · CH3), 2.36 [hept, 1H,
J = 7.0 Hz, CH(CH)3], 2.65 [hept, 1H, J = 6.8 Hz,
CH(CH)3], 2.93 (dd, 1H, J = 5.8, 13.7 Hz, HCH–CH),
3.0 (dd, 1H, J = 7.1, 13.6 Hz, HCH–CH), 5.00 (q, 1H,

4214
Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
J = 7.2 Hz, CH2CH–NH), 6.09 (d, 1H, J = 6.8 Hz, CH–
NH), 6.72 (s, 2H, Harom), 6.86 (s, 1H, Harom). 13C NMR
(CDCl3): d 16.87, 18.98, 19.26, 19.53 (4 · CH3), 21.14
(2 · CH3), 35.45 [CH(CH3)2], 3.66 (CH2), 38.68
[CH(CH3)2], 56.66 (CH–NH), 127.05, 128.58, 135.74,
137.94 (Carom), 176.22 (CONH), 212.89 (COCH). EI-
MS: m/z 289 (5%, M+), 148 (100%). Anal. Calcd for
C18H27NO2: C, 74.70; H, 9.40; N, 4.84. Found: C,
74.19; H, 9.71; N, 4.89.
J = 7.3 Hz, CH3CH2), 2.22 (s, 6H, 2 · CH3), 2.37 (q,
2H, J = 7.4 Hz, CH2CH3), 3.58 (s, 2H, CH2–Ar), 6.81
(s, 3H, Harom), 11.66 (s, 1H, NH), 11.71 (s, 1H, NH).
13C NMR (DMSO-d6): 13.88 (CH3CH2), 16.42 (CH2-
CH3), 20.82 (2 · CH3), 28.77 (CH2–Ar), 122.28 (C-4),
125.98 (C-5), 125.85, 127.54, 137.20, 138.84 (Carom).
EI-MS: m/z 246 (100%, M+). Anal. Calcd for
C14H18N2SÆ0.25H2O: C, 67.03; H, 7.23; N, 11.17.
Found: C, 66.62; H, 7.11; N, 11.07.
5.5. General procedure for the synthesis of a-aminoketone
hydrochlorides (5e,f)
5.6.2. 4-(3,5-Dimethylbenzyl)-5-isopropyl-1,3-dihydroimid-
azole-2-thione (6f). Yield 1.0 g (84%) as a white solid; mp
230–232 ꢁC. H NMR (DMSO-d6): d 1.11 [d, 6H, J =
1
A solution of compound 4 (10 mmol) in 6 M hydrochlo-
ric acid (55 mL) and ethanol (30 mL) was refluxed for
10 h, the solvent was removed under reduced pressure.
The residue was dissolved in ethanol (5 mL) and the
hydrochloride 5e,f was precipitated by the addition of
ether (30 mL), filtered off, and washed with ether
(30 mL).
7.0 Hz, (CH3)2CH], 2.22 (s, 6H, 2 · CH3), 2.91 [hept,
1H, J = 6.9 Hz, CH(CH3)2], 3.58 (s, 2H, CH2), 6.79 (s,
2H, Harom), 6.81 (s, 1H, Harom), 11.63 (s, 1H, NH),
11.74 (s, 1H, NH). 13C NMR (DMSO-d6): d 20.83
(2 · CH3), 21.73 [(CH3)2CH], 23.42 (CH), 28.80 (CH2),
121.17 (C-4), 125.80, 127.52, 137.19, 138.94 (Carom),
130.10 (C-5), 158.98 (C@S). EI-MS: m/z 260 (100%,
M+). Anal. Calcd for C15H20N2SÆ0.35H2O: C, 67.55;
H, 7.82; N, 10.50. Found: C, 67.37; H, 7.56; N, 10.37.
5.5.1. 2-Amino-1-(3,5-dimethylphenyl)pentan-3-one hydro-
chloride (5e). Yield 1.8 g (65%) as a white solid; mp
163–165 ꢁC. 1H NMR (DMSO-d6): d 0.86 (t, 3H,
J = 7.1 Hz, CH3CH2), 2.24 (s, 6H, 2 · CH3), 2.28–2.52
(m, 2H, CH2CH3), 2.98 (dd, 1H, J = 7.5, 13.7 Hz, HCH–
CH), 3.13 (dd, 1H, J = 6.0, 13.7 Hz, HCH–CH), 4.28
(br s, 1H, CH) 6.87 (s, 2H, Harom), 6.90 (s, 1H, Harom),
8.58 (s, 3H, NH3). 13C NMR (DMSO-d6): d 6.77
(CH3CH2), 20.79 (2 · CH3), 33.60 (CH2CH3), 35.38
(CH2–CH), 58.33 (CH), 126.96, 128.54, 134.75, 137.53
(Carom), 20.80 (CO). Anal. Calcd for C13H20ClNOÆ0.25-
H2O: C, 63.40; H, 8.39; N, 5.79. Found: C, 63.20; H,
8.16; N, 5.82.
5.7. Ethyl (5-benzyl-4-ethyl-1H-imidazol-2-ylthio)-ace-
tate (7)
Compound 6a (2.2 g, 10 mmol) was added to a stirred
solution of potassium carbonate (1.38 g, 10 mmol) in
dimethylformamide (15 mL) and the mixture was stirred
at rt for 1 h. Ethyl chloroacetate (1.06 mL, 10 mmol)
was added dropwise to the reaction mixture and stirred
for additional 3 h at rt. The solvent was removed under
reduced pressure and the residue was treated with water
(20 mL). The product was filtered off and recrystallized
from ethanol/water to afford compound 7. Yield 1.6 g
(53%) as a white solid; mp 53–55 ꢁC. 1H NMR
(DMSO-d6): d 1.04 (t, 3H, J = 7.4 Hz, CH3CH2), 1.11
(t, 3H, CH3CH2), 2.45 (br s, 2H, CH3CH2), 3.72 (br s,
2H, CH2Ph), 3.78 (s, 2H, CH2S), 4.02 (q, 2H,
J = 7.2 Hz, CH3CH2O), 7.15–7.23 (m, 5H, Ph), 11.10
(br s, 1H, NH). 13C NMR (DMSO-d6): 13.80
(CH3CH2), 14.39 (CH3CH2O), 17.15 (br s, CH3CH2),
32.44 (br s, CH2Ph), 35.25 (CH2S), 60.71 (CH3CH2O),
125.44, 128.09, 134.48 (Carom), 168.89 (CO). EI-MS:
m/z 304 (96%, M+), 230 (100%). Anal. Calcd for
C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C,
63.84; H, 6.61; N, 9.12.
5.5.2. 2-Amino-1-(3,5-dimethylphenyl)-4-methylpentan-3-
one hydrochloride (5f). Yield 2.0 g (80%) as a white solid;
1
mp 192–194 ꢁC. H NMR (DMSO-d6): d 0.85 (d, 3H,
J = 6.4 Hz, CH3CH), 1.03 (d, 3H, J = 6.9 Hz, CH3CH),
2.25 (s, 6H, 2 · CH3), 2.57 (hept, 1H, J = 6.8 Hz,
(CH3)2CH), 2.99 (dd, 1H, J = 7.3, 13.9 Hz, HCH–CH),
3.16 (dd, 1H, J = 6.0, 13.8 Hz, HCH–CH), 4,48 (br s,
1H, CH2–CH), 6.89 (s, 2H, Harom), 6.92 (s, 1H, Harom),
8.61 (s, 3H, NH3). 13C NMR (DMSO-d6): d 16.32
(CH3CH), 18.75 (CH3CH), 20.78 (2 · CH3), 35.57
(CH3CH), 37.71 (CH2–CH), 56.67 (CH2CH), 127.05,
128.57, 134.49, 137.51 (Carom), 209.91 (CO). Anal. Calcd
for C14H22ClNOÆ0.5H2O: C, 63.50; H, 8.76; N, 5.29.
Found: C, 63.41; H, 8.42; N, 5.49.
5.8. 2-(5-Benzyl-4-ethyl-1H-imidazol-2-ylthio)acetamide
(8a)
5.6. General procedure for the synthesis of 5-alkyl-4-(3,5-
dimethylbenzyl)-1,3-dihydroimidazole-2-thiones (6e,f)
A mixture of compound 7 (0.6 g, 2 mmol) and 30%
aqueous ammonia (10 mL) in ethanol (20 mL) was
heated at 60 ꢁC for 6 h. The solvent was evaporated un-
der reduced pressure. The residue was treated with
water, filtered off, dried, and chromatographed on a sil-
ica gel column with ethyl acetate to afford compound 8a.
To a hot solution of potassium thiocyanate (0.48 g,
5 mmol) in water (20 mL) was added compound 5
(5 mmol). The reaction mixture was refluxed for 3 h
and cooled to rt. The solid product formed was filtered
off, washed with ether (20 mL) and dried to give com-
pounds 6e,f.
1
Yield 0.1 g (18%) as a white solid; mp 128–130 ꢁC. H
NMR (DMSO-d6): d 1.06 (t, 3H, J = 7.4 Hz, CH3CH2),
2.45 (q, 2H, J = 6.8 Hz, CH3CH2), 3.61 (s, 2H, CH2Ph),
3.76 (s, 2H, CH2S), 7.16–7.28 (m, 5H, Harom), 7.72 (s,
2H, NH2), 11.91 (br s, 1H, NH). 13C NMR (DMSO-
d6): 14.43 (CH3CH2), 36.87 (CH2S), 125.64, 128.13,
5.6.1. 4-(3,5-Dimethylbenzyl)-5-ethyl-1,3-dihydroimidazole-
2-thione (6e). Yield 0.91 g (81%) as a white solid; mp
250–252 ꢁC. 1H NMR (DMSO-d6): d 1.05 (t, 3H,

Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
4215
135.83 (Carom), 170.00 (C@O). EI-MS: m/z 275 (100%,
M+). Anal. Calcd for C14H17N3OS: C, 61.07; H, 6.22;
N, 15.26. Found: C, 60.53; H, 6.24; N, 14.96.
and recrystallized from ethanol/water to give com-
pounds 8a–f.
5.10.1. 2-[5-(3,5-Dimethylbenzyl)-4-ethyl-1H-imidazol-2-yl-
thio]acetamide (8b). Yield 1.7 g (80%) as a white solid;
mp 160–162 ꢁC. H NMR (DMSO-d6): d 1.07 (t, 3H,
5.9. Synthesis of compounds 9 and 10
1
To a solution of compound 7 (0.61 g, 2 mmol) in meth-
ylene chloride (15 mL) under nitrogen was added N-eth-
yldiisopropylamine (EDIA) (0.36 mL, 2 mmol) followed
by addition of ethoxymethyl chloride (2 mmol). The
reaction mixture was stirred for 3 h at rt and quenched
with water (20 mL). Methylene chloride (20 mL) was
added and the two layers were separated. The organic
layer was dried (sodium sulfate), filtered, and the solvent
was removed under reduced pressure. The residual
material was chromatographed on a silica gel column
with CH2Cl2/EtOAc (5:1, v/v) to afford compounds 9
and 10.
J = 7.5 Hz, CH3CH2), 2.20 (s, 6H, 2 · CH3), 2.44 (q,
2H, J = 7.5 Hz, CH3CH2), 3.60 (s, 2H, CH2–Ar), 3.71
(s, 2H, CH2S), 6.77 (s, 3H, Harom), 7.15 (s, 1H, HNH),
7.73 (s, 1H, HNH), 11.89 (s, 1H, NH). 13C NMR
(DMSO-d6): d 14.34, 14.50 (CH3CH2), 17.11, 19.54
(CH3CH2), 20.85 (2 · CH3), 29.52, 32.45 (CH2–Ar),
36.76, 36.89 (CH2S), 125.85, 126.03, 126.93, 135.80,
136.83, 137.17, 140.89 (Carom), 127.38, 129.74 (C-4),
135.62, 135.98 (C-5), 139.27, 139.56 (C-2), 170.06
(C@O). HRMS (MALDI) m/z calcd for C16H22N3OS+
(MH+) 304.1510, found 304.1483.
5.10.2. 2-[5-(Cyclohexylmethyl)-4-ethyl-1H-imidazol-2-yl-
thio]acetamide (8c). Yield 1.6 g (82%) as a white solid;
mp 150–152 ꢁC. 1H NMR (DMSO-d6): d 0.82–0.93
(m, 2H, Hcy), 1.06–1.21 (m, 6H, CH3CH2 and Hcy),
1.45–1.61 (m, 6H, Hcy), 2.16–2.51 (m, 4H, CH3CH2
and CH2Cy), 3.58 (s, 2H, CH2S), 7.17 (s, 1H, HNH),
7.77 (s, 1H, HNH), 11.78 (s, 1H, NH). 13C NMR
(DMSO-d6): d 14.48, 14.57 (CH3CH2), 17.07, 19.55
(CH3CH2), 25.91, 26.01, 25.63, 32.39, 32.58 (Ccy),
31.30, 34.07 (CH2–Cy), 36.88, 37.93 (CH2S), 125.69,
129.67 (C-4), 135.30, 139.39 (C-5), 135.61, 139.36
(C-2), 170.14 (C@O). EI-MS: m/z 281 (43%, M+), 141
(100%). Anal. Calcd for C14H23N3OSÆ05H2O: C, 57.90;
H, 8.33; N, 14.47. Found: C, 57.71; H, 8.05; N, 14.43.
5.9.1. Ethyl [4-benzyl-1-(ethoxymethyl)-5-ethyl-1H-imid-
azol-2-ylthio]acetate (9). Yield 0.15 g (20%) obtained as
an oil. H NMR (CDCl3): d 1.04 (t, 3H, J = 7.5 Hz,
1
CH3CH2), 1.18 (t, 3H, J = 7.1 Hz, CH3CH2O), 1.19 (t,
3H, J = 7.2 Hz, CH3CH2OCO), 2.58 (q, 2H,
J = 7.5 Hz, CH3CH2), 3.49 (q, 2H, J = 7.1 Hz,
CH3CH2O), 3.77 (s, 2H, CH2S), 3.87 (s, 2H, CH2Ph),
4.09 (q, 2H, J = 7.2 Hz, CH3CH2OCO), 5.33 (s, 2H,
NCH2O), 7.14–7.27 (m, 5H, Ph). 13C NMR (CDCl3):
d 14.01 (CH3CH2), 14.39 (CH3CH2), 14.85 (CH3CH2),
17.01 (CH3CH2), 33.55 (CH2Ph), 37.19 (CH2S), 61.50
(CH3CH2OCO), 63.71 (CH3CH2O), 73.26 (NCH2O),
125.74, 128.14, 128.43, 137.98 (Carom), 132.13 (C-4),
137.88 (C-5), 140.58 (C-2), 169.17 (COO). FAB MS:
(CDCl3 + NBA) m/z 363 (100%, MH+).
5.10.3. 2-(5-Benzyl-4-isopropyl-1H-imidazol-2-ylthio)acet-
amide (8d). Yield 1.17 g (58%) as a white solid; mp
158–160 ꢁC. 1H NMR (DMSO-d6): d 1.11 [d, 6H,
J = 6.7 Hz, (CH3)2CH], 2.93 [hept, 1H, J = 6.7 Hz,
(CH3)2CH], 3.61 (s, 2H, CH2Ph), 3.78 (s, 2H, CH2S),
7.15–7.28 (m, 5H, Harom), 7.77 (s, 2H, NH2), 11.88 (br
s, 1H, NH). 13C NMR (DMSO-d6): d 22.73 [(CH3)2CH],
24.59 [br s, (CH3)2CH], 31.80 (br s, CH2Ph), 36.76
(CH2S), 125.66, 128.10, 128.14, 136.06 (Carom), 140.70
(br s, C-2), 170.12 (C@O). EI-MS: m/z 289 (100%,
M+). Anal. Calcd for C15H19N3OSÆ0.5H2O: C, 60.38;
H, 6.76; N, 14.08. Found: C, 60.50; H, 6.50; N, 14.10.
5.9.2. Ethyl [5-benzyl-1-(ethoxymethyl)-4-ethyl-1H-imi-
dazol-2-ylthio]acetate (10). Yield 0.25 g (35%) obtained
1
as an oil. H NMR (CDCl3): d 1.08 (t, 3H, J = 7.0 Hz,
CH3CH2O), 1.20 (t, 3H, J = 7.2 Hz, CH3CH2OCO),
1.21 (t, 3H, J = 7.5 Hz, CH3CH2), 2.55 (q, 2H,
J = 7.5 Hz, CH3CH2), 3.36 (q, 2H, J = 7.0 Hz,
CH3CH2O), 3.79 (s, 2H, CH2S), 4.00 (s, 2H, CH2Ph),
4.11 (q, 2H, J = 7.2 Hz, CH3CH2OCO), 5.13 (s, 2H,
NCH2O), 7.07–7.29 (m, 5H, Ph). 13C NMR (CDCl3):
d 14.03 (CH3CH2), 14.42 (CH3CH2), 14.69 (CH3CH2),
20.43 (CH3CH2), 29.22 (CH2Ph), 37.13 (CH2S), 61.49
(CH3CH2OCO), 63.58 (CH3CH2O), 73.38 (NCH2O),
126.38, 127.91, 128.51, 138.55 (Carom), 126.86 (C-4),
138.53 (C-5), 142.84 (C-2), 169.11 (COO). MALDI-
MS: m/z 263 (100%, MH+). Anal. Calcd for
C19H26N2O3S: C, 62.95; H, 7.23; N, 7.73. Found: C,
62.99; H, 7.36; N, 7.63.
5.10.4. 2-[5-(3,5-Dimethylbenzyl)-4-isopropyl-1H-imidazol-
2-ylthio]acetamide (8e). Yield 1.15 g (52%) as a white
solid; mp 130–132 ꢁC. 1H NMR (DMSO-d6):
d
1.12 [d, 6H, J = 6.9 Hz, (CH3)2CH], 2.21 (s, 6H,
2 · CH3), 2.93 [hept, 1H, J = 6.9 Hz, (CH3)2CH], 3.61
(s, 2H, CH2S), 3.69 (s, 2H, CH2Ph), 6.76 (s, 3H, Harom),
7.17 (s, 1H, HNH), 7.78 (s, 1H, HNH). 13C NMR
(DMSO-d6): d 20.85 (2CH3), 22.71 [(CH3)2CH], 24.61
[(CH3)2CH], 31.22 (CH2Ar), 36.74 (CH2S), 125.91,
127.11, 135.93, 136.95 (Carom), 140.34 (C-2), 170.13
(C@O). EI-MS: m/z 317 (100%, M+). Anal. Calcd for
C17H23N3OSÆ0.5H2O: C, 62.55; H, 7.41; N, 12.87.
Found: C, 62.71; H, 7.17; N, 12.89.
5.10. General procedure for the synthesis of 2-(4-alkyl-5-
substituted 1H-imidazol-2-ylthio)acetamides (8a–f)
Compound 6 (7 mmol) was added to a solution of potas-
sium hydroxide (0.4 g, 7 mmol) in methanol (15 mL)
and the mixture was stirred for 0.5 h. 2-Iodoacetamide
(1.3 g, 7 mmol) was added to the mixture and it was stir-
red at rt for 1 h. The solvent was removed under reduced
pressure, and water (25 mL) was added to the residual
material and the solid product formed was filtered off
5.10.5. 2-[5-(Cyclohexylmethyl)-4-isopropyl-1H-imidazol-
2-ylthio]acetamide (8f). Yield 1.7 g (82%) as a white
1
solid; mp 156–158 ꢁC. H NMR (DMSO-d6): d 0.82–

4216
Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
0.93 (m, 2H, Hcy), 1.09–1.15 [m, 9H, (CH3)2CH and
Hcy], 1.46–1.61 (m, 6H, Hcy), 2.22, 2.32 (2 · d, 2H,
J = 6.8, 7.0 Hz, CH2–Cy), 2.76, 2.87 [2 · hept, 1H,
J = 6.4, 6.4 Hz, (CH3)2CH], 3.57, 3.60 (s, 2H, CH2S),
7.16 (s, 1H, HNH), 7.78, 7.86 (2 · s, 1H, HNH), 11.68
(s, 1H, NH). 13C NMR (DMSO-d6): d 22.68, 23.16
[(CH3)2CH], 23.96, 25.31 [(CH3)2CH], 25.89, 26.06,
25.59, 25.72, 30.59, 32.39, 32.61, 36.55 (Ccy), 31.22,
34.13 (CH2–Cy), 36.78, 37.89 (CH2S), 124.72, 134.42
(C-4), 133.88, 143.41 (C-5), 135.28, 135.59 (C-2),
170.18, 170.29 (C@O). EI-MS: m/z 295 (10%, M+), 55
(100%). Anal. Calcd for C15H25N3OSÆ0.25H2O: C,
60.06; H, 8.57; N, 14.01. Found: C, 60.00; H, 8.41; N,
13.82.
2.60 (q, 2H, J = 7.5 Hz, CH3CH2), 3.69 (s, 2H, CH2S),
3.79 (s, 2H, CH2S), 4.90 (s, 2H, CH2N), 5.40 (s, 1H,
HNH), 5.72 (s, 1H, HNH), 6.54 (s, 3H, Harom), 6.71
(d, 2H, J = 5.1 Hz, Hpy), 6.77 (s, 1H, Harom), 6.82 (s,
2H, Harom), 6.88 (d, 2H, J = 5.1 Hz, Hpy), 8.01 (s, 1H,
HNH), 8.46 (d, 2H, J = 5.1 Hz, Hpy), 8.56 (d, 2H,
J = 5.1 Hz, Hpy), 8.83 (s, 1H, HNH). 13C NMR
(CDCl3): d 14.38, 14.53 (CH3CH2), 16.96, 20.35
(CH3CH2), 21.13, 2.24 (4 · CH3), 29.35, 33.29 (CH2Ar),
36.22, 36.64 (CH2S), 46.53, 46.79 (CH2N), 120.74,
120.80, 145.06, 145.34, 149.97, 150.34 (Cpy), 125.63,
126.29 (C-4), 126.98, 127.64, 128.33, 137.29, 137.79,
137.85, 138.28 (Carom), 139.98, 141.99 (C-2), 139.63,
140.11 (C-5), 172.02, 172.17 (CO); EI-MS: m/z 394
(100%, M+).
5.11. General procedure for the synthesis of compounds
11a–c and 12a–f
5.11.3. 2-[4-(Cyclohexylmethyl)-5-ethyl-1-(pyridin-4-yl-
methyl)-1H-imidazol-2-ylthio]acetamide (11c) and 2-[5-
(cyclohexylmethyl)-4-ethyl-1-(pyridin-4-ylmethyl)-1H-imid-
azol-2-ylthio]acetamide (12c). Yield 0.15 g (40%). 1H
NMR (CDCl3): d 0.81–1.29 (m, 16H, 2 · CH3CH2 and
Hcy), 1.54–1.71 (m, 12H, Hcy), 2.27 (d, 2H, J = 7.3 Hz,
CH2Cy), 2.36–2.54 (m, 6H, CH2Cy, 2 · CH3CH2),
3.51 (s, 2H, CH2S), 3.52 (s, 2H, CH2S), 5.09 (s, 2H,
CH2N), 5.12 (s, 2H, CH2N), 5.86 (br s, 1H, HNH),
6.86 (d, 4H, J = 4.3 Hz, Hpy), 8.56 (d, 4H, J = 4.5,
Hpy), 8.75 (br s, 1H, HNH), 8.84 (br s, 1H, HNH).
13C NMR (CDCl3): d 13.93, 14.64 (CH3CH2), 16.82,
20.36 (CH3CH2), 26.06, 26.44, 26.96, 26.18, 33.02,
33.18, 38.36 (Ccy), 34.75, 31.29 (CH2Cy), 46.47, 46.61
(CH2N), 120.68, 145.57, 145.60, 150.24, 150.28 (Cpy),
127.35, 131.29 (C-4), 138.01, 141.59 (C-5), 138.93,
139.22 (C-2), 172.17, 172.24 (CO). EI-MS: m/z 372
(100%, M+).
Compound 8 (1 mmol) was dissolved in dimethylform-
amide (10 mL) and sodium hydride (0.09 g, 55% suspen-
sion in paraffin oil, 2 mmol) was added to the solution
portionwise under ice cooling. The reaction mixture
was stirred for 0.5 h and 4-pyridylmethyl chloride
hydrochloride (0.164 g, 1 mmol) was added portionwise
to the reaction mixture under ice cooling and stirring at
rt was continued for 4 h. The solvent was removed un-
der reduced pressure and the residual material was trea-
ted with water (15 mL) and filtered off. The precipitate
was dried, and chromatographed on a silica gel column
with EtOAc/MeOH (20:1, v/v) to give compounds 11a–c
and 12a–f. We were unable to separate compounds
11a–c and 12a–c from each other by column
chromatography.
5.11.1. 2-[4-Benzyl-5-ethyl-1-(pyridin-4-ylmethyl)-1H-imid-
azol-2-ylthio]acetamide (11a) and 2-[5-benzyl-4-ethyl-
1-(pyridin-4-ylmethyl)-1H-imidazol-2-ylthio]acetamide
5.11.4. 2-[5-Benzyl-4-isopropyl-1-(pyridin-4-ylmethyl)-1H-
imidazol-2-ylthio]acetamide (12d). Yield 0.8 (30%) as a
white solid; mp 158–160 ꢁC. H NMR (DMSO-d6): d
1
1
(12a). Yield 0.15 g (41%). H NMR (CDCl3): d 0.88 (t,
3H, J = 7.4 Hz, CH3CH2), 1.19 (t, 3H, J = 7.4 Hz,
CH3CH2), 2.39 (q, 2H, J = 7.4 Hz, CH3CH2), 2.53 (q,
2H, J = 7.4 Hz, CH3CH2), 3.43 (s, 2H, CH2S), 3.49 (s,
2H, CH2S), 3.69 (s, 2H, CH2Ph), 3.80 (s, 2H, CH2Ph),
4.81 (s, 2H, CH2N), 5.02 (s, 2H, CH2N), 5.42 (s,
1H, HNH), 5.74 (s, 1H, HNH), 6.66 (d, 2H, J = 4.5
Hz, Hpy), 6.81 (d, 2H, J = 4.6 Hz, Hpy), 7.12–7.22
(m, 10H, Harom), 8.32 (s, 1H, HNH), 8.39 (d, 2H, J =
4.7 Hz, Hpy), 8.49 (d, 2H, J = 4.3 Hz, Hpy), 8.69 (s,
1H, HNH). 13C NMR (CDCl3): d 14.37, 14.51 (2 ·
CH3CH2), 16.94, 20.33 (2 · CH3CH2), 29.46, 33.47
(2 · CH2Ph), 36.27, 36.59 (2 · CH2S), 46.52, 46.76
(2 · CH2N), 120.77, 144.98, 145.28, 150.12, 150.34
(Cpy), 126.05, 126.80 (C-4), 126.63, 127.73, 128.34,
128.44, 128.74, 131.25, 137.48, 137.65 (Carom), 140.15
(C-2), 139.71, 140.27 (C-5), 171.93, 172.12 (CO). EI-
MS: m/z 366 (100%, M+).
1.22 [d, 6H, J = 6.9 Hz, (CH3)2CH], 3.03 [hept, 1H,
J = 6.9 Hz, (CH3)2CH], 3.79 (s, 2H, CH2S), 3.94 (s,
2H, CH2Ph), 5.25 (s, 2H, CH2N), 6.86 (d, 2H,
J = 5.1 Hz, Hpy), 7.06–7.22 (m, 5H, Ph), 7.22 (s, 1H,
HNH), 7.78 (s, 1H, HNH), 8.40 (d, 2H, J = 4.5 Hz,
Hpy). 13C NMR (CDCl3): d 22.48 [(CH3)2CH], 25.17
[(CH3)2CH], 28.19 (CH2Ph), 37.86 (CH2S), 46.54
(CH2N), 121.13, 145.83, 148.87 (Cpy), 126.71 (C-4),
126.24, 127.81, 128.32, 137.67 (Carom), 139.05 (C-5),
142.83 (C-2), 169.06 (CO). HRMS (MALDI) m/z calcd
for C21H25N4OS+ (MH+) 381.1747, found 381.1744.
5.11.5. 2-[5-(3,5-Dimethylbenzyl)-4-isopropyl-1-(pyridin-
4-ylmethyl)-1H-imidazol-2-ylthio]acetamide (12e). Yield
1
1 g (34%) as a white solid; mp 120–122 ꢁC. H NMR
(DMSO-d6): d 1.19 [d, 6H, J = 6.8 Hz, (CH3)2CH],
2.09 (s, 6H, 2 · CH3), 2.95 [hept, 1H, J = 6.8 Hz,
(CH3)2CH], 3.64 (s, 2H, CH2S), 3.78 (s, 2H, CH2Ar),
5.09 (s, 2H, CH2N), 6.53 (s, 2H, Harom), 6.66 (s, 1H, Har-
om), 6.74 (d, 2H, J = 5.5 Hz, Hpy), 7.15 (br s, 1H, HNH),
5.11.2.
2-[4-(3,5-Dimethylbenzyl)-5-ethyl-1-(pyridin-4-
ylmethyl)-1H-imidazol-2-ylthio]acetamide (11b) and 2-
[5-(3,5-dimethylbenzyl)-4-ethyl-1-(pyridin-4-ylmethyl)-1H-
imidazol-2-ylthio]acetamide (12b). Yield 0.23 g (59%). 1H
NMR (CDCl3): d 0.97 (t, 3H, J = 7.5 Hz, CH3CH2),
1.27 (t, 3H, J = 7.5 Hz, CH3CH2), 2.19 (s, 6H, 2CH3),
2.27 (s, 6H, 2CH3), 2.47 (q, 2H, J = 7.5 Hz, CH3CH2),
7.78 (br s, 1H, HNH), 8.37 (d, 2H, J = 5.5 Hz, Hpy). 13
C
NMR (DMSO-d6):
d
20.71 (2 · CH3), 22.98
[(CH3)2CH], 25.68 [(CH3)2CH], 28.34 (CH2Ar), 37.55
(CH2S), 45.98 (CH2N), 120.78, 145.78, 149.33 (Cpy),
126.62 (C-4), 125.66, 127.39, 137.13, 138.14 (Carom),

Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
4217
138.62 (C-2), 144.81 (C-5), 169.56 (CO). EI-MS: m/z 408
(100%, M+). Anal. Calcd for C23H28N4OSÆ0.25H2O: C,
66.88; H, 6.95; N, 13.56. Found: C, 66.70; H, 6.86; N,
13.48.
CH2Ph), 72.83 (NCH2O), 125.65 (C-4), 126.39, 127.63,
127.75, 128.12, 128.53, 136.51, 137.49, 137.78 (Carom),
140.02 (C-5), 140.34 (C-2). HRMS (MALDI) m/z calcd
for C24H30N3O2S+ (MH+) 424.2051, found 424.2051.
5.11.6. 2-[5-(Cyclohexylmethyl)-4-isopropyl-1-(pyridin-4-
ylmethyl)-1H-imidazol-2-ylthio]acetamide (12f). Yield
0.84 g (31%) as a white solid; mp 162–164 ꢁC. 1H
NMR (DMSO-d6): d 0.82–1.23 [m, 11H, (CH3)2CH
and Hcy], 1.47–1.65 (m, 6H, Hcy), 2.30 (d, 2H,
J = 6.9 Hz, CH2Cy), 2.83 [hept, 1H, J = 6.9 Hz,
[(CH3)2CH], 3.60 (s, 2H, CH2S), 5.21 (s, 2H, CH2N),
6.92 (d, 2H, J = 5.1 Hz, Hpy), 7.15 (br s, 1H, HNH),
7.79 (br s, 1H, HNH), 8.51 (d, 2H, J = 5.5 Hz, Hpy).
13C NMR (DMSO-d6): d 22.98 [(CH3)2CH], 25.57
[(CH3)2CH and Ccy], 25.68, 32.18, 37.53 (Ccy), 30.23
(CH2Cy), 37.37 (CH2S), 45.86 (CH2N), 120.80, 146.66,
149.75 (Cpy), 125.77 (C-4), 138.16 (C-2), 169.61 (CO).
HRMS (MALDI) m/z calcd for C21H31N4OS+ (MH+)
387.2224, found 387.2213.
5.12.3. 2-[4-(Cyclohexylmethyl)-1-(ethoxymethyl)-5-ethyl-
1H-imidazol-2-ylthio]acetamide (13e). Yield 0.11 g (22%)
as a white solid; mp 90–92 ꢁC. H NMR (CDCl3): d
1
0.87–0.98 (m, 2H, Hcy), 1.11–1.22 (m, 9H, CH3CH2,
CH3CH2O and Hcy), 1.56–1.69 (m, 6H, Hcy), 2.33 (d,
2H, J = 6.8 Hz, CH2Cy), 2.58 (q, 2H, J = 7.5 Hz,
CH3CH2), 3.48 (q, 2H, J = 7.0 Hz, CH3CH2O), 3.56
(s, 2H, CH2S), 5.23 (s, 2H, NCH2O), 5.56 (br s, 1H,
HNH), 8.83 (br s, 1H, HNH). 13C NMR (CDCl3): d
14.72 (CH3CH2), 14.83 (CH3CH2O), 16.72 (CH3CH2),
26.50, 26.25, 33.23, 38.13 (Ccy), 34.61 (CH2Cy), 36.68
(CH2S), 63.94 (CH3CH2O), 73.18 (NCH2O), 131.79
(C-4), 137.56 (C-5), 139.45 (C-2), 172.45 (C@O). EI-
MS: m/z 339 (16%, M+), 59 (100%). Anal. Calcd for
C17H29N3O2SÆ0.25H2O: C, 59.36; H, 8.64; N, 12.21.
Found: C, 59.41; H, 8.63; N, 12.04.
5.12. General procedure for the synthesis of compounds
13c–f and 14a–l
5.12.4. 2-[1-(Benzyloxymethyl)-4-(cyclohexylmethyl)-5-ethyl-
1H-imidazol-2-ylthio]acetamide (13f). Yield 0.13 g (22%)
obtained as an oil. H NMR (CDCl3): d 0.88 (m, 2H,
1
To a solution of compound 8 (1.5 mmol) in methylene
chloride (10 mL) under nitrogen was added N-ethyldi-
isopropylamine (EDIA) (0.27 mL, 1.5 mmol) followed
by addition of ethoxy or (benzyloxy)methyl chloride
(1 mmol). The mixture was stirred for 2 h at rt and
quenched with water (20 mL). Methylene chloride
(30 mL) was added and the two layers were separated.
The organic layer was dried using (sodium sulfate) and
the solvent was removed under reduced pressure. The
residual material was chromatographed on a silica gel
column with ethyl acetate to afford compounds 13c–f
and 14a–l.
Hcy), 1.09–1.28 (m, 6H, CH3CH2 and Hcy), 1.54–1.69
(m, 6H, Hcy), 2.33 (d, 2H, J = 6.9 Hz, CH2Cy), 2.58
(q, 2H, J = 7.5 Hz, CH3CH2), 3.56 (s, 2H, CH2S), 4.51
(s, 2H, CH2Ph), 5.29 (s, 2H, NCH2O), 5.56 (br s, 1H,
HNH), 7.26–7.35 (m, 5H, Ph), 8.78 (br s, 1H, HNH).
13C NMR (CDCl3):
d
14.72 (CH3CH2), 16.69
(CH3CH2), 26.48, 28.24, 33.21, 38.12 (Ccy), 34.60
(CH2Cy), 36.69 (CH2S), 70.44 (OCH2Ph), 72.84
(NCH2O), 127.71, 128.06, 128.49, 136.58 (Carom),
131.78 (C-4), 137.68 (C-5), 139.61 (C-2), 172.38 (CO).
HRMS (MALDI) m/z calcd for C22H32N3O2S+ (MH+)
402.2206, found 402.2210.
5.12.1. 2-[5-(3,5-Dimethylbenzyl)-1-(ethoxymethyl)-4-ethyl-
1H-imidazol-2-ylthio]acetamide (13c). Yield 0.15 g (28%)
as a white solid; mp 93–95 ꢁC. 1H NMR (CDCl3): d 1.05
(t, 3H, J = 7.5 Hz, CH3CH2), 1.12 (t, 3H, J = 6.9 Hz,
CH3CH2O), 2.18 (s, 6H, 2 · CH3), 2.56 (q, 2H,
J = 7.5 Hz, CH3CH2), 3.43 (q, 2H, J = 6.9 Hz,
CH3CH2), 3.63 (s, 2H, CH2S), 3.72 (s, 2H, CH2Ph),
5.17 (s, 2H, NCH2O), 5.27 (s, 1H, HNH), 6.76 (s, 3H,
Harom), 8.42 (s, 1H, HNH). 13C NMR (CDCl3): d
14.42 (CH3CH2), 14.77 (CH3CH2O), 16.76 (CH3CH2),
21.21 (2 · CH3), 32.56 (CH2Ar), 36.21 (CH2S), 64.29
(CH3CH2O), 73.48 (NCH2O), 126.35, 127.76, 136.42,
137.84 (Carom), 131.82 (C-4), 139.40 (C-5), 140.02
(C-2), 171.62 (C@O). HRMS (MALDI) m/z calcd for
C19H28N3O2S+ (MH+) 362.1892, found 362.1897.
5.12.5. 2-[5-Benzyl-1-(ethoxymethyl)-4-ethyl-1H-imidazol-
2-ylthio]acetamide (14a). Yield 0.15 g (30%) as a white
solid; mp 63–65 ꢁC. H NMR (CDCl3): d 1.09 (t, 3H,
1
J = 7.0 Hz, CH3CH2O), 1.23 (t, 3H, J = 7.5 Hz,
CH3CH2), 2.56 (t, 2H, J = 7.5 Hz, CH3CH2), 3.36 (t,
2H, J = 7.0 Hz, CH3CH2O), 3.62 (s, 2H, CH2S), 4.00
(s, 2H, CH2Ph), 5.04 (s, 1H, NCH2O), 5.73 (br s, 1H,
HNH), 7.08–7.31 (m, 5H, Harom), 8.78 (br s, 1H,
HNH). 13C NMR (CDCl3): d 14.20 (CH3), 14.64
(CH3), 20.15 (CH3CH2), 29.13 (CH2Ph), 36.50 (CH2S),
63.91 (CH3CH2O), 73.32 (NCH2O), 126.82 (C-4),
126.54, 127.87, 128.61, 138.21 (Carom), 140.57 (C-2),
141.83 (C-5), 172.40 (C@O). HRMS (MALDI) m/z calcd
for C17H24N3O2S+ (MH+) 334.1579, found 334.1584.
5.12.2. 2-[1-(Benzyloxymethyl)-5-(3,5-dimethylbenzyl)-4-
ethyl-1H-imidazol-2-ylthio]acetamide (13d). Yield 0.15 g
(24%) obtained as an oil. H NMR (CDCl3): d 1.12 (t,
5.12.6. 2-[5-Benzyl-1-(benzyloxymethyl)-4-ethyl-1H-imid-
azol-2-ylthio]acetamide (14b). Yield 0.23 g (38%) as a
white solid; mp 84–86 ꢁC. H NMR (CDCl3): d 1.13 (t,
1
1
3H, J = 7.5 Hz, CH3CH2), 2.26 (s, 6H, 2 · CH3), 2.63
(q, 2H, J = 7.5 Hz, CH3CH2), 3.56 (s, 2H, CH2S), 3.75
(s, 2H, CH2Ar), 4.51 (s, 2H, OCH2Ph), 5.21 (s, 1H,
HNH), 5.27 (s, 2H, OCH2N), 6.82 (s, 3H, Harom),
7.24–7.35 (m, 5H, Ph), 8.49 (s, 1H, HNH). 13C NMR
(CDCl3): d 14.68 (CH3CH2), 16.81 (CH3CH2), 21.25
(2 · CH3), 33.14 (CH2Ar), 36.12 (CH2S), 70.51 (O–
3H, J = 7.5 Hz, CH3CH2), 2.48 (q, 2H, J = 7.5 Hz,
CH3CH2), 3.56 (s, 2H, CH2S), 3.89 (s, 2H, CH2Ph),
4.31 (s, 2H, OCH2Ph), 5.01 (s, 2H, NCH2O), 5.47 (s,
1H, HNH), 6.94–7.27 (m, 10H, 2 · Ph), 8.73 (s, 1H,
NH). 13C NMR (CDCl3): d 14.24 (CH3CH2), 20.08
(CH3CH2), 29.13 (CH2Ph), 36.45 (CH2S), 70.37 (O–
CH2Ph), 72.98 (NCH2O), 126.91 (C-4), 126.66, 127.65,

4218
Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
127.92, 128.06, 128.49, 128.71, 136.53, 138.02 (Carom),
172.16 (C@O). HRMS (MALDI) m/z calcd for
C22H26N3O2S+ (MH+) 396.1744, found 396.1740.
Ph), 8.88 (br s, 1H, HNH). 13C NMR (CDCl3): d
13.89 (CH3CH2), 20.26 (CH3CH2), 26.27, 26.12, 33.17,
38.43 (Ccy), 31.07 (CH2Cy), 36.64 (CH2S), 70.42
(CH2Ph), 72.78 (NCH2O), 127.80 (C-4), 127.73,
128.07, 128.49, 136.58 (Carom), 139.99 (C-2), 141.19 (C-
5), 172.45 (CO). EI-MS: m/z 401 (6%, M+), 91 (100%).
Anal. Calcd for C22H31N3O2SÆ0.3H2O: C, 64.93; H,
7.86; N, 10.32. Found: C, 64.93; H, 7.81; N, 10.36.
5.12.7. 2-[5-(3,5-Dimethylbenzyl)-1-(ethoxymethyl)-4-ethyl-
1H-imidazol-2-ylthio]acetamide (14c). Yield 0.15 g (28%)
as a white solid; mp 93–95 ꢁC. 1H NMR (CDCl3): d 1.04
(t, 3H, J = 6.9 Hz, CH3CH2O), 1.15 (t, 3H, J =
7.5 Hz, CH3CH2), 2.18 (s, 6H, 2 · CH3), 2.47 (q, 2H,
J = 7.5 Hz, CH3CH2), 3.29 (q, 2H, J = 6.9 Hz,
CH3CH2O), 3.54 (s, 2H, CH2S), 3.83 (s, 2H, CH2Ph),
4.97 (s, 2H, NCH2O), 5.53 (s, 1H, HNH), 6.61 (s, 2H,
Harom), 6.76 (s, 1H, Harom), 8.79 (s, 1H, HNH). 13C
NMR (CDCl3): d 14.20 (CH3CH2), 14.71 (CH3CH2O),
20.15 (CH3CH2), 21.23 (2 · CH3), 28.95 (CH2Ar),
36.54 (CH2S), 63.94 (CH3CH2O), 73.36 (NCH2O),
127.07 (C-4), 125.71, 128.19, 138.04, 138.18 (Carom),
140.52 (C-2), 141.58 (C-5), 172.39 (C@O). EI-MS: m/z
361 (100%, M+). Anal. Calcd for C19H27N3O2SÆ0.2H2O:
C, 62.50; H, 7.56; N, 11.51. Found: C, 62.66; H, 7.65; N,
11.33.
5.12.11. 2-[5-Benzyl-1-(ethoxymethyl)-4-isopropyl-1H-imid-
azol-2-ylthio]acetamide (14g). Yield 0.22 g (43%) as a
1
white solid; mp 96–98 ꢁC. H NMR (CDCl3): d 1.08 (t,
3H, J = 7.0 Hz, CH3CH2), 1.23 [d, 6H, J = 6.8 Hz,
(CH3)2CH], 2.92 [hept, 1H, J = 6.8 Hz, (CH3)2CH],
3.35 (q, 2H, J = 7.0 Hz, CH3CH2), 3.61 (s, 2H, CH2S),
4.00 (s, 2H, CH2Ph), 5.00 (s, 2H, NCH2O), 5.70 (br s,
1H, HNH), 7.07–7.30 (m, 5H, Ph), 9.04 (br s, 1H,
HNH). 13C NMR (CDCl3): d 14.62 (CH3CH2), 22.91
[(CH3)2CH], 26.04 [(CH3)2CH], 28.98 (CH2Ph), 36.37
(CH2S), 63.92 (CH3CH2O), 73.28 (NCH2O), 125.66 (C-
4), 126.51, 127.83, 128.59, 138.29 (Carom), 140.80 (C-2),
145.77 (C-5), 172.59 (CO). EI-MS: m/z 347 (24%, M+),
59 (100%). Anal. Calcd for C18H25N3O2S: C, 62.22; H,
7.25; N, 12.09. Found: C, 62.18; H, 7.25; N, 12.09.
5.12.8. 2-[1-(Benzyloxymethyl)-5-(3,5-dimethylbenzyl)-4-
ethyl-1H-imidazol-2-ylthio]acetamide (14d). Yield 0.85 g
(40%) as a white solid; mp 108–110 ꢁC. 1H NMR
(CDCl3): d 1.23 (t, 3H, J = 7.5 Hz, CH3CH2), 2.23
(s, 6H, 2 · CH3), 2.55 (q, 2H, J = 7.5 Hz, CH3CH2),
3.60 (s, 2H, CH2S), 3.88 (s, 2H, CH2Ar), 4.39 (s, 2H,
O–CH2Ph), 5.09 (s, 2H, NCH2O), 5.49 (s, 1H, HNH),
6.61 (s, 2H, Harom), 6.82 (s, 1H, Harom), 7.21–7.35 (m,
5H, Ph), 8.86 (s, 1H, HNH). 13C NMR (CDCl3): d
14.23 (CH3CH2), 20.19 (CH3CH2), 21.23 (2 · CH3),
28.98 (CH2Ar), 36.52 (CH2S), 70.29 (O–CH2Ph), 72.92
(NCH2O), 127.09 (C-4), 125.72, 127.59, 128.02, 128.24,
128.48, 136.68, 137.99, 138.22 (Carom), 140.79 (C-2),
141.71 (C-5), 172.36 (C@O). EI-MS: m/z 423 (100%,
M+). Anal. Calcd for C24H29N3O2SÆ0.25H2O: C, 67.34;
H, 6.95; N, 9.82. Found: C, 67.78; H, 6.99; N, 9.76.
5.12.12. 2-[5-Benzyl-1-(benzyloxymethyl)-4-isopropyl-1H-
imidazol-2-ylthio]acetamide (14h). Yield 0.27 g (44%) as
a white solid; mp 102–104 ꢁC. 1H NMR (CDCl3): d
1.23 [d, 6H, J = 6.7 Hz, (CH3)2CH], 2.92 [hept, 1H,
J = 6.7 Hz, (CH3)2CH], 3.59 (s, 2H, CH2S), 3.98 (s,
2H, CH2Ph), 4.38 (s, 2H, OCH2Ph), 5.05 (s, 2H,
NCH2O), 5.59 (br s, 1H, HNH), 7.01–7.35 (m, 10H,
2Ph), 9.02 (br s, 1H, HNH). 13C NMR (CDCl3): d
22.93 [(CH3)2CH], 26.06 [(CH3)2CH], 28.98 (CH2Ph),
36.36 (CH2S), 70.38 (OCH2Ph), 72.91 (NCH2O),
125.69 (C-4), 126.57, 127.59, 127.87, 128.45, 128.66,
136.60, 138.19 (Carom), 141.06 (C-2), 145.83 (C-5),
172.51 (CO). EI-MS: m/z 409 (27%, M+), 91 (100%).
Anal. Calcd for C23H27N3O2SÆ1H2O: C, 64.61; H,
6.84; N, 9.83. Found: C, 64.68; H, 6.37; N, 9.76.
5.12.9. 2-[5-(Cyclohexylmethyl)-1-(ethoxymethyl)-4-ethyl-
1H-imidazol-2-ylthio]acetamide (14e). Yield 0.11 g (21%)
1
as a white solid; mp 100–102 ꢁC. H NMR (CDCl3): d
5.12.13. 2-[5-(3,5-Dimethylbenzyl)-1-(ethoxymethyl)-4-iso-
propyl-1H-imidazol-2-ylthio]acetamide (14i). Yield 0.34 g
(61%) as a white solid; mp 100–102 ꢁC. 1H NMR
(CDCl3): d 1.11 (t, 3H, J = 6.9 Hz, CH3CH2O), 1.24
[d, 6H, J = 6.8 Hz, (CH3)2CH], 2.92 [hept, 1H, J =
6.8 Hz, (CH3)2CH], 3.37 (q, 2H, J = 6.9 Hz, CH3CH2O),
3.61 (s, 2H, CH2S), 3.92 (s, 2H, CH2Ar), 5.03 (s, 2H,
NCH2O), 5.70 (s, 1H, HNH), 6.68 (s, 2H, Harom), 6.84
(s, 1H, Harom), 9.05 (s, 1H, HNH). 13C NMR (CDCl3):
d 14.66 (CH3CH2O), 21.20 (2CH3), 22.89 [(CH3)2CH],
25.99 [(CH3)2CH], 28.78 (CH2Ar), 36.43 (CH2S), 63.94
(CH3CH2O), 73.32 (NCH2O), 125.96 (C-4), 125.65,
128.14, 138.04, 138.13 (Carom), 140.64 (C-2), 145.42
(C-5), 172.58 (CO). EI-MS: m/z 375 (63%, M+), 59
(100%). Anal. Calcd for C20H29N3O2SÆ0.5H2O: C,
62.47; H, 7.86; N, 10.93. Found: C, 62.38; H, 7.61;
N, 10.76.
0.86–0.97 (m, 2H, Hcy), 1.14–1.25 (m, 9H, CH3CH2,
CH3CH2O and Hcy), 1.39–1.53 (m, 1H, Hcy), 1.64–1.75
(m, 5H, Hcy), 2.42–2.49 (m, 4H, CH3CH2 and CH2Cy),
3.47 (q, 2H, J = 7.0 Hz, CH3CH2O), 3.58 (s, 1H, CH2S),
5.21 (s, 2H, NCH2O), 5.61 (br s, 1H, HNH), 8.91 (br s,
1H, HNH). 13C NMR (CDCl3): d 13.90 (CH3CH2),
14.82 (CH3CH2O), 20.27 (CH3CH2), 26.30, 26.21,
33.20, 38.44 (Ccy), 31.09 (CH2Cy), 36.64 (CH2S), 63.91
(CH3CH2O), 73.18 (NCH2O), 127.79 (C-4), 139.80
(C-2), 141.10 (C-5), 172.54 (C@O). HRMS (MALDI)
m/z calcd for C17H30N3O2S+ (MH+) 340.2050, found
340.2053.
5.12.10. 2-[1-(Benzyloxymethyl)-5-(cyclohexylmethyl)-4-
ethyl-1H-imidazol-2-ylthio]acetamide (14f). Yield 0.1 g
(17%) as a white solid; mp 102–104 ꢁC. 1H NMR
(CDCl3): d 0.84–0.94 (m, 2H, Hcy), 1.10–1.21 (m, 6H,
CH3CH2 and Hcy), 1.38–1.47 (m, 1H, Hcy), 1.59–1.75
(m, 5H, Hcy), 2.40–2.49 (m, 4H, CH3CH2 and CH2Cy),
3.57 (s, 2H, CH2S), 4.50 (s, 2H, CH2Ph), 5.26 (s, 2H,
NCH2O), 5.54 (br s, 1H, HNH), 7.26–7.37 (m, 5H,
5.12.14. 2-[1-(Benzyloxymethyl)-5-(3,5-dimethylbenzyl)-4-
isopropyl-1H-imidazol-2-ylthio]acetamide (14j). Yield
1
0.31 g (48%) as a white solid; mp 92–94 ꢁC. H NMR
(CDCl3): d 1.24 [d, 6H, J = 6.8 Hz, (CH3)2CH], 2.23

Y. M. Loksha et al. / Bioorg. Med. Chem. 13 (2005) 4209–4220
4219
(s, 6H, 2CH3), 2.91 [hept, 1H, J = 6.8 Hz, (CH3)2CH],
3.59 (s, 2H, CH2S), 3.89 (s, 2H, CH2Ar), 4.39 (s, 2H,
OCH2Ph), 5.07 (s, 2H, NCH2O), 5.59 (s, 1H, HNH),
6.62 (s, 2H, Harom), 6.82 (s, 1H, Harom), 7.19–7.32 (m,
5H, Ph), 9.06 (s, 1H, HNH). 13C NMR (CDCl3): d
21.21 (2 · CH3), 22.95 [(CH3)2CH], 26.05 [(CH3)2CH],
28.79 (CH2Ar), 36.40 (CH2S), 70.34 (OCH2Ph), 77.00
(NCH2O), 125.93 (C-4), 125.68, 127.53, 127.96, 128.18,
128.44, 136.71, 138.03, 138.17 (Carom), 140.91 (C-2),
145.64 (C-5). EI-MS: m/z 437 (6%, M+), 91 (100%).
Anal. Calcd for C25H31N3O2S: C, 68.62; H, 7.14; N,
9.60. Found: C, 68.24; H, 7.15; N, 9.53.
medium containing the test dilutions of compound for
six days in parallel with virus-infected and uninfected
control cultures without compound added. Expression
of HIV in the cultures was indirectly quantified using
the MTT assay.28 Compounds mediating less than
30% reduction of HIV expression were considered with-
out biological activity. Compounds were tested in paral-
lel for cytotoxic effect in uninfected MT4 cultures
containing the test dilutions of compound as described
above. A 30% inhibition of cell growth relative to con-
trol cultures was considered significant.
The 50% inhibitory concentration (IC50) and the 50%
cytotoxic concentration (CC50) were determined by
interpolation from the plots of percent inhibition versus
concentration of compound.
5.12.15. 2-[5-(Cyclohexylmethyl)-1-(ethoxymethyl)-4-iso-
propyl-1H-imidazol-2-ylthio]acetamide
(14k).
Yield
1
0.24 g (45%) as a white solid; mp 90–92 ꢁC. H NMR
(CDCl3): d 0.87–0.98 (m, 2H, Hcy), 1,18–1.28 [m, 12H,
(CH3)2CH, CH3CH2 and Hcy], 1.31–1.69 (m, 6H, Hcy),
2.45 (d, 2H, J = 7.4 Hz, CH2Cy), 2.84 [hept, 1H,
J = 6.8 Hz, (CH3)2CH], 3.48 (q, 2H, J = 6.8 Hz,
CH3CH2O), 3.59 (s, 2H, CH2S), 5.20 (s, 2H, NCH2O),
5.49 (br s, 1H, HNH), 9.15 (br s, 1H, HNH). 13C
NMR (CDCl3): d 14.83 (CH3CH2), 22.89 [(CH3)2CH],
25.98 [(CH3)2CH], 26.32, 26.26, 33.23, 38.34 (Ccy),
30.97 (CH2Cy), 36.53 (CH2S), 63.98 (CH3CH2O),
73.20 (NCH2O), 126.72 (C-4), 140.07 (C-2), 145.04 (C-
5), 172.65 (CO). EI-MS: m/z 353 (18%, M+), 55
(100%). Anal. Calcd for C18H31N3O2SÆ0.7H2O: C,
59.05; H, 8.92; N, 11.48. Found: C, 59.02; H, 8.83; N,
11.42.
Acknowledgments
One of the authors (Y. M. Loksha) is greatly indebted to
the Danish International Development Agency (DAN-
IDA) for granting a fellowship.
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4220
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