668
R. L. Jarvest et al. / Bioorg. Med. Chem. Lett. 13 (2003) 665–668
Table 4. Antibacterial activity of selected compounds against panels
of staphylococci and enterococci, where MIC90 is the concentration
required to inhibit 90% of the organisms9
preference for non-polar substituents. Analogues from
both the phenyl series and the cyclised chroman and
tetrahydroquinoline series afford very good anti-
bacterial activity against panels of staphylococcal and
enterocccal clinical isolates. These results provide
encouragement for the potential of MRS as a target for
a novel class of Gram-positive antibacterial agents.
MIC90 (mg/mL)
S. aureus
S. epidermidis
E. faecalis
E. faecium
Amoxicillin
>16
2
8–16
2
>16
0.06
0.06
0.5
>16
35
47
49
81
82
86
84
ꢁ0.016
2
2
0.03
0.5
0.25
0.25
0.5
1
0.25
0.25
0.5
1
Acknowledgements
nd
nd
ꢁ0.016
0.03
0.25
0.06
We thank Mr. Alan Dyke for technical assistance.
0.06
ꢁ0.016
1
1
nd, not done.
References and Notes
1. Solberg, C. O. Scand. J. Infect. Dis. 2000, 32, 587.
2. Low, D. E.; Keller, N.; Barth, A.; Jones, R. N. Clin. Infect.
Dis. 2001, 32 (Suppl. 2), S133.
dihalo analogues. Mono-chloro substituted analogues
appeared optimal for MRS IC50 and antibacterial activity.
3. 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.
4. In the preparation of 10, addition of the crown ether was
designed to increase the amount of 4-substitution by reducing
the postulated complexation of sodium to the quinoline nitro-
gen10 which favours 2-substitution. Under these conditions,
the crown ether increased the ratio of 4-substitution to 2-sub-
stitution from 1:7 to 1:1.
5. The preferred array procedure utilised the aldehyde (0.1
mmol), amine 3 (0.12–0.15 mmol), and resin-bound cyano-
borohydride in methanol containing 1% acetic acid.
6. The crude reaction mixture was adsorbed onto Biotage
Quad 3 samplets followed by drying in a dessicator overnight.
Subsequent parallel chromatography was carried out on silica
gel cartridges eluting with increasing concentrations of
methanolic ammonia in dichloromethane (0–10%).
7. Kerr, C. A.; Rae, I. D. Aust. J. Chem. 1978, 31, 341.
8. Fukuyama, N.; Nishino, H.; Kurosawa, K. Bull. Chem.
Soc. Jpn. 1987, 60, 4363.
The excellent Gram-positive antibacterial activity of
some of these compounds was confirmed by testing
against panels of clinical isolates to determine their
MIC90 values (the concentration required to inhibit
90% of the organisms; Table 4). These panels of
S. aureus, Staphylococcus epidermidis, E. faecalis and
Enterococcus faecium include a range of resistant organ-
isms.9 In all cases, the MRS inhibitors maintain good
activity against these pathogens. Excellent activity was
seen against the enterococci. Particularly good anti-
bacterial activity against staphylococci was seen with the
5-methylthiophenyl analogue 49 and the chroman 81.
All the MRS inhibitors described were highly selective
for the bacterial enzyme, with no significant inhibition
of mammalian (rat liver) MRS up to the highest con-
centration tested (either 1 or 10 mM).
In summary, the topology of a 2,3,5-trisubstituted benzyl-
amino group has been identified as an optimal left-hand
side moiety, affording potent nanomolar MRS inhibition
and Gram-positive antibacterial activity. Cyclisation to the
benzylic a-position is tolerated, affording very active
chroman and tetrahydroquinoline analogues. The 3- and
5-positions are relatively constrained, and display a
9. The number of isolates in each profile were S. aureus,
n=31, S. epidermidis, n=10, E. faecalis, n=10, E. faecium,
n=10. The resistance profile has been reported.3 Testing was
carried out using the NCCLS protocol.
10. Osborne, A. G.; Miller, L. A. D. J. Chem. Soc., Perkin
Trans. 1 1993, 181.