Synthesis of Terminal Thiazoles from N-Protected Amino Acids and a Study of Their Antibacterial Activities

Full text of DOI:10.1080/00304948.2020.1721959

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Synthesis of Terminal Thiazoles from N-Protected
Amino Acids and a Study of Their Antibacterial
Activities
H. S. Lalithamba, K. Uma, T. S. Gowthami & G. Nagendra
To cite this article: H. S. Lalithamba, K. Uma, T. S. Gowthami & G. Nagendra (2020): Synthesis
of Terminal Thiazoles from N-Protected Amino Acids and a Study of Their Antibacterial Activities,
Organic Preparations and Procedures International, DOI: 10.1080/00304948.2020.1721959
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1721959
EXPERIMENTAL PAPER
Synthesis of Terminal Thiazoles from N-Protected Amino
Acids and a Study of Their Antibacterial Activities
H. S. Lalithambaa, K. Umaa, T. S. Gowthamia, and G. Nagendrab
b
aDepartment of Chemistry, Siddaganga Institute of Technology, Tumakuru, India; Department of
Chemistry, School of Applied Sciences, REVA University, Bengaluru, India
ARTICLE HISTORY Received 5 July 2019; Accepted 3 November 2019
Thiazoles have gained a particular significance in the field of organic chemistry. Amino
acid derived thiazoles comprise a common motif in biologically active substances such
as the thiopeptide antibiotics.1–8 Hence, the preparation and reactions of thiazoles are
important for the synthesis of pharmaceuticals and fine chemicals. A sequential proced-
ure for the preparation of 2,5-disubstituted thiazoles from sulfonyl azides, terminal
alkynes and thionoesters, by the elimination of the sulfonyl group, was reported.9
Cyclization reactions of thiosemicarbazide derivatives yielding thiazoles have also been
explored.10 In particular, we may note the production of thiazole esters from the cyc-
lization reaction of 4-substituted benzenenitriles and L-cysteine, followed by the esterifi-
cation with selected alcohols and oxidation of thiazoline esters mediated by BrCCl3/
DBU.11 Thiazole and its derivatives were efficiently prepared through a gold-catalyzed
oxidation at room temperature.12 Besides, the reaction of 11-bromo-10-oxoundecanoic
acid with acetamide and thiourea yielded the terminally located thiazole derivatives.13
Several methods for the synthesis of thiazoles have been reported as follows: (i) thiazole-
containing amino acids were synthesized by condensation-cyclization,14 (ii) Ling and his
group prepared 1,2,4-triazole-linked thiazole derivatives from the reaction of a-bromo sub-
stituted acetophenones and thiourea,15 (iii) Wardakhan and his co-workers synthesized sev-
eral thiazole derivatives from pyridazin-3-hydrazidic acids,16 and (iv) Khazi et al., have
reported a preparation of thiazole-fused diazepinones by the application of intramolecular
hydrazinolysis.17 Thiazoles were also synthesized by an alternative substitution method
using MnO2.18 Notwithstanding the ground that has been broken by these methods, some
disadvantages remain. In this context, we have developed a simple, well-ordered and prac-
tical method of synthesis of terminal thiazoles in good isolated yields.
In our work, we proceeded with the elaboration of Fmoc/Cbz-amino acids to yield the
required terminal thiazoles. The necessary thioamides were prepared by the reaction of N-
protected a-amino acid amides with the thionating agent P2S5 through an ultrasonication
mediated protocol. The thioamides were then refluxed with chloroacetaldehyde to obtain
the thiazole-linked molecules. N-Protected amino acid 1 was dissolved in tetrahydrofuran
(THF), followed by the addition of N-methyl morpholine (NMM) and ethyl chloroformate
(ECF) at -15 ꢀC. The reaction mixture was stirred for 15 minutes at the same temperature
CONTACT H. S. Lalithamba
lalithambasit@yahoo.co.in
Department of Chemistry, Siddaganga Institute of
Technology, B.H. Road, Tumakuru-572 103, Karnataka, India
ß 2020 Taylor & Francis Group, LLC

2
H. S. LALITHAMBA ET AL.
R1
R1
R1
R1
ClCH2CHO
N
P2S5
NMM, ECF
OH
NH2
PgHN
NH2
PgHN
PgHN
PgHN
S
NH4HCO3
O
S
O
1
2
3
4
Pg = Fmoc/Cbz group; R = Amino acid side chains
Scheme 1. Synthesis of Na-protected terminal thiazoles.
Scheme 2. Mechanism for the formation of thioamide from amide and P4S10.
and ammonium bicarbonate (NH4HCO3) was added to obtain the corresponding amide 2.
Simple work-up was done to yield the amide. The amide was then dissolved in THF and
treated with P2S5 to form the thioamide under ultrasonic conditions.19,20 The resulting thio-
amide 3 was reacted with chloroacetaldehyde (ClCH2CHO) under reflux to afford the target
N-protected thiazole 4 (Scheme 1). Using this procedure several terminal thiazoles were
synthesized from N-protected amino acids as shown in Table 1. The synthesized com-
1
pounds were fully characterized by H NMR, 13C NMR and HRMS techniques.
Na-Protected peptidyl thiazoles were also prepared (Scheme 3) starting from Fmoc-pep-
tide acids. The synthesized peptidyl thiazoles (Table 2, 8a-d) were also fully characterized.
The newly-synthesized compounds Fmoc-Val-Thiazole (4b) and Fmoc-Leu-Thiazole
(4c) were subjected to antibacterial studies. Compound 4c showed significant inhibitory
activity against Staphylococcus aureus.
In conclusion, we have developed an efficient protocol for the synthesis of terminal thia-
zoles from the corresponding thioamides derived from protected amino acids. All the syn-
thesized terminal thiazoles were isolated after simple work up and were fully characterized.
We hope that our method of preparation of terminal thiazoles will stimulate further
research into the chemistry and biological activity of these unique compounds.
Experimental section
All the chemicals were purchased from Sigma-Aldrich and Merck and were used with-
out purification except that solvents were freshly distilled before use. Melting points

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 1. Na-Protected terminal thiazoles.
Entry
Na-protected terminal thiazole
Yield (%)
89
Mp oC
121
N
FmocHN
4a
S
N
4b
4c
90
86
130
135
FmocHN
FmocHN
FmocHN
S
N
N
S
4d
4e
83
88
Gum
140
S
S
N
N
FmocHN
HO
4f
85
85
Gum
Gum
FmocHN
S
S
4g
N
FmocHN
CbzHN
S
N
4h
4i
80
86
118
122
S
N
N
CbzHN
CbzHN
S
S
4j
84
Gum
(continued)

4
H. S. LALITHAMBA ET AL.
Table 1. Continued.
Entry
Na-protected terminal thiazole
Yield (%)
90
Mp oC
Gum
N
4k
4l
CbzHN
S
88
128
N
CbzHN
S
R1
H
O
R1
S
R1
O
H
N
H
N
NMM, ECF
P2S5
N
PgHN
OH
PgHN
NH2
PgHN
NH2
NH4HCO3
O
R2
O
R2
O
R2
5
7
6
ClCH2CHO
R1
N
H
N
PgHN
S
O
R2
8
Pg = Fmoc/Cbz group; R1, R2 = Amino acid side chains
Scheme 3. Synthesis of Na-protected terminal peptide thiazoles.
were taken in open capillaries and are uncorrected. TLC analysis was carried out using
1
plates precoated with silica gel F254 (solvent system-EtOAc:hexane). H NMR and 13C
NMR spectra were done on a Bruker AMX 400 MHz spectrometer using Me4Si as an
internal standard and DMSO-d6 as the solvent. Elemental analyses were obtained using
a Vario Microselect CHNS analyzer. Mass spectra were recorded on a Micromass Q-
ToF Micro mass Spectrometer. The pathogenic bacterial strains were purchased from
the National Chemical Laboratory (NCL) Pune, India.
Synthesis of Na-protected amino/peptidyl terminal thiazoles from protected
amino acids
The appropriate N-protected amino/peptide acid (1.0 mmol) was dissolved in THF, to
which NMM (1.5 mmol) and ECF (1.5 mmol) were added at -15 ꢀC, followed by the
addition of NH4HCO3 (1.5 mmol) to obtain the corresponding amide. The reaction

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
5
Table 2. Na-Protected terminal thiazoles from peptide acids.
Entry
Na-protected terminal thiazoles
Yield (%)
Mp oC
N
H
N
8a
90
Gum
Gum
FmocHN
FmocHN
S
S
O
O
N
H
N
8b
88
N
N
H
N
FmocHN
FmocHN
8c
85
85
Gum
Gum
S
S
O
O
H
N
8d
S
mixture was stirred until the completion of the reaction and the progress of the reaction
was checked by TLC. After the removal of THF, the product was extracted into ethyl
acetate (15 mL) and the organic layer was washed with dilute HCl solution (10 mL) or
citric acid solution (10 mL) in the case of the Boc-protected compounds, then with
Na2CO3 solution (15 mL x 2), water (15 mL) and brine (15 mL). The organic extract was
dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The
amide thus formed was then treated with P2S5 (0.5 mmol) to form the thioamide under
ultrasonic conditions for 2-3 hrs. The resulting thioamide in dry THF was reacted with
chloroacetaldehyde (1.0 mmol) under reflux conditions for 2 hrs. N-Protected thiazoles
were obtained in good yield after simple acid-base work up and purified through col-
umn chromatography using EtOAc:hexane (3:7) as an eluent.
(S)-(9H-Fluoren-9-yl) methyl 1-(thiazol-2-yl) ethylcarbamate (4a)
1
Yield 89%; Solid; Melting Point 121 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 1.45
(d, J¼8.0 Hz, 3H), 4.36 (t, J¼6.8 Hz, 1H), 4.70 (d, J¼8.0 Hz, 2H), 4.95 (m, 1H), 6.0 (s,
1H), 7.12 (d, J¼8.0 Hz, 1H), 7.28-7.60 (m, 8H), 7.73 (d, J¼8.0 Hz,1H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 20.4, 46.7, 48.5 66.3 116.2, 126.4 128.0, 128.4, 128.6

6
H. S. LALITHAMBA ET AL.
140.8, 142.0, 143.4, 156.0, 168.8. MS: Calcd. for C20H18N2O2S m/z: 373.11 (Mþ þNa),
Found: 373.1098.
Anal. Calcd. for C20H18N2O2S: C, 68.55; H, 5.18; N, 7.99. Found: C, 68.30; H, 5.11;
N, 7.85.
(S)-(9H-Fluoren-9-yl)methyl 2- methyl 1-(thiazol-2-yl) propylcarbamate (4b)
1
Yield 90%, Solid, Melting Point 130 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 2.92
(m, 2H), 4.4 (m, 1H), 4.65 (d, J¼8.0 Hz, 2H), 5.26 (t, J¼6.8 Hz, 1H), 6.0 (s, 1H), 7.07-
7.68 (m, 15H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 40.7, 46.5, 54.2, 66.9, 118.0,
126.2, 126.8, 127.6, 128.0, 128.4, 128.6, 128.8, 139.0, 140.8, 142.0, 143.5, 155.3, 170.2.
MS: Calcd. for C22H22N2O4S m/z: 401.14 (Mþ þNa), Found: 401.1402.
Anal. Calcd. for C22H22N2O4S: C, 69.81; H, 5.86; N, 7.40. Found: C, 69.68; H, 5.47;
N, 7.22.
(S)-(9H-Fluoren-9-yl)methyl 3- methyl 1-(thiazol-2-yl) butylcarbamate (4c)
1
Yield 86%, Solid, Melting Point 135 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 0.98
(t, J¼6.8 Hz, 3H), 1.12 (d, J¼8.0 Hz, 3H),1.26 (m, 2H), 2.08 (m, 1H), 4.38 (t, J ¼ 6.8 Hz,
1H), 4.70 (d, J¼8.0 Hz, 2H), 4.83 (d, J¼8.0 Hz, 1H), 6.0 (s, 1H), 7.12-7.84 (m, 10H). 13C
NMR (100 MHz, DMSO-d6): d (ppm) 16.8, 32.5, 46.4, 57.2, 66.3, 118.0, 126.3, 128.0,
128.3, 128.6, 141.0, 141.9, 143.1, 155.8, 170.4. MS: Calcd. for C23H24N2O2S m/z: 415.16
(Mþ þNa), Found: 415.1600.
Anal. Calcd. for C23H24N2O2S: C, 70.38; H, 6.16; N, 7.14. Found: C, 70.00; H, 6.03;
N, 7.11.
(S)-(9H-Fluoren-9-yl)methyl (1S, 2R)-2- methyl 1-(thiazol-2-yl) butylcarbamate (4d)
1
Yield 83%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 0.96 (d, J ¼ 8.0 Hz, 6H), 1.80
(s, 2H), 1.83 (br, 1H), 4.4 (t, J ¼ 6.8 Hz, 1H), 4.73 (d, J ¼ 8.0 Hz, 2H), 4.82 (t, J ¼ 6.8 Hz,
1H), 6.0 (s, 1H), 7.10-7.82 (m, 10H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 22.5,
23.2, 46.0, 47.1, 51.8, 67.3, 118.0, 126.8, 128.1, 128.4, 128.7, 141.0, 142.2, 143.4, 155.8,
170.6. MS: Calcd. for C23H24N2O2S m/z: 415.16 (Mþ þNa), Found: 415.1558.
Anal. Calcd. for C23H24N2O2S: C, 70.38; H, 6.16; N, 7.14. Found: C, 70.25; H, 6.00;
N, 7.12.
(S)-(9H-Fluoren-9-yl)methyl 2-phenyl- 1-(thiazol-2-yl) ethylcarbamate (4e)
1
Yield 88%, Solid, Melting Point 140 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 2.96
(d, J ¼ 8.0 Hz, 2H), 4.42 (t, J ¼ 6.8 Hz, 1H), 4.68 (d, J ¼ 8.0 Hz, 2H), 4.83 (t, J ¼ 6.8 Hz,
1H), 6.0 (s, 1H), 7.08-7.78 (m, 15H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 11.6,
15.0, 25.4, 41.2, 46.9, 55.1, 67.2, 118.5, 126.8, 128.0, 128.4, 128.7, 141.0, 142.1, 143.5,
156.0, 170.4. MS: Calcd. for C26H22N2O2S m/z: 449.14 (Mþ þNa), Found: 449.1404.
Anal. Calcd. for C26H22N2O2S: C, 73.21; H, 5.20; N, 6.57. Found: C, 73.12; H, 5.26;
N, 6.65.

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
7
(S)-(9H-Fluoren-9-yl) methyl 2-hydroxy-1-(thiazol-2-yl) ethylcarbamate (4f)
1
Yield 85%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 1.96 (s, 1H), 3.85 (m, 2H),
4.42 (t, J¼6.8 Hz, 1H), 4.7 (d, J ¼ 8.0 Hz, 2H), 4.96 (d, J¼6.8 Hz, 1H), 6.0 (s, 1H), 7.12-
7.80 (m, 10H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 46.9, 58.5, 64.2, 67.7, 118.7,
126.8, 128.1, 128.6, 128.8, 141.0, 142.0, 143.6, 156.1, 170.6. MS: Calcd. for C20H18N2O3S
m/z: 389.10 (Mþ þNa), Found: 389.1007 .
Anal. Calcd. for C20H18N2O3s: C, 65.55; H, 4.95; N, 7.64. Found: C, 65.72; H, 4.79;
N, 7.60.
(S)-(9H-Fluoren-9-yl) methyl 3-(methylthio)-1-(thiazol-2-yl) propylcarbamate (4g)
Yield 85%, Gum; 1H NMR (400 MHz, DMSO-d6): d (ppm) 2.04 (s, 3H), 2.18 (t,
J¼6.8 Hz, 2H), 2.44 (t, J¼6.8 Hz, 2H), 4.4 (t, J¼6.8 Hz, 1H), 4.74 (d, J¼8.0 Hz, 2H), 4.81
(t, J¼6.8 Hz, 1H), 6.0 (s, 1H), 7.05-7.72 (m, 10H). 13C NMR (100 MHz, DMSO-d6): d
(ppm) 17.4, 29.9, 37.7, 47.0, 54.2, 67.4, 118.7, 126.8, 128.2, 128.4, 128.8, 140.8, 142.2,
143.6, 156.0, 170.2. MS: Calcd. for C22H22N2O2S2 m/z: 433.11 (Mþ þNa),
Found: 433.1099.
Anal. Calcd. for C22H22N2O2S2: C, 64.36; H, 5.40; N, 6.82. Found: C, 64.31; H, 5.28;
N, 6.92.
(S)-Benzyl 1-(thiazol-2-yl) ethylcarbamate (4h)
1
Yield 80%, Solid, Melting Point 118 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 1.52
(d, J¼8.0 Hz, 3H), 5.0 (m, 1H), 5.32 (s, 2H), 6.0 (s, 1H) 7.11 - 7.70 (m, 7H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 21.2, 48.7, 65.3, 118.4, 127.1, 127.6, 129.0, 141.2, 156.0,
170.7. MS: Calcd. for C13H14N2O2S m/z: 285.08 (Mþ þNa), Found: 285.0801.
Anal. Calcd. for C13H14N2O2S: C, 59.52; H, 5.38; N, 10.68. Found: C, 59.29; H, 5.18;
N, 10.82.
(S)-Benzyl 2-methyl-1-(thiazol-2-yl) propylcarbamate (4i)
1
Yield 86%, Solid, Melting Point 122 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 1.01
(d, J¼8.0 Hz, 6H), 2.82 (m, 1H), 4.83 (d, J¼8.0 Hz, 1H), 5.18 (s, 2H), 6.0 (s, 1H), 7.08 -
7.68 (m, 7H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 17.7, 33.4, 57.2, 68.9, 118.5,
127.0, 127.9, 129.1, 141.4, 142.2, 156.0, 170.3. MS: Calcd. for C15H18N2O2S m/z: 313.11
(Mþ þNa), Found: 313.1102.
Anal. Calcd. for C15H18N2O2S: C, 62.04; H, 6.25; N, 9.65. Found: C, 62.13; H, 6.09;
N, 9.80.
(S)-Benzyl 3-methyl-1-(thiazol-2-yl) butylcarbamate (4j)
1
Yield 84%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 1.0 (d, J¼8.0 Hz, 6H), 1.78
(d, J¼8.0 Hz, 2H), 1.80 (m, 1H), 4.8 (t, J¼6.8 Hz, 1H), 5.27 (s, 2H), 6.0 (s, 1H), 7.11-
7.72 (m, 7H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 22.7, 23.0, 45.9, 52.1, 65.5,

8
H. S. LALITHAMBA ET AL.
118.3, 127.1, 127.7, 129.0, 141.2, 142.2, 156.0, 170.3. MS: Calcd. for C16H20N2O2S m/z:
327.12 (Mþ þNa), Found: 327.1198 .
Anal. Calcd. for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.35; H, 6.51;
N, 9.17.
Benzyl (1S, 2R)-2-methyl-1-(thiazol-2-yl) butylcarbamate (4k)
1
Yield 90%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 0.92 (t, J¼6.8 Hz, 3H), 1.03
(d, J¼8.0 Hz, 3H), 1.27 (m, 2H), 2.62 (m, 1H), 4.86 (d, J¼8.0 Hz, 1H), 5.28 (s, 2H), 6.0
(s, 1H), 7.0-7.68 (m, 7H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 11.6, 14.8, 24.9,
40.8, 55.0, 65.4, 118.5, 127.1, 127.8, 129.0, 141.0, 142.6, 156.0, 170.1. MS: Calcd. for
C16H20N2O2S m/z: 327.12 (Mþ þNa), Found: 327.1203.
Anal. Calcd. for C16H20N2O2S: C, 63.13; H, 6.62; N, 9.20. Found: C, 63.22; H, 6.38;
N, 9.18.
(S)-Benzyl 2-phenyl-1-(thiazol-2-yl) ethylcarbamate (4l)
1
Yield 88%, Solid, Melting Point 128 ꢀC; H NMR (400 MHz, DMSO-d6): d (ppm) 2.92
(d, J¼8.0 Hz, 2H), 5.25 (t, J¼6.8 Hz, 1H), 5.31 (s, 2H), 6.0 (s, 1H), 7.05-7.73 (m, 12H).
13C NMR (100 MHz, DMSO-d6): d (ppm) 41.6, 53.8, 65.3, 118.3, 126.0, 127.3, 127.7,
127.9, 128.6, 129.0, 139.1, 141.9, 170.4. MS: Calcd. for C19H18N2O2S m/z: 361.11 (Mþ
þNa), Found: 361.1107.
Anal. Calcd. for C19H18N2O2S: C, 67.43; H, 5.36; N, 8.28. Found: C, 67.06; H, 5.31;
N, 8.22.
(9H-Fluoren-9-yl) methyl (S)-1-oxo-3-phenyl-1-((S)-1-(thiazol-2-yl) ethyylamino)
propan-2-ylcarbamate (8a)
1
Yield 90%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 1.55 (s, 3H), 2.90 (m, 2H),
4.43 (t, J¼6.8 Hz, 1H), 4.72 (d, J¼8.0 Hz, 2H), 4.97 (m,1H), 5.09 (m,1H), 6.0 (s,2H),
7.10-7.78 (m, 15H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 20.9, 36.4, 46.5, 47.3,
55.4, 66.8, 118.0, 126.2, 126.8, 127.6, 128.0, 128.2, 128.4, 128.8, 139.5, 141.0, 142.2,
143.5, 156.0, 170.4, 171.2. MS: Calcd. for C29H27N3O3S m/z: 520.18 (Mþ þNa),
Found: 520.1797.
Anal. Calcd. for C29H27N3O3S: C, 70.00; H, 5.47; N, 8.44. Found: C, 70.08; H, 5.46;
N, 8.36.
(9H-Fluoren-9-yl) methyl (S)-4-methyl-1-((S)-2-methyl-1-(thiazol-2-yl)
propylamino)-1-oxopentan-2-ylcarbamate (8b)
1
Yield 88%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 1.05 (d, J¼8.0 Hz, 12H),
1.62 (d, J¼8.0 Hz, 2H), 1.80 (m, 1H), 2.82 (m, 1H), 4.43 (m, 1H), 4.5 (d, J¼8.0 Hz, 1H),
4.70 (d, J¼8.0 Hz, 2H), 4.83 (d, J¼8.0 Hz, 1H), 6.0 (s, 2H), 7.1-7.84 (m, 10H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 17.4, 22.0, 22.5, 33.4, 41.0, 46.8, 53.1, 56.0, 67.3, 118.5,

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
9
126.8, 128.0, 128.4, 128.6, 141.0, 142.3, 143.6, 156.0, 170.7, 171.0. MS: Calcd. for
C28H33N3O3S m/z: 514.22 (Mþ þNa), Found: 514.2200.
Anal. Calcd. for C28H33N3O3S: C, 68.40; H, 6.77; N, 8.55. Found: C, 68.29; H, 6.52;
N, 8.50.
(9H-Fluoren-9-yl) methyl (2S, 3R)-3-methyl-1-oxo-1-((S)-1-(thiazol-2-yl) ethylamino)
pentan-2-ylcarbamate (8c)
1
Yield 85%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 0.92 (t, J¼6.8 Hz, 3H), 1.06
(d, J¼8.0 Hz, 3H), 1.20 (m, 2H), 1.58 (d, J¼8.0 Hz, 3H), 2.48 (d, J¼8.0 Hz, 1H), 4.46
(m, 1H), 4.52 (d, J¼8.0 Hz, 1H), 4.65 (d, J¼8.0 Hz, 2H), 5.0 (m, 1H), 6.0 (s, 2H), 7.12-
7.84 (m, 9H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 10.4, 14.2, 21.3, 24.8, 36.6, 47.0,
47.5, 57.8, 67.4, 118.6, 126.8, 128.2, 128.4, 128.8, 141.0, 142.1, 143.5, 156.0, 170.5, 171.0.
MS: Calcd. for C26H29N3O3S m/z: 486.19 (Mþ þNa), Found: 486.1897.
Anal. Calcd. for C26H29N3O3S: C, 67.36; H, 6.31; N, 9.06. Found: C, 67.32; H, 6.28;
N, 9.00.
(9H-Fluoren-9-yl) methyl (S)-1-((S)-3-methylthio-1-(thiazol-2-yl) propylamino)-1-
oxopropan-2-ylcarbamate (8d)
1
Yield 85%, Gum; H NMR (400 MHz, DMSO-d6): d (ppm) 1.45 (d, J¼8.0 Hz, 3H), 2.04
(s, 3H), 2.21 (m, 2H), 2.40 (m, 2H), 4.45 (t, J¼6.8 Hz, 1H), 4.68 (d, J¼8.0 Hz, 2H), 4.70
(m, 1H), 4.85 (t, J¼6.8 Hz, 1H), 6.0 (s, 1H), 7.08-7.74 (m, 10H). 13C NMR (100 MHz,
DMSO-d6): d (ppm) 17.0, 17.6, 29.7, 37.6, 47.0, 51.1, 52.5, 67.4, 118.7, 126.8, 128.0,
128.3, 128.8, 141.0, 142.2, 143.4, 156.0, 170.5, 171.7. MS: Calcd. for C25H27N3O3S2 m/z:
514.22 (Mþ þNa), Found: 514.2201.
Anal. Calcd. for C25H27N3O3S2: C, 62.34; H, 5.65; N, 8.72. Found: C, 62.40; H, 5.59;
N, 8.64.
In vitro antibacterial activity
Preparation of Bacterial Suspension
For each test, 2 ml normal saline (0.85% w/v) was taken in a test tube, plugged with cot-
ton, and wrapped with a newspaper. The test tubes were put in an autoclave for steril-
ization at 15 lbs for 20 min. After autoclaving, a loop was used to take 1-2 colonies of
bacteria from a sub-cultured bacterial plate. Colonies were dissolved in the normal
saline with rubbing and stirring.
Preparation of Mueller Hinton Agar Plates
Mueller Hinton agar medium (3.0 mg) was dissolved properly in 80 mL distilled water
in a 250 mL conical flask with stirring. The mouth of the conical flask was plugged with
cotton, wrapped with a newspaper and put in an autoclave for sterilization at 15 lbs for
20 min. After autoclaving, 20-25 mL of the warm medium was poured onto a petri dish
and left until it solidified.

10
H. S. LALITHAMBA ET AL.
Table 3. Antibacterial testing of the new thiazoles.
Inhibition zone (mm)
Sample Concentration
Organisms
Compound
50 ml
100 ml
150 ml
200 ml
Time (hrs)
E.coli
S.aureus
4b
4c
–
–
10 mm
15 mm
12 mm
18 mm
24
24
14 mm
17 mm
Preparation of sample solution
The test compound (5 mg) was dissolved in 1 mL of DMSO: PEG (1:10) in a test tube
with vertex stirring. The prepared plate was divided into four quadrants. One plate was
swabbed from one bacterial suspension with the use of a cotton swab. With the help of
a micro pipette, 50-200 ll sample solution was dropped per quadrant. All the plates
were put in an incubator for 18-24 hrs.
Agar well diffusion method
The bacterial strains (Escherichia coli and Staphylococcus aureus) were maintained on
the nutrient agar medium by sub culturing them at regular intervals. Nutrient broth
cultures of organisms, designated as inocula, were obtained after incubation for 24 hrs
at 37 ꢀC. The well was made using a 5 mm cork borer sterilized using flame and alcohol.
A sterile swab was dipped into the nutrient broth culture and was rotated firmly against
upper inside wall of the tube to expel the excess fluid. The entire surface of the Mueller
Hinton agar medium (MHA) was swabbed with the inoculum. As soon as the MHA
was partly solidified, the plates were inverted and left for 2 hrs. Samples (100 ml) dis-
solved in DMSO were introduced into the wells. The plates were incubated overnight at
37 ꢀC. Microbial growth was determined by measuring the diameter of the zone of
inhibition and compared with those of standard antibiotics (Table 3).
The synthesized compounds Fmoc-Val-Thiazole (4b) and Fmoc-Leu-Thiazole (4c)
were subjected to antibacterial studies against E. coli and S. aureus respectively. The
inhibition zones were recorded for different concentrations of the samples. In case of E.
coli, the synthesized terminal thiazole, 4b showed a moderate zone of inhibition of
12 mm at 200 ml sample concentration, whereas compound 4c showed significant activ-
ity of 18 mm against S. aureus at 200 ml.
Acknowledgments
We thank the Principal and Director of Siddaganga Institute of Technology, Tumakuru,
Karnataka, for the research facilities. One of the authors (HSL) is thankful to the Vision Group
of Science and Technology (VGST), Department of Information Technology, Biotechnology and
Science & Technology, Government of Karnataka, for providing funds under Centres of
Innovative Science Engineering and Education (CISEE) program (GRD No. 472) to carry out the
present research work.
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