A new class of phenazines with activity against a chloroquine resistant plasmodium falciparum strain and antimicrobial activity

Article abstract of DOI:10.1021/jm200302d

New phenazines were synthesized by oxygenation of 1- and 2-naphthol with transition metal peroxo complexes and in situ reaction with 1,2-diamines. The title compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum and chloroquine-resistant strains. Phenazines 12, 27, and 28 were most prominent in growth inhibition. In vivo protection against cerebral malaria was observed with the phenazines 11, 12, 20, and 27, whereas partial protection was provided by 19.

Full text of DOI:10.1021/jm200302d

BRIEF ARTICLE
pubs.acs.org/jmc
A New Class of Phenazines with Activity against a Chloroquine
Resistant Plasmodium falciparum Strain and Antimicrobial Activity
Hidayat Hussain,*,† Sabine Specht,‡ Salem R. Sarite,‡ Michael Saeftel,‡ Achim Hoerauf,‡ Barbara Schulz,§
and Karsten Krohn*,†
†Department of Chemistry, University of Paderborn, Warburger Strasse 100, 33098 Paderborn, Germany
‡Institute of Medical Parasitology, University of Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany
§Institute of Microbiology, University of Braunschweig, Spielmannstrasse 7, 38106 Braunschweig, Germany
S Supporting Information
b
ABSTRACT: New phenazines were synthesized by oxygenation of 1- and 2-naphthol with transition metal peroxo complexes and
in situ reaction with 1,2-diamines. The title compounds were evaluated for in vitro antimalarial activity against Plasmodium falciparum
and chloroquine-resistant strains. Phenazines 12, 27, and 28 were most prominent in growth inhibition. In vivo protection against
cerebral malaria was observed with the phenazines 11, 12, 20, and 27, whereas partial protection was provided by 19.
Scheme 1
’ INTRODUCTION
Malaria is still a worldwide problem of public health, affecting
300ꢀ00 million people and causing about 2.5 million deaths
annually, mainly among children less than 5 years old.1 Today,
chloroquine-resistant strains of P. falciparum (and to some extent
of P. vivax) are common in all endemic areas throughout the
world. The high incidence of resistance against chloroquine is the
most important reason for the increasing spread of malaria. New
families of active compounds are needed as well as polyche-
motherapy, associating molecules with independent mechanisms
of action, to decrease the risk of resistance.2 Natural and synthetic
phenazines have attracted considerable attention because of their
interesting biological activities, including broad-spectrum anti-
biotic, antimicrobial, trypanocidal, antihepatitis C viral replica-
tion, and antitumor activities.7 They have also been described as
antipasmodial3 and dual inhibitors of topoisomerases I and II.4
The interesting biological activities and the recent reports as
antiplasmodial agents prompted us to explore the development
of efficient and economical syntheses of new classes of phena-
zines and to investigate their antiplasmodial effects.
the phenazine synthesis. In the following section we describe the
systematic variation of the substitution pattern on the naphtha-
lene and the 1,2-diamine parts to create a large diversity of
different phenazines to be tested in our antimalaria program.
In the first series, differently substituted 2-naphthols (1 and
4ꢀ6) were treated with Mimoun’s oxodiperoxo molybdenum
complex (Mimoun complex, [Mo(O2)2O] Py HMPT) at room
temperature (Scheme 2), analogous to methods developed
previously in our laboratory.5a,b In addition, we investigated
the possibility of an in situ phenazine formation by addition of
o-phenylenediamine after completion of the oxidation process.
TLC analysis showed the rapid transformation of 2-naphthol (1)
to the o-quinone 2 and the Michael adduct 3, followed by in situ
conversion to phenazines 7 and 11, respectively, after addition of
o-phenylenediamine.
Thus, our existing method for the flexible and concise one-step
synthesis of o-quinones was extended to an operationally simple
one-pot phenazine synthesis. The simplest oxidant and the
mildest reaction conditions were possible using the Mimoun
complex, easily prepared in two steps from MoO3.7 The phena-
zines were formed from possible monomeric and “dimeric”
o-quinone intermediates 2 and 3 and could easily be separated by
silica gel chromatography because of the considerable difference in
molecular weight and structural differences. Using this simple
3
3
’ CHEMISTRY
Synthesis of Phenazines from 2-Naphthols. The chemical
basis of our synthesis of new phenazine derivatives was a
discovery made almost 20 years ago by our group.5 Treatment
of phenols such as 2-naphthol (1) with transition metal alkoxides
and tert-butyl hydroperoxide (TBHP) or other oxodiperoxo
complexes such as the Mimoun complex ([Mo(O2)2O] Py -
3
3
HMPT) afforded o-quinones such as 2. However, in the presence
of the transition metal catalysts, the unreacted phenols present in
the mixture immediately reacted with the o-quinones formed to
yield Michael adducts such as 3 (Scheme 1).5a
This kind of “dimerization” was previously also observed by
Wanzlick.6 In the present investigation, the simultaneous forma-
tion of o-quinones 2 and 3 was a welcome increase in diversity in
Received: February 5, 2011
Published: May 18, 2011
r
2011 American Chemical Society
4913
dx.doi.org/10.1021/jm200302d J. Med. Chem. 2011, 54, 4913–4917
|

Journal of Medicinal Chemistry
BRIEF ARTICLE
Scheme 2a
Scheme 4a
a Reagents and conditions: (a) 2,3-diaminopropionic acid, MeOH, reflux,
5 h; (b) aminoguanidine, MeOH, reflux, 4 h; (c) cyclohexanone, CH3-
CO2NH4, reflux, 1 h; (d) NH2OH.HCl, EtOH, room temp, 24 h; (e) 5,6-
diamino-2-mercaptopyrimidin-4-ol, AcOH, 35 °C, 8 h.
a Reagents and conditions: (a) [Mo(O2)2O] Py HMPT, room temp,
20 h, then C6H4(NH2)2, AcOH, room temp, 12 h.
3
3
Scheme 3
Scheme 5a
a Reagents and conditions: (a) Ti(O-i-Pr)4/TBHP, ꢀ6 °C, 7 h.
Scheme 6
Table 1. One Pot Synthesis of Phenazines 17ꢀ20
entry R1 R2 R3 amine minor phenazine (%) major phenazine (%)
1
2
Cl Cl CH 15
16
17 (9)
18 (7)
19 (82)
20 (78)
H
H N
procedure, we prepared a number of new types of the two classes
of phenazines, 7ꢀ10 derived from monomeric, and 11ꢀ14 from
the “dimeric” o-quinones by varying the substituents R1ꢀR3 on
the 2-naphthols (1, 4ꢀ6, Scheme 2).
To introduce further diversity in the synthesis of substituted
phenazines, the 1,2-diamine part was varied and 4,5-dichloro-
benzene-1,2-diamine (15) and pyridine-2,3-diamine (16) were
used for condensation with the initially formed o-quinones 2 and
3 (Scheme 3). The yields and conditions are listed in Table 1.
Next, nonaromatic 1,2-diamines are used to condense with
o-quinone 3. For this purpose, the o-quinone 3 was prepared
(59%) by our methodology,5a,b using the transition metal complex
Ti(O-i-Pr)4 with tert-butyl hydroperoxide (TBHP). Condensation
of the Michael adduct 3 with 2,3-diaminopropionic acid was
accompanied by spontaneous aromatization8 to yield the desired
21 in 67% yield (Scheme 4). Similarly, the 1,2,4-triazine 22 was
prepared in 73% yield by reaction of 3 with aminoguanidine in
ethanol.9 The conversion of o-quinone 3 to the corresponding 2,2-
spirocyclohexane derivative 23 occurred in 77% yield by refluxing in
acetic acid with cyclohexanone in the presence of excess NH4OAc.10
The open chain 1,2-dioxime 24 was readily prepared by reaction of 3
with hydroxylamine hydrochloride in 83% yield. Finally, the con-
densation of a heterocyclic ring to a phenazine was achieved by
condensation of o-quinone 3 with 5,6-diamino-2-mercaptopyrimi-
din-4-ol in the presence of acetic acid to afford 25 in 69% yield.
Synthesis of Phenazines from 1-Naphthol. Further diver-
sity was created by replacing the starting 2-naphthol (1)
with 1-naphthol (26) in the oxygenation with [Mo(O2)2O]
3
Py HMPT. In this reaction, apparently the same o-naphthoquinone
3
4914
dx.doi.org/10.1021/jm200302d |J. Med. Chem. 2011, 54, 4913–4917

Journal of Medicinal Chemistry
BRIEF ARTICLE
Table 2. One Pot Synthesis of Phenazines 7, 17, 18, and 27ꢀ29
entry
R1
R2
R3
amine
minor phenazine (%)
major phenazine (%)
1
2
3
H
Cl
H
H
Cl
H
CH
CH
N
o-phenylenediamine
7 (9)
27 (82)
28 (81)
29 (81)
4,5-dichlorobenzene-1,2-diamine (15)
pyridine-2,3-diamine (16)
17 (7)
18 (7)
Scheme 7a
Scheme 8a
a Reagents and conditions: (a) 2,3-diaminopropionic acid, MeOH, reflux,
5 h; (b) 5,6-diamino-2-mercaptopyrimidin-4-ol, AcOH, 35 °C, 8 h.
(2) was initially formed in the oxygenation of 26. However, a new
regioisomer 30 (Scheme 5) by addition to the o-naphthoquinone 3
was formed, generated from 2-naphthol (1).
In the in situ condensation reaction of the reaction mixture
from the oxygenation with [Mo(O2)2O] Py HMPT and the
3
3
aromatic diamines o-phenylenediamine, 15, and 16, the same
monomeric phenazines 7, 17, and 18 and the “dimeric”
phenazines 27ꢀ29 were formed as shown in Schemes 2 and
3 (Scheme 6, Table 2).
In the next series, the o-quinone 30 (61%) prepared in the
oxygenation of 1-naphthol (26) using the transition metal
complex Ti(O-i-Pr)4 with TBHP as described above, was reacted
with 5,6-diamino-2-mercaptopyrimidin-4-ol in the presence of
acetic acid to afford the corresponding phenazine 31 in 69% yield
(Scheme 7). Finally, condensation of the Michael adduct 30 with
2,3-diaminopropionic acid was accompanied by spontaneous
aromatization to yield the desired compound 32 in 68% yield.
In a final series, two known o-quinones 34 and 36 were used
as starting material to prepare the phenazines 33 and 37
(Scheme 8). The bisoxime 35, available from 34, was also included
in the test series. In a previous investigation we studied the
oxygenation of the anthracenol 38 to the corresponding o-anthra-
quinone 39 with[Mo(O2)2O] Py HMPT. The dimerization of 39
a Reagents and conditions: (a) C6H4(NH2)2, AcOH, 35 °C, 8 h; (b) HO-
NH2.HCl, EtOH, room temp, 24 h; (c) BBr3, CH2Cl2, ꢀ78 °C, 5 min.
Figures 1 and 2). These results encouraged us to prepare a
chemical library. Tables 3 and 4 give the IC50 values for derivatives
in which the “dimeric” 1,2-naphthoquinone core structure of 11
and 27 was unchanged, and only the quinoxaline region of the
molecule was modified. The nature of the substituents in this part
of the molecule (19 and 28) or change of the quinoxaline part to
pyridino[2,3-b]pyrazine (20 and 29), pyrazine (21 and 32),
pyrimidine (25 and 31), and 1,2,4-triazine (22) proved to be very
important for antimalarial activity. In general, the data show that
any structural deviation in this region, i.e., from quinoxaline to
pyrazine, pyrimidine, and 1,2,4-triazine, results in a loss of anti-
malarial activity. A comparison of the IC50 of compounds 27 and
29 clearly confirms the importance of change of the quinoxaline
part to the pyridino[2,3-b]pyrazine part in contributing to anti-
malarial activity. It suggests that the nitrogen atom in pyridine is
required for activity. Interestingly, comparison of the two phena-
zine regioisomers (11 and 27) with IC50 of 4.11 and 0.88 μM
(Tables 3 and 4), respectively, showed a difference of a factor of 4.
3
3
occurred by treatment with BBr3 to afford 40 in 44% yield. This
dimeric o-anthraquinone 40 was converted to the bis-phenazine 41
by treatment with o-phenylenediamine in the presence of AcOH.
’ STRUCTUREꢀACTIVITY RELATIONSHIPS (SARS)
The antiplasmodial activities of a selection representing the
chemical diversity of the synthesized compounds were tested in an
in vitro malaria assay against a chloroquine-sensitive strain
of P. falciparum, strain NF54, according to previously descri-
bed protocols of Moloney11 and Trager.12 Phenazines 11 and
27 showed significant antiplasmodial activities (Tables 3 and 4,
4915
dx.doi.org/10.1021/jm200302d |J. Med. Chem. 2011, 54, 4913–4917

Journal of Medicinal Chemistry
BRIEF ARTICLE
Table 3. In Vitro Activity (% Parasitemia ( Standard Error of the Mean) of 11, 12, 19, 20, 24, 27, and 28 against Plasmodium
falciparum NF54 at a Given Concentrationa
day
untreated
chloro-quine 0, 032 μM 11, 20 μMb 12, 10 μMb 19, 20 μMb 20, 20 μMb 24, 10 μMb
27, 3 μMb
28, 3 μMb
1
2
3
4
0.97 ( 0.10
1.20 ( 0.12
2.55 ( 0.21
2.73 ( 0.16
0.06 ( 0.003
0.00 ( 0
0.23 ( 0.05 0.14 ( 0.02 0.14 ( 0.02 0.04 ( 0.01 0.94 ( 0.10 0.27 ( 0.04 0.17 ( 0.03
0.07 ( 0.01 0.01 ( 0.01 0.01 ( 0.01 0.00 ( 0.00 0.20 ( 0.04 0.11 ( 0.02 0.15 ( 0.02
0.02 ( 0.01 0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00 0.04 ( 0.02 0.02 ( 0.01 0.00 ( 0.00
0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00 0.00 ( 0.00
0.00 ( 0
0.00 ( 0
IC50 (72 h)
0.012 μM (24 h)
4.11 μM
0.64 μM
5.05 μM
5.23 μM
3.73 μM
0.88 μM
0.51 μM
a Parasitemia on day 0 was 0.45 ( 0.05 for all groups. b Concentration of compound.
Table 4. In Vitro Activity of Phenazines Based on 3 and 30
against the Plasmodium falciparum Strain NF54
Figure 1. Survival of P. berghei infected mice treated with 11, 12, 19, 20,
and 27.
’ IN VIVO PROTECTION AGAINST CEREBRAL MALARIA
OF MICE INFECTED WITH P. BERGHEI ANKA
We further investigated whether the substances with higher
in vitro activity could protect C57BL/6 mice against cere-
bral malaria. Infection of C57BL/6 mice causes cerebral malaria
in 80ꢀ100% of infected mice. Substances were given ip from day
3 to day 9 after infection with P. berghei ANKA. We found that
in vivo protection against cerebral malaria was observed with
phenazine 20, whereas partial protection was provided by 11 and
19 (Figure 1). However, these substances did not clear the
parasites from the blood as did treatment with chloroquine, and
therefore, animals died of anemia after day 10 (Figure 2). Only
12 was able to reduce parasitemia significantly during days 5ꢀ7.
This indicates that other inhibitory effects might play a role, as
phenazines have been described as dual inhibitors of topoisome-
rases I and II and also are known to inhibit T cell proliferation
and interfere with oxidative burst.
In the next series, 12ꢀ14, the quinoxaline part of 11 was kept
constant, and only the right-hand side of the core structure was
modified by different substituents. The bromine substituted
phenazine 12 showed a more than 6-fold activity improvement
compared to 11. On the other hand, a substituent like CO2H
(13) and SO3H (14) decreased the activity (data not shown).
The dimeric 1,2-naphthoquinones 3 and 30 showed weak
antiplasmodial activity compared to 24, the oxime of 3, confirm-
ing the importance of nitrogen incorporation into the 1,2-
naphthoquinones. Acenaphthylene-1,2-dione, phenanthrene-
9,10-dione, and the dimeric quinone 40 were also converted to
the phenazines 33, 37, and 41, respectively, and did not show
significant antiplasmodial activity (data not shown).
In summary, the data indicate that substances from three out
of seven schemes of the phenazine class of compounds had
in vitro inhibitory effects against Plasmodium falciparum. The
phenazines 12, 27, and 28 were most prominent in growth
inhibition with IC50 ranging from 0.51 to 0.88 μM. The phenazine
11 and substitution in the phenylenediamine (19, 20), as well as
the related bisoxime 24, showed antiplasmodial activity but with
less efficiency.
In summary, structurally new antimalarial lead structures
chemically derived from simple naphthols are presented. It is
noteworthy that from the selected compounds, only the pseu-
dodimers were active, and only the phenazines, the azaphena-
zines, and the dichlorophenazines.
’ EXPERIMENTAL SECTION
Materials and Methods. For general methods and instrumenta-
tion see ref 13. In the 13C NMR spectra, some of the signals are
overlapping. The purity of tested samples was determined by elemental
analysis, and purity of all tested samples was more than 95%.
4916
dx.doi.org/10.1021/jm200302d |J. Med. Chem. 2011, 54, 4913–4917

Journal of Medicinal Chemistry
BRIEF ARTICLE
’ AUTHOR INFORMATION
Corresponding Author
*For H.H.: phone, (þ49)-5251-602172; fax, (þ49)-5251-603245;
e-mail, Hidayat110@gmail.com. For K.K.: phone, þ 5312198083;
fax, þ 5312259107; e-mail, k.krohn@uni-paderborn.de.
’ ABBREVIATIONS USED
CQ, chloroquine; TBHP, tert-butyl hydroperoxide; HMPT, hex-
amethylphosphotriamide; TLC, thin layer chromatography;
AcOH, acetic acid; Py, pyridine; MeoH, methanol
’ REFERENCES
(1) The World Health Report 1997; World Health Organization:
Geneva, 1997.
Figure 2. Parasitemia of mice infected with P. berghei and treated with
11, 12, 19, 20, and 27.
(2) Andrade-Neto, V. F.; Goulart, M. O. F.; Filho, J. F. S.; da Silva,
M. J.; Pinto, M. C. F. R.; Pinto, A. V.;Zalis, M. G.; Carvalhoa, L. H.; Krettli,
A. U. Antimalarial activity of phenazines from lapachol, β-lapachone and
its derivatives against Plasmodium falciparum in vitro and Plasmodium
berghei in vivo. Bioorg. Med. Chem. Lett. 2004, 14, 1145–1149.
(3) Makgatho, M. E.; Anderson, R.; O’Sullivan, J. F.; Egan, T. J.;
Freese, J. A.; Cornelius, N.; van Rensburg, C. E. J. Tetramethylpiper-
idine-substituted phenazines as novel anti-plasmodial agents. Drug Dev.
Res. 2000, 50, 195–202.
General Procedure for the Synthesis of Phenazines
(7ꢀ14). A solution of the respective 2-naphthol (1 mmol) in CH2Cl2
(10 mL) was treated with 6.01 g (2 mmol) of [Mo(O2)2O] Py HMPT
3
3
and stirred for 20 h at 20 °C. Then 10 mL of acetic acid and 6 g (4 mmol)
of the respective 1,2-diamine were added, and stirring was continued for
12 h at 20 °C. The organic layer was washed with NaHCO3, dried over
Na2SO4, and concentrated. The purification was carried out by flash
column chromatography, eluting with n-hexane/ethyl acetate. The
resulting residue was purified by column chromatography on silica gel,
eluting with n-hexane/EtOAc (90/10) to yield pure phenazines.
Benzo[a]phenazine (7). Yellow crystals, mp 230ꢀ233 °C. IR
νmax (CHCl3): 1707, 1434, 1363, 750, 700. 1H NMR (500 MHz,
CDCl3) δ 9.48 (1H, dd, J = 8.0, 1.5 Hz), 8.45 (1H, dd, J = 8.0, 1.5
Hz), 8.40 (dd, J = 8.0, 1.5 Hz, 1H), 8.09 (d, J = 8.0, 1H), 7.95 (m, 1H, m,
3H), 7.85 (m, 3H). HREIMS m/z C16H10N2 [M]þ calcd 230.0844,
found 230.0834. Anal. (C16H10N2) C, H, N.
3-Bromobenzo[a]phenazine (8). Yellow crystals, mp 290ꢀ
293 °C. IR νmax (CHCl3): 1707, 1434, 1363, 750, 700. 1H NMR
(500 MHz, CDCl3) δ 9.26 (1H, d, J = 8.0 Hz), 8.34 (1H, dd,
J = 8.0, 1.5 Hz), 8.28 (1H, dd, J = 8.0, 1.5 Hz), 8.05 (1H, d, J =
2.0 Hz), 8.01 (1H, s), 7.88 (4H, m). HREIMS m/z C16H9BrN2 [M]þ
calcd 307.9949, found 307.9929. Anal. (C16H9BrN2) C, H, N.
Benzo[a]phenazine-6-carboxylic Acid (9). Yellow crystals, mp
245ꢀ247 °C. IR νmax (CHCl3): 1700, 1430, 1363, 750, 700. 1H NMR
(500 MHz, CDCl3) δ 9.40 (1H, dd, J = 8.0, 1.5 Hz), 8.41 (1H, dd, J = 8.0,
1.5 Hz), 8.31 (dd, J = 8.0, 1.5 Hz, 1H), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 8.09
(s, J = 8.0, 1H), 7.92 (m, 2H), 7.85 (m, 2H). HREIMS m/z C17H10N2O2
[M]þ calcd 274.0742, found 274.0735. Anal. (C17H10N2O2) C, H, N.
Benzo[a]phenazine-3,6-disulfonic Acid (10). Yellow crystals,
mp 277ꢀ278 °C. IR νmax (CHCl3): 2930, 1700, 1430, 1363, 750, 700.
1H NMR (500 MHz, CDCl3) δ 9.39 (1H, dd, J = 8.0, 1.5 Hz), 8.40 (1H,
d, J = 1.5 Hz), 8.15 (dd, J = 8.0, 1.5 Hz, 1H), 8.01 (s, J = 8.0, 1H), 7.92
(m, 2H), 7.85 (m, 2H). HREIMS m/z C16H10N2O6S2 [M]þ calcd
389.998, found 389.990. Anal. (C16H10N2O6S2) C, H, N.
(4) Laursen, J. B.; Nielsen, J. Phenazine natural products: biosynthesis,
synthetic analogues, and biological activity. Chem. Rev. 2004, 104, 1663–1685.
(5) (a) Krohn, K.; Rieger, H.; Khanbabaee, K. A new synthesis of
ortho-quinones by transition-metal-mediated oxygenation of phenols
with tert-butylhydroperoxide and the Mimoun oxodiperoxo molybde-
num complex [Mo(O2)2O] Py HMPT. Chem. Ber. 1989, 122, 2323–
3
3
2330. (b) Krohn, K. Zirconium alkoxide catalyzed oxidation of phenols,
alcohols, and amines. Synthesis 1997, 1115–1127. (c) Adam, H.;
Khanbabaee, K.; Krohn, K.; K€upke, J.; Rieger, H.; Steingr€over, K.;
Vinke, I. Transition-Metal Alkoxide-Catalyzed Oxidation of Phenols,
Alcohols, and Amines with tert-Butyl Hydroperoxide. In Peroxide
Chemistry, Mechanistic and Preparative Aspects of Oxygen Transfer; Adam,
W., Ed.; Wiley-VCH: Weinheim, Germany, 2000; pp 469ꢀ493.
(6) Wanzlick, H.-W. Synthesen mit naszierenden Chinonen. Angew.
Chem. 1964, 76, 313–319. Angew. Chem., Int. Ed. Engl. 1964, 3, 401.
(7) Mimoun, H.; Serre de Roch, I.; Sajus, L. Covalent peroxide
complexes of molybdenum and tungsten with organic bases. Bull. Soc.
Chim. Fr. 1969, 1481–1492.
(8) Jones, P.; Villeneuve, G. B.; Fei, C.; DeMarte, J.; Haggarty, A. J.;
Nwe, K. T.; Martin, D. A.; Lebuis, A. M.; Finkelstein, J. M.; Gour-Salin, B. J.;
Chan, T. H.; Leyland-Jones, B. R. Synthesis and structureꢀactivity relation-
ships of 2-pyrazinylcarboxamidobenzoates and β-ionylideneacetamido-
benzoates with retinoidal activity. J. Med. Chem. 1998, 41, 3062–3077.
(9) Jiang, C.-W. Syntheses, characterization and DNA binding of
mono- and diruthenium(II) complexes containing 2,20-bis(1,2,4-
triazino[5,6-f]phenanthren-3-yl)-4,40-bipyridine and 2,20-bipyridine
ligands. Inorg. Chim. Acta 2005, 358, 1231–1236.
(10) Corey, E. J.; Lee, D.-H.; Sarshar, S. Convenient routes to
symmetrical benzils and chiral 1,2-diaryl-l,2-diaminoethanes, useful
controllers and probes for enantioselective synthesis. Tetrahedron:
Asymmetry 1995, 6, 3–6.
(11) Moloney,M.B.;Pawluk,A.R.;Ackland,N.R.Plasmodium falciparum
growth in deep culture. Trans. R. Soc. Trop. Med. Hyg. 1990, 84, 516–518.
(12) Trager, W.; Williams, J. Extracellular (axenic) development in
vitro of the erythrocytic cycle of Plasmodium falciparum. Proc. Natl. Acad.
Sci. U.S.A. 1992, 89, 5351–5355.
(13) Krohn, K.; Gehle, D.; Kamp, O.; van Ree, T. Highly deoxygenated
sugars. II. Synthesis of chiral cyclopentenes via novel carbocyclization of C-4
branched deoxysugars. J. Carbohydr. Chem. 2003, 22, 377–383.
’ ASSOCIATED CONTENT
S
Supporting Information. Synthesis details; elemental
b
analysis data and spectroscopic details of 8, 11ꢀ14, and
17ꢀ41; and antimicrobial activity of 3, 7-14, 21, 23, and 32-
35. This material is available free of charge via the Internet at
http://pubs.acs.org.
4917
dx.doi.org/10.1021/jm200302d |J. Med. Chem. 2011, 54, 4913–4917