Synthesis, antitumour and anti-HIV screening of oxazolidines and oxazolidinones derivatives

Article abstract of DOI:10.1211/146080899128734622

Some N-phenyl(thio)carbamoyl-2-iminooxazolidines and 2-oxazolidinones were synthesized via 2-amino-2-oxazolines and tested as antiviral and antitumour agents. Moderate antitumour activity was found for the 5-(1-phenyl-4-piperazinyl)methyl substituted compounds.

Full text of DOI:10.1211/146080899128734622

Pharm. Pharmacol. Commun. 1999, 5: 211±215
# 1999 Pharm. Pharmacol. Commun.
Synthesis, Antitumour and Anti-HIV Screening of Oxazolidines
and Oxazolidinones Derivatives
C. CHAIMBAULT, J. J. BOSC AND C. JARRY
Â
Â
Laboratoire de Chimie Physique, Universite Victor Segalen Bordeaux 2, 146 rue Leo Saignat, 33076
Bordeaux Cedex, France
Abstract
Some N-phenyl(thio)carbamoyl-2-iminooxazolidines and 2-oxazolidinones were synthe-
sized via 2-amino-2-oxazolines and tested as antiviral and antitumour agents.
Moderate antitumour activity was found for the 5-(1-phenyl-4-piperazinyl)methyl
substituted compounds.
HIV-1 protease is an essential retroviral enzyme
responsible for the processing of viral polyproteins
to structural proteins and enzymes. Extensive stu-
dies have been carried out in recent years giving
rise to a number of potent HIV-1 protease inhibi-
tors. The majority of the HIV protease inhibitors
reported are peptidic or peptidomimetic in nature
(Martin et al 1995). As an example of pharmaco-
modulation, compounds incorporating a (hydro-
xyethyl)urea dipeptide isostere have been described
as potent HIV protease inhibitors (Getman et al
1993). In connection with studies on 2-amino-2-
oxazolines we recently published a structural
investigation on the reaction with phenyl iso-
cyanate (Bosc et al 1996). As the isolated com-
pounds might be regarded as cyclized pseudo-
peptidomimetic ones we decided to synthesize
closely related 2-iminooxazolidines and 2-oxazoli-
dinones incorporating a (hydroxyethyl)urea moiety.
This work describes the synthesis and the antiviral
and antitumour screening of some 3-phenyl(thio)-
carbamoyl-2-iminooxazolidines and 2-oxazolidi-
nones. A typical (hydroxyethyl)urea derivative,
obtained by opening of the oxazolidine ring, was
also evaluated.
Melting points were determined with an SM-LUX-
POL Leitz hot-stage microscope and are uncor-
rected. The IR spectra were obtained with a Bruker
IFS 25 spectrophotometer. NMR data were recor-
ded with a Bruker AC-200 spectrometer. Chemical
shifts (d ppm) and coupling constants (J Hz) were
measured using tetramethylsilane as the internal
standard.
Preparation of 5-dimethylaminomethyl-2-amino-2-
oxazoline 1c
1-Dimethylamino-2,3-epoxypropane (0Á1 mol) was
added dropwise to a cold (0ꢀC) solution of mono-
sodium cyanamide salt (0Á1 mol) in methanol
(100 mL). The reaction mixture was stirred for 24 h,
and then concentrated under reduce pressure. The
residue was extracted with diethyl ether, then the
organic phase was evaporated. The crude 2-amino-
2-oxazoline 1c was recrystallized.
1
Yield 28%. Mp 118ꢀC (C2Cl3); IR n cm
(potassium bromide) 1697 (CN); 1H NMR (CDCl3)
d 7Á24 (s, 2H, NH2), 4Á69±4Á55 (m, 1H, CH), 3Á76
(dd, 1H, J ˆ 12Á0, 9Á0, C4 H2a), 3Á28 (dd, 1H,
J ˆ 12Á0, 7Á0, C4 H2b), 2Á58 (dd, 1H, J ˆ 13Á1, 8Á8,
CH2aN), 2Á25 (dd, 1H, J ˆ 13Á1, 3Á7, CH2bN), 2Á24
(s, 6H, CH3); 13C NMR (CDCl3) d 160Á7 (C ˆ N),
77Á8 (CH), 63Á7 (C4), 56Á4 (C6), 45Á8 (CH3). Cal-
culated for C6H13N2O: C, 50Á35; H, 9Á09; N, 29Á37.
Found: C, 50Á18; H, 9Á12; N, 29Á03.
Materials and Methods
Chemistry
Microanalyses were carried out at the Service
Central d'Analyse CNRS, Vernaison, France.
Preparation of 5-substituted 3-phenylcarbamoyl or
5-substituted 3-phenylthiocarbamoyl-2-iminooxa-
zolidines 2
Phenyl isocyanate or phenyl isothiocyanate
(0Á1 mol) in dry ethanol (20 mL) was slowly added
Correspondence: J. J. Bosc, Laboratoire de Chimie Physi-
Â
Â
que, Universite Victor Segalen Bordeaux 2, 146 rue Leo
Saignat, 33076 Bordeaux Cedex, France.

212
C. CHAIMBAULT ET AL
to a cold (0ꢀC) solution of 2-amino-2-oxazoline 1
(0Á1 mol) in dry ethanol (200 mL). The reaction
mixture was stirred for 1 h at room temperature.
The precipitate was rapidly collected, washed with
diethyl ether and recrystallized.
1H, CH), 3Á96 (t, 1H, J ˆ 9Á3, CH2aNH), 3Á70 (m, 1H,
CH2bNH), 3Á18 (m, 4H, CH2pip), 2Á71 (m, 6H, CH2pip
,
pipCH2);13CNMR(CDCl3)d(CS), (C9), 151Á1(C2),
138Á5, 129Á1, 128Á7, 125Á8, 124Á3, 122Á0, 119Á8, 116Á1
(Car), 75Á6 (CH), 60Á6 (C6), 53Á8 (C8), 49Á0 (C7), 46Á6
(C4). Calculated for C21H25N5OS: C, 63Á80; H, 6Á33;
N, 17Á72; S, 8Á10. Found: C, 63Á52; H, 6Á48; N, 17Á61;
S, 8Á01.
5-((1-Phenyl-4-piperazinyl)methyl)-3-phenylcarba-
moyl-2-iminooxazolidine 2a. Mp 148ꢀC (diisopro-
pyl ether) (mp 146ꢀC (Bosc et al 1996))
5-Dimethylaminomethyl-2-phenylcarbamoyl-2-imi-
nooxazolidine 3c. Yield 59%. Mp 166ꢀC (toluene);
5-((1-Phenyl-4-piperazinyl)methyl)-3-phenylthio-
carbamoyl-2-iminooxazolidine 2b. Mp 117ꢀC (dii-
sopropyl ether) (mp 117ꢀC (Bosc et al 1996))
1
IR n cm (potassium bromide) 1655 (CO), 1622
1
(CN); H NMR (d6-DMSO) d 9Á28 (s, 1H, NH),
8Á27 (s, 1H, NH), 7Á60±6Á85 (m, 5H, Har), 7Á30 (s,
1H, NH), 4Á79±4Á69 (m, 1H, CH), 3Á74 (t, 1H,
J ˆ 9Á1, CH2aNH), 3Á55 (dd, 1H, J ˆ 9Á3, 7Á5,
CH2bNH), 2Á62 (d, 2H, J ˆ 6Á0, C6 H2), 2Á30 (s,
6H, CH3); 13C NMR (d6-DMSO) d 164Á2 (CO),
161Á8 (C2), 140Á8, 128Á4, 121Á4, 118Á0 (Car), 74Á9
(CH), 61Á5 (C6), 45Á9 (C4, CH3). Calculated for
C13H18N4O2: C, 59Á54; H, 6Á87; N, 21Á37. Found:
C, 59Á09; H, 6Á92; N, 21Á28.
5-Dimethylaminomethyl-3-phenylcarbamoyl-2-imi-
nooxazolidine 2c. Yield 75%. Mp 115ꢀC (diisopro-
1
pyl ether); IR n cm (potassium bromide) 3167
(NH), 1705 (CO); 1H NMR (CDCl3) d 11Á58 (s, 1H,
NH), 7Á52±7Á00 (m, 5H, Har), 6Á00 (s, 1H,
C ˆ NH), 4Á69±4Á55 (m, 1H, CH), 4Á16 (dd, 1H,
J ˆ 10Á3, 8Á3, C4 H2a), 3Á71 (dd, 1H, J ˆ 10Á3, 7Á2,
C4 H2b), 2Á64 (dd, 1H, J ˆ 13Á4, 7Á6, C6 H2a),
2Á45 (dd, 1H, J ˆ 13Á4, 4Á4, C6 H2b), 2Á30 (s, 6H,
CH3); 13C NMR (CDCl3) d 155Á8 (CO), 150Á2 (C2),
138Á0, 128Á9, 123Á5, 119Á5 (Car), 73Á4 (CH), 62Á3
(C6), 47Á2 (C4), 46Á0 (CH3). Calculated for
C13H18N4O2: C, 59Á54; H, 6Á87; N, 21Á37. Found:
C, 59Á23; H, 6Á99; N, 21Á46.
Preparation of 5-((1-phenyl-4-piperazinyl)methyl)-
2-propylcarbamoyl-3-phenylcarbamoyl-2-iminoox-
azolidine 4a To a cold (0ꢀC) solution of 3-phenyl-
carbamoyl-2-iminooxazolidine 2a (0Á01 mol) in dry
acetone (100 mL) was slowly added propylisocya-
nate (0Á01 mol). The reaction mixture was stirred
for 3 h at room temperature. The collected solid
was recrystallized. Mp 125ꢀC (CCl4) (mp 126ꢀC
(Bosc et al 1996)).
Preparation of 5-substituted 2-phenylcarbamoyl or
5-substituted 2-phenylthiocarbamoyl-2-iminooxa-
zolidines 3
From 2-amino-2-oxazolines 1. Phenyl isocyanate
or phenyl isothiocyanate (0Á02 mol) was added to a
solution of 2-amino-2-oxazoline 1 (0Á02 mol) in
anhydrous toluene (50 mL). The mixture was
re¯uxed for 3 h. After cooling the precipitate was
®ltered and recrystallized.
Preparation of 5-substituted 3-phenylcarbamoyl-2-
oxazolidinones 5
Hydrochloric acid (1 M; 0Á05 mol) was added
rapidly to a boiling solution of 2 (0Á01 mol) in water
(50 mL). The mixture was re¯uxed for 2 h. After
cooling the solid was collected, washed with water
and recrystallized.
From 3-phenyl(thio)carbamoyl-2-iminooxazolidines
2. A solution of 2 (0Á02 mol) in toluene (50 mL)
was re¯uxed for 3 h. After cooling the precipitate
was ®ltered and recrystallized.
5-((1-Phenyl-4-piperazinyl)methyl)-3-phenylcarba-
moyl-2-oxazolidinone, hydrochloride 5a. Yield
1
44%. Mp 179ꢀC (C2H5OH); IR n cm (potassium
1
bromide) 1745 (NC ˆ OO), 1700 (NC ˆ ON); H
5-((1-Phenyl-4-piperazinyl)methyl)-2-phenylcarba-
moyl-2-iminooxazolidine 3a. Mp 166ꢀC (CCl4)
(mp 167ꢀC (Bosc et al 1990))
NMR (CDCl3) d 9Á82 (s, 1H, NH), 7Á51±6Á82 (m,
10H, Har), 4Á76 (m, 1H, CH), 4Á20 (t, 1H, J ˆ 9Á6,
CH2aNCO), 3Á89 (dd, 1H, J ˆ 10Á5, 7Á1, CH2bNCO),
3Á22±3Á17 and 2Á85±2Á66 (2m, 10H, CH2 Npip),
‡
5-((1-Phenyl-4-piperazinyl)methyl)-2-phenylthio-
carbamoyl-2-iminooxazolidine 3b. Yield 68%. Mp
134ꢀC (CCl4); IR n cm 1 (potassium bromide) 1613
(CN); 1H NMR (CDCl3) d 10Á77 (s, 1H, NH), 8Á63,
8Á27 (2s, 1H, NH), 7Á64±6Á81 (m, 10H, Har), 4Á85 (m,
1Á77 (br. s, 1H, NH ); 13C NMR (CDCl3) d 155Á15
(NCONH), 148Á88 (OC ˆ ON), 150Á97, 136Á91,
129Á07, 129Á02, 124Á30, 119Á91, 119Á89, 116Á13
(CAr). 72Á87 (CH), 60Á71 (CH2 CH), 53Á99,
49Á09, (CH2pip), 46Á08 (CH2N). Calculated for

OXAZOLIDINES AND OXAZOLIDINONES DERIVATIVES
213
C21H24N4O3: C, 60Á50; H, 6Á00; N, 13Á44. Found:
C, 60Á65; H, 6Á08; N, 13Á36.
Institute (Bethesda, MD). The procedure used to
evaluate the antiviral potency (Weislow et al 1989)
is designed to detect agents acting at any stage of
the virus reproductive cycle. The assay involves the
killing of T4 lymphocytes by HIV-1; compounds
that interact with virions, or virus gene-products to
interfere with viral activity, will protect cells from
cytolysis. The median effective concentration
(EC50) of the tested compounds using infected
cells was compared with their cytotoxic effect in
uninfected cultures. Infected and uninfected cul-
tures were incubated without the compounds to
serve as controls. Zidovudine (AZT)-treated cul-
tures were also used as a positive control. The
cytotoxic effect in uninfected cultures is expressed
as the molar concentration of compounds that cause
50% inhibition of cell growth (IC50).
5-((1-Phenyl-4-piperazinyl)methyl)-3-phenylthio-
carbamoyl-2-oxazolidinone 5b. Yield 46%. Mp
1
162ꢀC (C2H5OH); IR n cm (potassium bromide)
1747 (CO); 1H NMR (CDCl3) d 11Á62 (s, 1H, NH),
7Á59±6Á83 (m, 10H, Har), 4Á86±4Á72 (m, 1H, CH),
4Á54 (dd, 1H, J ˆ 10Á9, 8Á8, CH2aNCS), 4Á18 (dd,
1H, J ˆ 10Á9, 7Á1, CH2bNCS), 3Á23±3Á18 (m, 4H,
CH2pip), 2Á86±2Á72 (m, 6H, CH2pip, pipCH2); 13C
NMR (CDCl3) d 188Á5 (CS), 177Á3 (CO), 153Á9
(C2), 151Á0, 137Á8, 129Á1, 128Á9, 126Á8, 124Á7,
119Á9, 116Á1 (Car), 72Á6 (CH), 60Á7 (C6), 54Á0
(C8), 50Á9 (C7), 49Á1 (C4). Calculated for
C21H24N4O2S: C, 63Á64; H, 6Á06; N, 14Á14; S,
8Á08. Found: C, 63Á49; H, 6Á12; N, 14Á01; S, 7Á99.
5-Dimethylaminomethyl-3-phenylcarbamoyl-2-oxa-
Antitumour screening. The new compounds were
evaluated in the National Cancer Institute's in-vitro
disease-oriented antitumour screen, which deter-
mines a test agent's effect on growth against a
panel of approximately sixty human tumour cell
lines including leukaemia, non-small cell lung,
colon, central nervous system, melanoma, ovarian,
renal, prostate and breast cancers (Grever et al
1992). A 48-h continuous drug exposure protocol
was used, and a sulphorhodamine B protein assay
was used to estimate cell viability or growth. The
cytotoxicity data is expressed as log GI50 which
represents the log molar drug concentration
required to cause 50% inhibition of cell growth.
zolidinone 5c. Yield 38%. Mp 108ꢀC (C2H5OH);
1
IR n cm (potassium bromide) 1747 (NC ˆ OO),
1
1705 (NC ˆ ON); H NMR (CDCl3) d 9Á83 (s, 1H,
NH), 7Á50±7Á05 (m, 5H, Har), 4Á78±4Á70 (m, 1H,
CH), 4Á17 (dd, 1H, J ˆ 10Á3, 8Á8, CH2aNCO), 3Á83
(dd, 1H, J ˆ 10Á3, 7Á1, CH2bNCO), 2Á64 (t, 2H,
J ˆ 5Á0, CH2N(CH3)2), 2Á33 (s, 6H, CH3); 13C
NMR (CDCl3) d 155Á2 (NCON), 148Á9 (OCON),
137Á0, 129Á0, 124Á2, 119Á9 (Car), 72Á9 (CH), 62Á0
(C4), 46Á3 (CH3), 46Á1 (CH2N(CH3)2). Calculated
for C13H17N3O3: C, 59Á32; H, 6Á46; N, 15Á97.
Found: C, 59Á50; H, 6Á38; N, 15Á83.
Preparation of N-phenyl N0-(1-(3-(dimethylamino)-
propan-2-ol))urea 6c
A suspension of 5c (0Á01 mol) and 2 M sodium
hydroxide (0Á02 mol) in water (100 mL) was heated
at 100ꢀC for 4 h. After cooling the solid was col-
lected, washed with water and recrystallized.
Results and Discussion
5-Substituted 2-amino-2-oxazolines 1 were syn-
thesized by a previously described method (Jarry et
al 1986). When conducted at 25ꢀC, the reaction of
1 with one equivalent of phenyl isocyanate or iso-
thiocyanate afforded the corresponding 3-phe-
nylthiocarbamoyl-2-iminooxazolidine 2 (Figure 1).
The 2-phenylthiocarbamoyl-2-iminooxazolidine 3
was isolated when the reaction was conducted at
110ꢀC (Bosc et al 1996). At low temperature the
addition occurred on the most nucleophilic endo-
cyclic sp2 nitrogen atom of 1. Moreover, by heating
at 110ꢀC 2 underwent an intramolecular N=N0
rearrangement to yield the thermodynamically
stable 2-phenylthiocarbamoyl-2-iminooxazolidine
3. The ability to isolate the 3-phenylcarbamoyl-2-
iminooxazolidine 2a permitted the introduction of a
different substituent on the exocyclic nitrogen
atom. As an example, 4a was synthesized from 2a
by reaction with propyl isocyanate performed at
0ꢀC.
1
Yield 37%. Mp 135ꢀC (C2Cl4); IR n cm
1
(potassium bromide) 3376 (NH), 1647 (CO); H
NMR (CDCl3) d 7Á66 (s, 1H, NH), 7Á33±6Á95 (m,
5H, Har), 5Á87 (t, 1H, J ˆ 5Á6, NH), 3Á84±3Á72 (m,
1H, CH), 3Á49 (dd, 1H, J ˆ 6Á1, 3Á1, CH2aNH), 3Á42
(dd, 2H, J ˆ 6Á1, 3Á0, CH2bNH, O H), 2Á41±2Á13 (m,
2H, CH2N(CH3)2), 2Á23 (s, 6H, CH3); 13C NMR
(d6-DMSO) d 155Á4 (CO), 140Á7, 128Á6, 120Á8,
117Á5 (Car), 67Á5 (CH), 63Á6 (CH2NH), 45Á9 (CH3),
44Á0 (CH2N(CH3)2). Calculated for C12H19N3O2:
C, 60Á76; H, 8Á02; N, 17Á72. Found: C, 61Á02; H,
8Á12; N, 17Á51.
Biological evaluation
Antiviral testing. The synthesized compounds were
tested against HIV-1 virus by the National Cancer

214
C. CHAIMBAULT ET AL
R
X
1
2
3
4
5
6
1-Phenyl-4-piperazinyl
Dimethylamino
O
S
O
±
±
c
a
b
c
a
b
c
a
±
±
a
b
c
±
±
c
Figure 1. Reagents: i. PhNCX, EtOH; ii. PhNCX, toluene, re¯ux; iii. toluene, re¯ux; iv. PrNCO, CH3COCH3, 0ꢀC; v. 1 M HCl,
H2O, re¯ux; vi. 2 M NaOH, H2O, re¯ux.
5
The 5-substituted 3-phenyl(thio)carbamoyl 2-
oxazolidinones 5 were obtained from 2 by hydro-
lysis with hydrochloric acid at 80ꢀC (Harnden &
Rasmussen 1970). The N-phenyl N0-(1-(3-di-
methylpropan-2-ol))urea 6c was obtained from 5c
by opening of the oxazolidine ring operated by
hydrolysis in basic medium.
IC50 values were 4Á98, 6Á47 and 1Á66 6 10 M,
respectively.
Antitumour screening
The cytotoxicity data for selected tumour cell lines
are given in Table 1. Compounds 1c, 2c, 3c and 6c
with a 5-dimethylaminomethyl substituent showed
no cytotoxic activity against the tumour cell lines
used, even at high concentrations.
The IR and NMR spectra were in agreement with
the proposed structures. In the H NMR spectra of
1
all cyclized compounds, the protons at the C-4 and
C-5 formed a characteristic ABX system, the C-5
methine H was found at about 5 ppm. The NH
protons in 3 appeared closed to each other near
8 ppm, whereas they appeared at about 12 and
6 ppm in 2. The IR spectra of 5 showed two strong
The 5-(1-phenyl-4-piperazinyl)methyl substituted
compounds seemed to be more potent. Compound
2a was moderately but speci®cally cytotoxic to
leukaemia cells. The nature of the substituent on
the iminooxazolidine ring seems to have a sig-
ni®cant contribution on the antitumour activity. All
phenylcarbamoyl substituted compounds (2a and
3a) were found less active than the phenylthio-
carbamoyl substituted ones (2b and 3b). By com-
parison with 2b, 5b presented a weaker antitumour
activity, showing an in¯uence of the nature of the
heteroatom on the 2-position. The most active
compound was the 2,3-disubstituted 2-iminoox-
azolidine 4a which might be regarded as a tripep-
tide isostere.
1
absorptions at 1745 and 1700 cm assignable to
the carbonyl groups of the cyclic urethane and the
phenylcarbamoyl substituent, respectively.
Antiviral testing
Compounds showed no activity at the highest
4
concentration used (2 6 10 M). However, com-
pounds 3b, 4a and 5b were cytotoxic to the unin-
5
fected T4 cells at concentrations up to 10 M. The

OXAZOLIDINES AND OXAZOLIDINONES DERIVATIVES
Table 1. Inhibition (log GI50 (M)) of in-vitro tumour cell
growth.
215
Acknowledgements
We thank Professor John P. Bader, Antiviral
Evaluation Branch, and Dr. V. L. Narayanan, Drug
Synthesis and Chemistry Branch, National Cancer
Institute, MD, for carrying out the in-vitro biolo-
gical evaluations.
Compound
2a
2b
3a
3b
4a
5b
Leukaemia
CCRF-CEM
HL-60 (TB)
K-562
4Á36 4Á43
4Á27 4Á51
4Á22 4Á47
4Á24 4Á53
4Á52
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SR
4Á46
Non-small cell
lung cancer
A549/ATCC
EKVX
NCI-H226
NCI-H23
4Á02
4Á49
4Á10
4Á30
4Á21 4Á14
4Á04
5Á68
4Á53 4Á13
Colon cancer
COLO 205
HCT-15
4Á54 4Á48
4Á49
4Á04
HT-29
4Á30 4Á19 4Á38 4Á16 4Á45
CNS cancer
SNB-75
4Á51
4Á11 4Á18
Melanoma
LOX IMVI
SK-MEL-2
SK-MEL-5
UACC-62
4Á60
4Á23
4Á45
4Á31
4Á60 4Á17
4Á45 4Á34 4Á50
4Á45 4Á39
4Á40 4Á00
Ovarian cancer
IGROV1
OVCAR-4
4Á03
4Á31 4Á04
Renal cancer
RXF 393
TK-10
4Á39
4Á36
4Á43
4Á40 4Á36
4Á08
UO-31
4Á94 4Á52
Prostate cancer
PC-3
DU-145
4Á19
4Á40 4Á34
4Á25 4Á24
Breast cancer
NCI/ADR-RES
MDA-MB-435
T-47D
4Á34
4Á12
4Á45
4Á30
4Á15 4Á07
4Á53 4Á74
Only log GI50 > 4 are noted.