Synthesis and antimicrobial activity of 3-arylamino-1-chloropropan-2-ols

Article abstract of DOI:10.1016/j.bmcl.2008.01.080

A series of nine 3-arylamino-1-chloropropan-2-ols 2a-2i were synthesized and their anti-fungal activity against pathogenic strains of Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger and Candida albicans, and antibacterial activity against fou

Full text of DOI:10.1016/j.bmcl.2008.01.080

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 2156–2161
Synthesis and antimicrobial activity
of 3-arylamino-1-chloropropan-2-ols
Ashok K. Prasad,a,* Pankaj Kumar,a,b Ashish Dhawan,a Anil K. Chhillar,c
Deepti Sharma,a Vibha Yadav,c Manish Kumar,c Hirday N. Jha,b Carl E. Olsen,d
Gainda L. Sharmac and Virinder S. Parmara
aBioorganic Laboratory, Department of Chemistry, University of Delhi (North Campus), Mall Road, Delhi 110 007, India
bDepartment of Chemistry, M.M.H. College, C.C.S. University, Meerut 250 002, India
cInstitute of Genomics & Integrative Biology, Mall Road, Delhi 110 007, India
dUniversity of Copenhagen, Faculty of Life Sciences, Department of Natural Sciences, DK-1871 Frederiksberg C, Denmark
Received 26 July 2007; revised 18 January 2008; accepted 21 January 2008
Available online 30 January 2008
Abstract—A series of nine 3-arylamino-1-chloropropan-2-ols 2a–2i were synthesized and their anti-fungal activity against patho-
genic strains of Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger and Candida albicans, and antibacterial activity against
four pathogenic bacterial strains of Salmonella typhi, Pseudomonas aeruginosa, Streptococcus pneumonae and Staphylococcus aureus
were evaluated using different assay systems. 1-Chloro-3-(40-chlorophenylamino)-propan-2-ol was found to be the most active anti-
fungal compound against three pathogenic strains under study, i.e., A. fumigatus, A. flavus and A. niger; the compound showed more
than 90% inhibition of growth of A. fumigatus at a concentration of 5.85 lg/ml in disc diffusion assay. Interestingly, 1-chloro-3-(40-
chlorophenylamino)-propan-2-ol did not show any toxicity up to a concentration of 4000 lg/ml. Although 1-chloro-3-(40-chlorophe-
nylamino)-propan-2-ol was about 8 times less active than the standard compound amphotericin B, its toxicity was many more fold
less than the toxicity of amphotericin B. Further, 1-chloro-3-(20,60-dichlorophenylamino)-propan-2-ol and 1-chloro-3-(30,50-dichlor-
ophenylamino)-propan-2-ol were found to be the most active compounds against C. albicans. In the anti-microbial assay, 1-chloro-
3-(20,40-dichlorophenylamino)-propan-2-ol and 1-chloro-3-(30,50-dichlorophenylamino)-propan-2-ol were found to be the most
active compounds against Salmonella typhi and 1-chloro-3-(30,40-dichlorophenylamino)-propan-2-ol was found to be the most active
compound against P. aeruginosa. Although, the activities of 1-chloro-3-(20,40-dichlorophenylamino)-propan-2-ol and 1-chloro-3-
(30,50-dichlorophenylamino)-propan-2-ol are about half the activity of the standard anti-bacterial compound tetracycline, these
compounds also were many fold less toxic than the standard drug.
ꢀ 2008 Elsevier Ltd. All rights reserved.
The increasing number of pathogenic bacteria and fungi
which are resistant to commonly used therapies has been
a major worldwide health problem. The mortality
caused by aspergillosis, tuberculosis, etc. needs a very
systematic and focused approach to find out newer
and safer drugs to deal with the menace. Therefore it
is imperative to search for new antimicrobial agents with
novel modes of action. There are several groups of
researchers around the world who are engaged in syn-
thesizing molecules with different moieties and function-
alities, and are evaluating them for their antimicrobial
activities. Some of these synthetic molecules have been
derived from series of quinolines,1 imidazoles,2 quinal-
dines,3 demethoxyviridins,4 dihydropyridines,5 etc.
b-Amino alcohols are an important class of organic
compounds which have found much use in medicinal
chemistry.6 These compounds have been well recognized
as versatile intermediates in the synthesis of a vast range
of biologically active natural and synthetic products,7
unnatural amino acids8 and chiral auxiliaries.9 b-Amino
alcohols, like 3-arylamino-1-chloropropan-2-ols, have
been used as important intermediates, for the synthe-
sis of 1-[4,4-bis-(4-fluorophenyl)butyl]-4-[2-hydroxy-3-
(phenylamino)propyl]piperazine, which is
a potent
dopamine uptake inhibitor10 and is present as a key
functional group in natural products, such as sphingo-
sine, which exhibits a wide range of physiological activ-
ities.11 Some of the b-amino alcohols have also been
Keywords: 3-Arylamino-1-chloropropan-2-ols; Regioselectivity; Anti-
fungal agent; Aspergillosis; Candidiasis; Anti-bacterial activity.
*
Corresponding author. Tel.: +91 11 27666555; fax: +91 11
27667206; e-mail: ashokenzyme@yahoo.com
0960-894X/$ - see front matter ꢀ 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.01.080

A. K. Prasad et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2156–2161
2157
used as starting materials for the preparation of oxazo-
lines,12 insecticidal agents and as chiral ligands in asym-
metric synthesis.13 In view of this, the current study was
undertaken to synthesize a series of b-amino alcohol
derivatives and investigate their antimicrobial potential
against pathogenic fungi and bacteria.
isolated the compound as light brown solid. Spectral
data of the known compound 2h have been given in
the References and Notes section.26
The opening of epoxide ring in epichlorohydrin with
aromatic amines 1a–1i under these conditions proceeds
in a completely regioselective manner and results in
the exclusive formation of the secondary alcohol. The
secondary nature of hydroxyl group in aminoalcohols
2a–2i was confirmed by acetylation of one of the com-
Epoxides are versatile intermediates in organic chemis-
try and their reactions with different nucleophiles have
been the subject of extensive studies. Although transi-
tion metal salts typically catalyze aminolysis reactions
of epoxides, new catalytic systems are continuously
being explored in the search for improved efficiencies
and cost effectiveness. In this context, Lewis acids such
as calcium trifluoromethanesulfonate (calcium triflate),
alumina, zirconium sulfophenyl phosphonate, ceriu-
m(III) chloride, diisopropoxyaluminium trifluoroace-
tate, tantalum(V) chloride (TaCl5) and lithium triflate
(LiOTf) have been reported as catalysts.14 Regioselec-
tive ring opening of epoxides can also be accomplished
by using aminolead compounds; the reagent attacks
the less hindered carbon of the epoxide ring to give
the corresponding amino alcohols in good yields.15 Var-
ious metal salts like LiClO4, CaCl2, ZnCl2, NaClO4,
Mg(ClO4)2 and Zn(OTf)2 have also emerged as efficient
catalysts16 for selective aminolysis of 1,2-epoxides even
with amines of low nucleophilicity. The reaction pro-
ceeds under mild conditions and in aprotic solvents, like
acetonitrile.
pounds,
pan-2-ol (2h), and comparison of the chemical shift
1-chloro-3-(30,40-dichlorophenylamino)-pro-
1
value of the C-2H in the H NMR spectrum of alcohol
1
2h with the chemical shift value of the C-2H in the H
1
NMR spectrum of the resultant acetate 3. In the H
NMR spectrum of 2h, the C-2H resonated at d 4.06,
however the same proton in the corresponding acetate
3 resonated at d 5.17.27 The chemical shift values of
1
other protons in the H NMR spectra of the alcohol
2h and the acetate 3 remained almost at the same posi-
tions. The shift of 1.11 ppm in the chemical shift value
of C-2H of acetate with respect to the alcohol indicates
that the hydroxyl group in 2h is at the C-2 and thus sec-
ondary in nature. This was further confirmed by the
observation of a similar downfield shift in the chemical
shift value of the C-2 of the acetate 3 with respect to that
in the alcohol 2h in their 13C NMR spectra. The forma-
tion of O-acetylated compound 3 over N-acetylated
compound during acetylation of compound 2h may be
because of the secondary nature of the amino function,
which is also attached to a 3,4-dichlorophenyl ring.
Although different kinds of catalysts are available for
the nucleophilic opening of epoxide ring, calcium tri-
fluoromethanesulfonate [Ca(OTf)2] is the most sought
after reagent because it is inexpensive, can easily be pre-
pared and also because it performs reactions in a highly
regioselective manner.17 Calcium triflate is easily pre-
pared by reaction of two equivalents of trifluorometh-
anesulfonic acid with calcium carbonate suspended in
toluene at room temperature.17
The anti-Aspergillus activity of the 3-arylamino-1-chlo-
ropropan-2-ols 2a–2i was evaluated against pathogenic
strains of Aspergillus fumigatus, Aspergillus flavus and
Aspergillus niger using disc diffusion (DDA), microbroth
dilution (MDA) and percentage spore germination inhi-
bition (PSGI) assays.28 The results are shown in Table 1.
The analysis of results revealed that the anti-Aspergillus
activity of 1-chloro-3-(40-chlorophenylamino)-propan-2-
ol (2c) was the maximum in all three assay systems, i.e.,
DDA, MDA and PSGI against all three test pathogens,
except in the case of inhibition of A. niger, where the
activity of 2c equals the activity of compound 2a in
DDA assay. Thus, there was more than 90% inhibition
of the growth of A. fumigatus at the concentration of
5.85 lg/ml. Among the three mono-chlorophenylamino
alcohols, 1-chloro-3-(20-chlorophenylamino)-propan-2-
ol (2a) was the second highest active compound, fol-
lowed by 1-chloro-3-(30-chlorophenylamino)-propan-2-
ol (2b). The structure-activity relationship among the
three mono-chlorophenylamino alcohols revealed that
the presence of a chloro substituent at the para position
with respect to the amino group makes the compound
most active as in case of 2c. The activity decreases al-
most 2 and 4 times, when chlorine occupies ortho and
meta positions with respect to the amino group as in
the case of compounds 2a and 2b, respectively. In gen-
eral, the anti-Aspergillus activities of dichlorophenyla-
mino alcohols were less than those of the
monochlorophenylamino alcohols, except in case of
1-chloro-3-(30,40-dichlorophenylamino)-propan-2-ol (2h)
which exhibited almost the same order of activity as
All nine b-amino-alcohols, i.e., 1-chloro-3-(20-chlorophe-
nylamino)-propan-2-ol (2a), 1-chloro-3-(30-chlorophenyl-
amino)-propan-2-ol (2b), 1-chloro-3-(40-chlorophenylamino)-
propan-2-ol (2c), 1-chloro-3-(20,30-dichlorophenylami-
no)-propan-2-ol (2d), 1-chloro-3-(20,40-dichlorophenylamino)-
propan-2-ol (2e), 1-chloro-3-(20,50-dichlorophenylami-
no)-propan-2-ol (2f), 1-chloro-3-(20,60-dichlorophenyl-
amino)-propan-2-ol (2g), 1-chloro-3-(30,40-dichloro-
phenylamino)-propan-2-ol (2h) and 1-chloro-3-(30,50-
dichlorophenylamino)-propan-2-ol (2i) were prepared
by aminolysis of the racemic epichlorohydrin with the
corresponding aromatic amines (1a–1i) in acetonitrile
in the presence of calcium triflate following the proce-
dure of Cepanec17 et al. in 66–84% yields (Scheme 1).
The structures of 2a–2i were unambiguously established
1
from the analysis of their spectral data (IR, H, 13C
NMR and mass spectra). The structures of known com-
pounds 2a, 2c, 2e and 2h were further confirmed by com-
parison of their melting points and/or spectral data with
those reported in the literature.10,18–20 The spectral data
of the unknown compounds 2b, 2d, 2f, 2g and 2i are
21–25
given in the References and Notes section. Com-
pound 2h has earlier been obtained as oil, however we

2158
A. K. Prasad et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2156–2161
R1
R1
OH
H
N
R2
R2
R3
Cl
3'
NH2
R5
2
3
2h
Ca(OTf)2
1'
6'
3
1
O
+
Cl
acetonitrile
Ac2O-DMAP
dichloromethane
R3
R5
epichlorohydrin
yield 66 - 84 %
R4
R4
2a-2i
1a-1i
O
Compds.
1 and 2
a
b
c
d
e
f
g
h
H
i
O
CH3
Cl
H
N
R1
R2
R3
R4
R5
Cl
Cl
Cl
H
H
H
Cl Cl Cl Cl
H
H
H
H
Cl
H
H
H
H
Cl
H
Cl
H
H
H
H
Cl
H
H
H
H
Cl
H
H
H
H
Cl
Cl
Cl
H
3
Cl
H
yield 91 %
Cl
H
H
H
Scheme 1.
Table 1. In vitro antifungal activity of 3-arylamino-1-chloropropan-2-ols 2a–2i against A. fumigatus, A. flavus and A. niger using disc diffusion
(DDA), microbroth dilution (MDA) and percentage spore germination inhibition (PSGI), and against C. albicans using percent growth inhibition
assay (PGI)
OH
OH
OH
H3C
HO
H3C
O
O
O
O
OH OH
OH OH
COOH
CH3
Amphotericin B (4)
CH3
OH
O
NH2
OH
Compound
MICa (lg/disc)
A. flavus
A. fumigatus
A. niger
C. albicans
DDA
MDA
PSGI
DDA
MDA
PSGI
DDA
MDA
PSGI
PGI
2a
2b
11.71
23.43
5.85
31.25
62.50
15.62
125.00
62.50
125.00
125.00
31.25
125.00
1.95
31.25
62.50
15.62
62.50
62.50
125.00
125.00
31.25
125.00
1.95
23.43
46.87
11.71
46.87
46.87
93.75
46.87
23.43
46.87
0.73
63.50
62.50
31.25
31.25
62.50
15.62
125.00
62.50
62.50
62.50
31.25
125.00
1.95
23.43
46.87
23.43
93.75
93.75
93.75
93.75
46.87
93.75
0.73
62.50
62.50
31.25
62.50
62.50
31.25
250.00
125.00
62.50
62.50
62.50
62.50
31.25
125.00
31.25
—
2c
2d
46.87
23.43
46.87
46.87
11.71
46.87
0.73
125.00
125.00
125.00
125.00
62.50
125.00
125.00
125.00
250.00
62.50
125.00
125.00
125.00
125.00
62.50
2e
2f
2g
2h
2i
125.00
1.95
250.00
1.95
250.00
1.95
Amphotericin Bb
a Minimum inhibitory concentration.
b Amphotericin B (4) has been used as a standard drug.
1-chloro-3-(20-chlorophenylamino)-propan-2-ol
(2a).
ment of activity of the compound. Further, there is chlo-
rine at the para-position in dichlorophenylamino
alcohols 2e and 2h together with the other chlorine atom
at ortho- and meta-position with respect to the amino
group, respectively, and as expected these compounds
exhibited better anti-Aspergillus activity among six
experimental di-chlorosubstituted compounds 2d–2i.
Among these two di-chlorosubstituted amino alcohols
2e and 2h, the latter one with meta, para-di-chlorosubsti-
tution is more active than the former one with ortho-,
Among the dichlorophenylamino alcohols, compound
2h was the most active compound, followed by 1-
chloro-3-(20,40-dichlorophenylamino)-propan-2-ol (2e).
The other four dichlorophenylamino alcohols 2d, 2f,
2g and 2i had almost the same order of activity and it
was not significant. The placement of chlorine at para-
position with respect to the amino group in amino alco-
hol 2c efficiently attracts the lone pair of electrons on the
N-atom, which may be one of the reasons of enhance-

A. K. Prasad et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2156–2161
2159
para-di-chlorosubstitution. The anti-Aspergillus activity
of the most active compound 2c is less than the activity
of the standard compound amphotericin B (4).
noteworthy to see that the anti-candidal activity of
dichlorosubstituted amino alcohols is better than that
of the mono-chlorosubstituted amino alcohols. How-
ever the trend is in the other way in case of anti-Asper-
gillus activity. In general, 3-arylamino-1-chloropropan-
2-ols 2a–2i exhibited better anti-Aspergillus activity than
anti-candidal activity.
All the nine 3-arylamino-1-chloropropan-2-ols 2a–2i
were also evaluated for their in vitro antifungal activity
against pathogenic strain of C. albicans by percent
growth inhibition assay (PGI) following the method of
Iijima et al.29 (Table 1). 1-Chloro-3-(20,60-dichlorophe-
nylamino)-propan-2-ol (2g) and 1-chloro-3-(30,50-
dichlorophenylamino)-propan-2-ol (2i) were found to
be the most active compounds among the nine amino
alcohols evaluated for their anti-candidal activity. It
was observed that there was more than 90% inhibition
of growth of C. albicans cells in wells treated with
31.25 lg/ml of compounds 2g and 2i in PGI assay.28
The other three di-chlorosubstituted amino alcohols
2d, 2e and 2f, and one mono-chlorosubstituted amino
alcohol 2c exhibited almost half the activity of the most
active compounds 2g and 2i. 3-Arylamino-1-chloropro-
pan-2-ols 2a,2b and 2h were the least active compounds.
Among these three amino alcohols, the anti-candidal
activity of 2b and 2h was double than the activity of 1-
chloro-3-(20-chlorophenylamino)-propan-2-ol (2a). It is
Antibacterial activity of the chloropropanols 2a–2i was
evaluated against four pathogenic bacterial strains, Sal-
monella typhi, Pseudomonas aeruginosa, Streptococcus
pneumonae and Staphylococcus aureus using microbroth
dilution assay (MDA). Tetracycline was used as the ref-
erence drug. The percentage of inhibition of tested com-
pounds against pathogenic bacterial strains is shown in
Table 2. In general, amino alcohols 2a–2i were found
more active against S. typhi and P. aeruginosa than
against S. pneumonae and S. aureus. 3-Arylamino-1-
chloropropan-2-ols 2e and 2i were found most active
against S. typhi and amino alcohol 2h was found most
active against P. aeruginosa. Thus, there was more than
90% inhibition of growth of S. typhi cells in wells treated
with 31.25 lg/ml of compounds 2e and 2i, which is
about half the activity of the standard compound tetra-
cycline.28 Compound 2h showed more than 90% inhibi-
tion of growth of P. aeruginosa cells in wells treated with
31.25 lg/ml of the compound, but its activity is only
about one-fourth of the activity of the standard com-
pound tetracycline. The most active compounds against
S. pneumonae and S. aureus were 1-chloro-3-(20,30-
dichlorophenylamino)-propan-2-ol (2d) and 1-chloro-3-
(30,40-dichloro-phenylamino)-propan-2-ol (2h). How-
ever their activity is eight fold less than the activity of
standard compound tetracycline. The remaining com-
pounds did not show any appreciable activity against
any of the tested bacteria. It is interesting that all active
compounds against the bacterial strains are dichlorosub-
stituted amino alcohols.
Table 2. In vitro antibacterial activity of 3-arylamino-1-chloropropan-
2-ols 2a–2i against pathogenic bacterial strains of S. typhi, P.
aeruginosa, S. pneumonae and S. aureus using microbroth dilution
assay (MDA)
Compounds
MIC (lg/ml)
S. typhi P. aeruginosa S. pneumonae S. aureus
2a
2b
2c
2d
2e
2f
250.0
500.0
62.5
62.5
250.0
125.0
62.5
62.5
62.5
125.0
31.3
62.5
7.9
250.0
500.0
500.0
62.5
500.0
1000.0
1000.0
500.0
500.0
250.0
500.0
62.50
125.0
7.9
62.5
31.3
125.0
500.0
500.0
125.0
250.0
7.9
250.0
500.0
62.5
2g
2h
2i
The in vitro cell cytotoxicity of 3-arylamino-1-chloro-
propan-2-ols 2a–2i was investigated using haemolytic
assay.30,31 Interestingly, in dose dependent study, tested
compounds which showed antimicrobial activity against
31.3
Tetracyclinea 15.6
a Tetracycline has been used as a standard drug.
100
90
80
70
60
50
40
30
20
10
0
2a
2b
2c
2d
2e
2f
2g
2h
2i
Tetracycline
3.9
7.8
15.6 31.2 62.5 125 250 500 1000 2000 4000
Gentamycin
Conc. (µg/ml)
Amphotericin B
Figure 1. Cytotoxicity of compounds 2a–2i against erythrocytes using haemolytic assay.

2160
A. K. Prasad et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2156–2161
S.; Prasad, A. K.; Sharma, G. L. Bioorg. Med. Chem.
2006, 14, 973.
pathogenic fungal and bacterial strains were found to be
almost non-toxic up to concentrations of 250 lg/ml
(Fig. 1). The most interesting observation was that 2c
having strong activity against Aspergillus species did
not show any toxicity up to a concentration of
4000 lg/ml. The well-known drugs amphotericin B, tet-
racycline, and gentamycin lysed 100%, 11.68%, and
5.22% erythrocytes, respectively, at a concentration of
62.5 lg/ml. At a very low concentration (3.91 lg/ml),
the well-known drug gentamycin did not show any tox-
icity while amphotericin B and tetracycline lysed 5.52%
and 4.26% erythrocytes. Our results are in accordance
with the results of Cybulska et al.,32 who have reported
that 1.70 lg/ml of amphotericin B caused 50% haemo-
globin loss from erythrocytes.
6. Rogers, G. A.; Parsons, S. M.; Anderson, D. C.; Nilsson,
L. M.; Bahr, B. A.; Kornreich, W. D.; Kaufman, R.;
Jacobs, R. S.; Kirtman, B. J. Med. Chem. 1989, 32, 1217.
7. Johannes, C. W.; Visser, M. S.; Weatherhead, G. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 8340.
8. Li, G.; Chang, H. T.; Sharpless, K. B. Angew. Chem. Int.
Ed. 1996, 35, 451.
9. Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996,
96, 835.
10. Kimura, M.; Masuda, T.; Yamada, K.; Kawakatsu, N.;
Kubota, N.; Mitani, M.; Kishii, K.; Inazu, M.; Kiuchi, Y.;
Oguchi, K.; Namiki, T. Bioorg. Med. Chem. Lett. 2004, 14,
4287.
11. Carter, H. E.; Glick, F. J.; Norris, W. P.; Phillips, G. E. J.
Biol. Chem. 1947, 170, 285.
12. Jnaneshwara, G. K.; Deshpande, V. H.; Lalithambika,
M.; Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459.
13. Auvin-Guette, C.; Rebuffat, S.; Prigent, Y.; Bodo, B. J.
Am. Chem. Soc. 1992, 114, 2170.
14. Khodaei, M. M.; Khosropour, A. R.; Ghozati, K.
Tetrahedron Lett. 2004, 45, 3525, and references cited
therein.
15. Yamada, J.-I.; Yumoto, M.; Yamamoto, Y. Tetrahedron
Lett. 1989, 30, 4255.
16. Chini, M.; Crotti, P.; Macchia, F. Tetrahedron Lett. 1990,
31, 4661.
17. Cepanec, I.; Litvic, M.; Mikuldas, H.; Bartolincic, A.;
Vinkovic, V. Tetrahedron 2003, 59, 2435.
18. Rafiee, E.; Tangestaninejad, S.; Habibi, M. H.; Mirkhani,
V. Synth. Commun. 2004, 34, 3673.
19. Feth, G.; Richter, C. USP 1980, 4215220.
1-Chloro-3-(40-chlorophenylamino)-propan-2-ol
(2c)
was identified as the most active anti-fungal compound,
which exhibits more than 90% inhibition of A. fumigatus
in DDA assay at a concentration of 5.85 lg/ml per disc.
Compounds 2g and 2i were found to be the most active
against C. albicans; the MIC being 31.25 lg/ml. Com-
pounds 2e and 2i exhibited strong activity against S. ty-
phi whereas compound 2h was found to be the most
active against P. aeruginosa. Compound 2c emerged as
a potential lead for the development of anti-fungal drug
candidate even though its activity was less than that of
amphotericin B, but it was many fold less toxic than
the standard anti-fungal agent. Further, compounds 2e
and 2i having about half the activity of the standard
anti-bacterial compound tetracycline and less toxicity
than this standard compound may be potential candi-
dates for the development as anti-bacterial drug candi-
date/hit compound.
´
20. Laguerre, M.; Boyer, C.; Carpy, A.; Leger, J. M.; Panconi,
E.; Vaugien, B.; Cognic, F. Eur. J. Med. Chem. 1993, 28,
77.
21. 1-Chloro-3-(30-chlorophenylamino)-propan-2-ol (2b). It
was obtained as brown oil (1.60 g) in 73% yield.
Rf = 0.25 in 15% ethyl acetate in petroleum ether. IR
(nujol): 3401 (NH, OH), 2923, 1599, 1504, 1251, 1091, 988
Acknowledgments
1
and 766 cmꢀ1; H NMR (300 MHz, CDCl3): d 3.17 (1H,
We are thankful to the Council of Scientific and Indus-
trial Research (CSIR, New Delhi) and Department of
Scientific and Industrial Research (DSIR, New Delhi)
for the financial assistance.
dd, J = 13.2 and 7.2 Hz, C-3Ha), 3.42 (1H, dd, J = 13.2
and 4.3 Hz, C-3Hb), 3.63 (2H, m, C-1H), 4.04 (1H, m,
C-2H), 6.48 (1H, d, J = 8.0 Hz, C-60H), 6.61 (1H, br s,
C-20H), 6.69 (1H, d, J = 7.7 Hz, C-40H) and 7.07 (1H, t,
J = 8.1 Hz, C-50H); 13C NMR (75.5 MHz, CDCl3): d 45.82
and 46.61 (C-1 and C-3)), 68.79 (C-2), 110.60, 115.12 and
117.02 (C-20, C-40 and C-60), 129.33 (C-50), 134.12 (C-30)
and 144.05 (C-10); HRMS (ESI positive mode): calculated
for C9H11NOCl2 [M]+ 219.0218, observed [M]+ 219.0220.
22. 1-Chloro-3-(20,30-dichlorophenylamino)-propan-2-ol (2d).
It was obtained as colourless oil (2.00 g) in 79% yield.
Rf = 0.38 in 15% ethyl acetate in petroleum ether. IR
(nujol): 3415 (NH, OH), 2858, 1589, 1503, 1322, 1279,
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2008.01.080.
1
1040 and 762 cmꢀ1; H NMR (300 MHz, CDCl3): d 2.47
(1H, brs, OH), 3.32 (1H, dd, J = 12.4 and 6.1 Hz, C-3Ha),
3.43 (1H, dd, J = 13.0 and 4.5 Hz, C-3Hb), 3.67 (2H, m, C-
1H), 4.10 (1H, m, C-2H), 4.79 (1H, br s, NH), 6.60 (1H, d,
J = 8.1 Hz, C-60H), 6.82 (1H, d, J = 7.9 Hz, C-40H) and
7.06 (1H, t, J = 8.0 Hz, C-50H); 13C NMR (75.5 MHz,
CDCl3): d 46.95 and 47.63 (C-1 and C-3)), 69.88 (C-2),
109.43 (C-50), 118.85 (C-40 and C-60), 127.91 (C-30), 135.00
(C-20) and 145.34 (C-10); HRMS (ESI positive mode):
calculated for C9H10NOCl3 [M]+ 252.9828, observed [M]+
252.9815.
References and notes
1. Musiol, R.; Jampilek, J.; Buchta, V.; Silva, L.; Niedbala, H.;
Podeszwa, B.; Palka, A.; Majerz-Maniecka, K.; Oleksyn,
B.; Polanski, J. Bioorg. Med. Chem. 2006, 14, 3592.
2. De Luca, L. Curr. Med. Chem. 2006, 13, 1.
3. Jampilek, J.; Dolezal, M.; Kunes, J.; Buchta, V.; Silva, L.;
Kralova, K. J. Med. Chem. 2005, 1, 591.
4. Kiran, I.; Ilhan, S.; Akar, T.; Tur, L.; Erol, E. J. Biosci.
2005, 60, 686.
5. Chhillar, A. K.; Arya, P.; Mukherjee, C.; Kumar, P.;
Yadav, Y.; Sharma, A. K.; Yadav, V.; Gupta, J.;
Dabur, R.; Jha, H. N.; Watterson, A. C.; Parmar, V.
23. 1-Chloro-3-(20,50-dichlorophenylamino)-propan-2-ol (2f).
It was obtained as reddish oil (1.75 g) in 69% yield.
Rf = 0.44 in 15% ethyl acetate in petroleum ether. IR

A. K. Prasad et al. / Bioorg. Med. Chem. Lett. 18 (2008) 2156–2161
2161
(nujol): 3413 (NH, OH), 2922, 2854, 1594, 1507, 1417,
1288, 1094 and 791 cmꢀ1; 1H NMR (300 MHz, CDCl3): d
2.47 (1H, brs, OH), 3.28 (1H, dd, J = 12.1 and 6.4 Hz, C-
3Ha), 3.37 (1H, dd, J = 10.5 and 6.0 Hz, C-3Hb), 3.67 (2H,
m, C-1H), 4.10 (1H, brs, C-2H), 4.70 (1H, br s, NH), 6.62
and 6.65 (2H, m, C-40H and C-60H) and 7.16 (1H, d,
J = 8.2 Hz, C-30H); 13C NMR (75.5 MHz, CDCl3): d 46.64
and 47.67 (C-1 and C-3)), 69.80 (C-2), 111.51 and 117.82
(C-40 and C-60), 130.11 (C-30), 133.81 (C-20) 144.63 (C-50)
4.06 (2H, br s, C-2H and NH), 6.47 (1H, dd, J = 8.6 and
2.6 Hz, C-60H), 6.70 (1H, d, J = 2.6 Hz, C-20H) and 7.18
(1H, d, J = 8.6 Hz, C-50H); 13C NMR (CDCl3): d 47.03
and 47.72 (C-1 and C-3)), 69.91 (C-2), 113.15 and 114.42
(C-20 and C-60), 122.00 (C-50), 130.87 (C-40), 133.12 (C-30),
147.49 (C-10); HRMS(ESI positive mode): calculated for
C9H10NOCl3 [M]+ 252.9828, observed [M]+ 252.9815.
27. Synthesis of 2-acetoxy-1-chloro-3-(30,40-dichlorophenyla-
mino)-propane (3). To a solution of 1-chloro-3-(30,40-
dichlorophenylamino)-propan-2-ol (2h, 53 mg, 0.2 mmol)
and catalytic amount of dimethylaminopyridine (DMAP)
in dichloromethane (20 ml), acetic anhydride (0.044 ml,
0.235 mmol) was added and the reaction mixture was
stirred at room temperature for 3 h until TLC examination
indicated completion of the reaction. The reaction mixture
was washed with a saturated solution of sodium bicar-
bonate (3 · 15 ml) and brine solution (3 · 15 ml), dried
over sodium sulfate and evaporated under reduced
pressure to afford the crude product, which was purified
by column chromatography over silica gel using petroleum
ether and ethyl acetate as eluents to afford 2-acetoxy-1-
chloro-3-(30,40-dichlorophenylamino)-propane (3) as yel-
lowish oil (59 mg) in 91% yield. Rf = 0.52 in 15% ethyl
acetate in petroleum ether. IR (nujol): 3406 (NH), 2929,
1740 (CO), 1599, 1499, 1374, 1232, 1045 and 755 cmꢀ1; 1H
NMR (300 MHz, CDCl3): d 2.10 (3H, s, OCOCH3), 3.43
(2H, br d, J = 5.3 Hz, C-3H), 3.69 (2H, br d, J = 4.2 Hz,
C-1H), 3.96 (1H, br s, NH), 5.17 (1H, m, C-2H), 6.49 (1H,
d, J = 8.4 Hz, C-60H), 6.74 (1H, s, C-20H) and 7.19 (1H, d,
J = 8.4 Hz, C-50H); 13C NMR (75.5 MHz, CDCl3): d 21.26
(OCOCH3), 43.58 and 44.86 (C-1 and C-3), 71.80 (C-2),
113.00 (C-60), 114.51 (C-20), 122.40 (C-50), 132.59 and
133.38 (C-30 and C-40), 147.33 (C-10) and 170.77
(OCOCH3)
0
and 148.52 (C-1); HRMS (ESI positive mode): calculated
for C9H10NOCl3 [M]+ 252.9828, observed [M]+ 252.9818.
24. 1-Chloro-3-(20,60-dichlorophenylamino)-propan-2-ol (2g).
It was obtained as colourless oil (1.67 g) in 66% yield.
Rf = 0.50 in 15% ethyl acetate in petroleum ether. IR
(nujol): 3361 (NH, OH), 2923, 1582, 1568, 1450, 1249,
1
1081 and 768 cmꢀ1; H NMR (300 MHz, CDCl3): d 2.64
(1H, brs, OH), 3.34 (1H, dd, J = 12.9 and 7.3 Hz, C-3Ha),
3.56 (1H, dd, J = 13.2 and 3.5 Hz, C-3Hb), 3.66 (2H, m, C-
1H), 4.02 (1H, brs, C-2H), 4.35 (1H, brs, NH), 6.82 (1H, t,
J = 8.0 Hz, C-40H) and 7.24 (2H, d, J = 8.0 Hz, C-30H and
C-50H); 13C NMR (75.5 MHz, CDCl3): d 47.96 and 50.51
(C-1 and C-3), 71.29 (C-2), 122.89 (C-40), 127.30 (C-30 and
C-50), 129.30 (C-20 and C-60) and 142.52 (C-10); HRMS
(ESI positive mode): calculated for C9H10NOCl3 [M]+
252.9828, observed [M]+ 252.9797.
25. 1-Chloro-3-(30,50-dichlorophenylamino)-propan-2-ol (2i).
It was obtained as colourless oil (1.82 g) in 72% yield.
Rf = 0.33 in 15% ethyl acetate in petroleum ether. IR
(nujol): 3414 (NH, OH), 2923, 1594, 1573, 1316, 1091 and
1
798 cmꢀ1; H NMR (300 MHz, CDCl3): d 2.44 (1H, br s,
OH), 3.18 (1H, dd, J = 13.1 and 7.1 Hz, C-3Ha), 3.33 (1H,
dd, J = 13.1 and 4.0 Hz, C-3Hb), 3.64 (2H, m, C-1H), 4.06
(1H, brs, C-2H), 4.25 (1H, brs, NH), 6.50 (2H, d,
J = 1.5 Hz, C-20H and C-60H) and 6.70 (1H, d,
J = 1.5 Hz, C-40H); 13C NMR (75.5 MHz, CDCl3): d
46.73 and 47.68 (C-1 and C-3), 69.85 (C-2), 111.53 (C-20
and C-60), 117.96 (C-40), 137.01 (C-30 and C-50) and
149.40 (C-10); HRMS (ESI positive mode): calculated for
C9H10NOCl3 [M]+ 252.9828, observed [M]+ 252.9818.
26. Synthesis of 1-chloro-3-(30,40-dichlorophenylamino)-pro-
pan-2-ol (2h). It was obtained as a brownish solid
(1.77 g) in 70% yield. Mp = 59–61 ꢁC, lit.10 reported as
colourless oil. 1H NMR (300 MHz, CDCl3): d 2.46 (1H, br
s, OH), 3.18 (1H, dd, J = 7.1 and 13.0 Hz, C-3Ha) 3. 32
(1H, dd, J = 4.2 and 13.0 Hz, C-3Hb), 3.65 (2H, m, C-1H),
28. Dabur, R.; Sharma, G. L. J. Ethnopharmacol. 2002, 80,
193.
29. Iijima, R.; Kurata, S.; Natori, S. J. Biol. Chem. 1993, 268,
12055.
30. Latoud, C.; Peypoux, F.; Michael, G.; Genat, R.; Morgat,
J. Biochim. Biophys. Acta 1986, 35, 526.
31. Yadav, V.; Mandhan, R.; Dabur, R.; Chhillar, A. K.;
Gupta, J.; Sharma, G. L. J. Med. Microbiol. 2005, 54, 375.
32. Cybulska, B.; Gudomska, I.; Mazerski, J.; Grzybowska,
J.; Borowski, E.; Cheron, M.; Bolard, J. Acta Biochim.
Pol. 2000, 47, 121.