Synthesis and in-vitro antimicrobial activity of novel aminophosphinic acids containing cyclobutane and 1,3-thiazole

Article abstract of DOI:10.1080/10426507.2011.604660

The compounds {[4-(3-methyl-3-aryl(mesityl-phenyl-tetralino)cyclobutyl)-1, 3- thiazol-2-yl]amino}(aryl)methyl-phosphinic acids 2a-l were prepared by condensation of 2-amino-4-(3-aryl(mesityl-phenyl-tetralino)-3-methylcyclobutyl) thiazoles 1a-c with variou

Full text of DOI:10.1080/10426507.2011.604660

This article was downloaded by: [University of Prince Edward Island]
On: 10 November 2014, At: 14:47
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the
Related Elements
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/gpss20
Synthesis and In-Vitro Antimicrobial
Activity of Novel Aminophosphinic Acids
Containing Cyclobutane and 1,3-Thiazole
Pelin Koparir a , Muhsin Karaarslan b , Cahit Orek c & Metin Koparir c
a Department of Chemistry , Forensic Medicine Institute , TR-4400,
Malatya, Turkey
b Department of Chemistry , Aksaray University , TR-68100, Aksaray,
Turkey
c Department of Chemistry , Firat University , TR-23119, Elazığ,
Turkey
Published online: 31 Oct 2011.
To cite this article: Pelin Koparir , Muhsin Karaarslan , Cahit Orek & Metin Koparir (2011) Synthesis
and In-Vitro Antimicrobial Activity of Novel Aminophosphinic Acids Containing Cyclobutane and
1,3-Thiazole, Phosphorus, Sulfur, and Silicon and the Related Elements, 186:12, 2368-2376, DOI:
10.1080/10426507.2011.604660
To link to this article: http://dx.doi.org/10.1080/10426507.2011.604660
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Phosphorus, Sulfur, and Silicon, 186:2368–2376, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.604660
SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY
OF NOVEL AMINOPHOSPHINIC ACIDS CONTAINING
CYCLOBUTANE AND 1,3-THIAZOLE
Pelin Koparir,1 Muhsin Karaarslan,2 Cahit Orek,3
and Metin Koparir3
1Department of Chemistry, Forensic Medicine Institute, TR-4400 Malatya, Turkey
2Department of Chemistry, Aksaray University, TR-68100 Aksaray, Turkey
3Department of Chemistry, Firat University, TR-23119, Elazıg˘, Turkey
GRAPHICAL ABSTRACT
H
NH2
N
NH
R
N
R
R'-CHO
R'
H3C
S
H3C
Conc.HCl
Cl
S
1a-c
R: a) mesityl b) phenyl c) tetralino
H3PO2
H
O
OH
R
P
R'
H3C
R': a) 2-hydroxynaphthalen-1-yl b) 4-nitrophenyl
c) 4-methoxyphenyl d) 4-chlorophenyl
N
NH
S
2a-l
Abstract The compounds {[4-(3-methyl-3-aryl(mesityl-phenyl-tetralino)cyclobutyl)-1,3-
thiazol-2-yl]amino}(aryl)methyl-phosphinic acids 2a–l were prepared by condensation of
2-amino-4-(3-aryl(mesityl-phenyl-tetralino)-3-methylcyclobutyl) thiazoles 1a–c with various
aromatic aldehydes and hypophosphorous acid through a one-pot reaction. The characteri-
zations of these compounds were obtained by elemental analyses, infrared (IR) spectra, and
1H, 13C, and 31P NMR (nuclear magnetic resonance) techniques. The synthesized compounds
were tested in vitro against one Gram-positive and two Gram-negative bacterial strains, one
mycobacterial strain, and a fungus Candida albicans. Compound 2f showed significant activity
against Staphylococcus aureus, whereas the others had no remarkable activity on this strain.
Compound 2g was found to be more active than the others against Mycobacterium fortuitum
at an MIC (minimum inhibitory concentration) value of 32 µg/mL. The antibacterial and
antifungal activities of 2a–l were also compared with various standard drugs.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Biological Activities. Table S1. Figures S1–S6.]
Keywords Aminophosphinic acids; cyclobutane; thiazole
Received 13 June 2011; accepted 8 July 2011.
Address correspondence to Pelin Koparir, Department of Chemistry, Forensic Medicine Institute, TR-4400,
Malatya, Turkey. E-mail: pelin.kutulay@adalet.gov.tr
2368

SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY
2369
INTRODUCTION
Phosphinic acids are of growing importance in understanding and modulating
biological processes.1 In recent years, the synthesis of α-substituted phosphoryl derivatives
(phosphonic and phosphinic acids) has attracted significant attention due to their biological
activities which facilitate their broad application as enzyme inhibitors, antimetabolites,
and antibiotics.2
Among functionalized phosphinic acids, α-aminoalkylphosphinic derivatives have
potential biological activities, such as antibacterial,2 herbicidal,3 and fungicidal.4 1-
aminoalkylphosphinic acids, the phosphinic acid analogues of 1-amino carboxylic acids, are
an important class of compounds that exhibit a variety of interesting and useful properties. In
addition, the structure of the phosphinic functional group mimics the transition state of pep-
tide bond hydrolysis, and the symmetric nature of the phosphinic acid derivatives is expected
to be of benefit in their binding to the homodimer of HIV protease having C2-axis symmetry.
Proteolytic enzymes, responsible for cleavage of an amide bond in peptide substrates,
are involved in a variety of physiological and pathological processes, thus representing a
group of the most attractive targets for drug design and development.5,6 The discovery of
highly potent and selective inhibitors of proteases, which are able to discriminate between
different members of the same family of proteases, remains a continuous challenge. A
phosphinic moiety ( PO2−CH2–) is considered to mimic the high-energy tetrahedral tran-
sition state of peptide bond hydrolysis, and due to this ability, phospihinate pseudopeptides
attract considerable interest, providing a wide range of potent inactivators of proteolitic
enzymes, particularly metalloproteases.7–9
It is well known that 3-substituted cyclobutane carboxylic acid derivatives exhibit
anti-inflamatory and antidepressant activities and liquid crystal properties.10 Various thia-
zole derivatives show herbicidal, anti-inflamatory, antimicrobial, or antiparasitic activity.11
However, the syntheses and physiochemical properties of 1,1,3-trisubstituted cyclobu-
tane, substituted thiazole and its aminophosphinic acid derivatives containing the mesityl,
tetralino, or phenyl group have not been reported so far. These compounds, containing
cyclobutane, thiazole, and aminophosphinic acid functions in their molecules, seem to be
suitable candidates for further chemical modifications and may be pharmacologically active
and useful as ligands in coordination chemistry.
In light of the abovementioned observations, we have selected 1a–c as the starting
compounds, which were synthesized according to the literature procedure published pre-
viously12–15 for the synthesis of mainly cyclobutane, thiazole, and aminophosphinic acid
derivatives, as shown in Scheme 1.
In light of studies conducted on the synthetic chemistry of phosphinic acids dur-
ing last 15 years, we have also partly contributed to this progress by developing a new
aminophosphinic acid synthesis method. Finally, we have also partly contributed to this
progress by obtaining an aminophosphinic acid derivative which involves thiazole and
cyclobutane groups.
The newly synthesized compounds were evaluated for their in-vitro antimicrobial
activities, and the results are presented in Table S1.
RESULTS AND DISCUSSION
Chemistry
The reactions for the synthesis of 2a–l are shown in Scheme 1. When 2-hydroxy-1-
naphthaldehyde, 4-nitrobenzaldehyde, 4-methoxybenzaldehyde, and4-chlorobenzaldehyde

2370
P. KOPARIR ET AL.
were added to 2-amino-4-(3-aryl (mesityl-phenyl-tetralino)-3-methylcyclobutyl) thiazoles
1a–c in the presence of hypophosphorous acid, 2a–l were obtained.
H
NH2
N
NH
R
N
R
R'-CHO
R'
H3C
S
H3C
Conc.HCl
Cl
S
1a-c
R: a) mesityl b) phenyl c) tetralino
H3PO2
H
O
OH
R
P
R'
H3C
R': a) 2-hydroxynaphthalen-1-yl b) 4-nitrophenyl
c) 4-methoxyphenyl d) 4-chlorophenyl
N
NH
S
2a-l
Compound 2
R
R’
Compound 2
R
R’
a
b
c
d
e
f
Mesityl 2-hydroxynaphthalen-1-yl
Mesityl 4-nitrophenyl
Mesityl 4-methoxyphenyl
Mesityl 4-chlorophenyl
g
h
i
j
k
l
Phenyl
Phenyl
4-methoxyphenyl
4-chlorophenyl
Tetralino 2-hydroxynaphthalen-1-yl
Tetralino 4-nitrophenyl
Tetralino 4-methoxyphenyl
Tetralino 4-chlorophenyl
Phenyl
Phenyl
2-hydroxynaphthalen-1-yl
4-nitrophenyl
Scheme 1 Synthesis of the compound (2a–l).
The yields of 2b, 2f, and 2j were high. The reason for this could be the lack of
conjugation between n-electrons on nitrogen atoms with the aromatic ring in intermediate
compounds of 2b, 2f, and 2j. On the other hand, the yields of 2a, 2c, 2e, 2g, 2i, and 2k
were very poor because of an effective conjugation they have with the aromatic ring in
intermediate compounds of 2a, 2c, 2e, 2g, 2i, and 2k. In addition, lower yields were found
in the presence of substituents with higher electron attack power.
In the infrared (IR) spectrum of 2a–l, the most characteristic absorptions are at
3461–3533 cm−1 (OH), 3270–3309 cm−1 (NH), 1602–1613 cm−1 (C N), 1249–1258
1
cm−1 (P O), 980–1099 cm−1 (P O), and 2379–2401 cm−1 (P H). In the H NMR
spectra, characteristic signals due to the (NH) protons appeared at 5.43–5.49 ppm, signals
due to the (PH) protons appeared at 4.99–5.13 ppm, signals due to the (CH P) protons
appeared at 4.76–4.79 ppm, and signals due to the aromatic protons appeared as multiples at
6.73–8.16 ppm. The data for all compounds are given in the Experimental section. Spectra
for 2a (Figures S1–S3) and 2c (Figures S4–S6) can be found in the Supplemental Materials
available online.
Antimicrobial Screening
The synthesized compounds, 2a–l, were tested for antibacterial, antifungal, and an-
timycobacterial activities against various strains by the microdilution method.16–20 For the
determination of antibacterial activity, one Gram-positive and two Gram-negative bac-
terial strains were utilized. Antimycobacterial and antifungal assays of all compounds

SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY
2371
were also performed against Mycobacterium fortuitum ATCC 6841, a rapidly growing
mycobacterium, and the yeast Candida albicans ATCC 2091, respectively. The results are
summarized in Table S1 (Supplemental Materials online).
EXPERIMENTAL
Melting points were determined on a Thomas Hovver melting point apparatus and
uncorrected, but checked by differential scanning calorimeter (DSC). The IR spectra were
measured with a Perkin–Emler Spectrum One FTIR spectrophotometer. The 1H, 13C, and 31P
spectra were taken on a Bruker AC-300 and a Bruker AC-400 NMR spectrometer operating
1
at 400 MHz for H, 100 MHz for 13C, and 161.9 MHz for 31P NMR. Compounds were
dissolved in CDCl3 and DMSO, and chemical shifts were referenced to TMS (1H and 13
C
NMR) and 85% H3PO4 (31P NMR). Elemental analyses were done on a LECO-CHNS-938.
Starting chemicals were obtained from Merck or Aldrich.
General Procedure for the Synthesis of 1a–c
The synthesis of 1a–c [where the aryl group is mesityl (1a), phenyl (1b), or tetralino
(1c)] was carried out according to the method given in the literature.12–15
General Procedure for the Synthesis of 2a–l
In total, 0.05 mol of 1a–c was dissolved in 0.05 mol of concentrated HCl, and to
this solution, 0.05 mol of hypophosporus acid was added. The reaction mixture was put
inside a fuming cupboard, and to this, 0.05 mol of aldehyde (R1) was added.21–23 The
reaction mixture was refluxed for 12 h inside the fuming cupboard. The reaction mixture
was evaporated and cooled. Addition of water and methanol to this cooled solution resulted
in the formation of a solid product. The solid was filtered, washed thoroughly with water,
and recrystallized from the methanol–water mixture.
[(2-Hydroxynaphthalen-1-yl)({4-[3-Methyl-3-(2,4,6-
Trimethylphenyl)Cyclobutyl]-1,3-Thiazol-2-yl}Amino)Methyl]Phosphinic
Acid (2a)
◦
White solid, yield 49%, m.p. 327–328 C. IR (KBr, cm−1) υ: 3488 ( OH), 3293
( NH), 2385 ( P H), 1609 ( C N), 1254 ( P O), 1080 ( P O) cm−1. H NMR
1
(400 MHz, CDCl3, Me4Si, δ, ppm): 13.59 (s, 1H, OH), 8.81 (br, 1H, POH), 7.18–7.65
(m, 6H, Ar H), 6.73 (s, 2H, aromatics, in mesitylene), 6.01 (s, 1H, CH S in thiazole
ring), 5.44 (br, 1H, NH), 5.09 (d, 1H, PH), 4.78 (d, 1H, CHP), 3.93 (q, 1H, >CH in
cyclobutane ring), 2.63 (d, 4H, CH2– in cyclobutane ring), 2.21 (s, 3H, CH3), 2.15 (s, 6H,
CH3), 1.54 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 172.0, 167.0, 162.0, 161.4,
159.8, 136.1 131.3, 130.7, 130.2, 130.1, 129.7, 127.4, 127.3, 127.0, 126.9, 126.8, 101.9,
42.3, 40.5, 32.5, 32.2, 31.4, 29.9. 31P NMR (161.9 MHz, CDCl3, δ, ppm): 28.3; Elemental
analysis: C28H31N2O3PS Calculated: C, 66.38; H, 6.17; N, 5.53. Found: C, 66.40; H, 6.16;
N, 5.56.

2372
P. KOPARIR ET AL.
[({4-[3-Methyl-3-(2,4,6-Trimethylphenyl)Cyclobutyl]-1,3-
Thiazol-2-yl}Amino)(4-Nitrophenyl)Methyl]Phosphinic Acid (2b)
Shining white solid, yield 79%, m.p. 357–358 ◦C. IR (KBr, cm−1) υ: 3479 ( OH),
3299 ( NH), 2389 ( P H), 1607 (C N), 1255 ( P O), 1079 ( P O) cm−1. 1H NMR
(400 MHz, CDCl3, Me4Si, δ, ppm): 8.79 (br, 1H, POH), 7.48–8.16 (m, 4H, Ar H), 6.73
(s, 2H, aromatics, in mesitylene), 6.00 (s, 1H, CH S in thiazole ring), 5.43 (br, 1H, NH),
5.11 (d, 1H, PH), 4.78 (d, 1H, CHP), 3.94 (q, 1H, >CH in cyclobutane ring), 2.64 (d, 4H,
CH2 in cyclobutane ring), 2.21 (s, 3H, CH3), 2.16 (s, 6H, CH3), 1.55 (s, 3H, CH3). 13
C
NMR (100 MHz, CDCl3, δ, ppm): 171.9, 166.8, 162.4, 161.2, 157.8, 148.5, 148.0, 139.4,
139.0, 137.6, 133.3, 129.7, 126.9, 124.0, 99.8, 42.2, 31.8, 29.8. 31P NMR (161.9 MHz,
CDCl3, δ, ppm): 28.3; Elemental analysis: C24H28N3O4PS Calculated: C, 59.37; H, 5.81;
N, 8.65. Found: C, 59.47; H, 5.79; N, 8.69.
[(4-Methoxyphenyl)({4-[3-Methyl-3-(2,4,6-Trimethylphenyl)
Cyclobutyl]-1,3-Thiazol-2-yl}Amino)Methyl]Phosphinic Acid (2c)
◦
Yellow solid, yield 48%, m.p. 333–334 C. IR (KBr, cm−1) υ: 3485 ( OH), 3287
( NH), 2392 ( P H), 1609 ( C N), 1254 ( P O), 1082 ( P O) cm−1. 1H NMR (400
MHz, CDCl3, Me4Si, δ, ppm): 8.80 (br, 1H, POH), 6.88–7.21 (m, 4H, Ar H), 6.74 (s, 2H,
aromatics, in mesitylene), 5.99 (s, 1H, CH S in thiazole ring), 5.45 (br, 1H, NH), 5.10 (d,
1H, PH), 4.76 (d, 1H, CHP), 3.92 (q, 1H, >CH in cyclobutane ring), 3.79 (s, 3H, OCH3),
2.63 (d, 4H, CH2 in cyclobutane ring), 2.20 (s, 3H, CH3), 2.15 (s, 6H, CH3), 1.53 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm): 172.0, 166.9, 163.4, 161.2, 157.8, 148.5,
148.0, 139.8, 138.9, 137.6, 133.4, 129.4, 127.1, 127.0, 100.0, 56.0, 42.2, 38.3, 29.1. 31P
NMR (161.9 MHz, CDCl3, δ, ppm): 28.3; Elemental analysis: C25H31N2O3PS Calculated:
C, 63.81; H, 6.64; N, 5.95. Found: C, 63.79; H, 6.63; N, 6.00.
[(4-Chlorophenyl)({4-[3-Methyl-3-(2,4,6-Trimethylphenyl)
Cyclobutyl]-1,3-Thiazol-2-yl}Amino)Methyl]Phosphinic Acid (2d)
◦
White solid, yield 60%, m.p. 343–344 C. IR (KBr, cm−1) υ: 3498 ( OH), 3282
( NH), 2398 ( P H), 1611 ( C N), 1249 ( P O), 1083 ( P O) cm−1. H NMR
1
(400 MHz, CDCl3, Me4Si, δ, ppm): 8.81 (br, 1H, POH), 7.20–7.31 (m, 4H, Ar H), 6.73
(s, 2H, aromatics, in mesitylene), 6.03 (s, 1H, CH S in thiazole ring), 5.46 (br, 1H, NH),
5.12 (d, 1H, PH), 4.79 (d, 1H, CHP), 3.92 (q, 1H, >CH in cyclobutane ring), 2.63 (d, 4H,
CH2 in cyclobutane ring), 2.20 (s, 3H, CH3), 2.16 (s, 6H, CH3), 1.53 (s, 3H, CH3). 13
C
NMR (100 MHz, CDCl3, δ, ppm):171.8, 166.8, 162.4, 161.2, 157.8, 148.5, 148.0, 139.4,
139.1, 133.3, 129.7, 127.1, 126.8, 100.0, 42.2, 31.8, 26.4, 22.4, 29.2. 31P NMR (161.9
MHz, CDCl3, δ, ppm): 28.4; Elemental analysis: C24H28ClN2O2PS Calculated: C, 60.69;
H, 5.94; N, 5.90. Found: C, 60.71; H, 5.91; N, 5.89.
[(2-Hydroxynaphthalen-1-yl)({[4-(3-Methyl-3-Phenylcyclobutyl)-
1,3-Thiazol-2-yl]Amino})Methyl]Phosphinic Acid (2e)
◦
Yellow solid, yield 48%, m.p. 324–225 C. IR (KBr, cm−1) υ: 3498 ( OH), 3309
( NH), 2401 ( P H), 1602 ( C N), 1258 ( P O), 980 ( P O) cm−1. 1H NMR (400
MHz, CDCl3, Me4Si, δ, ppm): 13.64 (s, 1H, OH), 8.61 (br, 1H, POH), 7.16–7.56 (m, 11H,

SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY
2373
Ar H), 6.01 (s, 1H, CH S in thiazole ring), 5.49 (br, 1H, NH), 4.99 (d, 1H, PH), 4.77
(d, 1H, CHP), 3.94 (quint, 1H, J = 7 Hz >CH in cyclobutane ring), 2.61 (d, 4H, J =
9 Hz CH2 in cyclobutane ring), 1.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ,
ppm): 171.0, 167.0, 161.0, 157.8, 156.9, 148.5, 144.2, 139.2, 133.0, 130.0, 128.7, 127.4,
125.6, 111.3, 100.0, 42.7, 42.4, 36.4, 33.1, 31.1. 31P NMR (161.9 MHz, CDCl3, δ, ppm):
28.6; Elemental analysis: C25H25N2O3PS Calculated: C, 64.64; H, 5.42; N, 6.03. Found:
C, 64.74; H, 5.41; N, 6.09.
({[4-(3-Methyl-3-Phenylcyclobutyl)-1,3-Thiazol-2-yl]Amino}
(4-Nitrophenyl)Methyl]Phosphinic Acid (2f)
◦
Orange solid, yield 84%, m.p. 238–239 C. IR (KBr, cm−1) υ: 3503 ( OH), 3298
( NH), 2431 ( P H), 1612 ( C N), 1254 ( P O), 1079 ( P O) cm−1. H NMR
1
(400 MHz, CDCl3, Me4Si, δ, ppm): 8.61 (br, 1H, POH), 7.14–8.19 (m, 9H, Ar H), 5.99
(s, 1H, CH S in thiazole ring), 5.51 (br, 1H, NH), 5.01 (d, 1H, PH), 4.78 (d, 1H, CHP),
3.93 (quint, 1H, >CH in cyclobutane ring), 2.62 (d, 4H, CH2 in cyclobutane ring),
1.54 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm):172.0, 167.1, 162.0, 157.8, 148.4,
148.0, 144.2, 139.8, 131.2, 127.8, 125.9, 111.0, 42.4, 36.4, 33.8, 29.9. 31P NMR (161.9
MHz, CDCl3, δ, ppm): 28.6; Elemental analysis: C20H21N3O4PS Calculated: C, 55.81; H,
4.92; N, 9.76. Found: C, 55.79; H, 5.00; N, 9.75.
[(4-Methoxyphenyl)({[4-(3-Methyl-3-Phenylcyclobutyl)-1,3-
Thiazol-2-yl]Amino})Methyl]Phosphinic Acid (2g)
◦
Light yellow solid, yield 45%, m.p. 271–273 C. IR (KBr, cm−1) υ: 3461 ( OH),
3281 ( NH), 2379 ( P H), 1611 ( C N), 1253 ( P O), 1082 ( P O) cm−1. 1H NMR
(400 MHz, CDCl3, Me4Si, δ, ppm): 8.59 (br, 1H, POH), 7.16–7.39 (m, 9H, Ar H), 6.04
(s, 1H, CH S in thiazole ring), 5.49 (br, 1H, NH), 4.99 (d, 1H, PH), 4.76 (d, 1H, CHP),
3.94 (quint, 1H, >CH in cyclobutane ring), 3.81 (s, 3H, OCH3), 2.59 (d, 4H, CH2
in cyclobutane ring), 1.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm):172.6,
166.1, 161.8, 157.8, 149.2, 148.4, 144.1, 139.3, 131.2, 127.7, 125.8, 111.4, 100.3, 56.9,
42.4, 36.4, 32.1, 30.0. 31P NMR (161.9 MHz, CDCl3, δ, ppm): 28.4; Elemental analysis:
C22H25N2O3PS Calculated: C, 61.67; H, 5.88; N, 6.54. Found: C, 61.65; H, 5.90; N, 6.51.
[(4-Chlorophenyl)({[4-(3-Methyl-3-Phenylcyclobutyl)-1,3-
Thiazol-2-yl]Amino})Methyl]Phosphinic Acid (2h)
◦
Yellow solid, yield 65%, m.p. 251–252 C. IR (KBr, cm−1) υ: 3482 ( OH), 3290
( NH), 2392 ( P H), 1613 ( C N), 1254 ( P O), 1051 ( P O) cm−1. 1H NMR (400
MHz, CDCl3, Me4Si, δ, ppm): 8.58 (br, 1H, POH), 7.14–7.27 (m, 9H, Ar H), 6.03 (s, 1H,
CH S in thiazole ring), 5.47 (br, 1H, NH), 5.02 (d, 1H, PH), 4.78 (d, 1H, CHP), 3.93
(quint, 1H, >CH in cyclobutane ring), 2.62 (d, 4H, CH2 in cyclobutane ring), 1.53 (s,
3H, CH3). 13C NMR (100 MHz, CDCl3, δ, ppm):171.9, 167.0, 166.0, 161.1, 157.8, 148.0,
144.1, 139.0, 136.9, 134.0, 132.6, 129.7, 125.9, 110.1, 98.9, 42.4, 36.4, 32.0, 30.0. 31P NMR
(161.9 MHz, CDCl3, δ, ppm): 28.5; Elemental analysis: C21H22ClN2O2PS Calculated: C,
58.26; H, 5.12; N, 6.47. Found: C, 58.20; H, 5.09; N, 6.48.

2374
P. KOPARIR ET AL.
[(2-Hydroxynaphthalen-1-yl)({4-[3-Methyl-3-(5,6,7,8-
Tetrahydronaphthalen-2-yl)Cyclobutyl]-1,3-Thiazol-2-yl}Amino)
Methyl]Phosphinic Acid (2i)
◦
White solid, yield 54%, m.p. 280–281 C. IR (KBr, cm−1) υ: 3533 ( OH), 3299
( NH), 2391 ( P H), 1613 ( C N), 1255 ( P O), 1101 ( P O) cm−1. H NMR
1
(400 MHz, D2O + NaOD, δ, ppm): 6.86–7.79 (m, 9H, Ar H), 5.95 (s, 1H, CH S in
thiazole ring), 5.13 (d, 1H, PH), 4.79 (d, 1H, CHP), 3.52 (quint, 1H, J = 8.80 Hz >CH
in cyclobutane ring), 2.76–2.81 (m, 4H, the alicyclic protons of tetraline as two broad),
2.34–2.55 (m, 4H, CH2 in cyclobutane ring), 1.81–1.84 (m, 4H, the alicyclic protons of
tetraline), 1.54 (s, 3H, CH3). 13C NMR (D2O + NaOD, δ, ppm): 171.9, 167.0, 161.0, 157.8,
152.0, 138.8, 136.1, 131.0, 130.1, 129.7, 127.5, 127.0, 124.3, 102.2, 42.5, 40.1, 32.6, 31.5,
31.0, 25.3, 25.3, 22.1, 31P NMR (161.9 MHz, D2O + NaOD, δ, ppm): 28.6; Elemental
analysis: C29H31N2O3PS Calculated: C, 67.16; H, 6.03; N, 5.40. Found: C, 67.11; H, 5.99;
N, 5.39.
[({4-[3-Methyl-3-(5,6,7,8-Tetrahydronaphthalen-2-yl)Cyclobutyl]-
1,3-Thiazol-2-yl}Amino)(4-Nitrophenyl)Methyl]Phosphinic Acid (2j)
◦
White solid, yield 70%, m.p. 274–275 C. IR (KBr, cm−1) υ: 3463 ( OH), 3289
( NH), 2379 ( P H), 1605 ( C N), 1252 ( P O), 1091 ( P O) cm−1. H NMR
1
(400 MHz, D2O + NaOD, δ, ppm): 6.94–8.13 (m, 7H, Ar H), 5.98 (s, 1H, CH S in
thiazole ring), 5.12 (d, 1H, PH), 4.77 (d, 1H, CHP), 3.53 (quint, 1H, J = 8.80 Hz >CH
in cyclobutane ring), 2.78–2.81 (m, 4H, the alicyclic protons of tetraline as two broad),
2.33–2.55 (m, 4H, CH2 in cyclobutane ring), 1.82–1.84 (m, 4H, the alicyclic protons of
tetraline), 1.53 (s, 3H, CH3). 13C NMR (D2O + NaOD, δ, ppm):171.8, 167.0, 157.8, 152.0,
138.8, 136.1, 131.0, 129.7, 128.6, 127.5, 100.0, 40.1, 32.6, 31.5, 31.0, 25.3, 25.2, 22.1.
31P NMR (161.9 MHz, D2O + NaOD, δ, ppm): 28.3; Elemental analysis: C25H28N3O4PS
Calculated: C, 60.35; H, 5.67; N, 8.45. Found: C, 60.25; H, 5.47; N, 8.43.
[(4-Methoxyphenyl)({4-[3-Methyl-3-(5,6,7,8-Tetrahydronaphthalen-
2-yl)Cyclobutyl]-1,3-Thiazol-2-yl}Amino)Methyl]Phosphinic Acid (2k)
Shining white solid, yield 50%, m.p. 266–267 ◦C. IR (KBr, cm−1) υ: 3463 ( OH),
1
3270 ( NH), 2391 ( P H), 1601 ( C N), 1250 ( P O), 1077 ( P O) cm−1. H
NMR (400 MHz, D2O + NaOD, δ, ppm): 6.87–7.24 (m, 7H, Ar H), 5.99 (s, 1H, CH S
in thiazole ring), 5.13 (d, 1H, PH), 4.78 (d, 1H, CHP), 3.79 (s, 3H, OCH3), 3.53 (quint,
1H, J = 8.80 Hz >CH in cyclobutane ring), 2.76–2.80 (m, 4H, the alicyclic protons of
tetraline as two broad), 2.34–2.55 (m, 4H, CH2 in cyclobutane ring), 1.81–1.84 (m,
4H, the alicyclic protons of tetraline), 1.53 (s, 3H, CH3). 13C NMR (D2O + NaOD, δ,
ppm):172.5, 166.9, 160.8, 157.8, 157.0, 148.0, 139.3, 138.8, 136.2, 131.4, 130.4, 129.6,
124.5, 99.7, 42.5, 32.6, 31.4, 25.4, 25.1, 22.3. 31P NMR (161.9 MHz, D2O + NaOD, δ,
ppm): 28.3; Elemental analysis: C26H31N2O3PS Calculated: C, 64.71; H, 6.47; N, 5.80.
Found: C, 64.61; H, 6.37; N, 5.78.

SYNTHESIS AND IN-VITRO ANTIMICROBIAL ACTIVITY
2375
[(4-Chlorophenyl)({4-[3-Methyl-3-(5,6,7,8-Tetrahydronaphthalen-
2-yl)Cyclobutyl]-1,3-Thiazol-2-yl}Amino)Methyl]Phosphinic Acid (2l)
◦
White solid, yield 58%, m.p. 249–250 C. IR (KBr, cm−1) υ: 3465 ( OH), 3278
( NH), 2399 ( P H), 1609 ( C N), 1255 ( P O), 1099 ( P O) cm−1. H NMR
1
(400 MHz, D2O + NaOD, δ, ppm): 6.90–7.26 (m, 7H, Ar H), 6.00 (s, 1H, CH S in
thiazole ring), 5.12 (d, 1H, PH), 4.76 (d, 1H, CHP), 3.53 (quint, 1H, J = 8.80 Hz >CH
in cyclobutane ring), 2.74–2.81 (m, 4H, the alicyclic protons of tetraline as two broad),
2.33–2.55 (m, 4H, CH2 in cyclobutane ring), 1.81–1.85 (m, 4H, the alicyclic protons of
tetraline), 1.53 (s, 3H, CH3). 13C NMR (D2O + NaOD, δ, ppm):171.0, 165.9, 160.8, 157.8,
157.0, 148.0, 140.2, 139.6, 137.8, 136.2, 131.4, 129.7, 127.0, 103,6 100.1, 42.5, 32.6, 32.4,
31.5, 25.1, 22.2. 31P NMR (161.9 MHz, D2O + NaOD, δ, ppm): 28.3; Elemental analysis:
C25H28ClN2O2PS Calculated: C, 61.66; H, 5.80; N, 5.75. Found: C, 61.60; H, 5.79; N,
5.74.
Biological Screening
Compounds 2a–l were examined for their in-vitro growth inhibitory activity against
different bacterial strains (in addition to M. fortuitum ATCC 6841, a rapidly growing my-
cobacterium, and a yeast, C. albicans ATCC 2091). The bacterial strains utilized were
Staphylococcus aureus ATCC 29213 as Gram-positive, and Escherichia coli ATCC 25922
and Pseudomonas aeruginosa ATCC 27853 as Gram-negative bacteria. Antibacterial, anti-
fungal, and antimycobacterial assays wereall performedbythe two-foldserial microdilution
technique.16–20
Supplementary Data
Figures S1–S6 and Table S1 are available online in Supplemental Materials.
REFERENCES
1. (a) Engel, R. Chem. Rev. 1977, 77, 349–367; (b) Moonen, K.; Laureyn, I.; Stevens, C. V. Chem.
Rev. 2004, 104, 6177–6215.
2. Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629–647.
3. Kafarski, P.; Lejczak, B.; Tyka, R.; Koba, L.; Pliszczak, E.; Wieczorek, P. J. Plant. Growth Regul.
1995, 14, 199–203.
4. Ishiguri, Y.; Yanada, Y.; Kata, T.; Sasaki, M.; Mukai, K. European Patent Application, EP
82-301905, (1982); Chem. Abstr. 1983, 98, 102686.
5. Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305–341.
6. Babine, R. E.; Bender, S. L. Chem. Rev. 1997, 97, 1359–1472.
7. Collinsova, M.; Jiracek, J. Curr. Med. Chem. 2000, 7, 629–647.
8. Kafarski, P.; Lejczak, B.; Kukhar, V. P.; Hudson, H. H.; Eds., Aminophosphonic and Aminophos-
phinic Acids (Wiley, New York, 2000), pp. 407–422.
9. Yiotakis, A.; Georgiadis, D.; Matziari, M.; Makaritis, A.; Dive, V. Curr. Org. Chem. 2004, 8,
1135–1158.
10. Roger, E.; Pierre, C. J.; Pualette, V.; Gerard, G.; Chepat, J. P.; Robert, G. Eur. J. Med. Chem.
1977, 12, 501–509.
11. Foerster, H.; Hofer, W.; Mues, V.; Eue, L.; Schmidt, R. R. German Patent, 2, 822, 155, 1979;
Chem. Abstr. 1980, 92, 146, 754.

2376
P. KOPARIR ET AL.
12. Ahmedzade, M.; A. C¸ ukurovali; Koparir, M. J. Chem. Soc. Pak. 2003, 25, 51–55.
13. Koparir, M.; Cansiz, A.; Ahmedzade, M.; Cetin, A.,Heteroat. Chem. 2004, 15, 26–31.
14. Koparir, M.; Cansiz, A.; Ahmedzade, M.,Chem. Heterocycl. Comp. 2006, 3, 424–429.
15. Koparir, M.; Cansiz, A.; Ahmedzade, M.,Russ. J. Org. Chem. 2004, 40, 1813–1818.
16. Guinet, R.; Nerson, D.; Declosets, F.; Camet, J. D.; Kures, D.; Mariollet, M.; Parot, J. L.; Ros,
A.; Maugein, J. T.; Volle, P. J. J. Clin. Microbiol. 1988, 26, 2307–2312.
17. Hawkins, J. E., Wallace, R. J., Brown, B. A., Balows, A., Hausler, W. J., Herman, K. L., Isenberg,
H. O.; Shadomy, H. I., Eds., Manual of Clinical Microbiology (5th ed., American Society for
Microbiology, Washington, DC, 1991), pp. 1138–1152.
18. Mcginnis, M. R.; Rinaldi, M. G.; Lorian, V.; Eds., Antibiotics in Laboratory Medicine III
(Williams & Wilkins, Baltimore, MD, 1991), pp. 198–256.
19. National Committee for Clinical Laboratory Standards (NCCLS), Methods for dilution antimi-
crobial susceptibility tests for bacteria that grow aerobically. Fourth informational supplement,
approved standard, NCCLS document no. M 100 S4 (NCCLS, Villanova, PA, 1992).
20. Swenson, J. M.; Thornsberry, C.; Silcox, V. A.,Antimicrob. Agents Chemother. 1992, 22, 186–192.
21. Ramesh, S.; Rajeswari, S.; Maruthamuthu, S., In Proceedings of National Convention on Corro-
sion (CORCON-2002), East Asia Pacific Regional Conference, Goa, India, 2002.
22. Shaban, A.; Kalman, B.; Biczo, I. Corros. Sci. 1993, 35, 1463–1470.
23. Ramesh, S.; Rajeswari, S. Can. Metall. Quart. 2003, 42, 377–382.