Novel peptidomimetic cysteine protease inhibitors as potential antimalarial agents

Article abstract of DOI:10.1021/jm060405f

The synthesis of a new class of peptidomimetics 1a-j, based on a 1,4-benzodiazepine scaffold and on a C-terminal aspartyl aldehyde building block, is described. Compounds 1a-j provided significant inhibitory activity against falcipains 2A and 2B (FP-2A an

Full text of DOI:10.1021/jm060405f

3064
J. Med. Chem. 2006, 49, 3064-3067
Chart 1
Novel Peptidomimetic Cysteine Protease
Inhibitors as Potential Antimalarial Agents
Nicola Micale,*,# Alan P. Kozikowski,† Roberta Ettari,#
Silvana Grasso,# Maria Zappala`,# Jong-Jin Jeong,§
Ajay Kumar,‡ Manjit Hanspal,‡ and Athar H. Chishti§
Dipartimento Farmaco Chimico, UniVersity of Messina, Viale
Annunziata, 98168, Messina, Italy, Department of Medicinal
Chemistry and Pharmacognosy, UniVersity of Illinois at Chicago,
833 South Wood Street, Chicago, Illinois 60612, Department of
Pharmacology, UniVersity of Illinois College of Medicine, 909
South Wolcott AVenue, Chicago, Illinois 60612, and Center for Cell
Biology, Caritas St. Elizabeth’s Medical Center,
amino acid variations between FP-2 enzymes remain unclear.
Like FP-2A, the recombinant FP-2B also functions as a
hemoglobinase.
Several peptide-based FP-2 inhibitors have been identified.
These derivatives bear the most popular pharmacophores of
cysteine protease inhibitors such as vinylsulfones,6 ketones,7 and
aldehydes.8 The activity of these electrophilic moieties is
dependent on their capability to form a covalent bond with a
cysteine residue present in the active site of the enzyme.
Generally, peptidyl inhibitors have poor pharmacokinetic pro-
files because their amide bonds are susceptible to cleavage by
other proteases.9
In the field of peptidomimetics, incorporation of a nonpeptidic
scaffold into an amino acidic sequence and of unnatural amino
acids has potential advantages that include increased potency
and selectivity by stabilizing a biologically active conformation,
increased membrane permeability, and enhanced oral bioavail-
ability and stability toward degradation by enzymes.10 Moreover,
it is desirable to design reversible inhibitors (e.g., aldehydes)
to minimize the potential toxicity that can be observed with
irreversible inhibitors (e.g., vinylsulfones).
Taking into account these factors, we combined these
observations and designed new FP-2 inhibitors based on a 1,4-
benzodiazepine (BDZ) scaffold introduced internally to a peptide
sequence, which mimics the fragment D-Ser-Gly, and on a
C-terminal aspartyl aldehyde building block, which inhibits the
enzyme by forming a reversible covalent bond at the active
site.11 This approach, which employs the BDZ scaffold, has
already been successfully applied in the peptidomimetic field.
Furthermore, BDZs represent a well-known class of drugs that
are well tolerated and exhibit good oral bioavailability.12
We report herein the synthesis of a series of arylcarbamic
acid 1-[(2-hydroxy-5-oxotetrahydrofuran-3(S)-ylcarbamoyl)-
methyl]-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R)-yl
methyl esters (1a-i, Chart 1) and their activity as FP-2
inhibitors.
Boston, Massachusetts 02135
ReceiVed April 6, 2006
Abstract: The synthesis of a new class of peptidomimetics 1a-j, based
on a 1,4-benzodiazepine scaffold and on a C-terminal aspartyl aldehyde
building block, is described. Compounds 1a-j provided significant
inhibitory activity against falcipains 2A and 2B (FP-2A and FP-2B),
two cysteine proteases from Plasmodium falciparum.
Malaria, in particular that caused by Plasmodium falciparum,
remains a serious health problem in Africa, South America, and
many parts of Asia where it afflicts about 500 million people
and is responsible for the death of two million children each
year.1 The main reasons for the persistence of malaria are the
emergence of resistance to common antimalarial drugs,2 cross-
resistance to structurally unrelated drugs, inadequate control of
mosquito vectors, and the lack of effective vaccines. Therefore,
the identification and characterization of new targets for
antimalarial chemotherapy are of urgent priority.
Several proteases are involved in the life cycle of malaria
parasites,3 including aspartic proteases named plasmepsins,
cysteine proteases named falcipains, and a metalloprotease
named falcilysin. In the erythrocytic stage of infection, these
proteases participate in the hemoglobin hydrolysis within the
parasite food vacuole to provide amino acids required for
parasite survival. Among them, a cysteine protease from P.
falciparum, falcipain-2 (FP-2), has been perceived as one of
the most promising targets for antimalarial drug design because
of its dual function: (i) it degrades hemoglobin at the early
trophozoite stage; (ii) it cleaves ankyrin and protein 4.1, the
cytoskeletal elements vital to the stability of the red cell
membrane at the schizont stage.4
As described in Scheme 1, the preparation of oxazolidine
derivative 4, the key intermediate for the construction of the
3-hydroxymethyl-1,4-benzodiazepine nucleus, was easily achieved
starting from commercially available D-serine methyl ester
hydrochloride (2), according to the procedure developed by
McKillop et al.13
The acid 4, obtained from the hydrolysis of intermediate 3,
was then converted into a mixed anhydride with isobutyl
chloroformate in the presence of N-methylmorpholine and
condensed in situ with 2-aminobenzophenone to afford deriva-
tive 5. Intermediate 5 was refluxed under acidic conditions to
induce the Boc deprotection of the nitrogen and the cleavage
of the oxazolidine ring to afford the 3-hydroxymethyl substituted
1,4-benzodiazepine 6. The protection of the hydroxy group with
tert-butyldimethylsilyl chloride gave 7, which was subsequently
reacted with sodium hydride and ethyl bromoacetate in DMF
to introduce the side chain at N-1 of the BDZ nucleus (8).
Recently, it has been demonstrated that P. falciparum contains
two nearly identical copies of the FP-2 gene located on
chromosome 11, encoding two distinct enzymes, namely, FP-
2A and FP-2B.5 The FP-2A corresponds to the previously
known enzyme designated as FP-2. The FP-2A and FP-2B
enzymes are 97% identical at the amino acid level. Their amino
acid sequences differ at seven positions within their mature
forms, including three amino acid replacements localized close
to residues that are predicted to interact with substrate, and
consequently may affect its affinity or specificity. The physi-
ological role of FP-2B and the functional significance of the
* To whom correspondence should be addressed. Phone: +39 090
6766466. Fax: +39 090 355613. E-mail: nmicale@pharma.unime.it.
# University of Messina.
† University of Illinois at Chicago.
§ University of Illinois College of Medicine.
‡ Caritas St. Elizabeth’s Medical Center.
10.1021/jm060405f CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/09/2006

Letters
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11 3065
Scheme 3a
Scheme 1a
a Reagents: (a) aqueous NaHCO3/THF (2/8), (Boc)2O, room temp, 12
h (96%); (b) 2,2-DMP, BF3‚Et2O, acetone, room temp, 2 h (95%); (c) 1 N
LiOH, MeOH, 0 °C to room temp, 6 h (86%); (d) i-BuOCOCl, N-
methylmorpholine, CH2Cl2, 0 °C to room temp, 30 min, then 2-aminoben-
zophenone, reflux, 20 min, then room temp, 13 h (79%); (e) 5% HCl/MeOH
(1/5), reflux, 7 h (85%); (f) TBS-Cl, imidazole, CH2Cl2, 0 °C to room temp,
12 h (87%); (g) NaH, DMF, 0 °C to room temp, 30 min, then BrCH2COOEt,
0 °C to room temp, 5 h (78%); (h) 1 N LiOH, MeOH, 0 °C to room temp,
6 h (82%).
a Reagents: (a) CH3CN/Et2NH (5/1), room temp, 2 h; (b) EDCI, HOBt,
DMF/CH2Cl2, (1/1), room temp, 15 h (65%); (c) TBAF, THF, room temp,
5 h (84%); (d) ArNCO, CH2Cl2, room temp, 12 h (66-80%); (e) TFA/
CH2Cl2 (1/3), room temp, 6 h, then 37% HCHO/AcOH/MeOH (1/1/3), room
temp, 20 h (19-42%).
Table 1
compd
FP-2A IC50, µM
FP-2B IC50, µM
Scheme 2a
1a
1b
1c
1d
1e
1f
1g
1h
1i
21.54 (15.97-29.06)
11.19 (6.23-20.07)
8.79 (5.97-12.95)
15.04 (11.60-19.49)
16.34 (12.29-21.71)
13.51 (10.27-17.77)
19.15 (15.20-24.12)
8.25 (4.47-15.21)
8.68 (5.86-12.84)
10.29 (6.46-16.39)
5.0
19.79 (15.49-25.29)
17.94 (12.08-26.66)
14.01 (8.70-22.57)
9.53 (6.48-14.01)
11.95 (8.80-16.24)
14.70 (10.68-20.25)
21.39 (16.50-27.72)
11.19 (6.23-20.07)
25.90 (11.27-59.52)
19.31 (11.91-31.30)
5.0
1j
MDL 28170
a Reagents: (a) i-BuOCOCl, N-methylmorpholine, CH2Cl2, 0 °C to room
temp, 30 min, then MeONHMe‚HCl, room temp, 15 h (86%); (b) LAH,
THF, -65 °C to room temp, 2.5 h; (c) NH2NHCONH2‚HCl, CH3COONa,
EtOH/H2O (7/3), 0 °C to room temp, 15 h (55%).
1-hydroxybenzotriazole (HOBt) to give 14 (Scheme 3). Desi-
lylation of 14 followed by treatment with various aryl isocy-
anates afforded intermediates 15a-i in high yield (70-80%).
Finally, removal of tert-butyl ester and semicarbazone protecting
groups by treatment with TFA and formaldehyde/acetic acid/
methanol provided target compounds 1a-i.
All compounds were tested on recombinant FP-2A and FP-
2B expressed in E. coli as a fusion with maltose binding protein
(MBP), in a fluorescence-based assay, and the results, expressed
as IC50 values, are reported in Table 1.
The rate of hydrolysis of the fluorogenic substrate Z-Leu-
Arg-7-amino-4-methylcoumarin (Z-Leu-Arg-AMC) in the pres-
ence of inhibitors at various concentrations was compared with
the rate of hydrolysis in negative controls incubated with an
equivalent volume of DMSO and with positive controls
incubated with MDL 28170 (Z-Val-Phe-CHO), a standard
inhibitor of papain-like family cysteine proteases.20 As can be
seen from the data reported in Table 1, in general, all our new
peptidomimetic derivatives provided significant inhibition of FP-
2A and FP-2B with IC50 in the range 8-26 µM. It is not known
what effect, if any, the presence of the MBP tag has on the
IC50 of various inhibitors. Experimentally, the isolation and
biochemical separation of native FP-2A and FP-2B enzymes
from Plasmodium falciparum are not feasible at this stage.
Finally, the ethyl ester group was hydrolyzed with 1 N LiOH
to afford derivative 9, which represents the constrained form
of the dipeptidic fragment Ser-Gly.
To synthesize the aspartyl aldehyde building block, we chose
a method that entailed the use of the stereochemically stable
semicarbazone derivative 13 as a masked aldehyde equiva-
lent.14,15 This general strategy has been used fruitfully to prepare
other peptide aldehydes in solution14,16 and on a solid sup-
port.17,18
The reaction sequence used to construct semicarbazone 13
is shown in Scheme 2. Commercially available Fmoc-â-(tert-
butyl ester)-L-aspartic acid (10) was converted into its Weinreb
amide 11, followed by selective reduction of the amide moiety
with lithium aluminum hydride.19 The obtained crude aldehyde
12 was immediately reacted with semicarbazide hydrochloride
to afford semicarbazone 13.
This aspartyl aldehyde synthon 13, after removal of the Fmoc
protecting group by diethylamine, was coupled to the carboxylic
acid 9 by using ethyl(dimethylaminopropyl)carbodiimide (EDCI)/

3066 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 11
Letters
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Chart 2
In this test, phenyl derivative 1a is the least potent inhibitor
(IC50 ≈ 20 µM on both the enzymes). The insertion of an
electron-donating or electron-withdrawing group at position 4
of the phenyl ring of the carbamoyl moiety increased the
inhibitory activity (e.g., 1c).
(5) (a) Nielsen, K. M.; Kasper, J.; Choi, M.; Bedford, T.; Kristiansen,
K.; Wirth, D. F.; Volkman, S. K.; Lozovsky, E. R.; Hartl, D. L. Gene
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By introduction of a methyl (1h) or a trifluoromethyl (1i)
group at position 2 of 4-chloroderivative 1d, an enhancement
of the inhibitory properties was observed. Also, the extension
of the aromatic area (1b) seems to be fruitful.
It is noteworthy that our compounds inhibit FP-2A and FP-
2B at a similar level. This is of utmost importance, since a recent
gene disruption study on FP-2A knockout parasites revealed
that the loss of FP-2A seems to be compensated by the increased
expression of FP-2B.5b This implies that the drug discovery
process should be focused on the identification of compounds
capable of inhibiting all the essential FPs.5c
To check the selectivity toward other cysteine proteases, these
compounds were tested against a panel of active recombinant
human caspases (i.e., caspases 1-9) according to the published
procedure.21 These compounds did not show any inhibitory
activity up to 50 µM.
Another experimental focus was to evaluate the impact of
chirality at the P3 site on the inhibitory activity against FPs. In
1a-i, an unnatural serine is incorporated in the peptide
sequence. Thereby, in one of the most interesting compounds
(1i), we replaced this amino acid with its natural counterpart.
Compound 1j (Chart 2) was synthesized following the same
procedure described above but with L-serine methyl ester
hydrochloride used as the starting material.
A comparison of the IC50 of diastereomers 1i and 1j indicates
that the stereochemistry at the P3 site does not significantly affect
the inhibitory potency of this class of derivatives against FPs.
In summary, we synthesized a new class of peptidomimetics,
incorporating a 1,4-benzodiazepin-2-one framework, which
proved to inhibit FP-2A and FP-2B enzymes. Further biological
experiments will be required to assess the significance of these
findings to malaria infection in red blood cells both in vitro
and in vivo. These results will form the basis for the develop-
ment of novel antimalarial drugs.
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Acknowledgment. Financial support from NIH Grants
HL60961 (A.H.C.) and AI50600 (M.H.) is acknowledged.
Supporting Information Available: Experimental procedures,
characterization of new compounds, and references to known
procedures. This material is available free of charge via the Internet
at http://pubs.acs.org.
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