G Model
CCLET 5121 No. of Pages 4
L. Li et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
3
Table 2
Anti-MDR-MTB activity and cytotoxicity of selected compounds.
a
a
Compd.
MIC (m
g/mL)
Vero cells CC50
(m
g/mL)
Compd.
MIC (m
g/mL)
Vero cells CC50 (mg/mL)
MDR-1
MDR-2
MDR-1
MDR-2
1d
1e
1i
2c
2d
2e
2f
2g
2h
3b
3d
3e
<0.002
<0.002
<0.002
0.004
<0.002
<0.002
<0.002
<0.002
<0.002
<0.002
0.003
0.003
0.003
<0.002
0.007
<0.002
<0.002
<0.002
<0.002
<0.002
<0.002
0.005
19.65
>64
>64
>64
>64
58.80
>64
61.44
62.22
>64
3i
4h
5e
5g
5i
6c
6d
7e
Q203
PBTZ169
RFP
INH
<0.002
<0.002
<0.002
<0.002
<0.002
0.028
<0.002
<0.002
<0.002
<0.002
<0.002
0.030
0.003
0.003
<0.002
<0.002
>40
>64
36.57
>64
>64
>64
>64
>64
58.16
>64
>64
NT
0.003
<0.002
<0.002
<0.002
>40
>64
>64
<0.002
<0.002
>40
>40
NT
MDR-1 is MDR-MTB 16995 and MDR-2 is MDR-MTB 16833, which were isolated from patients in Beijing Chest Hospital; NT: not tested.
a
The 50% cytotoxic concentration.
Table 3
In vivo PK profiles of selected compounds dosed orally in ICR female mice at 25 mg/kg (n = 3).
Compd.
t1/2 (h)
tmax (h)
Cmax (ng/mL)
AUC0-1 (h ng/mL)
MRT (h)
2d
2f
5e
5g
0.736 ꢁ 0.15
1.24 ꢁ 0.14
1.04 ꢁ 0.08
4.74 ꢁ 0.55
0.25 ꢁ 0
218 ꢁ 71
120 ꢁ 39
0.736 ꢁ 0.17
0.769 ꢁ 0.08
1.37 ꢁ 0.20
4.27 ꢁ 0.12
0.25 ꢁ 0
3198 ꢁ 764
1555 ꢁ 299
763 ꢁ 267
2234 ꢁ 759
2466 ꢁ 1218
2835 ꢁ 671
0.42 ꢁ 0.14
0.667 ꢁ 0.29
of replicate bacterium-only controls. The MIC values of the
compounds along with isoniazid (INH), rifampicin (RFP), Q203,
PBTZ169 and the lead compound WZY02 for comparison are
presented in Table 1. Detailed procedures are shown in Supporting
information. The data reveal that most of them have good potency
Subsequently, the effect of the R1 and R2 groups on the anti-MTB
activity of other six 2,6-disubstituted IPA series with nine amine
moieties (a–i) was further investigated. With a few exceptions, as
shown in Table 1, replacement of the methyl group (R2) on the core
of 2,6-dimethyl IPA series 1a–i with ethyl (2a–i) results to slightly
increased potency, but cyclopropyl (c-Pr) as R2 (3a–i) has not
obvious influence on the activity, indicating that ethyl group as R2
is preferred over methyl and cyclopropyl. Moreover, the C-6
position of the IPA core is also well tolerated by another electron-
donating OMe group (1a–i vs 4a–i).
against this strain (MIC: < 0.05
found to show the same excellent activity (MIC: <0.016
Q203 and PBTZ169, while being more active than INH, RFP and
g/mL).
mg/mL). Twenty compounds were
m
g/mL) as
WZY02 (MIC: 0.031ꢂ0.059
m
We first investigated the potential impact of various amines on
the anti-MTB activity of the 2,6-dimethyl IPA series. Replacement
of the bromine atom on the para-position of the benzene ring of the
In further modifications, the methyl group of series 2 or 3 was
replaced by a halogen atom as the R1 group. 6-Chloro-2-ethyl IPA
derivatives 5 with the same core of Q203, As shown in Table 1,
lead WZY02 (MIC: 0.031
compound 1a leads to decreased activity (MIC: 0.118
the presence of piperidine in compound 1b demonstrates better
potent MIC value of 0.021 g/mL, suggesting that cyclic amine is
mg/mL) with dimethylamine group in
m
g/mL), but
display roughly the same activity (MIC: <0.016–0.052 mg/mL) as
the corresponding analogues 2. Replacement of the chlorine atom
of series 5 with bromine does not affect significantly the activity (5
vs 6). But the presence of cyclopropyl group instead of the ethyl as
the R2 group (5 vs 7), or chlorine instead of the methyl as the R1
group (3 vs 7) seems to be unfavorable. Overall, the above results
indicate that anti-MTB activity of the N-(2-phenoxy)ethyl IPA
derivatives is related to R1 and R2 groups of the IPA core as well as
W on the para-position of the benzene ring.
m
preferred over non-cyclic one. And this phenomenon is also
observed in compounds 1c and 1d containing morpholine and
thiomorpholine rings, the isostere of the piperidine (1b),
respectively.
Further investigation reveals that introduction of an electron-
withdrawing group, a methyloxime (a known functional moiety of
the third and fourth generational cephalosporins) or an aromatic
moiety on the para-position of the piperidine ring is acceptable,
Encouraged by their potent activity (MIC: <0.016
mg/mL)
against drug sensitive MTB H37Rv strain, 20 compounds were
evaluated against two clinical isolated MTB-MDR (16995 and
16833) strains resistant to both INH and RFP. As shown in Table 2,
such as compounds 1e–g with MIC of <0.016–0.027
expected, the piperidine ring of 1g could be replaced by its isostere
piperazine (1h, MIC: 0.018 g/mL) without obviously affecting the
anti-MTB potency. Interestingly, compound 1i with fused
nitrogen heterocycle (octahydro-1H-isoindole) shows the best
activity (MIC: <0.016 g/mL). However, introduction of an
mg/mL. As
m
all of them exhibit strong potency (MIC: <0.002–0.030
especially 13 compounds have the same best MIC values of
< 0.002 g/mL as Q203 and PBTZ169, suggesting their promising
mg/mL),
a
m
m
potential for both drug-sensitive and resistant MTB strains
(Tables 1 and 2).
additional piperidyl group on the para-position of the piperidine
ring of 1b is detrimental, and the resulting compound 1j shows
The above 20 compounds were also tested for mammalian cell
poor activity (MIC: 6.926
mg/mL) probably due to the alkaline of
cytotoxicity using Vero cells measured as a concentration
the terminal piperidine ring, indicating that 1,4'-bipiperidine is
unacceptable as the W group. The above results suggest that all the
amines with an exception of 1,4'-bipiperidine (j), could be ideally
suited as the W groups.
inhibiting 50% growth (CC50) as compared to a no-treatment
control [22]. As shown in Table 2, 14 compounds show low
cytotoxicity (CC50: > 64
mg/mL) comparable to Q203 and PBTZ169.
Detailed procedures are shown in Supporting information.
Please cite this article in press as: L. Li, et al., N-(2-Phenoxy)ethyl imidazo[1,2-a]pyridine-3-carboxamides containing various amine moieties:
Li, Linhu
