Synthesis and preliminary biological evaluation of a small library of hybrid compounds based on Ugi isocyanide multicomponent reactions with a marine natural product scaffold

Article abstract of DOI:10.1016/j.bmcl.2015.09.033

A mixture-based combinatorial library of five Ugi adducts (4-8) incorporating known antitubercular and antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring diisocyanide 3, via parallel Ugi four-center three-compo

Full text of DOI:10.1016/j.bmcl.2015.09.033

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and preliminary biological evaluation of a small library
of hybrid compounds based on Ugi isocyanide multicomponent
reactions with a marine natural product scaffold
Edward Avilés a, Jacques Prudhomme b, Karine G. Le Roch b, Scott G. Franzblau c, Kevin Chandrasena d,
Alejandro M. S. Mayer d, Abimael D. Rodríguez a,
⇑
a Department of Chemistry, University of Puerto Rico, PO Box 23346, U.P.R. Station, San Juan, PR 00931-3346, United States
b Department of Cell Biology and Neuroscience, University of California at Riverside, CA 92521, United States
c Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, United States
d Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL 60515, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A mixture-based combinatorial library of five Ugi adducts (4–8) incorporating known antitubercular and
antimalarial pharmacophores was successfully synthesized, starting from the naturally occurring
diisocyanide 3, via parallel Ugi four-center three-component reactions (U-4C-3CR). The novel
Received 14 August 2015
Revised 11 September 2015
Accepted 14 September 2015
Available online xxxx
a-acylamino amides obtained were evaluated for their antiinfective potential against laboratory strains
of Mycobacterium tuberculosis H37Rv and chloroquine-susceptible 3D7 Plasmodium falciparum.
Interestingly, compounds 4–8 displayed potent in vitro antiparasitic activity with higher cytotoxicity
in comparison to their diisocyanide precursor 3, with the best compound exhibiting an IC50 value of
3.6 nM. Additionally, these natural product inspired hybrids potently inhibited in vitro thromboxane
B2 (TXB2) and superoxide anion (OÀ2 ) generation from Escherichia coli lipopolysaccharide (LPS)-activated
rat neonatal microglia, with concomitant low short-term toxicity.
Keywords:
Tuberculosis
Malaria
Anti-neuroinflammatory activity
Ugi multicomponent reaction
Isocyanide
Ó 2015 Elsevier Ltd. All rights reserved.
Natural product hybridization
During the course of our investigations of new biologically
active compounds from Caribbean marine invertebrates, we have
focused our attention to discover new drugs for the treatment of
tropical diseases (TDs), which affect billions of people worldwide.1
Tuberculosis and malaria are two of the major TDs with the highest
rates of death.2 Current first-line drugs for the treatment of these
diseases include isoniazid (1) and chloroquine (2), respectively.
Owing to the emergence of microbes that are resistant to currently
available antiinfective drugs, there exist an urgent need for new,
effective and affordable backup drugs.3 As part of our strategy to
the discovery of novel drugs to combat TDs, we have paid particu-
lar attention to determine the antiinfective action of marine
isocyanides, since it was previously established that a number of
secondary metabolites belonging to this class of compounds
possess putative antitubercular and antiplasmodial activity.4
Moreover, recent investigations appear to support the hypothesis
that marine isocyanides and derivatives could become lead com-
pounds for the development of novel agents to modulate excessive
release of TXB2 by activated microglia cells in neuroinflammatory
disorders.5
While a number of amphilectane-based diterpene isocyanides
with interesting bioactivity profiles have been reported, effective
methods for their synthesis or for generating analogs are limited.6
⇑
Corresponding author.
E-mail address: abimael.rodriguez1@upr.edu (A.D. Rodríguez).
http://dx.doi.org/10.1016/j.bmcl.2015.09.033
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Avilés, E.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.09.033

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E. Avilés et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
This is not only due to the lack of compound supply, but equally
important, the limited availability of general methods based on
mild reaction conditions required for further functional group
manipulations. For instance, the synthesis of complex natural
products like 8,15-diisocyano-11(20)-amphilectene [(À)-DINCA]
(3)7 and analogs required for structure–activity relationship
(SAR) studies, poses a difficult challenge, often involving rather
lengthy syntheses with introduction of the isocyanide functionality
late in the synthesis.8 An alternative approach to drug discovery,
which we have explored previously, is to use an abundant natural
product as a scaffold or building block and to convert it into a small
focused library of analogs.9 Our intended target was 3, which is
accessible in milligram amounts and contains both the amphilec-
tane framework and two isocyanide moieties, one of which could
serve as a ‘handle’ with potential for further synthetic elaboration.
A mounting body of evidence, which suggest that both the
isocyanide functional groups and the diterpene skeleton are
responsible for the antituberculosis and antiplasmodial activity
of (À)-DINCA (3), provides further support for this approach.10
An ideal tool for accessing a small library of isocyanide analogs
of increased structural diversity, both quickly and in a synthetically
inexpensive way, is the use of isocyanide-based multicomponent
reactions (IMCRs).11 Over the past two decades the field of IMCR
research has experienced a steadfast growth with the discovery
and development of new variations of the classical Passerini and
Ugi IMCRs.12 Multicomponent reactions are defined as reactions
in which more than two starting compounds react to form a
product that incorporates essentially all of the carbon atoms. In
particular, the multicomponent isocyanide condensation discov-
ered by Ivar Ugi is a versatile four-component reaction involving
a carboxylic acid, an aldehyde, a primary or secondary amine,
and an isocyanide.12 Thus, the Ugi isocyanide-based multicompo-
nent reactions (Ugi IMCRs) are a powerful tool with which libraries
of new compounds that are potentially effective against infectious
diseases can be constructed in a single-stage reaction. Further-
more, Ugi IMCRs are typically easy to perform, tolerate a wide
range of group functionalities, and provide quick access to struc-
turally complex compounds that otherwise would require lengthy
syntheses.13 An example of this approach to drug discovery using
the Ugi IMCR is outlined below (Scheme 1).
component of the U-4CC reactions (Table 1).15 Our selection of
formaldehyde as the aldehyde component was driven by our desire
to synthesize low-molecular-weight adducts while avoiding the
formation of epimeric mixtures at C-23, thus simplifying the purifi-
cation process. Our choice for the isocyanide component was
limited to (À)-DINCA (3) because of its remarkable potency against
M. tuberculosis and chloroquine-resistant P. falciparum strains and
preponderance to react preferentially through its C-15 isocyanide
group.5,10 We expected that our natural product inspired molecular
hybridization approach would lead us to the expeditious develop-
ment of new hybrid molecules with noteworthy antiinfective
properties. Table 1 summarizes our selection of carboxylic acid,
amine, and aldehyde building blocks for the Ugi multicompo-
nent-based library.
To synthesize the quinoline-containing amine required for the
U-4CC, we reacted commercially available 4,7-dichloroquinoline
(9) with excess ethylenediamine in the absence of solvents at
80 °C for 1 h and at 135–140 °C for 3 h to afford 10 in 90% yield
(Scheme 2).13a The condensation of stoichiometric amounts of
the amine, aldehyde, carboxylic acid and diisocyanide
3 in
anhydrous EtOH at 20 °C furnished the desired Ugi adducts. A
summary of the synthesized target compounds 4–8 is provided
in Figure 1. Following solvent removal under reduced pressure,
purification of the crude reaction mixtures was easy achieved by
flash silica-gel chromatography to afford the products in modest
to good isolated yields (Table 1).
Compounds 4–8 were structurally analyzed on the basis of con-
ventional spectroscopic data (IR, UV, HRESI-MS, and 1D and 2D
NMR). For adducts 4 and 8, molecular characterization was swift
and straightforward because each compound was obtained as a
homogeneous stable entity. In the case of compounds 6 and 7,
the initial characterization by 1H and 13C NMR was complicated
because of the duplication of many of the proton and carbon sig-
nals. Rotation around the tertiary amide bond in these Ugi adducts
gave rise to two quickly interchanging rotational isomers with
notably different chemical shift values in a ratio of approximately
1:1. We confirmed this phenomenon by running the experiments
in DMSO-d6 and briefly observed the coalescence of the duplicating
peaks. The two sets of signals reappeared shortly thereafter (ꢀ2 h),
indicating that the two rotamers had reached equilibrium.
Rotational isomerization was observed only in the two latter
adducts, which is reasonable given the inherent conformational
flexibility introduced by the ethylenediamine bridge of 6 and 7
relative to that of 4, 5, and 8. As we predicted, the Ugi adduct 5
was obtained as a diastereomeric mixture (dr 67:33) that could
not be easily separated by flash silica-gel chromatography and
was therefore characterized as such without further optimization
(the isomer ratio was determined via the integration of selected
signals in the 1H NMR spectra of the reaction products).
In our ongoing investigations to discover novel compounds for
screening against Mycobacterium tuberculosis and the most com-
mon and deadly human malaria parasite, Plasmodium falciparum
(malaria tropica), we initially sought to design Ugi four-component
condensation (U-4CC) reaction adducts (a-acylamino amides) that
incorporate known pharmacophores found in two existing antitu-
bercular and antimalarial drugs, namely, isoniazid (1) and chloro-
quine (2).14 Combining these pharmacophores through the U-4CC
method has many attractive features, including the opportunity
to rationally design novel drugs aimed at multiple targets within
the tuberculosis bacterium and malaria parasite. These substruc-
tures would be incorporated as part of our amine or carboxylic acid
Compounds 3–8 were tested against M. tuberculosis H37Rv with
the results as shown in Table 2. From the modest library, com-
pound 3 with an MIC of 3.2 lg/mL exhibited the best activity, being
Scheme 1. Coupling of the four components utilized in the U-4CC reactions.
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E. Avilés et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
Building blocks for the Ugi multicomponent based library and isolated yields
Product
Carboxylic acid (R1)
Amine (R2)
Aldehyde (R3)
Yield (%)
61
O
NH2
NH2
O
4
OH
H
H
N
O
O
OH
H
5
6
53
71
N
O
NH2
NH2
O
O
O
HN
OH
H
H
H
H
H
H
Cl
N
O
HN
OH
7
8
67
42
N
Cl
N
O
NH3
OH
N
of the isocyanide group at the C-15 position in 3 to an a-acylamino
amide function, as in 4–8, results in a marked decrease in activity.
In general, it can be seen from the Table 3 that the antitubercular
activity decreases for all of the Ugi adducts whether based on
isonicotinic acid (e.g. 4, 5, 7, and 8) or aminoquinoline (e.g. 6)
pharmacophores.
As derivatives based on an antiparasitic natural product
scaffold, compounds 4–8 were also screened against a chloroquine
(CQ) non-resistant Plasmodium falciparum 3D7 strain to ascertain
their potentials as effective antimalarial agents. The antiplasmodial
activities were determined as the inhibitory concentrations at 50%
parasite survival (IC50) in the strain; the results are tabulated in
Table 2. The antiplasmodial activity and selectivity index (SI) of
CQ (2) are also shown for comparative purposes. Interestingly, all
Scheme 2. Synthesis of quinoline-containing amine 10.
nearly as potent in this strain as the powerful mycobactericide
isoniazid (1) (MIC = 0.44 g/mL). On the other hand, the MIC
values for the Ugi adducts obtained from 3, compounds 4–8, were
between 14.9 and 101.8 g/mL. Based on a comparison of the MIC
results obtained for these compounds, it appears that manipulation
l
l
Figure 1. Structural formulas of congeners 4–8 synthesized by U-4CC reactions with (À)-DINCA (3).
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E. Avilés et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
coli LPS-activated microglia TXB2 and OÀ2 generation in vitro. OÀ2
and TXB2 release, as well as short term cell viability, were assessed
as described in the Supplementary data. As shown in Table 3,
Table 2
In vitro antimycobacterial and antiplasmodial activities of compounds 3–8
Compound MABA MICa
g/mL)
3D7
Cytotoxicity
IC50 (nM)
Selectivity
indexc (SI)
(
l
IC50 SEb
(nM)
a
-acylamino amides 4, 5 and 8 (based on the isonicotinic acid
pharmacophore only) inhibited TXB2 generation with IC50’s = 3.0,
0.1 and 1.1 M, respectively, demonstrating minimal effect on
OÀ2 release (IC50 > 10
M) and minimal short-term toxicity
(LDH50 > 10 M). In contrast, 6 and 7, the only derivatives prepared
based on the aminoquinoline pharmacophore, potently inhibited
TXB2 generation (IC50 = 0.8 and 0.9
M, respectively) and O2À
release (IC50 = 1.7 and 5.0 M, respectively), but with evidence of
short-term toxicity (LDH50 = 5.0 M). Thus, in our in vitro
3
3.2
1.2 0.00004 99735
11.5 0.0027 19788
13.0 0.0034 49173
11.1 0.0006 28560
3.6 0.0003 25753
6.3 0.0005 NT
83112
1721
3782
2573
7154
—
l
4
14.9
56.4
17.9
52.0
101.8
—
l
5d
6
l
7
8
CQ
INH
l
6.6 0.0008 234470e
—
35526
—
l
0.44
—
l
a
experimental conditions, it appeared that inhibition of microglia
TXB2 generation by Ugi adducts 4, 5 and 8 resulted from a pharma-
cologic effect, in contrast with that of analogs 6 and 7 that were
toxic to the microglia cells. To summarize, comparison of the
Values are means of three experiments. Minimum inhibitory concentrations
(MIC) in g/mL.
l
b
The IC50 values are reported as means standard errors.
Selectivity index (SI) defined by the ratio: IC50 (in mammalian Vero cell lines)/
c
IC50 values of antiparasitic activity against 3D7 cell line.
d
IC50’s of starting diisocyanide 3 (IC50 ꢀ0.23
lM) and a-acylamino
Tested as a mixture of diastereomers.
Value obtained from Ref. 16. NT indicates that the compound was not tested
e
amides 4–8 supports the observation that the observed bioactivity
is mainly associated with the presence of an amphilectane
diterpenoid core bearing a C-8 isocyanide functionality. Within
the series of semi-synthetic products 4–8, analog 5 displayed the
due to insufficient material. CQ = chloroquine and INH = isoniazid (+Ctrls).
highest antineuroinflammatory activity (IC50 = 0.1
compared to 4, the least active congener bearing the isonicotinic
acid pharmacophore (IC50 = 3.0 M), the presence in 5 of a phenyl
lM), and when
of the
a-acylamino amides obtained from the U-4CC reactions
displayed potent antiplasmodial activity (IC50 values 613.0 nM)
against this strain. Compound 7, which was based on isonicotinic
acid and aminoquinoline pharmacophores, was observed to be
the most active (IC50 = 3.6 nM) of the investigated compounds,
although 8, which was based only on isonicotinic acid, was
nearly as active (IC50 = 6.3 nM) as 7. Compound 5, the only
adduct with a bulky group at C-23 that was analyzed to be a
mixture of diastereomers, was the least active against the 3D7
strain (IC50 = 13.0 nM). However, we speculate that the separa-
tion and testing of each diastereomer may result in a marked
increase in activity of one of the compounds. Inasmuch as
hybrids 4–8 showed excellent in vitro inhibitory activity (IC50
values in the range of 3.6–13.0 nM) when compared to the
standard drug CQ (IC50 = 6.6 nM), they showed more toxicity
(SI values in the range 19788–49173) than the CQ (SI = 35526).
Interestingly, our starting scaffold 3 proved to be the most
promising compound of the series (IC50 = 1.2 nM, SI = 83112),
which was 5.5 times more active and significantly less toxic than
the standard drug. When compared to 3, the observation that the
antiplasmodial activity of the new compounds is comparable to
that of the parent compound raises the question as to whether
the isocyanide group at C-15 in the natural product is responsible
for the observed activity.
l
residue at C-23 seems to further potentiate its biological activity.
On the other hand, substitution of R2 (Scheme 1) with bulkier
functional groups, as observed in compound 7, appears to lower
the activity. Moreover, comparison of the IC50’s of 4 and 8 suggests
that the presence of an isopentyl group (R2) also seems to play a
role in lowering the observed pharmacological activity. Lack of
OÀ2 inhibition in compounds 3–5 and
8 would appear to
suggest that they inhibit TXB2 synthesis through a cyclooxygenase-
dependent mechanism.
To summarize, Ugi IMCRs were used to accomplish four-compo-
nent couplings of amines, aldehydes, acids, and diisocyanide 3,
allowing for the design and construction of a small library of
a-acetylamino amides (4–8) that, while less active than isoniazid
(1), are as potent as the antimalarial drug chloroquine (2)
against the 3D7 strain of P. falciparum. All of the compounds in
our modest library exhibited IC50 values in the low nanomolar
range, with adduct
7 exhibiting the highest antiplasmodial
activity (IC50 = 3.6 nM, SI = 7154). To our delight, this hybrid was
twice as potent as chloroquine against the 3D7 strain (Table 2),
however, it showed the most toxicity. Although some general
trends related to the activities of the compounds are evident,
further exploration, including the synthesis and testing of addi-
tional compounds against multiple parasite strains with various
degrees of sensitivity and resistance, will be needed before definite
conclusions can be drawn. Notwithstanding, the results presented
herein clearly underscore the importance of isocyanide-based mul-
ticomponent reactions in antimalarial drug discovery, particularly
when combined with a rational choice of inputs based on known
antimalarial pharmacophores. Thus, hybrid approaches inspired
by natural products can lead to the rapid generation of novel
chemotypes for the development of diverse, biologically rich SAR
libraries.16 The development of new treatment strategies is of great
importance because parasitic resistance to existing antimalarial
agents is spreading rapidly. In time, this seemingly inevitable
predicament will diminish the effectiveness of the artemisinins,
the current mainstay of treatment against drug-resistant para-
sites.3 Finally, in addition to their pharmacologic effects on
enhanced TXB2 generation and their reduced cytotoxic effects, it
is perhaps of interest to note that derivatives 4–8 are more potent
inhibitors of rat microglia TXB2 generation than acetylsalicylic acid
Derivatives 4–8 along with scaffold 3 were screened further in
order to determine the effect of these compounds on Escherichia
Table 3
Antineuroinflammatory activity of compounds 3–8a
b
Compound
OÀ2 IC50
(
lM)
TXB2 IC50
(l
M)
LDH50
(
lM)
3
4
5c
6
7
8
>10
>10
>10
1.7
5.0
>10
0.23
3.0
0.1
0.8
0.9
1.1
>10
>10
>10
5.0
5.0
>10
a
Effect of compounds 3–8 on LPS-primed rat microglia PMA [1 lM]-stimulated
release of TBX2 [control release: 2555 718 pg/mL/70 min] and OÀ2 [control release:
12.6 2.4 nanomoles/70 min] and LDH. The antineuroinflammatory assay is
described in the Supplementary data. Data correspond to 1–4 independent
experiments.
b
LDH50 represents the concentration of the compound that caused 50% release of
the total LDH content of microglia cells. LDH was measured as described in the
Supplementary data.
(aspirin) (IC50 = 3.12–10.0
l
M)17,18 and flurbiprofen (apparent
IC50 = 100 nM),19 which are two clinically used NSAIDS.
c
Tested as a mixture of diastereomers.
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E. Avilés et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
5
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Acknowledgements
We are grateful to Dr. J. Marrero for the initial characterization
of (À)-DINCA (3) and L. Gómez for technical assistance during the
Ugi reactions. Mass spectral determinations were provided by the
Mass Spectrometry Laboratory of the University of Illinois at
Urbana–Champaign. Financial support to E. Avilés was provided
by the PRLSAMP-BDP, UPR-RISE, GK-12, and Eli Lilly del Caribe
Foundation fellowships. A.M.S.M. thanks the Office of Research
and Sponsored Programs at Midwestern University for a CCOM
Student Summer Research Award to support K.C. and Mary L. Hall
for expert technical assistance with the OÀ2 , TXB2 and LDH
assays. This research was supported by the NIH Grant
1SC1GM086271-01A1 awarded to A.D. Rodríguez.
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Please cite this article in press as: Avilés, E.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.09.033