Isothiazolopyridones: Synthesis, structure, and biological activity of a new class of antibacterial agents

Article abstract of DOI:10.1021/jm051066d

We report the syntheses of first-generation derivatives of isothiazolopyridones and their in vitro evaluation as antibacterial agents. These compounds, containing a novel heterocyclic nucleus composed of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the quinolizin-4-one), were prepared using a sequence of seven synthetic transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-2,4a- diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray diffraction. The prepared derivatives of desfluoroisothiazolopyridones exhibited (a) antibacterial activity against Gram-negative and Gram-positive organisms, (b) inhibitory activities against DNA gyrase and topoisomerase IV, and (c) no inhibitory activity against human topoisomerase II.

Full text of DOI:10.1021/jm051066d

J. Med. Chem. 2006, 49, 39-42
39
Isothiazolopyridones: Synthesis, Structure, and
Biological Activity of a New Class of
Antibacterial Agents
Jason A. Wiles,*,† Akihiro Hashimoto,† Jane A. Thanassi,†
Jijun Cheng,† Christopher D. Incarvito,‡ Milind Deshpande,†
Michael J. Pucci,† and Barton J. Bradbury†
Achillion Pharmaceuticals, Inc., 300 George Street,
New HaVen, Connecticut 06511-6653, and
X-ray Crystallographic Facility, Department of Chemistry,
Yale UniVersity, P.O. Box 208107,
New HaVen, Connecticut 06520-8107
ReceiVed October 21, 2005
Figure 1. Structurally related antibacterial agents.
novel molecules that combine a ring-fused isothiazolone with
a 2-pyridone heterocycle: first-generation isothiazolopyridones
(ITPs).
Abstract: We report the syntheses of first-generation derivatives of
isothiazolopyridones and their in vitro evaluation as antibacterial agents.
These compounds, containing a novel heterocyclic nucleus composed
of an isothiazolone fused to a quinolizin-4-one (at C-2 and C-3 of the
quinolizin-4-one), were prepared using a sequence of seven synthetic
transformations. The solid-state structure of 7-chloro-9-ethyl-1-thia-
2,4a-diazacyclopenta[b]naphthalene-3,4-dione was determined by X-ray
diffraction. The prepared derivatives of desfluoroisothiazolopyridones
exhibited (a) antibacterial activity against Gram-negative and Gram-
positive organisms, (b) inhibitory activities against DNA gyrase and
topoisomerase IV, and (c) no inhibitory activity against human
topoisomerase II.
We designed our synthetic pathway to yield an intermediate
compound having the novel ITP ring system with a leaving
group (i.e., a halide) at C-7. We considered this approach to
allow introduction of chemical diversity during the last step of
the synthetic process via nucleophilic substitution of the labile
group at C-7 with desired aminessa classical approach for the
related quinolones to efficiently produce analogues for biological
evaluation. Installation of a halide at C-7 also presents the
opportunity to prepare analogues containing carbon-linked
pendant groups via palladium-catalyzed cross-coupling meth-
odologies.
Fluorinated quinolones (fluoroquinolones) are an important
class of broad-spectrum antibacterial agents that operate bac-
tericidally by inhibiting DNA gyrase1,2 (bacterial topoisomerase
II, the classical target) and topoisomerase IV3 (a more recently
recognized target, important particularly in Gram-positive
pathogens).4 Despite more than four decades of intensive
investigation of quinolones, the 4-pyridone-3-carboxylic acid
structure (Figure 1) remains a common feature of most potent
inhibitors of DNA gyrase and topoisomerase IV. Positions C-3
and C-4 (the â-keto acid group collectively) are considered
necessary for the binding of quinolones to DNA gyrase in the
ternary complex.5 Substitution at the 3-position is generally
deleterious, although exceptions have been described. Replace-
ment of the 3-carboxylic acid group of quinolones with isosteres
such as sulfonic acid, acetic acid, hydroxamic acid, phosphoric
acid, and sulfonamide resulted in reduced antibacterial activi-
ties.6 One successful strategy for replacement of the 3-carboxylic
acid group with retained (or enhanced) antibacterial activity
employed a ring-fused isothiazolone group7 (Figure 1, isothia-
zoloquinolone). These fluorinated isothiazoloquinolones (ITQs)
exhibited in vitro antibacterial activity and inhibition of DNA
gyrase that were superior to their 3-carboxylic acid counterparts
(parent quinolones).8,9 More recently, 2-pyridones10 (quinolizin-
4-ones)sbioisosteres of quinolones where the nitrogen atom of
the quinolone core is interchanged with the bridgehead carbon
atom (Figure 1)shave emerged as outstanding broad-spectrum
antibacterial agents that are potent against organisms that are
resistant to many of the clinically utilized fluoroquinolones.11
Here, we report the syntheses and antibacterial evaluation of
The synthesis of ITPs began with low-temperature lithiation
of 4-chloro-2-picoline with lithium diisopropylamide (LDA)
followed by reaction of the generated lithium anion with ethyl
iodide to give propylpyridine 210 in 83% yield (Scheme 1). The
success of the synthesis of ITPs relied on the following key
steps that involved formation of quinolizinone 4 having sulfur
at C-2. Reaction of ketene dithioacetal 1a12 (generated by
successive reaction of diethyl malonate with sodium hydride,
carbon disulfide, and methyl iodide) with the lithium anion of
2 (generated at low temperature using LDA as base) effected
substitution of one of the thiomethyl units of 1a to generate 3a
via a Michael addition-elimination process. Subsequent ring-
closure of the Michael adduct 3a at 120 °C in solutions of
dimethyl sulfoxide (DMSO) furnished quinolizinone 4a in 47%
yield (based on 2). Further synthetic elaboration of the quino-
lizinone core, namely introduction of the fused isothiazolone
ring, presented a challenge. There are mild methods known for
preparing fused isothiazolones (1,2-benzisothiazol-3(2H)-ones)
from frameworks consisting of either a 2-mercaptobenzoic acid13
or a 2-mercaptobenzoate14 moiety. Our initial approach to
prepare this necessary scaffold was manipulation of the me-
thylated thiol 4a using a two-step process:14 first, oxidation of
methyl thioether 4a with m-chloroperbenzoic acid (m-CPBA)
to give the corresponding sulfoxide and, second, displacement
of the sulfinyl group of this sulfoxide with sodium hydrosulfide.
Reaction of 4a with m-CPBA in methylene chloride at room
temperature generated sulfoxide 5 in 88% yield; however,
reaction of 5 with sodium hydrosulfide did not effect displace-
ment of the sulfinyl group to give 6, but rather, effected only
displacement of the chloride at C-7. The necessity of having a
chloride at C-7 of the intermediate ITP for later amination
* To whom correspondence should be addressed. Phone: 203-624-7000.
Fax: 203-752-5454. E-mail: jwiles@achillion.com.
† Achillion Pharmaceuticals.
‡ Yale University.
10.1021/jm051066d CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/13/2005

40 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1
Letters
Scheme 1a
a Reagents and conditions: (a) NaH (2 equiv), DMF, 0 °C, 15-30 min,
then CS2 (2-3 equiv), 0 °C f rt, 1 h, then added alkyl halide (2-5 equiv),
rt, 15 h, 69-85%; (b) LDA (1.1 equiv), THF, -78 °C, 30 min, then EtI,
-78 f -30 °C, 1.5 h, 83%; (c) LDA (1.1 equiv), THF, -78 °C, 1.5 h,
then added 1 (1 equiv), -78 f -15 °C f rt, 2.5-4 h; (d) DMSO, 120 °C,
5.5-42 h, 24-47% (two steps); (e) m-CPBA (∼1.1 equiv), CH2Cl2, rt, 1
h, 88%; (f) TFA/anisole, 40 °C, 23 h; (g) hydroxylamine-O-sulfonic acid
(4 equiv), NaHCO3 (10 equiv), THF/H2O, 79% (two steps).
Figure 2. The solid-state structure of 7 as determined by X-ray
diffraction. ORTEP view showing the atom-labeling scheme with
thermal ellipsoids drawn at 30% probability (top) and view of hydrogen-
bonded chains along the crystallographic b-axis (bottom). Selected bond
lengths (Å) and angles (deg): S(1)-C(7), 1.7264(18); S(1)-N(2),
1.6913(16); N(2)-C(10), 1.377(2); O(2)-C(10), 1.227(2); C(8)-C(10),
1.466(2); C(8)-C(9), 1.412(3); O(1)-C(9), 1.231(2); N(1)-C(9),
1.449(2); C(8)-C(7)-S(1), 111.70(13); N(2)-S(1)-C(7), 90.82(8);
C(10)-N(2)-S(1), 116.43(13); N(2)-C(10)-C(8), 107.91(16); C(7)-
C(8)-C(10), 113.06(16).
reactions precluded the use of this method employing sodium
hydrosulfide. Our alternative strategy was replacement of the
methyl group of 4a with a protecting group that is susceptible
to cleavage under mild conditions (nonnucleophilic nor nonre-
ductive). We chose the 4-methoxybenzyl group for this purpose
because it is cleaved under acidic conditions15 and because it
was adopted successfully in the synthesis of thio-containing
quinolones.16,17 The 4-methoxybenzyl thioether 4b was prepared
in 24% yield from 2 using the methods described above for the
methyl analogue 4a. Treatment of 4b with trifluoroacetic acid
containing anisole afforded the thio derivative 6. To prevent
oxidative degradation of 6, we reacted this compound directly
(without purification) with hydroxylamine-O-sulfonic acid under
basic conditions to give the desired intermediate 7 in 79% yield
(based on 4b). Extensive 2D NMR experiments established the
proton-carbon and carbon-carbon connectivities within the
pyridone portion of 7, i.e., correlations were observed for all
carbons excluding the juxtaposed isothiazolo carbonyl carbon
(C-3) and quaternary carbon (C-3a). To obtain further structural
information, we labeled 7 with 15N via reaction of 6 with [15N]-
hydroxylamine-O-sulfonic acid.18 The 15N NMR spectrum of
[15N]-7 showed one resonance in the amido region19 at 104.6
ppm, indicating the presence of an isothiazolo moiety. Further-
more, its 13C NMR spectrum suggested that an isothiazolo ring
had formed with one carbon atom proximal to the 15N nucleus,
i.e., the carbonyl resonance at 166.8 ppm was observed as a
doublet (J ) 3.5 Hz), indicating a 15N-2-N/13C-3-C coupling.
An X-ray crystallographic study of a single crystal of 7
confirmed the proposed structure of the novel ITP heterocycle
(Figure 2). The amido hydrogen of the isothiazolo moiety, H(2),
was located from the electron difference map and refined to a
distance of 0.93(2) Å. The NH group was hydrogen bound to
the carbonyl groups of an adjacent molecule with H(2)-O
interatomic distances of 2.01 and 2.48 Å for O(1) and O(2),
respectively. This interaction created infinitely extending chains
of hydrogen-bonded molecules propagating along the crystal-
lographic b-axis. The N(2)-O interatomic distances were 2.92
Å for both O(1) and O(2) of the adjacent molecule and the
N(2)-H(2)-O angles were measured at 166.1 and 109.0 ° for
O(1) and O(2), respectively. In contrast, isothiazol-3-ols (the
hydroxy tautomers of isothiazol-3-ones) form hydrogen-bonded
dimers in the solid state.20
Our final synthetic step was adornment of the ITP nucleus
with traditionally favored nitrogen heterocycles and heteroaro-
matic carbon isosteres21 (Scheme 2). Displacement of the
chloride of 7 with excess (rac)-3-(dimethylamino)pyrrolidine
and piperazine proceeded smoothly under microwave irradiation
(MWI)22 in solutions of DMSO to give the corresponding
nitrogen-coupled ITPs 8a and 8b in 63% and 60% yield,

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 41
Scheme 2a
of their fluoro analogues compared with their respective
desfluoro analogues). We believe that installation of a fluoride
at C-6sgiving second-generation fluoroisothiazolopyridoness
should substantially improve the antibacterial activity of this
class of compounds. This strategy, involving adaptation of the
concise synthetic route described in this report, is the focus of
work underway in our laboratory.
Supporting Information Available: Experimental procedures
and characterization data for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
a Reagents and conditions: (a) amine (6 equiv), DMSO, MWI (120 °C),
5 min, 60-63%; (b) boronic acid (5 equiv), NaHCO3 (15 equiv), Pd(PPh3)4
(15 mol %), DMF/H2O, MWI (110 °C), 15 min, 76-79%.
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E. coli
S. aureus
MIC
compd
MIC
DNA gyrase
Topo IV
CIP
NOR
8a
0.02 (0.05)
0.06 (0.19)
4.0 (11)
0.3
0.6
24
0.25 (0.68)
0.50 (1.6)
8.0-16 (22-45)
16 (48)
2.3
3.5
79
8b
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14
37
8c
8d
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1.0 (2.6)
0.4
0.2
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8.1
6.3
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JM051066D