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B. Geng et al. / Bioorg. Med. Chem. Lett. 21 (2011) 5432–5435
Table 1
Variation of C-6 substitution X (Y = H, Z = H)
Compound
X
IC50
(lM) hERG Log D
MIC (
l
M)
Pae
IC50 (nM) Eco ParC
Sau
Spn
Spy
Hin
Mca
Eco
Eco (Tolc-) Kpn
1
2
3
4
c-Tetrazol
1-Hydroxyethyl
OH
>100
>100
>100
2.8
À0.8
0.3
0.5
>10.9 >10.9 >10.9 >10.9 >10.9
>10.9 >10.9 >10.9
>16.6 >16.6 1.1
>10.9 353
>16.6 NT
>17.7 36
>16.6 >16.6 >16.6 4.2
>16.6
0.1
17.7
0.1
8.8
0.3
1.1
NV
0.3
0.1
17.7
4.4
0.5
0.1
Br
1.4
<0.015 7.7
<0.02
3.9
18
5
6
7
8
CF3CONH–
Carboxyl
Methoxycarbonyl
Dimethylaminosulfonyl NT
Methylsulfonyl
Nitro
Ethylsufonyl
CF3O–
Acetyl
CN
>100
>100
14.8
0.2
>16.1 >16.1 >16.1 16.1
>13.5 >13.5 >13.5 >13.5 >13.5
16.1
>16.1 >16.1 8.1
>13.5 >13.5 >12.7
>16.1 NT
>13.5 4680
À1.6
0.8
1
8.1
2
0.5
0.1
>14.6
3.9
0
7.6
0.1
0.3
0
0.1
0
0.1
0.06
>16.1
4
0.1
16.1
NT
NT
NT
NT
NT
NT
4.3
NT
NT
NT
15.9
78
NT
NT
NT
NT
NT
NT
36
23
NT
NT
18
0.2
>14.6 >14.6 >14.6 14.7
>14.6 >14.6 7.3
9
50.7
À0.5
>15.5 15.5
0.3 0.5
>15.1 >15.1 15.1
15.5
0.3
3.9
0.1
7.6
0.1
0.3
0.1
0.1
0.1
0.1
0.3
>15.5 >15.5
5.9 0.5
1
10
11
12
13
14
15
16
17
18
24.3
>100
1.4
49.1
>44
3
8.5
12.9
1.3
NT
<0.02
À0.1
1.8
0.4
0.2
1.3
0.9
0.9
2.2
>15.1 >15.1 1.9
1
1
1
1
15.3
16.7
3.8
4.2
6.2
3.8
2.1
0.5
0.5
0.6
0.5
2.0
0.1
0.1
<0.02
<0.02
0.1
1
2.1
0.8
0.5
1.1
1.1
0.5
0.3
0.3
0.6
0.3
0.5
0.3
0.5
0.5
NV
2.0
Cl
F
MeO–
2-Furyl
8.6
15.9
0.1
0.06
Notes for table 1: hERG: Ionworks electrophysiological assay; Log D: experimental value measured by shake flask method with LC–MS detection; minimum inhibitory
concentration (MIC) was determined according to CLSI protocols8; Sau: Staphylococcus aureus; Spn: Streptococcus pneumoniae; Spy: Streptococcus pyogenes; Hin: Haemophilus
influenzae; Mca: Moraxella catarrhalis; Pae: Pseudomonas aeruginosa; Eco: Escherichia coli; Kpn: Klebsiella pneumoniae; IC50 was determined using the protocols in Ref. 12b.
6. Axten, J. M.; Brooks, G.; Brown, P.; Davies, D.; Galagher, T. F.; Markwell, R. E.;
potent, low single-digit lM hERG inhibition (such as compounds 4,
Miller, W. H.; Pearson, N. D.; Seefeld, M. WO2004058144, GlaxoSmithKline,
2004.
7. Breault, G.; Eyermann, C. J.; Geng, B.; Morningstar, M.; Reck, F. US 7,875,715 B2,
AstraZeneca, 2006. Final compounds (1–18) were synthesized as followings:
Compound 1 was synthesized from VI where X = CN; NaN3, TEA.HCl, NMP.
15, 18), a known issue in this series of inhibitors across the indus-
try. In this current survey, the cyano substitution (compound 14,
log D 0.2) seems to be ideal, giving balanced hERG profile and po-
tent antibacterial activity.
Compound
2 was synthesized from VI where X = acetyl; NaBH4, MeOH,
Based on the overall structural novelty, the antibacterial po-
tency/spectrum, and drug-like physical properties, including
aqueous solubility (the majority of compounds have >1 mM solu-
bility), this scaffold was deemed to be an excellent series for fur-
ther exploration to identify novel antibacterial agents with a
desirable spectrum. The SAR obtained from the benzoxazinone
LHS has proven to be applicable to other LHS fused bicyclic ring
systems. The series exhibits rapid bactericidal activity and has
shown no cross-resistance with marketed clinical antibacterial
agents (e.g., fluoroquinolones) at the target level. Further modifi-
cation of the bicyclic LHS, linker and RHS will be reported in due
course.11
TEA.HCl, NMP.
Compound 3 was synthesized from V where X = OCH3; BBr3 (1M), DCM.
Compound 4 was synthesized from I where X = Br, commercially available.
Compound 5 was synthesized from V where X = NO2, NH4.HCO2, Pd/C, acetyl
chloride, DCM.
Compound 6 was synthesized from VI where X = MeOCO-; LiOH, MeOH.
Compound 7 was synthesized from I where X = MeOCO-.
Compound 8 was synthesized from I where X = Me2NSO2-.
Compound 9 was synthesized from I where X = MeSO2-, which was prepared
through demethylation of 2-MeO–5-MeSO2 aniline with BBr3.
Compound 11 was synthesized from I where X = EtSO2-.
Compound 12 was synthesized from IV where X = CF3O.
Compound 13 was synthesized from IV where X = acetyl-.
Compound 14 was synthesized from V where X = CN. MS (ES): 463(MH+) for
C
24H26N6O4 (MW462.51); 1H NMR (CDCl3) d: 1.49 (m, 2H); 1.94 (m, 2H); 2.14
(m, 2H); 2.56 (m, 1H); 2.59 (t, J = 6.7 Hz, 2H); 2.94 (m, 2H); 3.84 (s, 2H); 4.03 (t,
2H); 4.62 (s, 2H); 4.67(s, 2H); 6.94 (d, 1H); 7.03 (d, 1H); 7.19 (d, 1H); 7.30 (dd,
1H); 7.46 (d, 1H).
Acknowledgments
Compound 15 was synthesized from I = Cl, commercially available.
Compound 16 was synthesized from I = F, commercially available.
Compound 17 was synthesized from IV = MeO.
Compound 18 was synthesized from VI = Br, through Suzuki coupling with 2-
furyl boronic acid.
The authors acknowledge the Biosciences Department at Astra-
Zeneca R&D Boston, for the determination of IC50 & MIC values,
Analytical Chemistry group for their technical support and we also
thank the Drug Metabolism & Pharmacokinetics Department at
AstraZeneca R&D Boston for physical property determinations.
8. (a) Clinical and Laboratory Standards Institute, Wayne, PA. (2006), Document
M07-A7.; (b) Bacterial susceptibility testing protocols: Compounds were tested
for antimicrobial activity by susceptibility testing in liquid media in a 96 well
format. Compounds were dissolved in dimethylsulfoxide and tested in 10
doubling dilutions in the susceptibility assays. The organisms used in the assay
were grown overnight on suitable agar media and then suspended in a liquid
medium appropriate for the growth of the organism. The starting suspension
was a 0.5 McFarland and a further 1 in 10 dilution was made into the same
References and notes
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