R. L. Jarvest et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3937–3941
3941
O
active configuration of the tetrahydroquinoline series
has been identified as possessing (R)-stereochemistry.
Ph
OMe
X
NH2
HN
Br
Br
Br
iii.
ii.
N
H
N
H
N
H
Br
Br
Br
54 (RS)
55 (R)
56 (S)
51 X = O
Acknowledgements
i.
53
iv.
52 X = NHOMe
v.
We thank Dr. J. Zukowski for performing the chiral cze
analysis and Dr. C. S. V. Frydrych for participation in
array synthesis.
NH2
H
vi.
vii.
N
N
17
Br
O
N
H
N
H
N
H
59
Br
viii.
N
57 (R)
58 (S)
HN
N
Br
References and notes
N
N
H
H
N
H
1. Jarvest, R. L.; Berge, J. M.; Berry, V.; Boyd, H. F.; Brown,
M. J.; Elder, J. S.; Forrest, A. K.; Fosberry, A. P.; Gentry,
D. R.; Hibbs, M. J.; Jaworski, D. D.; O’Hanlon, P. J.;
Pope, A. J.; Rittenhouse, S.; Sheppard, R. J.; Slater-
Radosti, C.; Worby, A. J. Med. Chem. 2002, 45, 1959.
2. Jarvest, R. L.; Berge, J. M.; Brown, M. J.; Brown, P.; Elder,
J. S.; Forrest, A. K.; Houge-Frydrych, C. S. V.; O’Hanlon,
P. J.; McNair, D. J.; Rittenhouse, S.; Sheppard, R. J.
Bioorg. Med. Chem. Lett. 2003, 13, 665.
Br
60 (R)
61 (S)
Scheme 3. Reagents and conditions: (i) MeONH2ÆHCl/NaOAc/EtOH/
H2O/D; (ii) ZrCl4/LiBH4/THF; (iii) (S)-PhCH(OMe)CO2H/EDC/
HOAt/N-Me-morpholine/DMF; (iv) silica gel chromatography/pet.
ether/EtOAc; (v) 8 M HCl/dioxan/D; (vi) (MeO)2CH(CH)2NH2/D; (vii)
1 M HCl/D; (viii) NaCNBH3/NaOAc/AcOH/MeOH.
3. Jarvest, R. L.; Berge, J. M.; Brown, P.; Houge-Frydrych, C.
S. V.; O’Hanlon, P. J.; McNair, D. J.; Pope, A. J.;
Rittenhouse, S. Bioorg. Med. Chem. Lett. 2003, 13, 1265.
4. The methoxy-thienopyridines were prepared from the 2,4-
dichloro precursors by treatment with sodium methoxide.
The thieno[3,2-b]pyridine isomer gave exclusively the
unwanted 2-methoxy isomer unless 15-crown-5 was added,
which resulted in an almost complete reversal of specificity
(81% 4-methoxy, 3% 2-methoxy). See Ref. 2 for a discus-
sion of a related but less-pronounced case.
Table 5. MRS inhibition and antibacterial activity of enantiomeric
tetrahydroquinolines
HN
N
N
Br
N
H
N
H
N
H
Br
5. 2-Chloro-3-cyano-1-(2-trimethylsilylethoxymethyl)-indole
was subjected to the following reaction sequence: i.
BocNH(CH2)3NH2/DMSO/D; ii. TFA/anisole then AcOH;
iii. 3,5-diBr-benzyl bromide/K2CO3/THF; iv. LiBF4/
MeCN/TFA/CH2(CH2SH)2.
Stereochemistry
IC50 (nM)
MIC (lg/mL)
S. aureus
S. aureus
E. faecalis 1
MRS
Oxford
46
60
61
RS
R
11
6.3
48
6 0.06
6 0.06
16
6 0.06
6 0.06
2
6. Based on STO-3G ab initio calculations of gas phase
energies using AM1 optimised geometries.
S
7. Colourless needle, 0.38 · 0.05 · 0.04 mm, orthorhombic,
ꢀ
space group P212121 (#19), T ¼ 150 K, a ¼ 4:8880ð4Þ A,
3
ꢀ
ꢀ
ꢀ
b ¼ 13:7295ð12Þ A, c ¼ 26:441ð2Þ A, V ¼ 1774:4ð3Þ A ,
Z ¼ 4, Dcalcd ¼ 1:700 Mg/m3, F ð000Þ ¼ 904, l(CuKa, k ¼
potent antibacterial activity. The compression of IC50
values <10 nM due to the limit of the enzyme concen-
tration in the assay (3 nM)1 makes it hard to calculate
the enantiomeric inhibitory ratio. However, the ratio of
the antibacterial activity of the two isomers suggests a
high degree of enantioselectivity, of the order of at least
two orders of magnitude.
1:54178 A) ¼ 5.902 mmÀ1, Bruker SMART 6000 diffractom-
ꢀ
eter, 11,989 reflections collected ð6:68ꢂ 6 2h 6 145:52ꢂÞ,
3430 unique reflections ðRint ¼ 0:0530Þ, Gaussian absorp-
tion correction (transmission ¼ 0.37514–0.80284), full-ma-
trix least-squares refinement (on F 2) of 226 variables,
R1 ¼ 0:0316 (wR2 ¼ 0:0789) for 3284 observed data with
I P 2rðIÞ, R1 ¼ 0:0327 (wR2 ¼ 0:0805) for all data, S ¼
2
1:037,
w ¼ 1=½r2ðFo2Þ þ
ð0:0604PÞ ꢀ
where
P ¼
½MaxðFo2; 0Þ þ 2Fc2ꢀ=3, residual electron density between
In conclusion, the key right hand side pharmacophore
for bacterial MRS inhibition has been defined as an
NH–C–NH unit in the context of a bicyclic heteroaro-
matic system. Potent non-quinolone analogues have
been obtained with excellent antibacterial activity
against staphylococci and enterococci, including anti-
biotic resistant isolates. In addition, the biologically
À3
ꢀ
)0.471 and 0.942 e A
, absolute structure parame-
ter ¼ )0.046(19). Crystallographic data for the structure
has been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication number CCDC
232517.
8. Fused silica 50 cm · 50 lm i.d., 20 kV, 100 mM sodium
phosphate buffer pH 2.5 containing 40 mM a-cyclodextrin.