Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
Tropical protozoal infections are a significant cause of morbidity and mortality worldwide; four in particular (human African trypanosomiasis (HAT), Chagas disease, cutaneous leishmaniasis, and malaria) have an estimated combined burden of over 87 million disability-adjusted life years. New drugs are needed for each of these diseases. Building on the previous identification of NEU-617 (1) as a potent and nontoxic inhibitor of proliferation for the HAT pathogen (Trypanosoma brucei), we have now tested this class of analogs against other protozoal species: T. cruzi (Chagas disease), Leishmania major (cutaneous leishmaniasis), and Plasmodium falciparum (malaria). Based on hits identified in this screening campaign, we describe the preparation of several replacements for the quinazoline scaffold and report these inhibitors' biological activities against these parasites. In doing this, we have identified several potent proliferation inhibitors for each pathogen, such as 4-((3-chloro-4-((3-fluorobenzyl)oxy)phenyl)amino)-6-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)quinoline-3-carbonitrile (NEU-924, 83) for T. cruzi and N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)-7-(4-((4-methyl-1,4-diazepan-1-yl)sulfonyl)phenyl)cinnolin-4-amine (NEU-1017, 68) for L. major and P. falciparum.
Several tropical diseases
are caused by protozoan parasites transmitted
by insects. Taken together, malaria (caused by Plasmodium species), human African trypanosomiasis (HAT, caused by Trypanosoma brucei), Chagas disease (caused by T.
cruzi), and leishmaniasis (caused by Leishmania species) represent diseases with an estimated combined burden of
over 87 million disability-adjusted life years.[1] While progress has certainly been made toward the discovery
of new hits, much work remains to translate these hits into promising
chemical lead series that may be advanced for drug development.One pragmatic method for launching such programs is “target
repurposing”, wherein inhibitors of human homologues of essential
parasite proteins are assessed for efficacy against parasite cells.[2] We have recently initiated the repurposing of
a variety of kinase inhibitors for parasitic diseases[3−7] and have also described the use of established human phosphodiesterase
inhibitors as starting points for lead discovery.[8]We have described the discovery of NEU-617 (1), a
derivative of the approved humancancer drug lapatinib (2), which acts as a potent, orally bioavailable growth inhibitor of T. brucei that showed a modest effect in a mouse model of
bloodstream infection.[6] We also reported
the association of lapatinib with four trypanosome protein kinases.[9] Based on the close phylogenetic relationship
between the kinomes of the trypanosomatid parasites (T. brucei, T. cruzi, and Leishmania major),[10] we hypothesized that all the pathogens
would be susceptible to these inhibitors. We have therefore tested 1, along with the other analogs synthesized during the course
of our hit-to-lead optimization program, against the two other kinetoplastid
parasites. Based on our previous observation that related chemotypes
show activity against Plasmodium falciparum,[11] we also screened this set of compounds against
cultures of drug-sensitive and drug-resistant strains of malaria.
In doing so, we noted differential structure–activity relationships
for these compounds’ growth inhibitory properties against each
of the parasites, thus launching a multiparasite optimization campaign
from the same lead series.In this paper, we describe these
cross-pathogen assay results and
outline our evaluation of replacements for the quinazoline scaffold
of 1 for each of the parasites. We posit that such a
cross-screening approach can be a highly fruitful method for identification
of new protozoan parasite growth inhibitors.
Results
First,
in order to ascertain antiparasitic activities of our 66
previously reported analogs,[6] we measured
their growth inhibitory activities against T. cruzi (intracellular amastigotes), L. major (promastigote
and intracellular amastigote life stages), and P. falciparum (D6, drug sensitive strain). The structures of the most potent compounds
for each parasite are shown in Figure 1 and
Table 1, and the complete set of screening
data for these is tabulated in the Supporting
Information (Tables S1–S7).
Figure 1
Program progression from 2 to four potent antiparasitic
leads. The quinazoline scaffold is highlighted in blue.
Table 1
Potent Quinazolines Identified via
Multiparasite Cross-Screening
SEM values within 50%. *% inh at
10 μM.
r2 values
>0.75.
Control compounds: T. brucei, suramin; T. cruzi, benznidazole; L. major, amphotericin B; P. falciparum, chloroquine.
Program progression from 2 to four potent antiparasitic
leads. The quinazoline scaffold is highlighted in blue.SEM values within 50%. *% inh at
10 μM.r2 values
>0.75.Control compounds: T. brucei, suramin; T. cruzi, benznidazole; L. major, amphotericin B; P. falciparum, chloroquine.From these
experiments, we observed that 15 morpholinosulfonamide
compounds were identified with activity against L. major promastigotes: seven of these were submicromolar inhibitors and
two were also submicromolar against intracellular amastigotes (the
most relevant life stage for humaninfections of leishmaniasis). The
des-fluoro analog NEU-551 (3) showed the highest activity
against promastigotes (EC50 = 0.50 μM). We initially
tested compounds against T. cruzi at a single concentration
and found that 32 compounds inhibited proliferation >65% at 10
μM
concentrations; of these 32 compounds, the homopiperazinyl sulfonamide-substituted
tail was preferred (NEU-628 (4), EC50 = 0.51
μM). The active compounds against P. falciparum (drug-sensitive D6 strain) all contained a basicnitrogen at the
end of the tail group with NEU-627 (5) being the most
potent with an EC50 of 27 nM. Though we note that the number
of headgroup replacement analogs tested was far smaller and less diverse
than the tail variations, the lapatinib headgroup 3-chloro-4-((3-fluorobenzyl)oxy)aniline
showed optimal potency against all of the parasites, except for both Leishmania life stages.Previous efforts focused on
the “head” (4-benzyloxyanilines)
and “tail” (denoted as R in Figure 1) regions of lapatinib, while maintaining the central quinazoline
scaffold (highlighted in blue in Figure 1).
Thus, we planned a broader evaluation of other bicyclic aromatic replacements
for the quinazoline scaffold that would test the important features
of the chemotype for activity. These scaffold replacements were selected
for exploration of the requisite nitrogen atom positioning in the
heteroaromatic ring (see the heterocycle precursors highlighted in
Figure 2, dihalides 6–9). In addition, the cyanoquinoline and thienopyrimidine scaffolds
(dihalides 10–12) were selected in
order to include other established tyrosine kinase inhibitor chemotypes.[12−15] For a matched exploration of these scaffolds, we elected to maintain
the four permutations of head/tail combinations that displayed the
most potency in each parasite (shown in Figure 1) in the new analogs that we prepared.
Figure 2
Quinazoline core replacements.
Quinazoline core replacements.We first set out to synthesize
the requisite dihalogenated scaffolds
shown in Figure 2. The syntheses of 6- and
7-bromo-4-chloroquinolines 6a and 6b were
carried out via the Gould–Jacobs sequence following previously
reported protocols.[16] A complementary set
of 1-aminoisoquinolines was devised to draw out essential interactions
with either nitrogen of the quinazoline scaffold. Thus, 7a and 7b were synthesized utilizing known transformations.[17−19] The 6-bromo-4-chlorothienopyrimidines 10 and 11 were prepared as previously reported.[20−25] The requisite cyanoquinoline template 12 was prepared
using established protocols similar to that of the 4-chloroquinolines.[26]Though few examples of cinnoline or phthalazine
based kinase inhibitors
exist in the literature,[27−30] we opted to prepare analogues utilizing both heterocycles
to test the required positioning of the two nitrogen atoms on the
scaffold. Preparation of 6-bromo-4-chlorocinnoline8a commenced with the bromination of o-aminoacetophenone 13 followed by diazotization of the amine and in situ cyclization to the 6-bromocinnolin-4(1H)-one 15 (Scheme 1).[31,32] Chlorination in neat POCl3 did not give the expected 8a as the major product. Instead, we observed high conversion
to 4,6-dichlorocinnoline 8b. We hypothesized that this
side reaction occurred via chloride displacement under the acidic
conditions of the reaction (Scheme S1, see Supporting
Information). A 10:1 product ratio of 8a to 8b could be achieved through the use of THF as solvent and
3 equiv of POCl3. The regiomeric 7-bromo-4-chlorocinnoline8c was prepared in a similar fashion starting instead with
the acylation of 3-bromoaniline 16 to 2-amino-4-bromoacetophenone 17, followed by diazotization and chlorination.[33]
Scheme 1
Synthesis of the Dihalocinnoline Core 8
Reagents and conditions: (a)
NBS, CH2Cl2, −10 °C → 23
°C, o.n.; (b) NaNO2, aq. HCl, H2O, 75 °C,
o.n.; (c) POCl3, THF, reflux, 2 h; (d) (i) BCl3, (CH2Cl)2, 0 °C; (ii) AlCl3, CH3CN, 80 °C, o.n.; (iii) aq. HCl, 80 °C,
30 min; (b) NaNO2, aq. HCl, H2O, 75 °C,
o.n.; (c) POCl3, THF, reflux, 2 h.
Synthesis of the Dihalocinnoline Core 8
Reagents and conditions: (a)
NBS, CH2Cl2, −10 °C → 23
°C, o.n.; (b) NaNO2, aq. HCl, H2O, 75 °C,
o.n.; (c) POCl3, THF, reflux, 2 h; (d) (i) BCl3, (CH2Cl)2, 0 °C; (ii) AlCl3, CH3CN, 80 °C, o.n.; (iii) aq. HCl, 80 °C,
30 min; (b) NaNO2, aq. HCl, H2O, 75 °C,
o.n.; (c) POCl3, THF, reflux, 2 h.The 7-bromo-1-chlorophthalazine template 9a was synthesized
as shown in Scheme 2. Aryl bromination of phthalide 19 was carried out in acidic medium with NBS to produce a
separable mixture of 4- and 6-bromophthalide 20. Benzylic
bromination was achieved using a modification of an established procedure,[34] and the resulting dibromides 21a,b were converted to the corresponding bromophthalazinone 22 upon treatment with hydrazine. As with 15, 22a was converted to the dichlorinated side product 9b on treatment with neat POCl3, though dilution
minimized this side reaction. Acetonitrile with 3 equiv of POCl3 provided a >10:1 ratio of the desired chlorination product 9a. The 6-bromo-1-chlorophthalazine scaffold 9c could be synthesized in an identical manner starting with the commercially
available 5-bromophthalide 20b.
Scheme 2
Synthesis of the
Dihalophthalazine Core 9
Reagents
and conditions: (a)
NBS, H2SO4, CF3CO2H, 23
°C, 40 h; (b) NBS, AIBN, CHCl3, reflux, 1 h; (c) N2H4, i-PrOH, reflux, 1.5 h; (d) POCl3, CH3CN, reflux, 3 h.
Synthesis of the
Dihalophthalazine Core 9
Reagents
and conditions: (a)
NBS, H2SO4, CF3CO2H, 23
°C, 40 h; (b) NBS, AIBN, CHCl3, reflux, 1 h; (c) N2H4, i-PrOH, reflux, 1.5 h; (d) POCl3, CH3CN, reflux, 3 h.Amination
of the dihalogenated quinoline, isoquinoline, cyanoquinoline,
and thienopyrimidine scaffolds was carried out by applying methods
similar to those we previously reported (Scheme 3).[6] However, low yields (∼20%)
resulted when these conditions were applied to the cinnoline and phthalazine
templates. Switching the solvent to toluene and using 4 equiv of amine
improved yields to 54–78%. Suzuki couplings using the requisite
boronates and 5–7 mol % Pd(PPh3)4 or
1 mol % Pd(OAc)2 provided the final analogs. Yields of
the cinnoline or phthalazine products were drastically improved by
switching to 2.5 mol % PdCl2(PPh3)2 or 5 mol % Pd(OAc)2 with extended reaction times. A higher
catalyst loading of Pd(OAc)2 was employed in lieu of PdCl2(PPh3)2 in situations where the PPh3O byproduct could not be separated from the products.
Scheme 3
Head and Tail Group Attachments to Quinazoline Core Replacements
See Tables 2 and 3 for product structures. Reagents and
conditions: (a) 1.1 equiv of amine, i-PrOH, reflux, o.n.; (b) 4 equiv
of amine, toluene, reflux, 2.5 h; (c) 4 equiv of amine, toluene, 50
°C, o.n.; (d) ArBpin, Et3N, Pd(OAc)2, 1:1
H2O/EtOH, MW, 120 °C, 1–3 h; (e) ArBpin, Et3N, PdCl2(PPh3)2, 1:1 H2O/EtOH, MW, 120 °C, 1 h; (f) ArBpin, aq. Na2CO3, Pd(PPh3)4, 3:2 glyme/EtOH,
N2, 85 °C, 7–12 h.
Head and Tail Group Attachments to Quinazoline Core Replacements
See Tables 2 and 3 for product structures. Reagents and
conditions: (a) 1.1 equiv of amine, i-PrOH, reflux, o.n.; (b) 4 equiv
of amine, toluene, reflux, 2.5 h; (c) 4 equiv of amine, toluene, 50
°C, o.n.; (d) ArBpin, Et3N, Pd(OAc)2, 1:1
H2O/EtOH, MW, 120 °C, 1–3 h; (e) ArBpin, Et3N, PdCl2(PPh3)2, 1:1 H2O/EtOH, MW, 120 °C, 1 h; (f) ArBpin, aq. Na2CO3, Pd(PPh3)4, 3:2 glyme/EtOH,
N2, 85 °C, 7–12 h.
Table 2
Antiparasitic Activity of Quinoline,
Isoquinoline, Cinnoline, Phthalazine, and 3-Cyanoquinoline Analogs
All SEM values
within 25% unless
noted otherwise. *% inh at 5 μM.
SEM values within 40%.
SEM = 0.89.
n = 1.
All r2 values >0.9 unless noted otherwise.
r2 values
>0.75.
Table 3
Antiparasitic
Activity of Thienopyrimidine
Analogs
All SEM
values within 20% unless
noted otherwise. *% inh at 5 μM.
n = 1.
All r2 values >0.9 unless
noted otherwise.
r2 values
>0.75
With this set of new analogs that are matched to the previously
described antiparasitic agents,[6] we set
out measuring these analogs’ activities against T.
brucei̧, T. cruzi, L. major, and P. falciparum, and counter-screened against
host cells (NIH 3T3 and HepG2 cell lines) using assays that we previously
reported.[7] The HepG2 data is summarized
in Tables 2 and 3. A
small number of compounds showed activity against NIH 3T3 cells; these
are summarized in the Supporting Information, Table S8.All SEM values
within 25% unless
noted otherwise. *% inh at 5 μM.SEM values within 40%.SEM = 0.89.n = 1.All r2 values >0.9 unless noted otherwise.r2 values
>0.75.All SEM
values within 20% unless
noted otherwise. *% inh at 5 μM.n = 1.All r2 values >0.9 unless
noted otherwise.r2 values
>0.75
Discussion and Conclusions
Compound 1 remained the most potent T. brucei growth inhibitor among this set of analogs. A pair of quinoline-based
compounds, 50 and 52, each with a basic
aliphatic amine on the tail group show double digit nanomolar potency
(79 and 87 nM, respectively). The potency of these compounds seems
to be driven by the aliphatic amine in the tail region rather than
by the placement of nitrogen atoms in the scaffold, because the analogous
isoquinoline analogue 58 is approximately equipotent
(100 nM) to 50.The quinoline analogs 50, 51, and 52 displayed submicromolar potency
against intracellular amastigotes
of T. cruzi. Most other analogs showed a complete
loss of activity, perhaps due to issues with penetration into both
the host cell and the parasite. (With intracellular parasites, we
note that compensating effects from interactions with host cell targets
cannot be ruled out.) However, the 3-cyanoquinoline analogue 83, shows a 5-fold improvement in potency over the matched
original quinazoline analog 4. In the headgroup region,
the 3-fluoro substituent affords a 10-fold increase in potency over
the matched des-fluoro analog (cf. 83 vs 84). The quinoline 51 displayed a slight drop in potency
compared with the quinazoline 4, and the matched isoquinoline 59 is 10-fold less potent. Taken together with the cyanoquinoline
analog 83, this data demonstrates the apparent importance
of two H-bond acceptor motifs in the scaffold.In the case of L. major, 47 showed
a 2.5-fold increase in potency from the matched quinazoline analogue 3 (0.20 versus 0.50 μM respectively) against the promastigote
life stage of L. major. The corresponding isoquinoline
compound 55 showed a complete loss in activity, reinforcing
the essentiality of the N1 atom of the quinazoline. Interestingly,
there was no activity observed against the amastigote life stage of
the parasite for 47. In contrast, the 7-substituted quinoline 52 displayed submicromolar potency against both life stages
(0.40 μM against promastigotes and 0.89 μM versus amastigotes).
Compared with the quinazoline compound 4, the analogous
cinnoline 68 displayed increased potency against amastigotes
(0.24 μM) albeit with a significant decrease in potency against
the promastigote form. This lack of correlation of compounds between
promastigote and amastigote life stages of the parasite has been reported
by us and others recently.[7,35] Other compounds displaying
modest potency include 76 and 91, both containing
the N-methylhomopiperazinyl sulfonamide tail.In P. falciparum cultures, three isoquinoline
compounds with a basic amine at the terminus of the tail region showed
modest potency highlighted by 57 being nearly equipotent
to the parent quinazoline 5 (40 vs 27 nM). Though the
matching quinoline 49 showed a complete loss in activity,
its regioisomer 50 was slightly more active than 5 (EC50 = 19 nM). The four quinoline analogs without
a basic amine on the tail group were within 2-fold of 5 with 48 being the most potent with an EC50 = 16 nM. Similarly, all four thienopyrimidine analogs with a basic
tail group amine (89–92) were potent,
within 4-fold of 5. Among these compounds there was no
preference for either thienopyridine isomer; the N-methylpiperazinyl tail group was 2.5- to 4-fold more potent than
the N-methylhomopiperazinyl tail on each scaffold.Among the phthalazines, 74 and 76, both
with a basicnitrogen on the tail and substituted at the 6-position
(regiomeric to 5) were equipotent to 5.
Also requiring a basic amine on the tail region, the cinnoline analogs
with piperazinyl and homopiperazinyl moieties (65–68) showed modest to high potency against P. falciparum D6 strain. Excitingly, the 7-substituted isomers (66 and 68) were highly potent antiplasmodial agents (14
and 3 nM, respectively).Since we observed that the most potent
compounds against P. falciparum were 4-aminoquinolines
(similar to the prototypical
antimalarial agent chloroquine), we tested them against drug resistant
parasite strains W2 and C235. We were gratified to observe that all
of the compounds tested are similarly active against drug resistant
strains of P. falciparum (Table S9, Supporting Information), suggesting that despite the shared
scaffold, these analogs likely display a mechanism of action or mechanism
of resistance that differs from those of chloroquine.Our studies
demonstrate which of these scaffolds are the most promising
for further optimization on a parasite-by-parasite basis. Figure 3 highlights the range of antiparasite potencies
for each scaffold. By inspection, it is clear that the quinoline scaffold
is significantly active across all four pathogens. We note that cinnoline
(C) and quinoline (A) generally provide the most potent antiplasmodial
agents, and the 7-position substitutions are slightly favored in both
of these templates. For T. brucei, the 7-substituted
quinolines and 6-substituted isoquinolines appear optimal (noting
that, despite the differential numbering of the scaffolds, these two
particular scaffolds present the same relative regiochemistry). Analogous
diagrams for the other pathogens are also provided in Figure 3 (and a diagram for Leishmania promastigotes
is in the Supporting Information (Figure
S1). A summary of the preferred bicyclic scaffold for each parasite
is shown in Figure 3E, noting that none appear
to be markedly better than the others against Leishmania intracellular amastigotes.
Figure 3
Bar chart showing range of potencies for each
scaffold (as labeled
in Tables 2 and 3) for
(A) malaria, (B) T. brucei, (C) L. major (amastigotes), and (D) T. cruzi. Regiochemical
information is shown by the suffix number (e.g., scaffold A-7 is the
7-substituted quinoline scaffold). Quinolines are shown in blue, isoquinolines
in green, cinnolines in yellow, phthalazines in orange, cyanoquinolines
in red, thieno[3,2-d]pyrimidines in purple, thieno[2,3-d]pyrimidines in light gray, and quinazolines in dark gray.
(E) Summary of preferred scaffolds on a per-parasite basis.
Bar chart showing range of potencies for each
scaffold (as labeled
in Tables 2 and 3) for
(A) malaria, (B) T. brucei, (C) L. major (amastigotes), and (D) T. cruzi. Regiochemical
information is shown by the suffix number (e.g., scaffold A-7 is the
7-substituted quinoline scaffold). Quinolines are shown in blue, isoquinolines
in green, cinnolines in yellow, phthalazines in orange, cyanoquinolines
in red, thieno[3,2-d]pyrimidines in purple, thieno[2,3-d]pyrimidines in light gray, and quinazolines in dark gray.
(E) Summary of preferred scaffolds on a per-parasite basis.For all parasites except for T. brucei, we also
note a preference for tail substituents with a basic amine present.
Considering only the most “potent” compounds (EC50 ≤ 0.1 μM for the extracellular parasites T. brucei and P. falciparum; EC50 ≤ 1 μM for the intracellular parasites L. major and T. cruzi), we note that the N-methylpiperizine and N-methylhomopiperazine are
preferred among analogs that were tested, over the less-basicmorpholine
or nonbasic morpholinosulfonamide substituents (Table 4). At this point, we cannot discern whether this is an effect
that is mediated by the biological target(s) involved in proliferation
inhibition, by parasite permeation, or by a combination of both; this
will be a matter for further investigation.
Table 4
Summary
of the Relative Prevalence
of Each of the Four Tail Motifs among “Potent” Proliferation
Inhibitors
“Potent” compounds
are EC50 ≤ 0.1 μM.
“Potent” compounds
are EC50 ≤ 1 μM.
“Potent” compounds
are EC50 ≤ 0.1 μM.“Potent” compounds
are EC50 ≤ 1 μM.We have previously observed that molecules bearing
these head and
tail combinations possess problematic physicochemical properties,
likely due to the molecular size and lipophilicity. The intent of
the present work was to explore the central scaffold functionality,
rather than to address these shortcomings. Nonetheless, we selected
five representative compounds from among the most potent to be tested
for their physicochemical properties (Table 5). Not unexpectedly, compounds tested were >99% plasma protein
bound
with limited thermodynamic aqueous solubility (<1 μM). Such
properties are undoubtedly a result of the high molecular weights
and clogP values; these issues remain the focus of ongoing efforts,
which are now focused on specific scaffolds for each pathogen.
Table 5
Physicochemical Properties of Some
of the Most Potent Antiparasitic Agents
compound
molecular weight
clogP
logD
plasma protein binding (% free)
solubility (uM)
Human
liver microsomes median CLint (μL/(min·mg))
male rat hepatocytes median CLint (μL/(min·106 cells))
1
541
7.31
3.2
<1
<1
63.03
44.5
47
586
6.22
3.5
<1
<1
78.87
13.93
50
617
6.43
a
<1
a
142.7
20.24
68
632
5.51
a
<1
<1
99.32
36.72
83
656
6.35
a
<1
a
151.8
37.95
Not determined.
Not determined.In summary, through a cross-parasite
screening campaign of existing
quinazolineT. brucei proliferation inhibitors, we
uncovered new hits against three other protozoan parasites. Encouraged
by that initial success, we focused on exploring the central heterocycle
scaffold, an exercise that has uncovered additional highly potent
compounds. Scaffold variations have revealed heteroatom positioning
essential for activity within this chemotype, while variations to
regiochemical attachment points have introduced a new set of regioisomers
with multiparasite potency. Thus, we have established a new lead series
for each of these protozoan parasites, which can be now advanced in
parallel for drug discovery against four different parasitic diseases.
With this in mind, further optimization of physicochemical properties
and cellular selectivity of each is ongoing, with a specific focus
on the “head” and “tail” regions. These
results will be reported in due course.
Experimental
Section
Chemical Synthesis
Unless otherwise noted, reagents
were obtained from Sigma-Aldrich, Inc. (St. Louis, MO), Fisher Scientific,
Frontier Scientific Services, Inc. (Newark, DE), or Matrix Scientific
(Columbia, SC) and used as received. Boronic acids and esters and
aniline reagents were purchased, except for those whose syntheses
are listed in the Supporting Information. Reaction solvents were dried by passage through alumina columns
on a purification system manufactured by Innovative Technology (Newburyport,
MA). Microwave reactions were performed using a Biotage Initiatior-8
instrument. NMR spectra were obtained with Varian NMR systems, operating
at 400 or 500 MHz for 1H acquisitions as noted. LCMS analysis
was performed using a Waters Alliance reverse-phase HPLC, with single-wavelength
UV–visible detector and LCT Premier time-of-flight mass spectrometer
(electrospray ionization). All newly synthesized compounds that were
submitted for biological testing were deemed >95% pure by LCMS
analysis
(UV and ESI-MS detection) prior to submission for biological testing.
Preparative LCMS was performed on a Waters Fraction Lynx system with
a Waters MicroMass ZQ mass spectrometer (electrospray ionization)
and a single-wavelength UV–visible detector, using acetonitrile/H2O gradients with 0.1% formic acid. Fractions were collected
on the basis of triggering using UV and mass detection. Yields reported
for products obtained by preparative HPLC represent the amount of
pure material isolated; impure fractions were not repurified.
6-Bromo-4-chlorocinnoline
(8a)
In a flame-dried
250 mL round-bottom flask were added 6-bromocinnolin-4(1H)-one (1.00 g, 4.44 mmol), anhydrous tetrahydrofuran (45 mL), and
phosphorus oxychloride (1.25 mL, 13.41 mmol). The mixture was refluxed
for 1 h at which point a deep green/blue solution had resulted. The
solution was cooled to 0 °C and was quenched by the dropwise
addition of sat. aq. NaHCO3 (70 mL). The mixture was allowed
to warm to room temperature and stir for an additional 1 h. Water
(50 mL) was added, and the mixture was extracted with dichloromethane
(3 × 100 mL). The combined organic layers were washed with sat.
aq. NaHCO3 (50 mL), washed with brine (50 mL), dried over
Na2SO4, concentrated on to silica, and purified
by flash column chromatography using a gradient of 1–5% methanol
in dichloromethane to yield an inseparable 10:1 mixture of 8a and 8b as a brown solid in 85% yield. 1H
NMR (500 MHz, CDCl3) δ 9.36 (s, 1 H), 8.43 (d, J = 8.8 Hz, 1 H), 8.36 (d, J = 2.0 Hz,
1 H), 7.98 (dd, J = 9.3, 2.0 Hz, 1 H). LCMS found
242.9 [M + H]+.
7-Bromo-4-chlorocinnoline (8c)
In a flame-dried
25 mL round-bottom flask were added 7-bromocinnolin-4(1H)-one (166 mg, 0.74 mmol), anhydrous tetrahydrofuran (7 mL), and
phosphorus oxychloride (0.2 mL, 2.15 mmol). The mixture was refluxed
for 1 h at which point a deep green/blue solution had resulted. The
solution was cooled to 0 °C and was quenched by the dropwise
addition of sat. aq. NaHCO3 (12 mL). The mixture was allowed
to warm to room temperature and stir for an additional 1 h. Water
(12 mL) was added, and the mixture was extracted with dichloromethane
(3 × 25 mL). The combined organic layers were washed with sat.
aq. NaHCO3 (20 mL), washed with brine (20 mL), and dried
over Na2SO4 to yield 8c as a dark
brown solid in 92% yield. 1H NMR (500 MHz, CDCl3) δ 9.39 (s, 1 H), 8.76 (d, J = 2.0 Hz, 1
H), 8.09 (d, J = 9.3 Hz, 1 H), 7.95 (dd, J = 9.0, 1.7 Hz, 1 H). LCMS found 242.9 [M + H]+.
7-Bromo-1-chlorophthalazine (9a)
In a
flame-dried 25 mL round-bottom flask were added 7-bromophthalazin-1(2H)-one (205 mg, 0.91 mmol), anhydrous acetonitrile (9 mL),
and phosphorus oxychloride (0.3 mL, 3.22 mmol). The mixture was refluxed
for 2 h, then cooled to 0 °C, diluted with dichloromethane (20
mL), and quenched with a dropwise addition of sat. aq. NaHCO3 (20 mL). The biphasic mixture was stirred vigorously and allowed
to warm to room temperature. After 1 h, the layers were separated
and the aqueous was extracted with dichloromethane (2 × 30 mL).
The combined organic layers were washed with sat. aq. NaHCO3 (25 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated to yield 9a as an orange solid
in 91% yield. 1H NMR (500 MHz, CDCl3) δ
9.45 (s, 1 H), 8.49–8.51 (m, 1 H), 8.10 (dd, J = 8.8, 2.0 Hz, 1 H), 7.91 (d, J = 8.8 Hz, 1 H).
LCMS found 242.9 [M + H]+.
6-Bromo-1-chlorophthalazine
(9c)
In a
flame-dried 50 mL round-bottom flask were added 6-bromophthalazin-1(2H)-one (402 mg, 1.78 mmol), anhydrous acetonitrile (18 mL),
and phosphorus oxychloride (0.5 mL, 5.36 mmol). The mixture was refluxed
for 2 h, then cooled to 0 °C, diluted with dichloromethane (40
mL), and quenched with a dropwise addition of sat. aq. NaHCO3 (40 mL). The biphasic mixture was stirred vigorously and allowed
to warm to room temperature. After 1 h, the layers were separated,
and the aqueous was extracted with dichloromethane (2 × 50 mL).
The combined organic layers were washed with sat. aq. NaHCO3 (40 mL), washed with brine (30 mL), dried over Na2SO4, and concentrated to yield 29c as a yellow solid
in 94% yield. 1H NMR (500 MHz, CDCl3) δ
9.39 (s, 1 H), 8.17–8.21 (m, 2 H), 8.10 (dd, J = 8.8, 2.0 Hz, 1 H). LCMS found 242.9 [M + H]+.
6-Bromocinnolin-4(1H)-one (15)
In a 250 mL round-bottom
flask were added 1-(2-amino-5-bromophenyl)ethanone
(8.34 g, 39.0 mmol), water (30 mL), and conc. hydrochloric acid (30
mL, 987 mmol). The mixture was cooled to 0 °C in an ice bath
and allowed to stir for 15 min until a suspension resulted. Aqueous
sodium nitrite (2 M, 20 mL, 40.0 mmol) was then added dropwise with
an addition funnel. The resulting solution was allowed to warm to
room temperature over 1.5 h and was stirred at room temperature overnight,
then refluxed for 6 h. The mixture was cooled to room temperature,
water (200 mL) was added, and the mixture was extracted with ethyl
acetate (3 × 200 mL). The combined organic layers were then washed
with brine (50 mL), dried over sodium sulfate, filtered, and concentrated
onto silica. The crude product was then purified by flash column chromatography
using a gradient of 1–10% methanol in dichloromethane to yield 15 as a dark brown solid in 82% yield. 1H NMR (500
MHz, DMSO-d6) δ 14.09 (br. s., 1
H), 8.09 (d, J = 2.2 Hz, 1 H), 7.92 (dd, J = 8.8, 2.2 Hz, 1 H), 7.79 (s, 1 H), 7.71 (d, J = 9.1 Hz, 1 H). LCMS found 224.9 [M + H]+.
7-Bromocinnolin-4(1H)-one (18)
In a 50 mL round-bottom
flask were added 1-(2-amino-4-bromophenyl)ethanone
(712 mg, 3.33 mmol), water (3 mL), and conc. hydrochloric acid (3
mL, 99 mmol). The mixture was cooled to 0 °C in an ice bath and
allowed to stir for 15 min until a suspension resulted. Aqueous sodium
nitrite (2 M, 1.84 mL, 3.68 mmol) was then added dropwise with an
addition funnel. The resulting solution was allowed to warm to room
temperature over 1.5 h and was stirred at room temperature overnight,
then refluxed for 6 h. The mixture was cooled to room temperature,
water (35 mL) was added, and the mixture was extracted with ethyl
acetate (3 × 40 mL). The combined organic layers were then washed
with brine (20 mL), dried over sodium sulfate, filtered, and concentrated
onto silica. The crude product was then purified by flash column chromatography
using a gradient of 20–50% ethyl acetate in hexanes, then ethyl
acetate to yield 18 as a light brown solid in 26% yield. 1H NMR (500 MHz, DMSO-d6) δ
13.49 (s, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.76 (s,
1 H), 7.73 (d, J = 2.0 Hz, 1 H), 7.53 (dd, J = 8.8, 2.0 Hz, 1 H). LCMS found 225.0 [M + H]+.
6-Bromoisobenzofuran-1(3H)-one (20a)
In a 100 mL round-bottom flask was dissolved isobenzofuran-1(3H)-one (4.01 g, 29.9 mmol) in trifluoroacetic acid (14 mL,
182 mmol) and sulfuric acid (6.5 mL, 122 mmol). N-Bromosuccinimide (7.95 g, 1.49 mmol) was added portionwise over
8 h, and the solution was stirred at room temperature for an additional
87 h. The solution was diluted with water (40 mL) and ethyl acetate
(40 mL). The pH of the aqueous layer was neutralized with 1 M aq.
NaOH and sat. aq. NaHCO3. The organic layer was separated,
and the aqueous layer was extracted with ethyl acetate (3 × 50
mL). The combined organic layers were washed with brine (25 mL), dried
over Na2SO4, and concentrated onto silica. The
crude product was then purified by flash column chromatography using
10–20% ethyl acetate in hexanes to yield 20a as
white solid in 57% yield. 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 1.5 Hz, 1 H), 7.77 (dd, J = 8.3, 1.5 Hz, 1 H), 7.40 (d, J = 8.3
Hz, 1 H), 5.27 (s, 2 H). LCMS found 212.9 [M + H]+.
3,6-Dibromoisobenzofuran-1(3H)-one (21a)
In a 50 mL round-bottom
flask were added 6-bromoisobenzofuran-1(3H)-one (1.00
g, 4.69 mmol), N-bromosuccinimide
(958 mg, 5.38 mmol), 2,2′-azobis(2-methylpropionitrile) (75
mg, 0.46 mmol), and chloroform (23 mL). The mixture was refluxed for
2.5 h, then cooled to room temperature and quenched with sat. aq.
NaHCO3 (25 mL). The organic layer was removed, washed with
water (20 mL), washed with brine (15 mL), and concentrated onto silica.
The crude product was purified by flash column chromatography using
a gradient of 5–10% ethyl acetate in hexanes to yield 21a as a white solid in 61% yield. 1H NMR (500
MHz, CDCl3) δ 8.06 (d, J = 1.5 Hz,
1 H), 7.90 (dd, J = 8.1, 1.7 Hz, 1 H), 7.52 (d, J = 8.3 Hz, 1 H), 7.37 (s, 1 H). GCMS found 289.9 [M]+•.
3,5-Dibromoisobenzofuran-1(3H)-one (21b)
In a 25 mL round-bottom flask were
added 5-bromoisobenzofuran-1(3H)-one (499 mg, 2.34
mmol), N-bromosuccinimide
(421 mg, 2.37 mmol), 2,2′-azobis(2-methylpropionitrile) (38
mg, 0.23 mmol), and chloroform (10 mL). The mixture was refluxed for
2.5 h, then cooled to room temperature and quenched with sat. aq.
NaHCO3 (10 mL). The organic layer was removed, washed with
water (10 mL), washed with brine (5 mL), and concentrated onto silica.
The crude product was purified by flash column chromatography using
10% ethyl acetate in hexanes to yield 21b as a white
solid in 49% yield. 1H NMR (500 MHz, CDCl3)
δ 7.74–7.83 (m, 3 H), 7.36 (s, 1 H). GCMS found 289.8
[M]+•.
7-Bromophthalazin-1(2H)-one
(22a)
In a 25 mL round-bottom flask was dissolved
3,6-dibromoisobenzofuran-1(3H)-one (143 mg, 0.49
mmol) in ethanol (5 mL). Hydrazine
monohydrate (0.12 mL, 2.48 mmol) was then added via a syringe, and
the solution was refluxed for 1.5 h. The solution was cooled to room
temperature, and ice water (15 mL) was added to the reaction mixture.
The precipitate was vacuum filtered and dried under a vacuum overnight
to yield 22a as a white solid in 56% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.82
(br. s., 1 H), 8.39 (s, 1 H), 8.30 (d, J = 2.0 Hz,
1 H), 8.11 (dd, J = 8.5, 2.2 Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H). LCMS found 225.0 [M + H]+.
6-Bromophthalazin-1(2H)-one (22b)
In a 25 mL round-bottom flask was dissolved 3,5-dibromoisobenzofuran-1(3H)-one (302 mg, 1.04 mmol) in ethanol (10 mL). Hydrazine
monohydrate (0.25 mL, 5.18 mmol) was then added via a syringe, and
the solution was refluxed for 1.5 h. The solution was cooled to room
temperature, and ice water (30 mL) was added to the reaction mixture.
The precipitate was vacuum filtered and dried under a vacuum overnight
to yield 22b as a white solid in 73% yield. 1H NMR (500 MHz, DMSO-d6) δ 12.78
(br. s., 1 H), 8.33 (s, 1 H), 8.23 (d, J = 2.0 Hz,
1 H), 8.12 (d, J = 8.3 Hz, 1 H), 8.00 (dd, J = 8.3, 2.0 Hz, 1 H). LCMS found 224.9 [M + H]+.
General Procedure A for the Amination of 4-Chloro-6-iodoquinoline-3-carbonitrile
and 4-Chlorothienopyrimidines
To a solution of the appropriate
aryl chloride (1 equiv) in 2-propanol (0.15 M) was added 3-chloro-4-((3-fluorobenzyl)oxy)aniline
or 4-(benzyloxy)-3-chloroaniline (1.1 equiv). The resulting mixture
was refluxed overnight. The formed precipitate was collected by vacuum
filtration to obtain the desired products.
General procedure B for
the Amination of 4-Chloroquinolines
and 1-Chloroisoquinolines
To a solution of the appropriate
aryl chloride (1 equiv) in 2-propanol (0.15 M) was added 3-chloro-4-((3-fluorobenzyl)oxy)aniline
or 4-(benzyloxy)-3-chloroaniline (1.1 equiv). The resulting mixture
was refluxed overnight. The mixture was diluted with water, basified
with 3 M aq. NaOH to pH 12, and extracted with dichloromethane (3×).
The combined organic layers were washed with water, washed with brine,
dried over Na2SO4, and concentrated. The crude
products were purified by flash column chromatography to obtain the
desired products.
General Procedure C for the Amination of
4-Chlorocinnolines
A solution of the appropriate 4-chlorocinnoline
(1 equiv) and 3-chloro-4-((3-fluorobenzyl)oxy)aniline
or 4-(benzyloxy)-3-chloroaniline (4 equiv) in toluene (0.1 M) was
refluxed for 2.5 h and cooled to room temperature. Triethylamine (4
equiv) was added, and the mixture was returned to reflux for an additional
30 min. The mixture was cooled back to room temperature, and the formed
yellow precipitate was vacuum filtered, washed with ethyl acetate,
concentrated onto silica, and purified by flash column chromatography.
General Procedure D for the Amination of 1-Chlorophthalazines
A solution of the appropriate 1-chlorophthalazine (1 equiv) and
3-chloro-4-((3-fluorobenzyl)oxy)aniline or 4-(benzyloxy)-3-chloroaniline
(4 equiv) in anhydrous toluene (0.2 M) was heated at 50 °C overnight.
Water was added, and the mixture was neutralized with 1 M aq. NaOH
and was extracted with 5% methanol in dichloromethane. The combined
organic layers were washed with brine, dried over Na2SO4, concentrated onto silica, and purified by flash column chromatography.
Synthesized
by general procedure A as a light brown solid in 63% yield. 1H NMR (500 MHz, DMSO-d6) δ ppm
9.94 (s, 1 H), 8.49 (s, 1 H), 8.19 (s, 1 H), 8.02 (d, J = 2.4 Hz, 1 H), 7.68 (dd, J = 8.8, 2.4 Hz, 1 H),
7.49 (m, 2 H), 7.41 (m, 2 H), 7.34 (m, 1 H), 7.27 (d, J = 9.3 Hz, 1 H), 5.21 (s, 2 H). LCMS found 445.9 [M + H]+.
General Procedure A for Suzuki Couplings
In a 2–5
mL microwave vial equipped with a stir bar were added aryl bromide
(1 equiv), boronic ester (1.3 equiv), 1:1 water/ethanol (0.04 M),
triethylamine (3 equiv), and palladium(II) acetate (0.01 M in acetone,
1 mol %). The vial was sealed with a septum, and the contents were
irradiated to and held at 120 °C with stirring for 1 h. The reaction
mixture was cooled to room temperature, diluted with water (8 mL),
and extracted with dichloromethane (3 × 8 mL). The combined organic
layers were washed with aq. NaOH (1 M, 2 × 5 mL), water (5 mL),
and brine (5 mL). The organic layer was then dried over Na2SO4 and concentrated onto silica. The crude product was
purified by flash column chromatography.
General Procedure B for
Suzuki Couplings
In a 2–5
mL microwave vial equipped with a stir bar were added aryl bromide
(1 equiv), boronic ester (1.3 equiv), 1:1 water/ethanol (0.04 M),
triethylamine (3 equiv), and bis(triphenylphosphine)palladium(II)
chloride (2.5 mol %). The vial was sealed with a septum, and the contents
were irradiated to and held at 120 °C with stirring for 1 h.
The reaction mixture was cooled to room temperature, diluted with
water (8 mL), and extracted with dichloromethane (3 × 8 mL).
The combined organic layers were washed with aq. NaOH (1 M, 2 ×
5 mL), water (5 mL), and brine (5 mL). The organic layer was then
dried over Na2SO4 and concentrated on to silica.
The crude product was purified by flash column chromatography.
General
Procedure C for Suzuki Couplings
In a 2–5
mL microwave vial equipped with a stir bar were added aryl bromide
(1 equiv), boronic ester (1.3 equiv), 1:1 water/ethanol (0.04 M),
triethylamine (3 equiv), and palladium(II) acetate (5 mol %). The
vial was sealed with a septum, and the contents were irradiated to
and held at 120 °C with stirring for 3 h. The reaction mixture
was cooled to room temperature, diluted with water (8 mL), and extracted
with dichloromethane (3 × 8 mL). The combined organic layers
were washed with aq. NaOH (1 M, 2 × 5 mL), water (5 mL), and
brine (5 mL). The organic layer was then dried over Na2SO4 and concentrated on to silica. The crude product was
purified by flash column chromatography.
General Procedure D for
Suzuki Couplings
To a solution
of the appropriate aryl iodide (1 equiv) in 3:2 dimethoxyethane/ethanol
(0.05 M) were added the appropriate aryl boronic ester (1.1 equiv),
aq. 2 M Na2CO3 (6 equiv), and Pd(PPh3)4 (5 mol %). The mixture was purged with nitrogen and
heated at 85 °C for 7 h. The mixture was cooled to room temperature
and filtered, and the filtrate was concentrated. The residue was dissolved
in ethyl acetate, washed with water, washed with brine, dried over
Na2SO4, and purified by flash column chromatography.
General Procedure E for Suzuki Couplings
To a solution
of the appropriate aryl bromide (1 equiv) in 3:2 dimethoxyethane/ethanol
(0.05 M) were added the appropriate aryl boronic ester (1.2 equiv),
aq. 2 M Na2CO3 (6 equiv), and Pd(PPh3)4 (7 mol %). The mixture was heated at 85 °C for
12 h, then cooled to room temperature, and the solvents were removed
under reduced pressure. The residue was purified by silica column
chromatography (hexanes/ethyl acetate) and then by reverse phase chromatography
(water/acetonitrile) unless otherwise mentioned.
Authors: Nicholas D Bland; Cuihua Wang; Craig Tallman; Alden E Gustafson; Zhouxi Wang; Trent D Ashton; Stefan O Ochiana; Gregory McAllister; Kristina Cotter; Anna P Fang; Lara Gechijian; Norman Garceau; Rajiv Gangurde; Ron Ortenberg; Mary Jo Ondrechen; Robert K Campbell; Michael P Pollastri Journal: J Med Chem Date: 2011-11-08 Impact factor: 7.446
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Figure 1
Figure 2
Scheme 1
Scheme 2
Scheme 3
Figure 3