Structure-activity relationship of cytochrome bc1 reductase inhibitor broad spectrum antifungal ilicicolin H

Article abstract of DOI:10.1016/j.bmcl.2013.03.023

Ilicicolin H is a broad spectrum antifungal agent showing sub micro g/mL MICs against Candida spp., Aspergillus fumigatus and Cryptococcus spp. It is a potent inhibitor (C₅₀ 2-3 ng/mL) of the mitochondrial cytochrome bc1 reductase with over 1000-fold selectivity against rat liver cytochrome bc1 reductase. Structure-activity relationship of semisynthetic derivatives by chemical modification of ilicicolin H and its 19-hydroxy derivative produced by biotransformation have been described. Basic 4′-esters and moderately polar N- and O-alkyl derivatives retained antifungal and the cytochrome bc1 reductase activities. 4′,19-Diacetate and 19-cyclopropyl acetate retained antifungal and enzyme activity and selectivity with over 20-fold improvement of plasma protein binding.

Full text of DOI:10.1016/j.bmcl.2013.03.023

Bioorganic & Medicinal Chemistry Letters 23 (2013) 3018–3022
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationship of cytochrome bc1 reductase
inhibitor broad spectrum antifungal ilicicolin H
⇑
Sheo B. Singh , Weiguo Liu, Xiaohua Li, Tom Chen, Ali Shafiee, Sarah Dreikorn, Viktor Hornak,
Maria Meinz, Janet C. Onishi
Departments of Medicinal Chemistry and Infectious Disease, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Ilicicolin H is a broad spectrum antifungal agent showing sub micro g/mL MICs against Candida spp.,
Aspergillus fumigatus and Cryptococcus spp. It is a potent inhibitor (C50 2–3 ng/mL) of the mitochondrial
cytochrome bc1 reductase with over 1000-fold selectivity against rat liver cytochrome bc1 reductase.
Structure–activity relationship of semisynthetic derivatives by chemical modification of ilicicolin H
and its 19-hydroxy derivative produced by biotransformation have been described. Basic 40-esters and
moderately polar N- and O-alkyl derivatives retained antifungal and the cytochrome bc1 reductase activ-
ities. 40,19-Diacetate and 19-cyclopropyl acetate retained antifungal and enzyme activity and selectivity
with over 20-fold improvement of plasma protein binding.
Received 25 January 2013
Accepted 6 March 2013
Available online 15 March 2013
Keywords:
Ilicicolin H
Antifungal activity
Cytochrome bc1 reductase inhibitor
Structure–activity relationship
Ó 2013 Elsevier Ltd. All rights reserved.
Many human fungal infections are caused by opportunistic
fungi: Candida spp., Aspergillus spp., and Cryptococcus spp. These
infections can be life-threatening particularly in patient popula-
tions that are immunocompromised.1 Serious fungal infections
are generally treated by mainly three classes of drugs including
azoles (e.g., fluconazole)2 macrocyclic polyenes (e.g., amphoteri-
cin)3 and echinocandins (e.g., caspofungin, micafungin and anidu-
lafungin).4 Unfortunately, limitations exist for each treatment
option, including in some cases development of drug resistant
fungal strains. It is desirable to develop new broad spectrum anti-
fungal agents with unique modes of action.
undertook a systematic approach for medicinal chemistry optimiza-
tion of ilicicolin H including biotransformation, enzymatic transfor-
mations and chemical modifications. Chemical modification around
b-diketone generally led to compounds with reduced antifungal and
enzymatic activities.5,11 Biotransformation of ilicicolin H produced a
series of oxidized metabolites generally with significant loss of
activity with an exception of a few derivatives.12 In this Letter, we
describe the chemical modification of ilicicolin H which encompass
a systematic derivatization of the molecule. The derivatives were
evaluated for their antifungal activity against Candida albicans, and
for activity against the yeast and rat liver cytochrome bc1 reduc-
tase.5 Structure–activity relationship of semisynthetic analogs for
antifungal and enzyme inhibitory activity along with plasma protein
binding is described herein.
We recently described ilicicolin H (1) as a potent and broad spec-
trum antifungal agent with MICs ranging from 0.04 to 1.56 lg/mL
against Candida spp., Cryptococcus spp., and Aspergillus fumigatus.
Ilicicolin H has no cross-resistance to fluconazole resistant Candida
albicans. The compound inhibits fungal growth by specifically and
selectively inhibiting yeast mitochondrial cytochrome bc1 reduc-
tase (IC50 2–3 ng/mL).5 The corresponding enzyme from rat and rhe-
sus liver was more than 1000-fold less sensitive. Its cytochrome bc1
reductase activity has been extensively studied.6–10 Ilicicolin H
showed in vivo antifungal efficacy but was limited by high plasma
protein binding. Reduction of plasma protein binding while retain-
ing the antifungal activity, spectrum and enzyme specificity is one
of the major goals of the lead optimization program. Structurally
ilicicolin H is comprised of a substituted decalin connected by a
b-diketone to a 5-hydroxyphenyl substituted 2/4-pyridone. We
CH3
HO
O
O
OH
4'
H
CH3
12
8
5
3
1
N
H
H
CH3
1
Ilicicolin H ( )
Reaction of 1 with dimethyl sulfate in THF and potassium car-
bonate at room temperature afforded exclusively N-methyl deriv-
ative (2) in 60% yield. Reaction with trimethyl tetrafluoroborate
and proton sponge in methylene chloride gave two mono alkylated
products 2 (16%), O-methyl (3, 22%) and trace of N,O-dimethyl (4)
⇑
Corresponding author. Tel.: +1 7325943222; fax: +1 7325943007.
E-mail address: sheo.singh@merck.com (S.B. Singh).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.03.023

S. B. Singh et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3018–3022
3019
ilicicolin H. The trimethyl derivative 5 was prepared in about 10%
yield by refluxing ilicicolin H and dimethyl sulfate in acetone in the
presence of potassium carbonate. Likewise the reaction of 1 with
triethyl tetrafluoroborate produced a 1:1 mixture of two mono
ethyl derivatives 6 and 7. Alkylation of 1 with corresponding alkyl
iodide and potassium carbonate in THF afforded 8–13. Reaction of
ilicicolin H with 2-bromo-t-butyl acetate in THF and potassium
carbonate yielded the mono (30%) and di t-butyl (23%) acetate
The mono methyl derivatives 2 and 3 retained C. albicans cyto-
chrome bc1 reductase activity of ilicicolin H (1), but lost C. albicans
whole cell activity and rat liver enzyme selectivity by approxi-
mately 10-fold (Table 1). The N-ethyl derivative (6) showed anti-
fungal activity similar to the N-methyl analog (2). N-Propenyl
derivative (8) was 50-fold less active than 1 in the antifungal assay
but only ꢀ4-fold less active in the enzyme assay. Slightly polar
N-alkyl substitutions (e.g., CH2CONH2, 9 and CH2CN, 11) retained
antifungal activity with either retention of the fungal enzyme
activity (11) or with ꢀ20-fold diminution of fungal enzyme activity
(9). While small alkyl ester groups (e.g., methyl, 3) retained both
cellular and enzyme activities larger groups such as ethyl (7) led
to significant loss of activities. Modestly polar ester group substitu-
tions for example, cyano methyl (12) allowed for retention of the
activities. Dialkylation of N- and phenolic groups (10, 13, 15, 17)
or substitution of either of the groups with larger groups (14) or
polar groups (16 and 18) led to the complete loss of activities.
The acyl derivatives (20–30, 33–36) were prepared by reaction of
ilicicolin H and 2–3 equiv of the corresponding carboxylic acids in
the presence of DMAP and EDC at room temperature for 2–48 h.
FMOC deprotection of 28 with piperidine produced glycine ester
which was unstable and produced ilicicolin H. N-t-Boc deprotection
of 29 and 30 with TFA afforded the 4-aminobutanoate (31) and 5-
aminopentanoate (32). 40-p-Bromo-phenyl carbamate ilicicolin H
(37) was exclusively prepared in ꢀ50% yield by reaction of ilicicolin
H with p-bromophenyl-isocyanate.
derivatives
14
and
15.
Treatment
of
these
t-butyl esters with TFA in methylene chloride afforded the free
acids 16 and 17. Reaction of ilicicolin H with ꢀ1 equiv of diethyl
amino ethyl bromide gave N-triethyl amino derivative 18 almost
exclusively in <10% yield. All compounds were purified by re-
versed-phase HPLC and characterized by MS and NMR, and 2D
NMR when necessary.
R2O
HO
OR3
OH
N
O
O
O
H
H
H
H
N
OMe
R1
2
3
4
5
6
7
8
9
19
: R1 = CH3, R2 = H, R3 = H
: R1 = H, R2 = CH3, R3 = H
: R1 = CH3, R2 = CH3, R3 = H
: R1 = CH3, R2 = CH3, R3 = CH3
: R1 = CH2CH3, R2 = H, R3 = H
: R1 = H, R2 = CH2CH3, R3 = H
: R1 = CH2CH=CH2, R2 = H, R3 = H
: R1 = CH2CONH2, R2 = H, R3 = H
R
O
OH
O
O
H
O
10
: R1 = CH2CONH2, R2 = CH2CONH2, R3 = H
: R1 = CH2CN, R2 = H, R3 = H
11
12
13
14
15
16
17
18
N
H
: R1 = H, R2 = CH2CN, R3 = H
H
: R1 = CH2CN, R2 = CH2CN, R3 = H
: R1 = CH2CO2-t-Bu, R2 = H, R3 = H
: R1 = CH2CO2-t-Bu, R2 = CH2CO2-t-Bu, R3 = H
: R1 = CH2CO2H, R2 = H, R3 = H
: R1 = CH2CO2H, R2 = CH2CO2H, R3 = H
: R1 = CH2CH2N(CH2CH3)2, R2 = H, R3 = H
20
21
22
23
24
25
26
27
28
29
: R = CH2CH3
: R = N-t-Boc-aminopropyl
30: R = N-t-Boc-aminobutyl
31
: R = Cyclopropyl
: R = Cyclobutyl
: R = Cyclopentyl
: R = Cyclohexyl
: R = Phenyl
: R = Aminopropyl
32: R = Aminobutyl
33
: R = 3-Furanyl
34: R = 3-Thiophenyl
35
: R = 3-(Thiophenyl)-E-ethenyl
: R = Benzyl
: R = E-cinnamyl
: R = Fmoc-aminomethyl
36: R = 3-(Imidazolyl)-E-ethenyl
37: R = NH-p-Bromo-phenyl
Table 1
Esters with small alkyl groups (20–22) continue to retain anti-
fungal and enzyme activities and maintained the selectivity
against rat reductase enzyme (Table 2). As the size of the ester
group increased (e.g., 23–25, 34) the antifungal activity diminished
significantly with the exception of furanyl ester (33) which re-
tained antifungal activity of ilicicolin H with only a 4- to 5-fold loss
of enzyme activity. When the branching of the acyl group was sep-
arated away from the keto group by at least one atom (26–30) thus
reducing the steric crowding, both the antifungal and the enzyme
activity reversed to the level of the propyl ester (20). Thiophenyl
esters (34, 35) regardless of the branching point showed signifi-
cantly reduced activities. The esters with free terminal amine such
as aminobutanoate (31) and aminopentanoate (32) or imidazolyl
ethenyl (36) retained potent antifungal and Candida enzyme activ-
ity though with significant loss of enzyme specificity. p-Bromophe-
nyl carbamate (37) showed much lower activities.
The 19-hydroxy ilicicolin H (38) and its acetate (39) was pre-
pared by biotransformation as described earlier.12 The acyl deriva-
tives 40–46 were prepared by coupling of 39 and 2–3 equiv of
corresponding carboxylic acids, EDC and DMAP providing a mix-
ture of mono and diesters which were purified by reversed phase
HPLC. The reaction was often pushed to form the diacyl deriva-
tives; then phenolic acyl group was hydrolyzed at pH 9 by reaction
with 0.01% LiOH in MeOH at room temperature to give 19-hydroxy
derivatives.
C. albicans antifungal and NADH:cytochrome c1 oxidoreductase activity and selec-
tivity against rat liver NADH:cytochrome c1 oxidoreductase of N- and O-alkyl analogs
of ilicicolin H
Compd #
MY1055a
(MIC, ng/mL)
MY1055b
(IC50, ng/mL)
Ratc
(IC50, ng/mL)
1
2
3
4
5
6
7
8
20–40
250–625
250
>1000
>1000
312
>5000
1000
31
>1000
62
2–3
1.6
3
8–80
1000
NT
1000
8
2000–5000
250
200
NT
NT
NT
1000
1000
NT
>1000
800
9
40
200
1
10
11
12
13
14
15
16
17
18
19
125
6
1000
NT
1000
>5000
>5000
>5000
>5000
>1000
>1000
100
>1600
>1600
>1000
>1000
20
1600
1600
1000
1000
>1000
>1000
20
NT = not tested.
a
C. albicans MY1055 in glycerol media.
C. albicans MY1055 NADH:cytochrome bc1 reductase.
Rat liver NADH:cytochrome c1 reductase.
b
c

3020
S. B. Singh et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3018–3022
Table 2
Table 4
C. albicans antifungal and NADH:cytochrome c1 oxidoreductase activity and selec-
tivity against rat liver NADH:cytochrome c1 oxidoreductase of O-acyl and carbamate
analogs of ilicicolin H
C. albicans antifungal and NADH:cytochrome c1 oxidoreductase activity and selec-
tivity against rat liver NADH:cytochrome c1 oxidoreductase of oxidized analogs of
ilicicolin H
Compd #
MY1055a
MY1055b
Ratc
Compd #
MY1055a
MY1055b
Ratc
(MIC, ng/mL)
(IC50, ng/mL)
(IC50, ng/mL)
(MIC, ng/mL)
(IC50, ng/mL)
(IC50, ng/mL)
1
20–40
125
62
2–3
0.81
15
2
10
400
8
0.5
20
6
2000–5000
>1600
>800
>800
>800
>1600
1000
1000
1600
1000
>1000
>1000
45
1
20–40
625
>5000
>5000
NT
>1000
>1000
>5000
>5000
>5000
5000
2–3
5.2
2000–5000
1000
1000
1000
NT
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
47
48
49
50
51
52
53
54
55
56
57
58
>1000
>1000
NT
>1000
NT
>1000
>1000
1000
200
1000
NT
62
1000
>1000
1000
250
312
125
125
250
31
NT
NT
1000
1000
1000
1000
1000
NT
4
5
>5000
>5000
0.2
0.1
10.5
5
500
1
31
40
NT = not tested.
62.5
1000
1000
31
>1000
>1000
>1000
8
a
C. albicans MY1055 in glycerol medium.
C. albicans MY1055 NADH:cytochrome bc1 reductase.
Rat liver NADH:cytochrome c reductase.
b
c
5000
200
1000
the diacetate (41). Mono- (42) and dipropionates (43) showed similar
activities which was approximately fourfold diminished than ilicicolin
H. While fungal enzyme activity of the three cyclopropyl acid esters
(44–46) were within twofold of each other and were within the range
of the activity of 1, the antifungal activity of the mono ester (44) was
fourfold less than 46. The antifungal activity of 19-cyclopropyl ester
(46) was about twofold lower than 1. The diester (45) was inactive in
the antifungal assay. Surprisingly, cyclopropyl esters significantly lost
the fungal enzyme specificity.
NT = not tested.
a
C. albicans MY1055 in glycerol medium.
C. albicans MY1055 NADH:cytochrome bc1 reductase.
Rat liver NADH:cytochrome c1 reductase.
b
c
R1O
OH
O
O
H
H
OR2
Epoxidation of ilicicolin H (1) with stoichiometric amount of
MCPBA produced a mixture of products 47 (yield 4%), 48 (37%),
49 (5.3%) and 50 (10%). The epoxidation of the D16,17 olefin leads
N
H
38
39
40
41
42
43
44
45
46
: R1 = H, R2 = H
: R1 = H, R2 = COCH3
to an
a-epoxide which was not isolated and readily converted to
: R1 = COCH3, R2 = H
: R1 = COCH3, R2 = COCH3
: R1 = COCH2CH3, R2 = H
: R1 = COCH2CH3, R2 = COCH2CH3
: R1 = CO-cyclopropyl,R2 = H
: R1 = CO-cyclopropyl,R2 = CO-cyclopropyl
: R1 = H, R2 = CO-cyclopropyl
pyrones 48 and 49. The hydrolysis of the epoxide leads to forma-
tion of the diol 50. The diepoxide was not isolated.
O
HO
HO
OH
N
O
O
OH
O
O
H
H
H
N
H
The hydroxylation at C-19 (38) caused significant loss of antifungal
H
OH
and enzyme activities compared to ilicicolin H (Table 3). Acetylation of
the 19-hydroxy group (39) restored the fungal enzyme activity and
specificity to the level of ilicicolin H but without any improvement of
the antifungal activity. 40-Acetate analog (40) showed reduced anti-
fungal and enzyme activities, but both activities were restored with
47
48
50
O
HO
HO
OH
N
O
O
OH
O
H
H
N
H
O
Table 3
HO
H
HO
OH
C. albicans antifungal and NADH:cytochrome c1 oxidoreductase activity and selec-
tivity against rat liver NADH:cytochrome c1 oxidoreductase of O-acyl analogs of
biotransformation product of ilicicolin H
49
MY1055a
MY1055b
Ratc
Selenium dioxide oxidation of ilicicolin H (1) in chloroform and
Compd #
formic acid gave two products, 51 (yield 46%) and 52 (15%). These
products were formed after allylic hydroxylation at C-8 and/or C-9
and C-15 followed by dehydration in the presence of acid. The pyr-
one derivative 51 and the aromatic compound 52 were not active
in the assays tested (Table 4).
(MIC, ng/mL)
(IC50, ng/mL)
(IC50, ng/mL)
1
20–40
250
500
500
62
250
125
250
>5000
62
2–3
400
2.1
160
15
8
10
2
0.8
1.2
2000–5000
400
38
39
40
41
42
43
44
45
46
>1600
>800
>800
>800
>800
8
CH3
CH3
HO
HO
OH
N
O
O
OH
O
O
H
H
CH3
CH3
10
40
N
H
NT = not tested.
a
CH3
CH3
C. albicans MY1055 in glycerol medium.
C. albicans MY1055 NADH:cytochrome bc1 reductase.
Rat liver NADH:cytochrome c reductase.
b
c
51
52

S. B. Singh et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3018–3022
3021
Table 5
C. albicans antifungal and NADH:cytochrome c1 oxidoreductase activity of selected ilicicolin H analogs tested with/or without mouse plasmaa
f
Compd #
MY1055b (IC50, ng/mL)
40% MPd
MY1055c (MIC, ng/mL)
10% MPd
clogD7.4
No MPd
FRe
No MPd
FRe
1
0.5
20
0.2
0.1
3.5
15
70
5000
30
140
250
150
300
43
7
20
192
40
>1000
>1000
>1000
>25
4.33
6.05
3.7
18
31
32
36
41
46
47
30
4.0
150
100
40
62.5
125
31.3
1000
1000
1000
250
16
8
8
4.02
2.89
3.59
3.41
2
5.2
1000
>1000
a
b
c
d
e
f
With or without plasma activity data presented in table were recorded in parallel.
C. albicans MY1055 NADH:cytochrome bc1 reductase.
C. albicans MY1055 in glycerol medium.
MP = mouse plasma.
FR = fold reduction of activity after addition of mouse plasma.
Calculated lodD7.4 using ACD software.
CH3
H
CH3CO
HO
H
N
O
O
OH
-CH2OCOCH3
-CH2OCOCH(CH2)2
CH3
O
N
N
H
H
CH3
Figure 1. Position of modifications of ilicicolin H highlighted in red. Ester groups in box with retained or improved activity and plasma protein binding.
Bromination of ilicicolin H (1) with 1 equiv of N-bromosuccini-
or acidity of the compounds. Since the results of the chemical mod-
ification of b-diketone showed that the acidic b-diketone group of
ilicicolin H was essential for activity, efforts to reduce protein bind-
ing focused on increasing basicity and polarity of the compound.
Selected compounds were evaluated for plasma protein binding di-
rectly in the biological assays with/or without mouse plasma. The
data are summarized in Table 5. The parent lead ilicicolin H (1,
clogD7.4 4.33) showed 140-fold reduction of fungal enzyme activ-
ity when tested in the presence of 40% mouse plasma and over 25-
fold reduction in Candida albicans MIC in the presence of 10% of
mouse plasma. No improvement in the protein binding was ob-
served by substituting an N1-alkyl amine (e.g., 18, clogD7.4 6.05)
or 40-amino-alkyl esters (e.g., 31, 32, clogD7.4 3.7–4.0). However,
substitution with a 40-imidazolyl ester (36, clogD7.4 4.02) had a po-
sitive effect on the plasma protein binding. Increased polarity (e.g.,
47, clogD7.4 3.41) did not improve protein binding. The diacetate
(41, clogD7.4 2.89) and the C-19 cyclopropyl acetate (46, clogD7.4
3.59) showed most improvement in the protein binding with only
7- to 8-fold reduction of enzyme and antifungal activities in the
presence of plasma. While these data suggest that protein binding
by derivatization can be significantly improved these acetates are
unlikely to be metabolically stable and are not expected to improve
in vivo efficacy.
Ilicicolin H is a polyketide natural product with broad spectrum
antifungal activity. It selectively inhibited fungal mitochondrial
cytochrome bc1 reductase as compared to corresponding mamma-
lian reductase activity. Lead optimization of ilicicolin H by biotrans-
formation, enzymatic reactions, and chemical transformation on all
parts of the molecule led to modifications at 21 of 32 non-hydrogen
atoms of the molecule exemplified by N-alkyl, O-alkyl, O-acyl, aro-
matic halides, oxime, hydrazonyl, heterocycles and the oxidized
derivatives of unactivated carbons (Fig. 1). While many derivatives
retained varying degrees of activities b-diketone appears to be crit-
ical for the activities. The most interesting derivatives that retained
the activities are the 40-imidazolyl-ethenyl (36), 19-acetyl (46) and
40, 19-diacetate (41). These compounds showed about 20-fold
mide in THF produced a mixture of mono (53, yield 35%), di (54,
19%) and tri (55, 6%). Similar halogenation reactions with N-chloro-
succinimide produced a mono-chloro pyrone (56, 35%) and with
N-iodosuccinmide gave a mono (57, 50%) and di (58, 8%) iodo-
pyrones, respectively.
R1
HO
R
2 OH
O
H
H
N
O
R
53: R = Br, R1 = R2 = H
54: R = R1 = Br, R2 = H
55: R = R1 = R2 = Br
56: R = Cl, R1 = R2 = H
57: R = I, R1 = R2 = H
58: R = R1 = I, R2 = H
The mono epoxide 47 lost significant antifungal activity but re-
tained most of the enzyme activity and selectivity (Table 4). The loss
of the whole cell activity may be due to poor cell penetration. Cycli-
zation to the pyrone ring led to the complete loss of antifungal activ-
ity as well as fungal enzyme activity and selectivity. Previously, we
established a bioactive conformation which requires decalin right
hand side to be rotated perpendicular relative to the left hand side
of ilicicolin.5 Clearly, the pyrone containing analogs lock the mole-
cule in a coplanar arrangement, which would not fit into the binding
pocket thereby rationalizing the total loss of activity. Therefore,
many chemical modifications around b-diketone are detrimental
to the biological activity of ilicicolin H. TheC. albicans MIC of epoxide
47 shifted to >1000 ng/mL in the presence of 50% mouse serum.
Effect of plasma on the activity of analogs. One of the goals of
the medicinal chemistry optimization of this program was to re-
duce the plasma protein binding and improve in vivo efficacy.
The plasma protein binding is generally correlated to lipophilicity

3022
S. B. Singh et al. / Bioorg. Med. Chem. Lett. 23 (2013) 3018–3022
4. Georgopapadakou, N. H. Expert Opin. Investig. Drugs 2001, 10, 269.
5. Singh, S. B.; Liu, W.; Li, X.; Chen, T.; Shafiee, A.; Card, D.; Abruzzo, G.; Flattery,
A.; Gill, C.; Thompson, J. R.; Rosenbach, M.; Dreikorn, S.; Hornak, V.; Meinz, M.;
Kurtz, M.; Kelly, R.; Onishi, J. C. ACS Med. Chem. Lett. 2012, 3, 814.
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7. Ding, M. G.; di Rago, J. P.; Trumpower, B. L. J. Biol. Chem. 2006, 281, 36036.
8. Gutierrez-Cirlos, E. B.; Merbitz-Zahradnik, T.; Trumpower, B. L. J. Biol. Chem.
2004, 279, 8708.
improvements in plasma protein binding. These studies provide a
guideline for future modification at C-40 and C-19 to produce com-
pounds that could further reduce plasma protein binding and
improve in vivo efficacy. The aromatic ring could be reasonably
replaced by a variety of heterocyclic moieties by feeding appropri-
ate aromatic heterocyclic amino acids.
9. Lancaster, C. R. D.; Hunte, C.; Kelley, J.; Trumpower, B. L.; Ditchfield, R. J. Mol.
Biol. 2007, 368, 197.
10. Rotsaert, F. A.;Ding, M. G.; Trumpower, B. L. Biochim. Biophys. Acta 2008, 1777, 211.
11. Liu, W. G.; Guan, Z. Q.; Singh, S. B. Tetrahedron Lett. 2005, 46, 8009.
12. Singh, S. B.; Li, X.; Chen, T. Tetrahedron Lett. 2011, 52, 6190.
References and notes
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2. Zonios, D. I.; Bennett, J. E. Semin. Respir. Crit. Care Med. 2008, 29, 198.
3. Gallis, H. A.; Drew, R. H.; Pickard, W. W. Rev. Infect. Dis. 1990, 12, 308.