α-Amino acid-derived 2-phenylimidazoles with potential antimycobacterial activity

Article abstract of DOI:10.2478/s11532-012-0087-1

α-Amino acid-derived 2-phenylimidazole derivatives were designed, synthesized, and further investigated as potential antimycobacterial agents. The synthesis of target imidazole derivatives involved the transformation of Cbz-protected α-amino acids (Ala, Val, Phe, Leu, iLe, and Pro) into α-diazoketones and α-bromoketones, respectively. Subsequent treatment of α-bromoketones with (4-nitro) benzamidine afforded imidazole derivatives bearing α-amino acid residue appended to the imidazole C4 and (4-nitro)phenyl ring in the position C2. Antimycobacterial activities of both series of compounds against M. tuberculosis, M. avium, and M. kansasii were screened and basic structure-activity relationships were further evaluated.

Full text of DOI:10.2478/s11532-012-0087-1

Cent. Eur. J. Chem. • 10(5) • 2012 • 1681-1687
DOI: 10.2478/s11532-012-0087-1
Central European Journal of Chemistry
a-Amino acid-derived 2-phenylimidazoles
with potential antimycobacterial activity
Research Article
1
2
1*
Daniel Cvejn , Věra Klimešová , Filip Bureš
1Institute of Organic Chemistry and Technology, Faculty of Chemical
Technology, University of Pardubice, CZ-53210 Pardubice, Czech Republic
2Department of Inorganic and Organic Chemistry,
Faculty of Pharmacy in Hradec Králové, Charles University in Prague,
CZ-50005 Hradec Králové, Czech Republic
Received 22 March 2012; Accepted 13 June 2012
Abstract: α-Amino acid-derived 2-phenylimidazole derivatives were designed, synthesized, and further investigated as potential antimycobacterial
agents. The synthesis of target imidazole derivatives involved the transformation of Cbz-protected α-amino acids (Ala, Val, Phe,
Leu, iLe, and Pro) into α-diazoketones and α-bromoketones, respectively. Subsequent treatment of α-bromoketones with (4-nitro)
benzamidine afforded imidazole derivatives bearing α-amino acid residue appended to the imidazole C4 and (4-nitro)phenyl ring in
the position C2. Antimycobacterial activities of both series of compounds against M. tuberculosis, M. avium, and M. kansasii were
screened and basic structure-activity relationships were further evaluated.
Keywords: Imidazole • a-Amino acid • Antimycobacterial agents • SAR
©
Versita Sp. z o.o.
1
. Introduction
Five-membered heterocycles (azoles) such as
pyrroles [4], isoxazoles [5], oxadiazoles [6], and
Despite the recent progress in treatment of infectious imidazoles [7] constitute one of the structural motives
diseases caused by Mycobacterium spp., these used for the design of therapeutic agents to date. Di(tri)
microorganisms continue to represent a considerable azole derivatives found wide applications as antifungal
problem in world health control. Over 2 billion people agents (e.g. flukonazole, itraconazole, clotrimazole).
are infected by Mycobacteria (mostly M. tuberculosis) Imidazole-derived antibiotic agents belong to a large
and each tenth of them suffers from apparent form of sub-class of the aforementioned drugs, from which
these infections (e.g. tuberculosis) [1]. Distribution of metronidazole and its derivatives are certainly the most
mycobacterial infections in the world’s population steadily widely applied antibiotics against anaerobic bacteria and
increases,mainlyduetotheraisinghumanmobilityaswell protozoa (Fig. 1) [8]. 2-(Hetero)arylazole linkage was
as the raising resistance of particular strains. Nowadays, recently recognized as efficient structural arrangement in
the tuberculosis strains become multi drug resistant pyrrole, oxazole, and oxadiazole derivatives that feature
(MDR-TB), extensively drug resistant (XDR-TB), and very respectable antimycobacterial activities (Fig. 1) [4-6].
recently also totally drug resistant (TDR-TB). Moreover,
Recently, we have screened the antimycobacterial
some species of Mycobacteria such as M. avium do activities of various 2-phenylimidazoline [9] as well
not have any universally efficient treatment protocol [2]. as benzimidazole, benzthiazole, and benzoxazole
The increasing strains resistance, especially the cross- derivatives [10]. This screening revealed very promising
resistance, led to the current extensive explorations and activities of compounds 1-2 (Fig. 1). In general, these
studies on new antituberculotics featuring improved or derivatives possess the following important structural
different mechanism of action [3].
features: – i) central azole derivative, ii) 2-(hetero)aryl
*
E-mail: filip.bures@upce.cz
1681

a-Amino acid-derived 2-phenylimidazoles
with potential antimycobacterial activity
Nitroimidazole derivatives
Selected 2-(hetero)arylazoles
NO2
N
O N
2
O
2
N
N
N
O
N
OH
N
N
C15H31
N
N
O
N
N
O
O
N
Cl
N
OCF3
Cl
Recently and newly investigated imidazol(in)es
O
R
O
Ph
O
N
H
N
X
NH
N
N
N
S
CF
3
H
N
O
R'
O
NO2
1
2
5
-6
Figure 1. Imidazole- and 2-(hetero)arylazole-derived antimycobacterial agents [4-6], our recently investigated derivatives 1-2 [9-10]
and general structure of newly synthesized N-Cbz a-amino acid-derived 2-phenylimidazoles 5-6.
linkage, and iii) carbamate moiety known as active and 39.51 ppm). Apparent resonance multiplicities
functional group of many AChE inhibitors [11]. Inspired are described as s (singlet), br s (broad singlet), d
by the success of these particular structural features, (doublet) and m (multiplet). Some N-Cbz protected
we have proposed to investigate N-Cbz α-amino acid- 2-phenylimidazole derivatives showed in d -DMSO
6
derived 2-phenylimidazoles 5 (Fig. 1). These derivatives, strongly hindered rotation in the carbamate moiety and
whichwereoriginallyintendedasopticallyactivenitrogen slow imidazole tautomerism which may result in a set of
ligands for asymmetric catalysis [12], combine all of the two signals, broad signals or no observable signals [12b].
aforementioned structural features into one molecule. Mass spectra were measured on a GC/MS configuration
According to our previous studies on the terminal nitro comprised of an Agilent Technologies – 6890N gas
group effect on the antimycobacterial activity [10], the chromatograph equipped with a 5973 Network MS
series of compounds 5a-g was further completed with detector (EI 70 eV, mass range 33−550 Da). IR spectra
nitro analogs 6a-g.
were recorded on a Perkin Elmer FT-IR Spectrum BX
spectrometer. Optical rotations were measured on a
Perkin Elmer 341 polarimeter using the sodium D line
2
. Experimental procedure
(
589 nm), specific rotations [α] are given in units of deg
2
-1
3
cm g and concentration c is 1 g per 100 cm MeOH.
2
.1. General
Elemental analyses were performed on a Thermo Flash
Reagent and solvents were reagent-grade or HPLC- 2000 CHNS experimental organic analyzer.
grade and were purchased from Penta, Aldrich and
N-Cbz protected α-amino acids [13], α-diazoketones
Acros and used as received. Tetrahydrofuran (THF) 3a-g, α-bromoketones 4a-g, and imidazole derivatives
was distilled from sodium benzophenone ketyl radical. 5a-g were synthesized according to the literature
Thin-layer chromatography (TLC) was conducted on procedure and their analytical data were in accordance
aluminium sheets coated with silica gel 60 F254 obtained with those previously published [12a].
from Merck, with visualisation by UV lamp (254 or
1
13
3
4
65 nm). H and C NMR spectra were recorded at 2.2. Synthesis
00 MHz and 100 MHz, respectively, with a Bruker Preparation of 4-nitrobenzamidine hydrochloride
AVANCE 400 instrument at 25°C. Chemical shifts are (modification of [14])
reported in ppm relative to the signal of Me Si. The
Sodium methoxide (0.165 g; 3.1 mmol) was added
4
1
13
residual solvent signal in the H and C NMR spectra to a solution of 4-nitrobenzonitrile (4.8 g, 32.4 mmol)
was used as an internal reference (d -DMSO – 2.55 in dry methanol (15 mL) and the reaction was refluxed
6
1682

D. Cvejn, V. Klimešová, F. Bureš
for 12 h (monitored by TLC and GC/MS). Ammonium
2-(4-Nitrophenyl)-4-(1-(R)-benzyloxycarbony-
chloride (2.85 g, 53.3 mmol) was added and the reaction laminoethyl)-1H-imidazole (6b)
mixture was allowed to cool to 25°C. The resulting
The title compound was synthesized from
yellow suspension was filtered off and the filtration cake α-bromoketone 4b (8.7 g, 29.0 mmol) following the
was washed with dry methanol and diethylether to afford general method. Yellowish solid, yield 3.9 g (37%).
the title compound as a yellow solid. Yield 3.85 g (59%). M. p. 176-178°C. R = 0.7 (SiO ; EtOAc/hexane 2:1);
f
2
2
0
1
M. p. 288-291°C (Lit. [14] m.p. 285-287°C). R = 0.3 [α]D = +32.0 (c 1.0, MeOH); H (400 MHz,d -DMSO):
f
6
3
(
(
1
SiO ; EtOAc; free base); MS (EI), free base: m/z = 166 δ = 1.46 (d, J (H,H) = 7.4 Hz, 3H, CH ), 4.77-4.80
2
3
+
[M ], 80), 150 (100), 120 (20), 104 (35), 92 (25), 76 (33); (m, 1H, CBzNHCH), 5.09 ppm (s, 2H, PhCH OCO),
H-NMR (400 MHz; d -DMSO): δ = 8.15 (d, J (H,H) = 7.03+7.21 ppm (2×s, 1H, CH ), 7.36-7.42 (m, 5H,
2
3
6
im
3
3
9
8
9
.0 Hz, 1H, ArH), 8.23 (d, J (H,H) = 9.0 Hz, 1H, ArH), CH PhH), 7.62 (br s, 1H, NHCBz), 8.19 (d, J (H,H)
2
3
3
3
.43 (d, J (H,H) = 9.0 Hz, 1H, ArH), 8.45 (d, J (H,H) = = 8.8 Hz, 2H, PhHNO ), 8.35 (d, J (H,H) = 8.8 Hz,
.0 Hz, 1H, ArH), 8.54 ppm (br s, 4H, C(NH2)NH2); C- 2H, PhHNO ), 12.85 ppm (br s, 1H, NH ); C NMR
2
13
13
2
im
NMR (100 MHz; d -DMSO): δ = 123.8 (CH), 124.4 (CH), (100 MHz, d -DMSO): δ = 21.1, 45.1, 65.3, 124.3,
6
6
1
30.0 (CH), 134.1 (C), 134.2 (CH), 150.3 (C), 164.5 (C) 125.4, 127.8, 128.4, 136.6, 137.3, 143.0, 146.4,
ppm. 155.5 ppm (3 signals missing); FT-IR(HATR):
Preparation of 2-phenylimidazoles 6a-g – general ν = 1047, 1347, 1407, 1445, 1520, 1677, 3300 cm ;
-1
procedure (modification of [12a])
Found: C 64.2, H 5.1, N 15.5. C H N O requires C
19 18 4 4
A solution of α-bromoketone 4a-g (29.0 mmol) 64.3, H 4.9, N 15.3.
in THF (50 mL) was added dropwise into a refluxing
solution of 4-nitrobenzamidine hydrochloride (5.85 g; amino-2-methylpropyl)-1H-imidazole (6c)
9.0 mmol) and anhydrous sodium carbonate (12.3 g, The title compound was synthesized from
16.0 mmol) in THF (80 mL) and water (20 mL) and the α-bromoketone 4c (9.5 g, 29.0 mmol) following the
2-(4-Nitrophenyl)-4-(1-(S)-benzyloxycarbonyl-
2
1
reaction mixture was further refluxed for the indicated general method. Yellow-red solid, yield 1.1 g (10%).
time (Table 1, monitored by TLC). The crude reaction M. p. 185-187°C. R = 0.75 (SiO ; EtOAc/hexane 2:1);
f
2
2
0
1
mixture was concentrated in vacuo and the residue [α]D = −58.1 (c 1.0, MeOH); H (400 MHz, d -DMSO):
6
3
was portioned between dichloromethane (40 mL) δ = 0.89 (d, J (H,H) = 6.6 Hz, 3H, CH ), 0.92 0.89
and water (40 mL), the layers were separated, and (d, J (H,H) = 6.6 Hz, 3H, CH ), 2.08-2.20 (m, 1H,
3
3
3
the water layer was extracted with dichloromethane CH(CH ) ), 4.50-4.65 (m, 1H, CBzNHCH), 5.05-5.13 (m,
3
2
(
2 × 60 mL). Combined organic layers were washed with 2H, PhCH OCO), 7.07+7.25 (2×s, 1H, CH ), 7.35-7.41
2
i
m
3
water (100 mL), brine (100 mL), dried (Na SO ), and the (m, 5H, CH PhH), 7.54+7.75 (2×d, J (H,H) = 9.3 Hz,
solvent was evaporated in vacuo. The crude product 1H, NHCBz), 8.19 (d, J (H,H) = 8.8 Hz, 2H, PhHNO ),
was purified by column chromatography (SiO ; EtOAc/ 8.35 (d, J (H,H) = 8.8 Hz, 2H, PhHNO ), 12.76+12.86
hexane 1:1).
2
4
2
3
2
3
2
2
13
(2×br s, 1H, NH );
C
(100 MHz, d6-DMSO):
im
2
-(4-Nitrophenyl)-4-(1-(S)-benzyloxycarbonyl- δ = 18.4, 19.6, 32.2+32.7, 55.4, 65.2+65.5, 116.3, 124.3,
aminoethyl)-1H-imidazole (6a) 125.3, 127.7, 127.8, 128.3, 136.6, 137.3, 142.7, 144.5,
The title compound was synthesized from 146.3, 156.0 ppm; FT-IR(HATR): ν = 1047, 1297, 1345,
-1
α-bromoketone 4a (8.7 g, 29.0 mmol) following the 1417, 1445, 1541, 1673, 3300 cm ; Found: C 63.8,
general method. Yellowish solid, yield 2.7 g (25%). M. H 5.6, N 14.0. C H N O requires C 63.9, H 5.6,
21
22
4
4
2
0
p. 178-179°C. R = 0.7 (SiO ; EtOAc/hexane 2:1); [α]
D
N 14.2.
2-(4-Nitrophenyl)-4-(1-(S)-benzyloxycarbonyl-
f
2
1
=
−31.6 (c 1.0, MeOH); H NMR (400 MHz, d -DMSO):
δ = 1.46 (d, J (H,H) = 7.4 Hz, 3H, CH ), 4.77-4.80 (m, amino-2-phenylethyl)-1H-imidazole (6d)
6
3
3
1
7
7
H, CBzNHCH), 5.09 ppm (s, 2H, PhCH OCO), 7.03+
The title compound was synthesized from
2
.21 ppm (2×s, 1H, CH ), 7.36-7.42 (m, 5H, CH PhH), α-bromoketone 4d (10.9 g, 29.0 mmol) following the
im
2
3
.62 (br s, 1H, NHCBz), 8.19 (d, J (H,H) = 8.8 Hz, 2H, general method. Red solid, yield 2.1 g (16%). M. p.
3
PhHNO ), 8.35 (d, J (H,H) = 8.8 Hz, 2H, PhHNO ), 163-165°C. Rf
=
0.7 (SiO2; EtOAc/hexane 2:1);
2
2
13
20
1
12.85 ppm (br s, 1H, NH ); C NMR (100 MHz, d6- [α]D
=
−18.4 (c
=
1.0, MeOH); H (400 MHz,
im
DMSO): δ = 21.1, 45.1, 65.3, 124.3, 125.4, 127.8, 128.4, d6-DMSO):
δ
=
3.01–3.05 (m, 1H, CHCH Ph),
2
1
36.6,137.3,143.0,146.4,155.5ppm(3signalsmissing); 3.20-3.31 (m, 1H, CHCH Ph), 4.90-4.93 (m, 1H,
2
2
FT-IR(HATR): 1047, 1347, 1407, 1445, 1520, 1677, CBzNHCH), 5.01 (dd, J (H,H) = 12.8 and 8.4 Hz, 2H,
-1
3300 cm ; Found: C 62.2, H 5.0, N 15.4. C H N O
PhCH OCO), 7.08+7.18 (2×s, 1H, CH ), 7.23-7.39 (m,
19
18
4
4
2
i
m
3
requires C 62.3, H 4.9, N 15.3.
10H, 2×PhH), 7.73+7.91 (2×d, J (H,H) = 8.8 Hz, 1H,
1683

a-Amino acid-derived 2-phenylimidazoles
with potential antimycobacterial activity
3
NHCBz), 8.21 (d, J (H,H) = 8.8 Hz, 2H, PhHNO ), 8.36 2.3. Biological activity
2
3
(
d, J (H,H) = 8.8 Hz, 2H, PhHNO ), 12.89 ppm (br s, The antimycobacterial activity screening was carried
2
1
3
1
6
1
1
1
H, NH ); C (100 MHz, d -DMSO): δ = 40.6, 51.2, out in the Laboratory for Mycobacterium diagnostics
i
m
6
5.0+65.2, 116.1, 124.3, 125.4, 126.0, 127.4, 127.6, of the Institute of Public Health in Ostrava. The
28.1, 128.3, 129.3, 136.5, 137.4, 138.9, 142.9, 145.1, antimycobacterial activities of the compounds 5-6 were
46.4, 155.6 ppm; FT-IR(HATR): ν = 1047, 1347, evaluated in vitro against Mycobacterium tuberculosis
-1
407, 1443, 1518, 1660, 3300 cm ; Found: C 67.6; CNCTC My 331/88, M. kansasii CNCTC My 235/80,
H 5.0; N 12.5. C H N O requires C 67.9; H 5.0; M. kansasii 6509/96 and M. avium CNCTC My 330/88.
25
22
4
4
N 12.7.
-(4-Nitrophenyl)-4-(1-(S)-benzyloxycarbonyl- inhibitionconcentration(MIC)wasused.Alltestedstrains
amino-2-methylbutyl)-1H-imidazole (6f)
wereobtainedfromtheCzechNationalCollectionofType
Micromethod for the determination of the minimum
2
The title compound was synthesized from Cultures (CNCTC), except of M. kansasii 6509/96, which
α-bromoketone 4f (9.9 g, 29.0 mmol) following the was clinically isolated. The activities of the compounds
general method. Orange solid, yield 0.8 g (7%). were determined in the Šula semisynthetic medium
M. p. 98 – 101 °C. R = 0.8 (SiO ; EtOAc/hexane 2:1); (SEVAC, Prague). The compounds were added to the
f
2
2
0
1
[
α]D = −26.6 (c 1.0, MeOH); H (400 MHz,d -DMSO): medium in dimethylsulfoxide solutions. The following
6
3
δ = 0.83 (d, J (H,H) = 6.7 Hz, 3H, CHCH ), 0.90 concentrations were used: 1000, 500, 250, 125, 62,
t, J (H,H)
3
3
-1
(
=
7.3 Hz, 3H, CH2CH ), 1.14-1.18 32, 16, 8, 4 and 2 mmol L (binary dilution steps). The
3
(
m, 1H, CH CH ), 1.50-1.56 (m, 1H, CH CH ), 1.89- MIC values were determined upon incubation at 37°C
2
3
2
3
1
5
1
.94 (m, 1H, CHCH ), 4.55-4.66 (m, 1H, CBzNHCH), for 14 and 21 days and in the case of M. kansasii 7,
3
.03-5.08 (m, 2H, PhCH OCO), 7.05+7.25 (2×s, 14, and 21 days, respectively. The MIC values were
2
H, CH ), 7.35-7.41 (m, 5H, PhH), 7.54+7.75 determined as the lowest concentration of a substance
im
3
3
(2×d, J (H,H) = 8.8 Hz, 1H, NHCBz), 8.18 (d, J
in binary dilution steps performing the inhibition of the
3
=
8.8 Hz, 2H, PhHNO ), 8.35 (d, J = 8.8 Hz, 2H, growth of Mycobacteria. Isonidazid (INH) was used as
2
13
PhHNO ), 12.77+12.86 ppm (2×brs, 1H, NH );
C
a standard.
2
im
(
100 MHz, d -DMSO): δ = 11.3, 15.8, 24.9, 38.7, 54.1,
6
65.3, 116.1, 124.3, 125.3, 127.7, 127.8, 128.4, 136.6,
1
37.4, 142.7, 144.3, 146.3, 156.9 ppm; FT-IR(HATR): 3. Results and discussion
ν = 841, 934, 1113, 1335, 1410, 1445, 1530, 1685,
-1
3
300 cm ; Found: C 64.5; H 5.9; N 13.5. C H N O 3.1. Synthesis of target compounds
22
24
4
4
requires C 64.7; H 5.9; N 13.7.
The synthesis of target compounds 5 and 6 is outlined
2
-(4-Nitrophenyl)-4-(1-benzyloxycarbonyl) in Scheme 1. The synthesis started from commercially
pyrrolidine-2-(S)-yl-1H-imidazole (6g)
available nonpolar α-amino acids such as (S)-Ala (a),
The title compound was synthesized from (R)-Ala (b), (S)-Val (c), (S)-Phe (d), (S)-Leu (e), (S)-
α-bromoketone 4g (9.5 g, 29.0 mmol) following the iLe (f), and (S)-Pro (g) and their N-protection using
general method. Yellow solid, yield 3.1 g (28%). M. benzylchloroformate to afford N-Cbz protected α-amino
p. 101-102°C. R = 0.7 (SiO ; EtOAc/hexane 2:1); acids in the yields of 93-97% [13]. Activation of the
f
2
20
1
[
α]D = −54.4 (c 1.0, MeOH); H (400 MHz, d -DMSO): carboxylic acids via formation of mixed anhydride and
6
δ = 1.93-1.96 (m, 1H, CH ), 2.03-2.07 (m, 2H, CH ), its subsequent treatment with ethereal diazomethane
2
2
2
.18-2.3 (m, 1H, CH ), 3.40-3.50 (m, 1H, NCH ), solution afforded smoothly α-diazoketones 3a-g in the
2
2
3
.59-3.63 (m, 1H, NCH ), 4.96-5.01 (m, 1H, yields of 90-98%. These α-diazoketones easily release
2
CBzNHCH),
5.07-5.15
(m,
2H,
PhCH OCO), nitrogen if treated with hydrobromic acid (48%), yielding
2
3
6
8
2
.98-7.42 (m, 6H, PhH+CH ), 8.19 (d, J (H,H) = α-bromoketones 4a-g. Compounds 4a-g proved to be
.8 Hz, 2H, PhHNO ), 8.35 (d, J (H,H) = 8.8 Hz, veryuseful1,2-dielectrophilesandmayreactwithavariety
im
3
2
H, PhHNO ), 12.76+12.86 ppm (2×br s, 1H, NH ); of nucleophiles, e.g. the reaction with 1,3-dinucleophiles
2
im
1
3
C (100 MHz, d -DMSO): δ = 22.6+23.5, 31.8+32.9, such as amidines led to imidazole derivatives [15].
6
4
1
1
6.1+46.6, 55.2+55.6, 65.4+65.7, 115.9+116.1, 124.3, Thus, the condensation of either commercially
25.3, 126.9+ 127.4, 127.3+127.7, 128.1+128.4, 136.6, available
37.3, 142.9, 145.3+145.9, 146.3, 153.9+154.0 ppm; hydrochlorides in the system of THF/H O/Na CO
3
benzamidine
or
4-nitrobenzamidine
2
2
FT-IR(HATR): ν = 1047, 1347, 1407, 1445, 1520, 1677, afforded target 2-phenylimidazole derivatives 5 and
-1
3
300 cm ; Found: C 64.2; H 5.1; N 14.7. C H N O
6. Starting 4-nitrobenzamidine was prepared from
21
20
4
4
requires C 64.3; H 5.1; N 15.0.
4-nitrobenzonitrile and its sodium methoxide-catalyzed
1684

D. Cvejn, V. Klimešová, F. Bureš
conversion to imidoester and subsequent treatment with proceeded smoothly within 12 h affording the desired
ammonium chloride in 59% overall yield [14]. Whereas 2-phenylimidazole derivatives 5a-g in good yields
the reaction of α-bromoketones 4a-g with benzamidine (42-89%),
the
reaction
with
electron
poor
4
-nitrobenzamidine required significantly prolonged
Table 1. Isolated yields, optical rotations, and melting points of
-phenylimidazoles 5 and 6.
2
reaction times up to 72 h. However, the attained reaction
yields were modest (7-37%, Table 1). The compound
6e (derived from (S)-Leu) was detected in the crude
reaction mixture, however, its attempted isolation was
always unsuccessful.
Comp.
Yields
[α]D20
(c 1, MeOH)
M.p.
[°C]
a
[
%]
5
5
5
5
5
5
5
a/6a
b/6b
c/6c
d/6d
e/6e
f/6f
89/25
85/37
76/10
65/16
88/0
-25.4/-31.6
+24.9/+32.0
-45.2/-58.1
152-153/178-179
158-159/176-178
138-139/185-187
171-172/163-165
146-147/---
3
.2. Antimycobacterial activities
b
-13.5 /-18.4
The antimycobacterial activities of both series of
compounds 5a-g and 6a-g were screened in vitro
against M. tuberculosis, M. avium, and two strains of
M. kansasii and their minimum inhibition concentrations
-48.7/---
-50.2/-26.6
-34.2/-54.4
b
42/7
128-129/98-101
52-54/101-102
g/6g
70/28
(MIC) were compared with the MIC values of the
a
Isolated yields after 12/72 h. Measured in CHCl (c = 1).
3
conventional antimycobacterial agent - isoniazid (INH).
Table 2. The MIC values of target compounds 5 and 6.
Comp.
Inhibiting activity (µmol L-1
)
M. tuberculosis
My 331/88
M. avium
My 330/88
14/21 days
M. kansasii
My 235/80
7/14/21 days
M. kansasii
My 6509/96
7/14/21 days
14/21 days
5
5
5
5
5
5
5
6
6
6
6
6
6
a
b
c
d
e
f
125/125
125/125
16/62.5
125/250
250/250
125/250/250
125/250/250
125/125/125
62.5/125/125
32/62.5/62.5
>250/>250/>250
>125/>125/>250
32/32/32
>250/>500
>250/>500
>250/>500
>250/>500
>250/>500
>125/>125
>125/>125
>125/>125
>62.5/>62.5
>125/>125
>250/>250
>250/>250
62.5/62.5/62.5
>250/>500/>500
>250/>500/>500
32/62.5/62.5
500/>250
125/>250
32/125
g
a
b
c
d
f
62.5/62.5
32/62.5/62.5
62.5/62.5/62.5
>125/>125/>125
>125/>125/>125
16/32/32
>125/>125
>125/>125
16/16
>125/>125/>125
>125/>125/>125
32/62.5/62.5
16/16
16/32/>62.5
8/16/16
16/32
32/62.5/62.5
16/16/32
g
32/32
62.5/125/250
32/62.5/62.5
2/4/8
INH
0.5/1
>250/>250/>250
1
. ClCOOCH
3
/TEA
R
R
R
R
R
CbzCl/NaOH(aq.)
93-97%
2. CH N /THF
HBr/AcOH
95-99%
2
2
OH
OH
CHN2
CH Br
2
H N
CBzHN
CBzHN
90-98%
CBzHN
CBzHN
4a-g
2
O
O
N
O
O
3
a-g
a, R = (S)-CH [(S)-Ala]
b, R = (R)-CH
c, R = (S)-CH (CH ) [(S)-Val]
d, R = (S)-CH Ph [(S)-Phe]
3
O
NH2
NH
3
[(D)-Ala]
HN
4a-g
.
HCl
2
3 2
Cbz =
O
Ph
2
THF/H O/Na CO
3
2
2
e, R = (S)-CH CH(CH ) [(S)-Leu]
2
3 2
f, R = (S)-CH(CH )CH CH [(S)-iLe]
3
2
3
g, R = (S)-(CH CH CH ) [(S)-Pro]
2
2
2 c
R'
5a-g, R' = H
a-g, R' = NO2
R'
6
Scheme 1. Synthetic approach to a-amino acid-derived N-Cbz protected 2-phenylimidazoles 5 and 6.
1685

a-Amino acid-derived 2-phenylimidazoles
with potential antimycobacterial activity
The results are summarized in Table 2. The MIC values from the commercially available N-Cbz protected
of compounds 5 and 6 against M. tuberculosis My α-amino acids in a three step synthesis involving
331/88 and M. kansasii 6 509/96 (clinical isolate) are formation of α-diazoketones, α-bromoketones, and their
generally higher than those observed for INH. However, subsequent condensation with amidines. The yield of
the antimycobacterial activities against M. avium My the final condensation step was strongly affected by the
330/88 and M. kansasii My 235/80 are comparable or, electron behavior of the benzamidine pendant. However,
in some cases, slightly higher. In contrast to INH, the target compounds 5a-g and 6a-g can be obtained in a
compounds were comparably active against both M. multigram scale in this way.
kansasii strains. The structure-activity relationships
indicate that the nitro substituted 2-phenylimidazoles and 6 were tested in vitro against four strains. Whereas
a-g possess higher antimycobacterial activities the activities against M. tuberculosis were lower than
The anitmycobacterial activities of compounds 5
6
than unsubstituted analogs 5a-5g. Whereas the those of commercial isoniazid, the activities against M.
absolute configuration of the α-amino acid side chain avium and M. kansasii CNTCT exceeded the activity
did not play any role on the antimycobacterial activity of INH. The main structural features affecting the
(compare 5a/5b or 6a/6b), the activity is mostly antimycobacterial activities of tested compounds 5 and 6
affected by the increasing bulkiness of the substituent are i) the presence of nitro group and ii) the bulkiness of
´
R (6c-f). Thus, compound 6d (R = benzyl, R = NO ) is the α-amino acid residue. 2-Phenylimidazole derivatives
2
the most active compound from the evaluated series of bearing nitro group and larger α-amino acid residue such
agents.
as iPr, Bn or iBu (6c-f) showed to be the most effective
compounds from the studied series.
4
. Conclusions
Acknowledgement
Wehavedesigned,synthesized,andfurthertestedN-Cbz
protected α-amino acid-derived 2-phenylimidazoles Support of the specific research from the Ministry of
as potential antimycobacterial agents. Overall thirteen Education, Youth and Sport of the Czech Republic is
compounds with different α-amino acid side chains (a-g) gratefully acknowledged. We are indebted to dr. Jiřina
and 4-nitro substitution at the appended phenyl ring Stolařiková (Institute of Public Health, Ostrava) for the
were investigated. These compounds were accessible antimycobacterial evaluation.
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