The structure-activity relationships of mansonone F, a potent anti-MRSA sesquiterpenoid quinone: SAR studies on the C6 and C9 analogs

Article abstract of DOI:10.1016/j.bmcl.2005.09.024

For the systematic SAR study on mansonone F, a series of C6 and C9 analogs of mansonone F have been synthesized and their anti-MRSA activities were evaluated. Most of the analogs exhibited good or excellent anti-MRSA activities. In particular, the 6-n-butylmansonone F showed fourfold higher antibacterial activities compared to that of vancomycin.

Full text of DOI:10.1016/j.bmcl.2005.09.024

Bioorganic & Medicinal Chemistry Letters 16 (2006) 142–145
The structure–activity relationships of mansonone F, a potent
anti-MRSA sesquiterpenoid quinone: SAR studies
on the C6 and C9 analogs
Young-Ger Suh,a,* Sun Nam Kim,a Dong-Yun Shin,b Soon-Sil Hyun,a Do-Sang Lee,a
Kyung-Hoon Min,a Sae Mi Han,a Funan Li,a Eung-Chil Choia and Seong-Hak Choic
aCollege of Pharmacy, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Gu, Seoul 151-742, Republic of Korea
bLife Science Division, Korea Institute of Science and Technology, PO Box 131 Cheongryang, Seoul 130-650, Republic of Korea
cResearch Laboratories, Dong-A Pharmaceutical Company, 47-5, Sangal-Ri, Kiheung-Up,
Yongin-Si, Kyunggi-Do 449-900, Republic of Korea
Received 1 August 2005; revised 5 September 2005; accepted 12 September 2005
Available online 19 October 2005
Abstract—For the systematic SAR study on mansonone F, a series of C6 and C9 analogs of mansonone F have been synthesized
and their anti-MRSA activities were evaluated. Most of the analogs exhibited good or excellent anti-MRSA activities. In particular,
the 6-n-butylmansonone F showed fourfold higher antibacterial activities compared to that of vancomycin.
Ó 2005 Published by Elsevier Ltd.
Life-threatening infection caused by methicillin-resistant
Staphylococcus aureus (MRSA) is one of the most seri-
ous problems for the management of nosocomial infec-
tions. Particularly, S. aureus is known to be easily able
to develop resistance to the commonly used antibiotics
due to its high adaptability.1 Though several new anti-
bacterial agents such as quinupristin/dalfopristin,2 lin-
ezolid,3 vancomycin as well as teicoplanin4 are
currently available, the increase of resistant strains to
those antibiotics is still a major clinical problem. This
prompted many scientists to investigate a new class of
anti-MRSA agents having a new mode of action.
O
O
6
3
O
9
2
Figure 1. Structure of mansonone F (1).
Our preliminary SAR studies on mansonone F have re-
vealed that (1) both the quinone moiety and the tricyclic
system of mansonone F are essential for anti-MRSA
activities, (2) the alkyl and the electron-withdrawing
groups at C-3 do not significantly affect antibacterial
activities, (3) the polar substituents at C-3 eliminate
the antibacterial activities, and 4) the C2,3-olefin is
slightly beneficial for the higher antibacterial activities.5c
Recently, we have reported isolation, synthesis, and pre-
liminary SAR study of mansonone F, which is structur-
ally unique and highly potent in anti-MRSA activity.5
The structural feature of mansonone F may impose that
the mode of antibiotic action would be different from
that of the antibiotics currently used for anti-MRSA
therapies. The new mode of action has been expected
to provide a solution to overcome the resistance prob-
lem of the common antibacterial agents (see Fig. 1).
We herein report the syntheses and anti-MRSA activi-
ties of the C6 and C9 mansonone F analogs for the sys-
tematic structure–activity relationships of mansonone F.
In particular, a novel candidate for the promising anti-
MRSA therapy is also reported.
Keywords: MRSA; Mansonone F; Anti-bacterial agent; Sesquiterpe-
noid quinone.
All analogs were synthesized via a divergent synthetic
route developed in our laboratory. The 5-alkyl-1-meth-
oxynaphthalenes (3a–3c) were synthesized from the
*
Corresponding author. Tel.: +82 2 880 7875; fax: +82 2 888 0649;
e-mail: ygsuh@snu.ac.kr
0960-894X/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2005.09.024

Y.-G. Suh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 142–145
143
tetralone 2 by a sequence of organocerium reactions,
dehydroaromatization and demethylation, to provide
the naphthols 4a–4c. The naphthol 4d was prepared by
monoetherification of 1,5-dihydroxynaphthalene. The
ortho methyl groups of 4a–4d were introduced by
hydroxymethylation of the corresponding 4a–4d fol-
lowed by hydrogenolysis of the resulting alcohols to af-
ford 5a–5d. The 2-methylnaphthol 5e is commercially
available. O-Alkylation of 5a–5e with bromoacetate fol-
lowed by ester hydrolysis and ring closing Friedel–
Crafts acylation gave the tricyclic ketones 6a–6e, which
were transformed into the alcohols 7a–7e by two-step
process of Grignard reaction and nitration. Finally,
the quinones 8a–8e were prepared by sequential catalyt-
ic hydrogenation of the nitro group, Teuber oxidation6
of the resulting amines, and dehydration (Scheme 1).
carried out by analogy with the procedure employed
for 8a–8e.
The syntheses of the C9 mansonone F analogs (19a–19f)
are summarized in Scheme 3. The bromonaphthol 15,
prepared by bromination of 5-methylnaphthol,5b was
transformed into the 9-bromo-2,3-dihydrooxaphenalene
16 via combination of the procedure employed for 6 in
Scheme 1 and Grignard reaction. The 9-substituted
dihydrooxaphenalenes 17b–17e, prepared from 16 by
palladium-catalyzed coupling reaction,8 were converted
to 19a–19f by analogy with 8a–8e. It is noticeable that
the reduction condition (Pd/C, HCO2NH4 in MeOH)
for 18a also induced a debromination, which resulted
in production of 19f (Scheme 3).
The synthesized mansonone F analogs were tested for
anti-MRSA activities.9,10 Most of the C6 mansonone
analogs exhibited good antibacterial activities against
the standard MRSAs as shown in Table 1. The analogs
possessing alkyl substituent at C6 displayed almost equi-
The C6-substituents of 14a–14e were introduced by
palladium-catalyzed coupling reaction of the O-triflate
12 with the corresponding tin reagents7 (Scheme 2).
The transformations of 13a–13e into 14a–14e were
O
R1
R1
R1
iv, v
i, ii
iii
vi - viii
OMe
OMe
3a-c
OH
4a-d
OH
2
5a-e
R1
NO2 R1
O
O
R1
a; R1 = CH2(CH2)2CH3
b; R1 = CH2(CH2)3CH3
c; R1 = CH2(CH2)4CH3
d; R1 = OMe
O
ix, x
xi - xiii
O
6a-e
O
O
OH
e; R1 = H
7a-e
8a-e
Scheme 1. Reagents and conditions: (i) RMgX, CeCl3, Et2O, À78 °C; (ii) Pd/C, triglyme, reflux; (iii) BBr3, CH2Cl2, À78 °C, 65–87% for three steps;
(iv) PhB(OH)2, (CH2O)n, C2H5CO2H, C6H6, reflux; (v) Pd/C, H2, c-HCl, MeOH/THF(1/3), rt, 68–82%; (vi) BrCH2CO2Me, NaH, THF, 40 °C, 89–
95%; (vii) LiOH, THF/H2O (3/1); (viii) (COCl)2, C6H6; reflux; then AlCl3, CH2Cl2, 0 °C, 74-87% for two steps; (ix) MeMgI, Et2O, rt; (x) Cu(NO3)2–
xH2O, Ac2O, 77–83% for two steps; (xi) Pd/C, H2, MeOH, rt; (xii) FremyÕs salts, 0.06 M NaH2PO4, acetone, rt, 64–81% for two steps; (xiii) H2SO4/
EtOH (1/20), reflux, 34–72%. a; R1 = CH2(CH2)2CH3, b; R1 = CH2(CH2)3CH3, c; R1 = CH2(CH2)4CH3, d; R1 = OMe, e; R1 = H.
OTBS
OTf
OTf
OH
i - v
vi, vii
viii
O
O
O
OH
O
O
OH
9
10
11
12
O
O
R1
R
O
a ; R = CHCH2
a ; R1 = CH2CH3
ix
x - xiii
b ; R = CH2CHCH2
c ; R = CH2CHC(CH3)2
d ; R = CH(CH3)2
e ; R = CO2Me
b ; R1 = CH2CH2CH3
c ; R1 = CH2CH2CH(CH3)2
d ; R1 = CH(CH3)2
e ; R1 = CO2Me
O
OH
13a-e
14a-e
Scheme 2. Reagents and conditions: (i) TBSCl, imidazole, DMF, rt, 65%; (ii) Et2AlCl, (CH2O)n, CH2Cl2, 0 °C; (iii) Pd-C, H2, MeOH, rt, 52% for two
steps; (iv) BrCH2CO2Me, NaH, THF, 50 °C, 97%; (v) BBr3, CH2Cl2, À5 °C, 50%; (vi) TBAF, THF, rt; (vii) Tf2O, pyridine, CH2Cl2, 0 °C, 70% for
two steps; (viii) MeMgI, Et2O, rt, 71%; (ix) Pd(0) catalyzed reaction7, 80–91%; (x) Cu(NO3)2–xH2O, Ac2O, 43–78%; (xi) Pd/C, H2, MeOH, rt; (xii)
FremyÕs salts, 0.06M NaH2PO4, acetone, rt, 56–81% for two steps; (xiii) H2SO4/EtOH(1/20), reflux, 37–52%. a; R = CHCH2 b; R = CH2CHCH2, c;
R = CH2CHC(CH3)2, d; R = CH(CH3)2, e R = CO2Me, a; R1 = CH2CH3, b; R1 = CH2CH2CH3, c; R1 = CH2CH2CH(CH3)2, d; R1 = CH(CH3)2 e;
R1 = CO2Me.

144
Y.-G. Suh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 142–145
i
vi
ii - v
Br
R
Br
O
O
OH
vii
OH
OH
OH
15
16
17a-e
NO2
O
a; R2 = Br
b; R2 = CH2CH3
c; R2 = CH2CH2CH3
d; R2 = C(O)CH3
e; R2 = CO2Me
f; R2 = H
O
a; R = Br
viii - x
b; R = CHCH2
c; R = CH2CHCH2
d; R = C(O)CH3
e; R = CO2Me
R2
R
O
O
OH
18a-e
19a-f
Scheme 3. Reagents and conditions: (i) NBS, t-BuNH2, CH2Cl2, 0 °C, 40%; (ii) BrCH2CO2Me, NaH, THF, 40 °C, 94%; (iii) LiOH, THF/H2O (3/1);
(iv) (COCl)2, C6H6; then AlCl3, CH2Cl2, 83% for two steps; (v) MeMgI, THF, rt, 67%; (vi) Pd(0) catalyzed reaction8, 60–81%; (vii) Cu(NO3)2–xH2O,
Ac2O, 45–81%; (viii) Pd/C, H2, MeOH, rt for 18b–18e and Pd/C, HCO2NH4, MeOH, rt for 18a and 18f; (ix) FremyÕs salts, 0.06 M NaH2PO4,
acetone, rt, 41–83% for two steps; (x) H2SO4/EtOH (1/20), 32–48%. a; R = Br, b; R = CHCH2, c; R = CH2CHCH2, d; R = C(O)CH3, e; R = CO2Me,
a; R2 = Br, b; R2 = CH2CH3, c; R2 = CH2CH2CH3, d; R2 = C(O)CH3, e; R2 = CO2Me, f; R2 = H.
Table 1. Antibacterial activities of the synthesized mansonone F analogs against MRSAs
Compound
R1
R2
MIC50 (lg/ml)
MIC90 (lg/ml)
Vancomycin
2
2
1 (Mansonone F)
8e
CH3
H
CH2CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
2
8
4
8
14a
14b
14d
8a
8
16
4
CH2CH2CH3
CH(CH3)2
CH2(CH2)2CH3
CH2(CH2)3CH3
CH2CH2CH(CH3)2
CH2(CH2)4CH3
OCH3
1
4
16
0.5
8
0.5
4
8b
O
O
R1
14c
8c
8
16
16
8
8
O
8d
14e
8
16
R2
CO2CH3
16
19f
19a
19b
19c
20
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
Br
8
8
16
16
CH2CH3
CH2CH2CH3
CH2Br
COCH3
CO2CH3
16
4
>32
8
16
16
16
16
32
19d
19e
32
21
H
H
>32
>32
The clinical isolates were obtained from Seoul National University Hospitals in Seoul, Korea.
potent anti-MRSA activities compared with mansonone
F (1). In particular, the 6-n-butylmansonone F (8a)
exhibited 0.5 lg/ml of MIC90, which is fourfold potent
than that of vancomycin and it turned out to be the
most potent analog among the C6-analog series. Con-
trary to our expectations, neither the electron-donating
group (8d) nor the electron-withdrawing one (14e) at
C6 enhanced the anti-MRSA activities. However, the
lipophilicity of the C6 substituents seems quite impor-
tant, and the butyl substituent is likely to impose the
optimal length of the C6 alkyl chain.
anti-MRSA activities. The analogs 19a, 19d, and 19e
possessing the electron-withdrawing substituents at C9
such as bromide, acetyl or methoxycarbonyl group were
disappointingly less potent than the parent mansonone
F (1). The 9-bromomethyl analog 20 exhibited only
16 lg/ml of MIC90 and the 6,9-demethylmansonone F
(21) showed no anti-MRSA activities up to 32 lg/ml.
The antibacterial activity of the 6-butylmansonone F
(8a) was further examined against additional MRSAs
and other Gram-positive strains. As shown in Table 2,
the 6-butylmansonone F (8a) exhibited more potent
The C9 substituents were anticipated to provide signifi-
cant effects on the anti-MRSA activities because they
are adjacent to quinone moiety, which proved to be cru-
cial for the anti-MRSA activity of the mansonone F in
the preliminary studies.5c However, the C9 alkyl substit-
uents of the analogs 19b, 19c, and 19f have little effect on
antibacterial activities than mansonone
vancomycin.
F
and
A series of the C6 and C9 mansonone F analogs were
synthesized and their antibacterial activities were evalu-
ated for the investigation of the substituent effects on

Y.-G. Suh et al. / Bioorg. Med. Chem. Lett. 16 (2006) 142–145
Table 2. Antibacterial activities of 8a against MRSA and Gram-positive strains
145
Strains
MIC (lg/ml)
Mansonone F
8a
Vancomycin
1
2
B. subtilis ATCC 6633
B. cereus ATCC 27348
S. aureus ATCC 25923
S. aureus ATCC 6538P
S. epidermidis ATCC12228
K. pneumoniae ATCC10031
S. aureus TMS 33
2
0.5
1
0.5
4
4
3
1
0.25
0.25
0.25
2
8
4
4
1
5
0.5
8
8
>32
6
7
8
0.5
4
8
4
4
4
1
4
8
M. luteus ATCC 9341
S. aureus ATCC 29213
M. luteus ATCC 10240
S. aureus TMS 64
1
0.25
0.25
0.25
0.25
0.25
0.25
9
4
10
11
12
13
1
8
S. aureus TMS 417
S. aureus Smith
4
4
The clinical isolates were obtained from Seoul National University Hospitals in Seoul, Korea.
5. (a) Shin, D.-Y.; Kim, H.-S.; Min, K.-H.; Hyun, S.-S.;
Kim, S.-A.; Huh, H.; Choi, E.-C.; Choi, Y.-H.; Kim, J.;
Choi, S.-H.; Kim, W.-B.; Suh, Y.-G. Chem. Pharm. Bull.
2000, 48; (b) Suh, Y.-G.; Shin, D.-Y.; Min, K.-H.; Hyun,
S.-S.; Jung, J.-K.; Seo, S.-Y. Chem. Commun. 2000, 1203;
(c) Shin, D.-Y.; Kim, S. N.; Chae, J.-H.; Hyun, S.-S.; Seo,
S.-Y.; Lee, Y.-S.; Lee, K.-O.; Kim, S.-H.; Lee, Y.-S.;
Jeong, J. M.; Choi, N.-S.; Suh, Y. G. Bioorg. Med. Chem.
Lett. 2004, 14, 4519.
anti-MRSA activities. A variety of the formidable
mansonone F analogs were synthesized by the palladi-
um-catalyzed reaction of the C6-triflate and the C9-bro-
mide. The quantitative structure–activity relationships
of mansonone F were established via our intensive sys-
tematic studies on the antibacterial activities of C6 and
C9 mansonone F analogs. The steric effect (lipophilicity)
of the substituents turned out to be more important than
the electronic effect. In particular, the 6-butylmanso-
none F (8a), which is fourfold potent than vancomycin,
was identified as a new candidate for MRSA therapy.
Currently, the optimization of 8a is in progress and
the successful result will be reported in due course.
6. Zimmer, H.; Lankin, D. C.; Horgan, S. W. Chem. Rev.
1971, 71, 229.
7. Pd(0) catalyzed reaction conditions: Pd(PPh3)4,
Bu3SnCHCH2 (for 14a), Bu3SnCH2CHCH2 (for 14b) or
Bu3SnCH2CHC(CH3)2 (for 14c), LiCl, DTBMP, DMF,
98 °C, 90–91%; Pd(OAc)2, DPPF, (CH3)2CHMgCl, tolu-
ene, rt, 80% for 14d; Pd(OAc)2, DPPF, CO(g), MeOH,
Et3N, THF, 81% for 14e.
Acknowledgment
8. Pd(0) catalyzed reaction conditions: Pd(PPh3)4,
Bu3SnCHCH2, DTBMP, THF, reflux, 78% for 17b;
Pd(PPh3)4, Bu3SnCH2CHCH2, DTBMP, THF, reflux,
81% for 17c; Pd(PPh3)4, Bu3SnC(OCH2CH3)CH2, tolu-
ene, 80–100 °C, 60% for 17d; Pd(OAc)2, DPPF, CO(g),
MeOH, Et3N, DMF, 60 °C, 80% for 17e.
This research work was supported by the grant from
Center for Bioactive Molecular Hybrids, Yonsei
University.
9. Bacterial strains; Clinical isolates were obtained from
hospitals in Seoul, Korea, between 1997 and 1999 and
were stored at À70 °C until use Choi, K. H.; Hong, J. S.;
Kim, S. K.; Lee, D. K.; Yoon, S. J.; Choi, E. C. J.
Antimicrob. Chemother. 1997, 39, 509.
10. MICs were determined by an agar dilution method with
Mueller–Hinton agar (MHA, Difco Laboratories, Detroit,
MI) following the National Committee for Clinical
Laboratory Standards (NCCLS) procedure. The detailed
procedure is described in the Ref. 5a.
References and notes
1. Cafferkey, M. T. Methicillin-Resistant Staphylococcus
aureus; Marcel Dekker Inc.: New York, 1992.
2. Allington, D. R.; Rivey, M. P. Clin. Ther. 2001, 23, 24.
3. Barbachyn, M. R.; Ford, C. W. Angew. Chem., Int. Ed.
2003, 42, 2010.
4. Boger, D. L. Med. Res. Rev. 2001, 21, 356.