Review
Falcipain inhibitors as potential
1. Introduction
2. FP-2 inhibitors developed at
GlaxoSmithKline Beecham
3. FP-2 inhibitors developed at
Enanta Pharmaceuticals
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13
4. FP-2 inhibitors developed at
Corvas International, Inc.
5. FP-2 inhibitors developed at
Medivir & Birch Steward
Kolasch & Birch
6. FP-2 inhibitors developed at
The Regents of the University
of California
7. FP-2 inhibitors developed at
Cartias St. Elizabeth’s Medical
Center of Boston, Inc.
For personal use only.
8. FP-2 inhibitors developed at
Jaume University
9. FP-2 inhibitors developed at
Second Military Medical
University and East China
University of Science and
Technology
10. FP-2 inhibitors developed at
Julius Maximilians University
of Wuerzburg and Technical
University Carolo Wilhelmina,
Brunswick
11. FP inhibitors developed at
Amura Therapeutics Ltd.
12. Miscellaneous peptidic FP
inhibitors
13. Expert opinion
10.1517/13543776.2013.743992 © 2013 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674
All rights reserved: reproduction in whole or in part not permitted
therapeutics for resistant strains
of malaria: a patent review
Uttam Rajaram Mane, Ramesh C Gupta, Sunil Sadanand Nadkarni,
Rajani R Giridhar, Prashant Prakash Naik & Mange R Yadav†
†
The M. S. University of Baroda, Pharmacy Department, Faculty of Tech. and Engg, Gujarat,
India
Introduction: There is an urgent need to discover new antimalarial drugs due to
emergence of resistance in the parasite to the existing drugs. Malarial cysteine
proteases falcipin-2 (FP-2) and falcipain-3 (FP-3) are attractive targets for anti-
malarial chemotherapy. The structures and functions of FP-2/3, their binding
domains and their interactions with small- and macro-molecules are well
studied. These studies could provide important insight into rational designing
of FP inhibitors as potential antimalarial drugs.
Areas covered: This review is focused on a selection of interesting patents
published during 1999 -- 2011 on peptidic and nonpeptidic chemotypes of
the FP-2/FP-3 inhibitors.
Expert opinion: It is a known fact that malaria is a serious health problem
worldwide due to the emergence of resistant strains. Hence, development
of novel, potent and affordable antimalarial drugs devoid of side effects is
of great significance and in great demand. FPs, the malarial cysteine proteases
are potential targets for development of new antimalarial drugs. Assessing
the available literature on FP-2/3 and their inhibitors it could be speculated
that these inhibitors have the potential to enter the clinical stages of
development for the treatment of malaria in the years to come.
Keywords: cysteine protease, falcipain, falcipain-2, falcipain-3, malaria, Plasmodium falciparum,
trophozoite cysteine protease
Expert Opin. Ther. Patents (2013) 23(2):165-187
1. Introduction
None of the parasitic diseases has had as enormous an impact on humans as malaria,
which is one of the major causes of morbidity and mortality of human civilizations in
the past, and even today it remains one of the deadliest diseases on the planet. Malaria
is a complex disease that varies widely in epidemiology and clinical manifestations in
different parts of the world. Malaria, particularly the one caused by Plasmodium falci-
parum, remains a serious health problem in Africa, South America and many parts of
Asia. An estimated 600 million people are at risk of malaria infection and the disease
kills more than 1 million children and a large number of pregnant women every year.
About 90% of these casualties occur in tropical Africa and a great majority of them are
children under the age of 5 [1,2]. The drug resistance-associated parasitic mutations to
antimalarial drugs in the malaria parasite are a major contributor to the re-
emergence of the disease and its spread in new locations and populations [3]. WHO
aims for the global rollback of malaria with intensified efforts in providing access to
affordable, safe and effective antimalarial treatments worldwide along with preventive
measures [1]. Science still has no magic bullet for malaria and doubts persist whether
such a single solution will ever come into existence.
165
 U. R. Mane et al.
Article highlights.
. Many problems are associated with the existing
antimalarial therapeutics forcing the scientific
community to develop newer antimalarial drugs.
. Malarial cysteine proteases FP-2 and FP-3 play key
roles in the energy deriving and other vital metabolic
processes of the parasite hence, are logical targets
for the development of new antimalarial drugs.
. Inhibition of cysteine protease, in particular the
inhibition of FP-2 and FP-3 by various chemotypes
blocks parasite development and growth.
.
A systematic study of these peptidic/nonpeptidic
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13
molecules active as FP inhibitors can afford important
structural insights to facilitate the design of potential
antimalarial agents in future.
The box summarizes key points contained in the article.
Control of malaria has been severely compromised as
the malaria parasites particularly the P. falciparum have devel-
oped resistance to nearly all antimalarial drugs used for
prophylaxis and treatment. There is an urgent and compelling
need for the discovery of new antimalarial drugs to save
lives and reduce morbidity and mortality [4]. Although a
For personal use only.
major medical need exists for the development of new anti-
malarials but unfortunately most of the people affected
by the disease are from developing countries with a little
market potential for the commerce-driven research and
development programs.
Business travels to malaria endemic areas have caused the
spread of the disease to the developed countries again where
it was thought to be totally eradicated a long back. The pro-
phylaxis of the disease is also complex because of the issues
related to resistance, safety and tolerance to the existing drugs,
so very limited antimalarial drug options are available
at present.
There are several reasons for the re-emergence and spread
of malaria infection across the globe. The most common
ones are the development of resistance by the parasite against
the first- and second-line antimalarial drugs, inadequate con-
trol of the mosquito vector and non-availability of effective
vaccine against the disease. The other major factors aggra-
vating the problems are increased population density, global
warming, continuing poverty and political instability in the
affected countries. All these factors have driven researchers
for identification and characterization of new targets for anti-
malarial chemotherapy. P. falciparum genome sequencing has
revealed a number of new targets for the development of new
drugs and vaccines and falcipains (FPs) the cysteine proteases
are some of them [4]. A new drug development program for
malaria must meet the challenges like the drug should be
cheap, efficacious, orally bioavailable and active against
drug-resistant cases. It also should have sufficient safety
margins so that it could be used in curing the infection of
infants and in pregnancy [5].
166 Expert Opin. Ther. Patents (2013) 23(2)
Medicine for Malaria Venture (MMV) is an organization
dealing with collaborative research by forming a sandwich
partnership between ‘public and private entities’ like pharma
industry, academia, institutes and government organizations
to discover, develop and deliver new drugs for the treatment
of malaria. Its product portfolio aims to deliver safe and effi-
cacious medicines that are affordable, accessible and appropri-
ate for use in malaria-endemic areas and to develop products
which could provide efficacy against drug-resistant strains of
P. falciparum and have the potential for intermittent treat-
ments with greater safety margins (infants and pregnancy).
The product should be efficacious against Plasmodium vivax
(including radical cure) and against severe malaria, and be
transmission-blocking. Their extensive product development
pipeline includes developing combination therapy of artemisi-
nins with the other antimalarials and antibiotics against
drug-resistant malaria and also developing new drugs against
existing and novel targets that are under various stages of
clinical development. Six combination therapy-based projects
have qualified the Phase IV studies. Tafenoquine, an
8-aminoquinoline derivative, and azithromycin-chloroquine
combination can be used to treat the parasite infection in
pregnancy. The other two artmesinin-based products that
can be used to treat pediatric patients are in Phase IIb/III
developmental stage. There are two projects in Phase IIa,
the first one is synthetic peroxide-based compounds
(OZ439) while the other one is on spiroindolone-based
compounds (NITD609) for treating blood stage of the
disease. Imidazolopiperazine-based compounds (GNF-156)
are in Phase I developmental stage. There are multiple
projects in preclinical and discovery stages of development,
like dihydroorotate dehydrogenase inhibitors, antifolates,
quinolones (ELQ300) and pyrazoles (21A092), etc. to fight
back the drug-resistant parasite [5]. At present, no effective
vaccine is available due to the high mutability of the genome
of P. falciparum, while drug resistance of malaria parasites
to available conventional drug therapy is becoming an
increasingly serious problem.
Although chloroquine (CQ), a 4-aminoquinoline derivative,
is a safe and cheap therapeutic antimalarial drug used for
decades, CQ-resistant strains of P. falciparum are now common
in malaria endemic areas. Drug resistance is most commonly
seen in P. falciparum [1]. Some other important antimalarial
drugs include antifolates such as diaminopyrimidines (e.g.,
pyrimethamine); biguanides (e.g., proguanil); sulfonamides
(e.g., sulfadoxine) and sulfones; derivatives containing a
quinoline core such as quinine and 8-aminoquinolines like
primaquine; arylaminoalcohols such as mefloquine, halofan-
trine and lumefantrine; hydroxynaphthoquinones (e.g., atova-
quone); artemisinin (the active principle of Artemisia annua,
an age-old herbal remedy used in China for the treatment of
fevers) and its semi-synthetic derivatives, such as artemether
and artesunate [6-8].
Of late, resistance has emerged to all classes of antimalarial
drugs except artemisinins, therefore, most of the African
 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review
countries have adopted artemisinin-based combination ther-
apy (ACT) as first-line treatment for uncomplicated malaria.
Among the several existing ACTs, artesunate-amodiaquine
(AS/AQ), artesunate-mefloquine and artesunatepyrimeth-
amine/sulfadoxine (AS/SP) and artensunate-chlorproguanil/
dapsone (AS/CD) and artemether-lumefantrine (AL) are
currently widely adopted in Africa and represent the recom-
mended therapy for uncomplicated malaria in over a dozen
countries. AL however has important limitations like need
for twice-daily dosing, irregular pharmacokinetics and high
risk of reinfection soon after therapy in high transmission
areas. Dihydroartemisinin-piperaquine (DP) is a new alterna-
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13
tive ACT for uncomplicated malaria. DP therapy has recently
become available in Africa as it is relatively inexpensive and
possesses some advantages: i) once a day dosing; ii) long
post-treatment prophylactic effect; iii) excellent safety and
iv) lower risk of recurrent malaria compared with AS/AQ
and AL [8,9].
The hemoglobin degradation pathway of the parasite
involving several parasite-specific enzymes like the plasmep-
sins and initially known as trophozoite cysteine protease
(TCP) and now as FPs play an important role in parasite
food assimilation [10]. One possibility to strike against
the parasite is to inhibit a key enzyme within this pathway,
For personal use only.
interrupting the nutrition source and therefore eliminating
the parasite by starvation [6]. Erythrocytic form of the
malaria parasite degrades hemoglobin as the principal source
of amino acids for parasite protein synthesis. A potential
target for antimalarial chemotherapy could be some enzyme
involved in the processing of hemoglobin, like cysteine
protease FP-2 or FP-3 [7].
Identification of enzymes responsible for hemoglobin
degradation led to the characterization of ‘plasmepsins’ the
aspartyl protease enzymes and ‘falcipains’ initially known
to be trophozoite food vacuole cysteine proteases, metallo-
proteases (named falcilysins) [11] and the lately discovered
dipeptidyl aminopeptidases (DPAP) [12]. FP-2, a cysteine
protease from P. falciparum is one of the most promising
targets for antimalarial drug design. It is a key enzyme in
the life cycle of P. falciparum as it degrades hemoglobin
in early trophozoite stage at acidic pH in the food vacuole
and cleaves ankyrin and protein 4.1, the cytoskeletal
elements vital to the stability of red blood cell membrane
in schizont stage [13-16].
Recent studies identified and characterized FPs a family of
papain-like cysteine proteases comprising FP-1, FP-2 and
FP-2¢, and FP-3 [17]. FP 2A (FP-2) and 2B (FP-2¢) share
97.5% amino acid sequence and differ only in three amino
acids, none of which is located at the active site of
the enzymes. FP-2 and FP-3 (65% amino acid identity) are
predominantly expressed in the acidic food vacuole of troph-
ozoites and schizonts. FP-3 expressed later in the life cycle is
also an efficient hemoglobinase [18-20]. Cysteine protease
inhibitors that inhibit FP-2 and FP-3 consistently block
hemoglobin hydrolysis and parasite development, suggesting
Expert Opin. Ther. Patents (2013) 23(2)
that these two proteases are key target enzymes. Knockout
studies of FP-2 led to transient blockade of hemoglobin
hydrolysis in trophozoites and increased sensitivity of
parasite to protease inhibitors, though parasites recovered
from this defect later on in the life cycle, presumably
because of expression of FP-3. Knockout of FP-3 remained
unsuccessful, although replacement of the FP-3 gene with
a functional copy was readily achieved; suggesting that
FP-3 is an essential enzyme in erythrocytic parasites [21,22].
FP-2¢, a nearly identical copy of FP-2, has unknown
functions, as disruption of the FP-2¢ gene did not lead to
noticeable alterations in erythrocytic parasites [23]. The role
of FP-1 remains unknown; knockout of this protease led
to no apparent changes in the erythrocytic parasites [24].
In any event, cysteine protease inhibition, in particular
the inhibition of FP-2 and FP-3, blocks parasite deve-
lopment and are thus logical targets for antimalarial
chemotherapy [25-27].
The complex of FP-2 and FP-3 with small and macromole-
cular inhibitors can provide a structural insight to facilitate the
design of potent compounds. The major classes of FP-2,
FP-3 and other cysteine protease inhibitors reviewed in the
literature are peptides or peptidomimetics bearing the most
popular pharmacophores of cysteine protease inhibitors apart
from some recent references on non-peptidic FP inhibi-
tors [26,28]. The peptidic and peptidomimetic FP inhibitors
reported against FP-2 and FP-3 at nanomolar concentrations
are vinyl sulfones [29,30], halomethyl ketones [31], a-ketoamides
and aldehydes [32]. Other chemotypes that have been identi-
fied as inhibitors of FP-2 include isoquinolines, thiosemicarba-
zones and chalcones. Chalcone-artemisinin combination
therapies have been reported to show synergistic or additive
effect in the treatment of malaria [33].
2-Pyrimidinecarbonitriles have been reported to be active
in nanomaolar/picomolar concentrations against FP-2 and
FP-3 [26]. The other FP-2 inhibitors reportedly active in low
micromolar concentrations were 2-(3,4-dihydro-4-oxothieno
[2,3-d]pyrimidin-2-ylthio)acetamides [34], 2-amido-3-(1H-
indol-3-yl)-N-substituted-propanamides [35] and dihydroarte-
misinin-based (thio)semicarbazones [36]. A series of 1-aryl-6,
7-disubstituted-2H-isoquinolin-3-ones were studied for inhibi-
tion of FP-2, rhodesain and other cysteine proteases like
cathepsin B, L and were found to be non-selective FP-2
inhibitors [37]. Azadipeptide nitriles were observed to be potent
FP-2 and FP-3 inhibitors [38], peptidomimetics-thioacylals
bearing protected aspartyl protease aldehyde warhead were
studied for inhibition of protozoal cysteine proteases FP-2 and
rhodesain [39], b-amino alcohol thiolactone-chalcone (IC50
ranged from 0.68 to 6.08 µM) showed better activity profile
than isatin-chalcone hybrids in W2 strain of P. falciparum but
only the isatin-chalcone hybrids were active against FP-2 [40].
Artemisinin-vinyl sulfone hybrid molecules with the potential
to act in the parasite food vacuole via endoperoxide activation
and FP inhibition showed activity at 2 -- 5 nM level in
W2 strain of P. falciparum and despite having required
167
 U. R. Mane et al.
structural features essential for activity these compounds showed
FP-2 inhibition in micromolar range only [41]. In another com-
bination chemotherapy through single prodrug approach,
carbonyl-based protease inhibitors were converted into endoper-
oxide hybrids 1,2,4-trioxolanes masking the carbonyl group and
the prodrugs release the peroxide radical in vivo that chelates
iron of heme and the carbonyl moiety (aldehyde/ketone)
inhibits FP-2; the hybrid compounds showed activity in
nanomolar concentration against FP-2, FP-3 and 3D7 strains
of P. falciparum [42]. In a multi-target therapy approach a series
of small molecules were designed and synthesized showing dual
inhibition of FP-2 and dihydrofolate reductase as antimalarial
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13
agents and their potency was increased six to eight times to
that of individual inhibitors [43].
Some virtual screening and docking studies have been per-
formed to identify new non-peptidic FP inhibiting templates.
Virtual screening of ChemBridge database (consisting of
approximately 2,41,000 compounds) was performed in an
attempt to identify non-peptide inhibitors of parasitic cysteine
proteases as novel drugs exhibiting FP-2 and FP-3 inhibition
with few of them showing preferential selectivity for FP-2 [44].
The SPECS database was screened against FP-2 with two
different docking methods to identify structurally diverse
but potent non-peptidic inhibitors [45].
For personal use only.
In this review, the authors have summarized earlier
reports on inhibition of TCP known as FPs consisting of
the well-studied FP-2 and later reports on FP-2 and
FP-3 inhibitors. FP-3 with 65% amino acid sequence iden-
tity to FP-2 is an equally important hemoglobinase so com-
pounds showing activity against FP-2 should also show
considerable activity against FP-3 as both are essential hemo-
globinases in the blood stage. They have tried to incorporate
the information on patents reported on inhibitors of other
cysteine proteases claiming their utility as FP (FP-2, FP-3)
inhibitors.
2.FP-2 inhibitors developed at
GlaxoSmithKline Beecham
GlaxoSmithKline (GSK) along with University of California
and MMV were the first to start work on FP inhibitors.
GSK is actively involved in the development of potent FP
inhibitors. GSK and MMV are jointly developing antima-
larial drugs aiming at different targets and development of
FP inhibitors is one of them.
2.1 Hydrazides and amide derivatives
Thompson et al. in one of the early inventions on cysteine
protease FP has reported peptidic hydrazides and amides
as TCP (i.e., FPs) inhibitors to treat parasitic diseases such
as malaria. They have evaluated 18 peptidic compounds
for inhibition of FP. The reported compounds were having
very high binding affinity for FPs and showed activity in
nanomolar concentrations. The dissociation constant (Ki)
values for the compounds ranged from 9.5 to 550 nM.
168 Expert Opin. Ther. Patents (2013) 23(2)
The compounds (1 -- 5) (Figure 1) were very potent FP inhi-
bitors with Ki values of 9.5, 15, 28, 22 and 18 nM,
respectively [46,47].
2.2 Azepan-3-one derivatives
Novel peptidic 4-aminoazepan-3-one derivatives have been
reported by Tew et al. as cysteine protease inhibitors. The
peptidic 4-aminoazepan-3-one derivatives were active against
seven parasitic proteases which included FP, cruzain,
rhodesain, leishmania B and L and schistosoma B1 and
B2 enzymes. Out of the 222 compounds screened for inhibi-
tion of these seven parasitic proteases, 59 compounds were
evaluated for FP inhibition assay. The binding affinities for
majority of the compounds were observed to be below
10 nM and values varied between 1.9 and 96 nM when tested
for FP-2 inhibition. Compounds (6, 7) (Figure 2) exhibited
the IC50 values of 1.9 and 2 nM, respectively [48,49].
There are certain reports claiming the use of compounds
for inhibition of some other cysteine proteases but these
have also been claimed to be FP inhibitors. Among them,
Cummings et al. in their patents have reported peptidic
azepan-3-one class of compounds (8-16) (Figure 3) [50-53];
Jeong et al. have reported different substituted 3,7-dioxo
azepan-4-yl amides (17-18) [54,55]; 6-oxo[1,2]diazepan amides
(19, 20) [56,57]; 7-substituted 3,6-dioxooctahydropyrrolo
[1,2-a]azepines (21, 22) [58]; substituted 1,1,4-trioxo[1,2]thia-
zepan-5-ylamides (23) [59-61]; substituted dioxohexahy-
drodiazepino[1,2-b]phthalazine amide class of compounds
(24) [62,63]. Clark et al. have reported peptidic benzofuran-
2-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-oxo-
1-(pyridine-2-sulphonyl)azepan-4-ylcarbamoyl]butyl}amides
(25) as cathepsin K and FP inhibitors [64,65].
2.3 Pyrimidinenitriles
Castro et al. in their patent have reported novel peptidic 2,4-sub-
tituted pyrimidinenitriles (26, 27) (Figure 4) as FP-2/FP-3 inhib-
itors for the treatment of malaria and also cathepsins K, L, S and B
inhibitors. The compounds were reported to be active below
100 nM concentrations for FP-2 inhibition [66].
Castellote et al. have reported a novel pyrimidinenitrile
class of compounds as cysteine protease inhibitors. Twenty
substituted pyrimidinenitrile compounds were evaluated for
their FP-2, FP-3 binding affinities and also for some other
cysteine proteases like vivapain-2, cathepsins K, L, S and B
and serine proteases. Almost all of the compounds exhibited
very good activity; compounds (28-31) (Figure 4, Table 1)
showed the dissociation constant (Ki) values of 1 nM each
for FP-2, 2.5 nM each for FP-3 and in whole cell assay 28
showed (Ki) value of 2.5 nM and others (29-31) were having
binding affinity at 15 nM [67].
Chaparro et al. in their patent have reported 80 substituted
pyrimidinenitriles as cysteine protease FP-2 inhibitors. The
compounds were also active against other cysteine proteases
like FP-3, cathepsins K, L, S and B and serine proteases.
Almost all of the compounds were having very high binding
 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

CH3
CH3
O O H O
H
N N
O N N N N O
H H H O H
O

1 Ki = 9.5 nM
O O
H O
O N H
N N
CH3
CH3 H3C O
O H O O
N N N CH3
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13

N N 2 Ki = 15 nM
H O H
S
N
O
3 Ki = 28 nM
CH3
O H O
N N
N N N CH3
O H O H
H3C O S
N
CH3 H3C
CH3 4 Ki = 22 nM
O H O
N N
O N N
H O H
N S

5 Ki = 18 nM
For personal use only.

Figure 1. Hydrazides and amides as falcipain inhibitors (GSK).

F
CH3
H3CO H
CH3 O N
O O O
H H
N N N
N O
N N
H O
O S H
H3CO O N S O
O O H3C
CH3

6 IC50 = 1.9 nM 7 IC50 = 2 nM

Figure 2. Azepan-3-one falcipain inhibitors (GSK).

affinity for FP-2. Compounds (32 and 33) (Figure 4, Table 1)
were active with (Ki) values of 1 nM each for FP-2 and at
2.5 nM each for FP-3 while both possessed Ki values of
15 nM in whole cell assay [68]. Lopez et al. have reported
243 novel pyrimidinenitrile compounds as inhibitors of
cysteine proteases like FP-2, FP-3 and cathepsins K, L, S
and B. Both compounds (34 and 35) (Figure 4, Table 1)
exhibited Ki values of 15 nM for FP-2, 150 nM for
FP-3 while compound (35) in whole cell assay was active at
15 nM concentration [69]. In another patent, Lopez et al.
have reported 85 substituted pyrimidinenitrile compounds.
Compounds (36 -- 38) (Figure 4, Table 1) were active at 1 nM
concentration when tested for FP-2 inhibition and com-
pound (36) in whole cell assay was active at 1 nM while com-
pounds (37, 38) were active at 150 nM concentrations in
whole cell assay. All of the compounds (36-38) showed Ki
values of 2.5 nM each against FP-3 enzyme [70].
Lopez et al. in yet another patent have reported novel substi-
tuted pyrimidines. The substituted 2-pyrimidinenitrile salts
were evaluated against cysteine proteases like FP-2 and
FP-3, and in whole cell assay their IC50 values varied
between 1 and 400 nM. Two of the compounds (39, 40)
(Figure 4, Table 1) exhibited very high binding affinity for
FP-2 with Ki value of 1 nM each and 2.5 nM each in whole

Expert Opin. Ther. Patents (2013) 23(2) 169

 U. R. Mane et al.

CH3 CH3 CH3

CH3 CH3 CH3
O H O O O O O
H H
N N N
N N N N N N
H O N S O H O H O
O H3CO O N S O O N S O
H3CO
O O O
H3C H3 C CH3

8 9 10

CH3 CH3 CH3

CH3 CH3 CH3
O O O H O O H O
H N
N N
N N N N N
N H H
H O S O N S O S O N S O
O N S O
O O
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13

O
CH3 H3C H3C

11 12 13

CH3 CH3 CH3

CH3 CH3 CH3
O H O O H O H3C O O
H
N N N
N N N N N N
S H O S H O N S O N H
S N S O S O O N S O
O O O
H3C H3C CH3
14 15 16

CH3 CH3 CH3

CH3 CH3 CH3
O H O O O O H O
H
For personal use only.

N N N N
N N O
H O H O O H O N
O N O N
N O
O O CH3
17 18 19

CH3 CH3 CH3

CH3 CH3
O CH3
H O O O O O
H H
N N N
N N N
H N H O
O O N O O N H O
O O N
N O
CH3
20 21 22

CH3 CH3 CH3

CH3 CH3
CH3
O O H O H3C O O
H O H
N N
N N
N O N N
H O H
H O N O N S O
O O N O
N
S O O
O CH3
O
23 24 25

Figure 3. Azepan-3-one as falcipain inhibitors (GSK).

cell assay while both showed binding affinity for FP-3 with
Ki values of 15 nM each [71].
2.4 Purinenitriles
Novel purinenitriles have been reported as cysteine protease
inhibitors by Lopez et al. The substituted purinenitriles were
evaluated against cysteine proteases FP-2 and FP-3. The
compounds showed activity in the range of 1 -- 15 nM.
When tested for FP-2 inhibitory activity, compounds (41-44)
(Figure 5, Table 2) were active at 1 nM concentrations and
compound (45) was active at 2.5 nM. In the whole cell
assay, compounds (41-44) showed Ki values of 150 nM each
while compound (45) was active at 250 nM in the in vitro
assay [72].

170 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

Cl N Cl H3C O

NH
N N
H H
HN N N O N N
N N N N
O H3C CH3 O CH3
CH3
CH3 CH3
26 27

Br Br
N N N N
H H
N N H3C N N
N N N N N N
N O O
H3C H3C

28 29
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13

H3C N Br Br
N N N N
H H
N N N N N
N N N N
O N O
H3 C
30 31
N Br Br
N N
H N
H3C N N N N H N
N N N N
N
N O CH3 O
N CH3
H3C
32 CH3 33 CH3

F F
For personal use only.

Br Br
N N
H
H N N N N
N N N N N N N
N
O N O
N CH3 CH3
N H3C
H3 C 34 H3C 35

Br Cl
N N HO
H N N
N H
N CH3 N N
N N N N N
N O O
H3C
36 CH3 37

OH H3 C
N Br
Cl N N
N N H
H N N
CH3 N N N N
N N
O
O

38 39

Cl
N N
H
N N
N N N
N O
H3C
40

Figure 4. Pyrimidinenitriles as falcipain inhibitors (GSK).

Expert Opin. Ther. Patents (2013) 23(2) 171

 U. R. Mane et al.

Table 1. In vitro FP-2 and FP-3 inhibition and Ki values novel FP inhibitors (Figure 7). They have reported 34 novel
in whole cell assay. compounds. The IC50 values for FP inhibition of the peptidic
derivatives varied from 10 to 100 nM [75].
Compound Ki values (nM)
5. FP-2 inhibitors developed at Medivir &
FP-2 FP-3 Whole cell assay
Birch Steward Kolasch & Birch
28 1 2.5 2.5
29 1 2.5 15 5.1 Peptidic furanones
30 1 2.5 15 Quibell et al. have reported novel peptidic tetrahydrofura-
31 1 2.5 15
32 1 2.5 15 none derivatives as FP and cathepsin K inhibitors in their
33 1 2.5 15 invention entitled ‘cysteine protease inhibitors’ [76]. They
34 15 150 150 have synthesized peptidic furanones by using solution
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35 15 150 15 as well as solid phase synthesis. The observed (Ki), the

36 1 2.5 1 dissociation constant of the non-covalent complex enzyme--
37 1 2.5 150
38 1 2.5 150 inhibitor which is the measure of the binding affinity at
39 1 15 2.5 pH 7 for the compounds (57-62) (Figure 8) ranged from
40 1 15 2.5 0.5 to 2.5 µM [77].
Quibell et al. have reported novel peptidic tetrahydrofura-
FP: Falcipain.
none compounds (63-67) (Figure 8) as FP and cathepsin S
inhibitors in another patent. They have synthesized peptidic
In another patent, Lopez et al. have reported the substituted furanonamides as cathepsin S [78,79] or cathepsin K [80,82]
2-purinenitrile salts for inhibition of FP-2, FP-3 and in whole and FP-2 inhibitors for the prophylaxis and treatment of
cell assay. Their IC50 values ranged between 1 and 1000 nM. malaria. The FP-2 binding affinities (Ki) for the compounds
Compounds (46 -- 48) (Figure 5, Table 2) displayed in vitro at pH 7 ranged from 0.5 to 3 µM [78,79] and 0.5 to
2.7 µM [80-82].
For personal use only.

binding affinity with (Ki) values of 1 nM each for

FP-2 inhibition and for FP-3 Ki values were 150, 2.5 and
15 nM, respectively but these were not that effective in whole
cell assay (150 -- 1000 nM) [73].
3. FP-2 inhibitors developed at Enanta
Pharmaceuticals
6.FP-2 inhibitors developed at The Regents
of the University of California
University of California is one of the MMV FP project part-
ner and actively involved in research on the enzyme FP.

3.1Bifunctional inhibitors of malarial cysteine 6.1 Thiosemicarbazone and semicarbazone inhibitors

proteases
Ekstein et al. have developed non-peptidic bifunctional protease
inhibitors that could inhibit parasitic aspartyl and cysteine pro-
teases in submicromolar concentrations. They have adopted an
approach of combining characteristic features of potent plas-
mepsin and FP inhibitors into one single molecule by replacing
the amide bond to construct the bifunctional inhibitors (49-52)
(Figure 6), so that one single molecule could exhibit inhibitory
activity against both types of proteases. This could prove to be
a more effective strategy against malarial parasite than inhibiting
individual proteases. Simultaneous dual inhibition of the
enzymes may exert the synergistic effect by targeting both of
the essential parasitic enzymes and it may also check develop-
ment of resistance against the inhibitors in the parasite [74].
4. FP-2 inhibitors developed at Corvas
International, Inc.
4.1Dipeptidic acrylates, acrylamides, a-ketoamides
and aldehydes
Lim-Wilby et al. have reported the dipeptidic acrylates (53),
acrylamides (54), a-ketoamides (55) and aldehydes (56) as
Cohen et al. have reported novel cysteine protease inhibitors
for antimalarial, antitrypanosomial, antileishmanial and
anticancer activities. The thiosemicarbazones, semicabazones
and their cyclized pyrazoline analogs were tested for cysteine,
cruzain and FP-2 protease inhibition. The compounds
(68, 69) (Figure 9) showed IC50 values of 32 µM and
150 nM, respectively, against P. falciparum; and in another
strain P. falciparum GHANE compound (68) had IC50 value
of 16 µM. Most of the compounds were reported to be
non-cytotoxic [83,84].
Chibale et al. have reported a set of 73 substituted thiose-
micarbazone and semicarbazone derivatives. They have
studied the effect of these compounds against cruzain, rhode-
sain and the P. falciparum W2 strains. The effect of various
substituents on thiosemicarbazone motif on biological activity
has also been studied by them. For one set of derivatives
evaluated against P. falciparum W2 strain the IC50 values
were found to range from 10 to > 20 µM (Table 3) and the
ED50 ranged from 4 to > 20 µM while for another set of com-
pounds IC50 ranged from 10 to > 20 µM and the ED50
ranged from 0.03 to > 20 µM (Table 4). Most of the reported
compounds were found to be non-toxic. Compounds (70-74)

172 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

CH3 CH3
N N
N CH3
N N N
N N
H H
H3C O N N H3C N N
N N N N N
H3C O
CH3 O N

41 42
O
O
N
N N CH
N 3
N N CH N
3
N N N
H
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N
H N N N
H3C O N N H3C N N
N N O
H3C
CH3 O

44
43
O CH3
N CH3 N
N N N
H3C N
N CH3 N
N H
N
H N N N
H3C O N N N N
N N
H3C O
CH3 O
For personal use only.

46
45

O
O
N N
N N CH
N N CH 3
3 N
N N
N H
H H3 C O N N
H3C O N N N N
N N H3C
H3C CH3 O
CH3 O

48
47

Figure 5. Purinenitrile falcipain inhibitors (GSK).

Table 2. In vitro FP-2 and FP-3 inhibition and Ki values (Figure 10) showed IC50 values of 0.013, 0.013, 0.008,
in whole cell assay. 0.025 and 0.028 µM, respectively. Some of the compounds
were active in P. falciparum W2 strains with IC50 values
Compound Ki values (nM) ranging from 0.008 to > 20 µM [85,86].
FP-2 FP-3 Whole cell assay
6.2 Fluoregenic compounds
41 1 150 150
42 1 150 150 Renslo et al. in their patent have reported prodrugs and
43 1 2.5 150 fluoregenic compounds for the treatment of malaria, schistoso-
44 1 15 150 miasis, trypanosomiasis and cancer. They have reported 13
45 2.5 150 250 fluoregenic compounds and out of them five compounds were
46 1 150 150 evaluated for FP inhibition. Compounds (75-78) (Figure 11)
47 1 2.5 250
48 1 15 1000 exhibited FP inhibition with EC50 values of 24, 4.9, 15,
62 nM, respectively in W2 strain of P. falciparum and 16, 9,
FP: Falcipain. 16, 38 nM, respectively in 3D7 strain of P. falciparum [87].

Expert Opin. Ther. Patents (2013) 23(2) 173

 U. R. Mane et al.

H3C CH3 H3C CH3

Si Si
O O O O O O O O
H O H O
N N S N N S
N N
O O O O

49 50

O OH OH O
H O
N N S O OH O
N O
S
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13

O O N N N
H
O OH O

51
52

Figure 6. Bifunctional falcipain inhibitors (Enanta Pharmaceuticals).

For personal use only.

H O
H O
H3C O N N
O N OCH3 N
N H3C H
H CH3 O O
O O CH3
CH3
CH3
CH3
54
53

OCH3

O O O O
H H
O N N N H
N N N
H H O H O
O O
CH3
CH3

55 56

Figure 7. Dipeptidic acrylate, acrylamide, a-ketoamide and aldehyde falcipain inhibitors (Corvas International, Inc.).

7. FP-2 inhibitors developed at Cartias
St. Elizabeth’s Medical Center of Boston, Inc.
7.1 Peptides derived from ankyrin and the protein 4.1
Hanspal et al. have reported a particular region in the sequence
of ankyrin and protein 4.1 which is the site of cleavage at
carboxyl terminal by FP-2. Cysteine protease FP-2 cleaves
erythrocyte membrane ankyrin and erythrocyte membrane
protein 4.1. The discovery of Hanspal et al. could be helpful
in using particular sequence of amino acids or the nucleic acids
encoding the sequence for discovering new therapeutics for the
treatment of malaria. Peptides derived from ankyrin Ank P1
(sequence NVSARFWLSD (SEQ. ID NO.: 1, Ank P1))
(Table 5) is a 10 amino acid peptide corresponding to
amino acid residues 1206 -- 1215 of human erythrocyte
ankyrin. The protein 4.1-derived peptide, 4.1 P1 (sequence

174 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

H3 C H3C
H3C O N
O O O
O H H O
H N N
N O N N
N H O H
H O O O
O O CH3
CH3 CH3
58 CH3 59 CH3
57 CH3

N
O N
H3C H3C H3C
N O N O
O O
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H O H H O
H
N N N
N N N
O H O H O H O
O O
CH3 CH3 CH3
60 CH3 61 CH3 62 CH3

CH3 N
H3C H3C H3C
N HO O S
H3C O O O
O H H O
H
N N N
N N N
H O H O H O
O O O
CH3 CH3 CH3
63 CH3 64 CH3 65 CH3
For personal use only.

H H3C
H3C H3C N O
O H O
H O
O N
N N
N H O
H O O
O CH3
CH3
67 CH3
66 CH3

Figure 8. Peptidic furanone falcipain inhibitors (Medivir).

Cl cell rupture and malaria parasite release in the schizont stage.

Cl
S S
N N
Br N NH2
H H
H3C H3C
68 69
Figure 9. Thiosemicarbazone and semicarbazone inhibitors
as falcipain inhibitors (The Regents of the University of
California).
DLDKSQEEIKKHHASI (SEQ. ID NO.: 5, 4.1 P1)) is a
16 amino acid peptide corresponding to amino acid residues
428 -- 443 of the spectrin/actin binding (SAB) domain of
human erythrocyte protein 4.1 amino acid sequence; the cyto-
skeletal element vital for erythrocytic membrane stability. Each
of these peptides have no apparent sequence homology, either
alone or in combination with one another. Protein 4.1 and
erythrocyte membrane ankyrin are believed to inhibit host
The other protein 4.1 peptides within SAB domain do not
appear to exhibit this inhibitory effect. The development of
N NH2 trophozoites and schizonts was markedly inhibited by the fused
peptide Ant-Ank P1 (Table 5) to less than 10% of the new ring-
stage compared with the control. These results demonstrated
the potential efficacy of Ank P1 peptide in terms of its
ability to inhibit growth and development of P. falciparum
trophozoites in vivo [88].
8.FP-2 inhibitors developed at Jaume
University
8.1 Peptidic epoxides
Adelantado et al. have reported novel peptidic epoxides
(Figure 12) as selective inhibitors of cysteine protease FP,
cruzain, rhodesain over cathepsin B. Ethyl (2S,3S)-3-[(2S)-
2-((2S)-2-benzyloxycarbonylamino-3-phenylpropionyla-
mino)-4-phenylbutyryl]oxirane-2-carboxy-late (79) (Figure 12)
showed IC50 value of 71 nM while compound (80) the

Expert Opin. Ther. Patents (2013) 23(2) 175

 U. R. Mane et al.

Table 3. Thiosemicarbazone inhibitors of FP-2.

CH3
H
N R2
N
R1
S

Compound R1 R2 FP-2 IC50 (mM) Plasmodium Host

falciparum ED50 (mM) toxicity

A 2¢-Phenyl NH2 > 20 > 20 None

B 3¢-Phenyl NH2 > 20 > 20 None
C 4¢-Phenyl NH2 10 > 20 Toxic
D 2¢-NH-phenyl NF2 > 20 > 20 None
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E 3¢-NH-phenyl NH2 > 20 > 20 None

F 4¢-NH-phenyl NH2 > 20 9.9 None
G 3¢-O-phenyl NH2 > 20 > 20 Toxic
H 4¢-O-phenyl NH2 > 20 > 20 Toxic
I 3¢-Br NH2 > 20 > 20 None
J 3¢-NMe2 NH2 > 20 > 20 None
K 2¢-OH NH2 > 20 > 20 None
L 3¢-OH NH2 > 20 > 20 None
M 3¢-Br SMe > 20 > 20 None
N 3¢-Br Piperidyl > 20 > 20 Toxic
O 3¢-Br N-Methylpiperazinyl > 20 4 Toxic
P 3¢-Br NEt2 > 20 > 20 None

FP: Falcipain.
For personal use only.

Table 4. Biological data of thiosemicarbazone derivatives.

R1
CH3
H
N R2
Z N
Y X S

Compound R R1 R2 X Y Z FP-2 IC50 (mM) Plasmodium Host

falciparum ED50 (µM) toxicity

A H H NH2 N CH CH > 20 0.08 None

B H H NH2 CH N CH > 20 > 20 None
C H H NH2 N CH N 10 > 20 None
D H H SMe N CH CH > 20 0.03 None
E C(Me)=NNHC(S)NH2 H NH2 CH CH CH > 20 > 20 None
F C(Me)=NNHC(S)NH2 K NH2 N CH CH > 20 0.03 None
G C(Me)=NNHC(S)NH2 Me NH2 CH CMe N > 20 > 20 None

FP: Falcipain.

diastereomer of oxirane (79) exhibited an IC50 value of 44 nM
against enzyme FP-2 [89,90].
9. FP-2 inhibitors developed at Second
Military Medical University and East China
University of Science and Technology
9.1Flavonoid glycoside compounds
Weidong et al. revealed the flavone glycosides [91-93] as
FP-2 inhibitors for the treatment of malaria in their patent.
The compounds were studied for their binding affinities to
FP-2 inhibition. cynanversicoside C has Ki (FP-2) value
of 5.78 µM and the IC50 values of 26.4 µM (D6 strain) and
88.6 µM (W2 strain) [91]. In another patent, they have
reported that the stenopalustroside D (82) (Figure 13, Table 6)
and silver linden glycosides showed in vivo activity of
64% parasitic inhibition at a dose of 50 mg/kg by i.p. route,
while the other compounds reported in the patent
showed in vivo activity with parasitic inhibition ranging
from 30 to 60% [92,93].

176 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

S S S
HN N HN N HN N
N O N N
N N
N CH3 N
CH3 CH3 CH3

70 IC50 = 0.013 μM 71 IC50 = 0.013 μM 72 IC50 = 0.008 μM

S S

HN N CH3 HN N

N N
N CH3 N

CH3 CH3
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73 IC50 = 0.025 μM 74 IC50 = 0.028 μM

Figure 10. Thiosemicarbazones as falcipain inhibitors (The Regents of the University of California).

Cl

O O

O N O O N N
O H
Cl
O O O O
O O
HN HN
For personal use only.

N N

75 O 76 O

O N
O

O N O O N N
O
CH3 O
O O O O Cl
O O
HN HN
N N
77 78 O
O

Figure 11. Fluoregenic compounds as falcipain inhibitors (The Regents of the University of California).

Table 5. Effect of ankyrin on the peptide growth and 10.FP-2 inhibitors developed at Julius
development of Plasmodium falciparum trophozoites in Maximilians University of Wuerzburg and
culture. Technical University Carolo Wilhelmina,
Brunswick
Treatment Concentration (mM) % of ring
parasites
10.1 Guanidine-substituted furans, thiophenes and
DMSO -- 100
Ank P1 250 100 pyrroles
Ant 250 95 Schimeister et al. have reported guanidine-substituted furans,
Ant-Ank P1 50 73 thiophenes and pyrroles as FP-2, FP-3 and other cysteine pro-
100 40 tease inhibitors for the treatment of diseases such as parasitic
250 < 10
diseases, autoimmune diseases and cancer. The compounds
Scrambled Ant-Ank P1 250 100
were having IC50 values ranging from 1.1 to 190 µM for
Ant: Antennapedia peptide; DMSO: Dimethyl sulfoxide. FP-2 with the most potent compounds (86, 88) (Figure 14)

Expert Opin. Ther. Patents (2013) 23(2) 177

 U. R. Mane et al.

O H O
O H O N OC2H5
N OC2H5 O N
O N H O
O O O
H O O

79 80

Figure 12. Peptidic epoxides as falcipain inhibitors (Jaume University).

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HO HO

O OH O OH

O O
HO O OH HO O
O OH
O
O O
O OH O O OH O OH O O OH

OH HO
For personal use only.

81 Stenopalustroside A 82 Stenopalustroside D

HO HO

O OH O OH
HO
O O
HO O OH O O OH
O O
O
HO HO CH3
OH O O O O

HO
OH OH
83 Kaempferol 3β-O-(6′-caffeoyl glucopyranoside) 84 Kaempferol 3β-O-(2,4-di-E-p-coumaroyl rhamnoside)

Figure 13. Flavonoid glycoside compounds as falcipain inhibitors (Second Military Medical University and East China
University of Science and Technology).

Table 6. FP-2 inhibition data of flavone glycosides

S. No. Compound % Inhibition (10 mM) IC50 (mM)

1 Stenopalustroside A (81) 53.03 1.45

2 Stenopalustroside D (82) 39.40 --
3 Silver linden glycosides 64.36 13.13
4 Kaempferol-3b-O-(6¢-caffeoyl glucopyranoside) (83) 53.03 13.52
5 Kaempferol-3b-O-(2,4-di-E-p-coumaroyl rhamnoside) (84) 49.37 --

FP: Falcipain.

178 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

H3C O H H
H
H3C N N N O
H3C O N N
H H O NH O
O
85

H H H H
N N N O
O N
N
H O
O O O NH
86
H
O N
H H H
N N O
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O N
N
H O
O O NH

87

H
O N
H H H
O N N N O
N
H O
O O NH

88

Figure 14. Guanidine-substituted pyrroles as falcipain inhibitors (Julius Maximilians University of Wuerzburg and Technical
University Carolo Wilhelmina, Brunswick).
For personal use only.

exhibiting IC50 values of 1.12 and 1.1 µM, respectively and
the other two compounds (85, 87) showing IC50 values of
2.62 and 1.87 µM, respectively. The compound (85) was
evaluated for its in vitro toxicity with its measured cytotoxic
concentration of 18.69 µM [94].
11.FP inhibitors developed at Amura
Therapeutics Ltd.
12.2 Peptidic nitrile derivatives
Cameron et al. in their invention entitled ‘Cathepsin cysteine
protease inhibitors for the treatment of various diseases’ have
discussed the peptidic nitriles (129, 130) (Figure 17) as cathep-
sin inhibitors and have also claimed these compounds to be
FP inhibitors for the treatment of malaria [140].
13. Expert opinion

11.1Furopyrrol-3-ones, other furanone and
diazapentalene derivatives
Quibell et al. have reported the tetrahydrofuro[3,2-b]pyrrol-
3-ones (89, 90, 95-118) (Figure 15), tetrahydrofuranones
(91-94), hexahydrocyclopentylfuranone amides (119, 120)
and hexahydropyrrolopyrrolone compounds (121-124) as cru-
zipain inhibitors, inhibitors of cathepsins like cathepsin K and
S and of some other cysteine proteases. These chemotypes
were also claimed for FP inhibition and for therapeutic target
validation [95-136]. Quibell et al. in another patent reported the
diazapentalene derivatives (125-127) as cysteine proteinase
CAC1 inhibitors. The CAC1 family proteinase includes cath-
epsins, FP and cruzipain [137,138].
12. Miscellaneous peptidic FP inhibitors
12.1 Peptidic boronic acid derivatives
Bachovchin et al. in their patent entitled ‘Protease inhibitors’
have reported the peptidic boronic acid (Figure 16) derivative
(128) for DPP-IV inhibition and the compound has also been
claimed to be FP inhibitor [139].
Malaria is one of the neglected diseases. The failure rate of
novel antimalarials is very high primarily because of the
drug resistance-associated mutations in the parasite and the
number of research programs focusing on novel antimalarials
are insufficient to sustain the antimalarial product pipeline.
The major hurdles in development of new antimalarials are
the development of resistance to well-established antimalarial
drugs, inadequate control of mosquito vectors and lack of
effective vaccine and these are also the common factors for
re-emergence of the disease across the globe. Due to the devel-
opment of resistance to almost all the known antimalarial
drugs there exists an unmet need to explore new potential
targets for the discovery of potent, safe, affordable and orally
bioavailable new drug molecules. Efforts to develop new anti-
malarials are increasing dramatically in recent years but unfor-
tunately no significant breakthrough research outcome has
been reported till date. MMV is a public/private partnership
working in the direction of development of new molecules
for the treatment of malaria.
The understanding of cysteine proteases of malaria parasite
has increased markedly in recent years and they play a key

Expert Opin. Ther. Patents (2013) 23(2) 179

 U. R. Mane et al.

HO
HO H3C
O
O
O
N
O O H O
O O N
N N
N H
H H3C O O
O O 91
H3C CH 90
89 3

H3C
O
O H3C CH3
S H3C H3C
O N H3C O O
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H O H O O
H
N N
N N
O H CH3 O H CH3 O
O

92
93 OH 94
OH

CH3
H3C O O
O O O O N
N N N
N N H
H H O O
N O O N O O N
H3C N N H3C N N
N 97
S S H3C
For personal use only.

95 96

F
Cl
O O
O O N O O
N N
N H N
H O O N
O O N H
N O O
N 99 N
N 98 H3C 100
H3C N
H3C

CH3
H3C O O
O O N
N N
N H O
H O
O N
O
N N
H3C 102
N
H 3C 101

Figure 15. Furo pyrrol-3-ones and other furanone and diazapentalene derivatives as falcipain inhibitors (Amura).

role in blood stage of the parasite. A cysteine protease FP-2 chemotherapeutic target. FP-3 with 65% amino acid sequence
degrades hemoglobin in the acidic food vacuole in early identity is also an equally important hemoglobinase. Knockout
trophozoite stage and cleaves ankyrin and protein 4.1, the studies and other reports proved their importance as they
cytoskeletal elements vital to the stability of red blood cell play very crucial role in the hydrolysis of host hemoglobin,
membrane in the schizont stage. FP-2 inhibition can arrest erythrocyte invasion and erythrocyte rupture in the blood stage
the parasite’s life cycle and can serve as a promising of parasites life cycle. Hence, FP-2 and FP-3 are very critical

180 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

CH3
CH3
H 3C O O
O O N
N N
N H O O
H O O
O
N O 104
H3C N 103
H3C CH3
H3C
CH3
O O
O O N
N
S N H
N O O
N N
H O O
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N 106
105 H3CO

O O
O O N
N
N H O
N O
H N
O O
N H 3C N 108
N 107
H 3C
H3C CH3 OCH3
OCH3 H3C
CH3
H3C O O
N
O O N
For personal use only.

N H O
N O
N
H O O N 110
N H3C
109
N
H 3C
OCH3 OCH3

O O O O
N N
N N
H O H O
H3C N N O N O
N H 3C N N
S 111 112
S

CH3 CH3

Cl
Cl
N N
O O
O O N N N
N N
N H
H O O
O O
113 114

CH3 OH CH3 NH2

H3C H3C
O O O O
N N
N N
H O H O
O O
N N
N 115 N 116
H3CO H3CO

Figure 15. Furo pyrrol-3-ones and other furanone and diazapentalene derivatives as falcipain inhibitors (Amura) (continued).

Expert Opin. Ther. Patents (2013) 23(2) 181

 U. R. Mane et al.

CH3 CH3
CH3
H3C
O O
O O N
N N
N H O
H O O
O N
N
N
N H3C 118
H 3C 117

H3C CH3
H O
H3 C O
H N O
N O N
N O H
H O
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O O

120 OH
119 OH

CH3
O
CH3 H3C
O
H3C O N
O N N N
N
N H
N H3C O O
H O H3C
S O
CH3 122
121
For personal use only.

O CH3
O O
NH
CH3 CH3 N
N H3C
O N O N
H3C H3C CH3
O O O
O H3C
H3C CH3
124
123
H3C CH3
O CH3
O H3C CH3 O
O CH3 N
N O N
N N O
O N O OH
O H
H 3C CH3 OH
CH3
126 127
125

Figure 15. Furo pyrrol-3-ones and other furanone and diazapentalene derivatives as falcipain inhibitors (Amura) (continued).

F
F
O
H3C
S O S
CF3 CF3
H H
OH N N
N N N N
B N
N OH H H O
N O O H O Br
Br
H
128 129 130

Figure 16. Peptidic boronic acid falcipain inhibitor. Figure 17. Peptidic nitrile falcipain inhibitors (Merck).

182 Expert Opin. Ther. Patents (2013) 23(2)

 Falcipain inhibitors as potential therapeutics for resistant strains of malaria: a patent review

hemoglobinases important for the growth of the parasite and
are proven potential targets for arresting P. falciparum infection.
A wide range of peptidic and non-peptidic chemotypes apart
from natural products have been studied for FP-2/
FP-3 inhibition. Companies like GSK, Amura Therapeutics
and University of California are working for the development
of peptidic/peptidomimetics small molecules, as FP-2, FP-3
inhibitors.
GSK has reported peptidic amide and hydrazide derivatives
and peptidic aminoazepan-3-one class of derivatives active in
nanomolar concentrations. GSK has also reported purines
and pyrimidine nitriles as potent molecules active at 1 nM
Expert Opin. Ther. Patents Downloaded from informahealthcare.com by University of Sussex Library on 01/20/13
Second Military Medical University and East China Univer-
sity of Science and Technology have evaluated the naturally
occurring flavone glycosides as FP-2 inhibitors for the treat-
ment of malaria. The natural flavone glycosides cynanversico-
side C, stenopalustroside A, stenopalustroside D and silver
linden glycosides have shown very good in vivo activity. Julius
Maximilians University and Technical University Carolo
Wilhelmina have evaluated the N-protected guanidines for
FP-2 inhibitory activity showing efficacy in micromolar
concentrations.
The current antimalarials are in clinical use for a long time
now leading to the development of resistance against them in

concentration. The pyrimidinenitrile class of FP-2/FP-3
inhibitors has advanced into the preclinical discovery stage
of development. Corvas has developed the dipeptidic acryla-
mide, acrylate derivatives, a-ketoamide and aldehyde type of
novel compounds active at 10 nM concentration. Novel
peptidic furanones have been developed by Medivir as FP
inhibitors active in the range of 0.5 -- 2.5 µM concentrations.
University of Jaume has developed novel peptidic epoxides as
FP inhibitors active in nanomolar concentrations. Several
thiosemicarbazones and semicarbazones were developed by
University of California active in the nanomolar range when
tested for FP-2/FP-3 inhibition. They have also reported
For personal use only.
the parasites. Identification of new molecular targets in the
parasite is a great opportunity for the medicinal chemists to
develop novel antimalarial drugs. FPs (both FP-2 and FP-3)
are such worthy targets which should be exploited for discov-
ering new drug molecules acting on them. The current litera-
ture on the patented molecules exhibiting FP inhibiting
activities is indicative of discovering new antimalarial agents
for treating resistant cases in the near future.
Declaration of interest
The authors declare no conflict of interest and have received

fluoregenic compounds active at about 9 nM concentration. no payment in preparation of this manuscript.

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Affiliation
Uttam Rajaram Mane1,2, Ramesh C Gupta2,
Sunil Sadanand Nadkarni2, Rajani R Giridhar1,
Prashant Prakash Naik1 & Mange R Yadav†1
†
Author for correspondence
1
The M. S. University of Baroda,
Pharmacy Department,
Faculty of Tech. and Engg,
Vadodara, 390001, Gujarat, India
Tel: +91 265 2434187;
Fax: +91 265 2418927;
E-mail: mryadav11@yahoo.co.in
2
Torrent Research Centre,
Village Bhat,
Dist. Gandhinagar, 382421,
Gujarat, India
187