Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and malaria pathogens

Article abstract of DOI:10.1016/j.bmcl.2020.127037

Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm infection, and it has been reported to have antiparasitic and antimicrobial activities. Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these compounds against malaria parasite P. falciparum 3D7 revealed analogs with better antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC₅₀ of 23 nM and 60 nM against P. falciparum 3D7, respectively. These compounds were also effective against drug-resistant malaria parasite P. falciparum Dd2 with IC₅₀ of 53 nM and 97 nM, respectively. The cytotoxicity against CHO-K1, HEK and NRK-49F cells revealed better selectivity index for these new analogs compared to pyrvinium. Additionally, this series of compounds showed activity against M. tuberculosis H37Rv; particularly compounds 10, 13, 14 and 16 showed equipotent antitubercular activity to that of pyrvinium pamoate. The compounds 14 and 16 should be taken forward as leads for further optimization.

Full text of DOI:10.1016/j.bmcl.2020.127037

Journal Pre-proofs
Synthesis and efficacy of pyrvinium-inspired analogs against tuberculosis and
malaria pathogens
Vikas R. Gaikwad, Uttam B. Karale, Gokulapriya Govindarajalu, Navin
Adhikari, E. Vamshi Krishna, Vagolu Siva Krishna, Sunil Misra,
Dharmarajan Sriram, Puran Sigh Sijwali, Haridas B. Rode
PII:
S0960-894X(20)30109-8
DOI:
Reference:
https://doi.org/10.1016/j.bmcl.2020.127037
BMCL 127037
To appear in:
Bioorganic & Medicinal Chemistry Letters
Received Date:
Revised Date:
Accepted Date:
9 October 2019
12 February 2020
13 February 2020
Please cite this article as: Gaikwad, V.R., Karale, U.B., Govindarajalu, G., Adhikari, N., Krishna, E.V., Krishna,
V.S., Misra, S., Sriram, D., Sijwali, P.S., Rode, H.B., Synthesis and efficacy of pyrvinium-inspired analogs
against tuberculosis and malaria pathogens, Bioorganic & Medicinal Chemistry Letters (2020), doi: https://
doi.org/10.1016/j.bmcl.2020.127037
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
©
2020 Published by Elsevier Ltd.

Synthesis and efficacy of pyrvinium-inspired analogs against
tuberculosis and malaria pathogens
a
a,b
c
c
Vikas R. Gaikwad , Uttam B. Karale , Gokulapriya Govindarajalu , Navin Adhikari , E.
b,d
e
b,d
e
Vamshi Krishna , Vagolu Siva Krishna , Sunil Misra , Dharmarajan Sriram , Puran Sigh
b, c
a,b
Sijwali* , Haridas B. Rode*
a
Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology,
Tarnaka, Hyderabad-500 007, India
bAcademy of Scientific and Innovative Research, Ghaziabad, Uttar Pradesh- 201 002, India
cCSIR-Centre for Cellular and Molecular Biology, Habsiguda, Uppal Road, Hyderabad-500007
dDepartment of Applied Biology, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad-500 007,
India
eDepartment of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar,
Shameerpet mandal, R.R. District, Hyderabad- 500 078, India
KEYWORDS: Pyrvinium analogs, malaria, antitubercular compounds, heterocyclic compounds

ABSTRACT:
Herein, we report the synthesis and evaluation of pyrvinium-based antimalarial and
antitubercular compounds. Pyrvinium is an FDA approved drug for the treatment of pinworm
infection, and it has been reported to have antiparasitic and antimicrobial activities.
Pyrvinium contains quinoline core coupled with pyrrole. We replaced the pyrrole with
various aryl or heteroaryl substituents to generate pyrvinium analogs. The profiling of these
compounds against malaria parasite P. falciparum 3D7 revealed analogs with better
antimalarial activity than pyrvinium pamoate. Compound 14 and 16 showed IC of 23 nM
5
0
and 60 nM against P. falciparum 3D7, respectively. These compounds were also effective
against drug-resistant malaria parasite P. falciparum Dd2 with IC50 of 53 nM and 97 nM,
respectively. The cytotoxicity against CHO-K1, HEK and NRK-49F cells revealed better
selectivity index for these new analogs compared to pyrvinium. Additionally, this series of
compounds showed activity against M. tuberculosis H37Rv; particularly compounds 10, 13,
1
4 and 16 showed equipotent antitubercular activity to that of pyrvinium pamoate. The
compounds 14 and 16 should be taken forward as leads for further optimization.

Infectious diseases affect human population at large, and the emergence of drug-resistant
pathogens has further complicated treatment of these diseases, including malaria and
tuberculosis. According to the WHO report, the estimated malaria cases jumped to 219
million in 2017 from 217 million in 2016. Globally, there were about 435000 deaths from
1
2
malaria in 2017 and an estimated 1.3 million deaths were due to tuberculosis. This scenario
emphasizes the need of new drugs for these diseases. Subsequently, increased efforts in drug
discovery resulted in potent leads targeting such diseases (figure 1). These leads include,
antimalarial MK-4815, which selectively accumulates in infected blood cells and is highly
3
4
effective against trophozoite/early schizont stages , the PfPI4K inhibitor UCT943 and the
5
inhibitor of Plasmodium cytochrome bc1 complex ELQ-300 . The synthetic trioxolane
6
7
7
OZ439 , spiroindolone analogue Cipargamin , KAE609 and dihydroorotate dehydrogenase
8
9
inhibitor DSM265 are under clinical evaluation.
F
OH
H N
2
N
N
NH2
NH
Cl
O
NH
N
N
H
F3C
NH
MK-4815
UCT943
O
Cl
Cipargamin
Br
N
N
O2N
OCF3
N
N
OH
O
N
O
NH
F3CO
O
Cl
Q203
N
O
N
Pretomanid
Bedaquiline
Figure 1: Structures of selected antimalarial and antitubercular agents
In the case of tuberculosis, imidazo[1,2-a]pyridine based Q20310 and quinoline analogue
TBAJ-87611 and oxazolidinone TBI-22312 are promising candidates. The diarylquinoline
1
1
TBAJ-876 is in preclinical development. Bedaquiline has been approved for the treatment

1
3
of multidrug-resistant (MDR) tuberculosis while Pretomanid in combination with Linezolid
and Bedaquiline has been approved in 2019 for extensively drug-resistant (XDR) tuberculosis
or non-responsive MDR-TB patients.14
Pyrvinium is an FDA approved drug for the treatment of pinworm (Enterobius vermicularis)
infection in humans15-17. Especially, pyrvinium pamoate salt in children was highly
1
8
successful . It is important to note that the treatment of oxyuriasis (thread worm infection)
using a single dose of pyrvinium embonate19 and pyrvinium pamoate20 was a milestone
2
1
22
discovery. It has antitubercular , antibacterial against S. aureus and C. albicans biofilm
2
3
inhibition activities. Further, its antitumor activity against human pancreatic cancer cell line
PANC-1 in SCID mice and nude mice, when administered orally, was successfully
demonstrated.24 Off note, Sullivan et al. reported its in vitro activity against Entamoeba
histolytica with IC50 of 4-5 µM25 while IC against P. falciparum 3D7 is in nanomolar
50
concentration.26 These multiple pharmacological activities of pyrvinium inspired us to
synthesize its analogs to generate more potent inhibitors for infectious diseases like malaria
and tuberculosis. This is in line with our efforts towards the development of lead compounds
against infectious diseases.27-32 With this background, herein, we report the pyrvinium
analogs that showed potent activity against drug-resistant malaria and tuberculosis.
Pyrvinium has a quinoline core connected to pyrrole ring system. It is chemically tractable
and we believed that its chemical modification could result in more potent inhibitors. We
began the study by synthesizing pyrvinium. Two methods have been reported for the
3
3
synthesis of pyrvinium. The J. E. Macdonald et al.'s route for the synthesis of pyrvinium
makes use of Paal-Knorr and Vilsmeier-Haack as key reactions, while the other route
described by Jing et al.34 makes use of 2-amino-5-(dimethylamino)benzaldehyde as key
intermediate. Our strategy uses the synthesis of 2-methylquinoline from N,N-Dimethyl-1,4-
phenylenediamine (1, scheme 1) using Döbner-Miller reaction. Briefly, the reaction between

1
and 2 in the presence of HCl afforded 2-methylquinoline 3. The treatment of 3 with methyl
iodide in a sealed tube gave quinaldinium salt 4 in quantitative yield. Finally, the
condensation between 4 with various aldehydes in the presence of piperidine afforded
quinolinium compounds 5-16 (scheme 1, table 1). This way, pyrvinium iodide (5) was
obtained as dark red solid. The 5 was treated with sodium pamoate to afford pyrvinium
pamoate (5a).
HCl,Toluene,
reflux
N
N
O
65%
NH2
N
1
2
3
O
MeI,
N
N
110-110 °C, 8 h
R
H
quantitative
N
Piperidine, MeOH,
reflux, 4 h
N
R
I
I
4
5-16
Scheme 1: Synthesis of quinolinium derivatives
Thus synthesized compounds were screened for inhibition of P. falciparum 3D7 erythrocytic
2
6
stage development and the results are shown in table 1. Earlier, Sullivan et al and Tilley et
al.35 described nanomolar antimalarial activity of pyrvinium pamoate (5a) against P.
2
6
falciparum 3D7. Sullivan et al reported the IC value of 3 nM for pyrvinium pamoate (5a)
5
0
whereas our screen showed IC50 of 342 nM (figure 2) against P. falciparum 3D7. This
difference in IC value can be augmented to the differences in screening protocols (96 hours
5
0
2
6
treatment in Sullivan et al.'s protocol versus 50 hours in our protocol). To understand the
influence of treatment duration, we assessed the effect of pyrvinium pamoate (5a) on parasite
growth upon 96 hours treatment. A significant decrease in IC values for 5a (5.04 ± 1.6 nM)
5
0
upon 96 hours treatment was observed as compared to the 50 hours treatment (IC = 342
5
0
nM). This clearly indicates that the potency of pyrvinium pamoate increased with longer

exposure time. Pyrvinium iodide (5) showed IC50 of 774 nM against P. falciparum 3D7,
which is about twice the IC50 of pyrvinium pamoate. The N-pyridyl-pyrrole derivative 6
showed potent antimalarial activity with IC of 228 nM, whereas mono-substituted pyrrole 7
5
0
was less effective than pyrvinium iodide. This could be due to the hydrogen bond acceptor
character of pyridine substituent of 6. We then assessed non pyrrole quinolinium iodide
derivatives 8-16 for inhibition of P. falciparum 3D7 erythrocytic stage development. As
expected, compound 8 and 9 retained potent antimalarial activity likely due to the hydrogen
bond acceptor character of nitrile substituent. The lower activity in case of compound 7, 10
and 11 might augment to their hydrogen bond donor ability. Compound 12, which has nitro
substituent, showed lowest antimalarial activity with IC of 3.60 µM in the series. Important
5
0
to note that the presence of hydrophobic substituents, like chloro, in compound 13 and 14
showed high antimalarial activity. Between these two, the positional isomer i.e. 2,6-
dichlorophenyl (in case of 14, IC = 23 nM) is preferred over the 3,4-dichlorophenyl (in case
5
0
of 13, IC = 87 nM) for the antimalarial activity. Compound 14 was found to be the most
5
0
potent (IC = 23 nM) among all the derivatives against P. falciparum 3D7 erythrocytic stage
5
0
development. Importantly, a significant decrease in IC50 values (2.37 ± 0.44 nM) for
compound 14 upon 96 hours treatment was also observed. Even the compound with
unsubstituted phenyl ring (compound 15) retained potent antimalarial activity. Compound 16
which has indole substituent showed IC of 60 nM. When compared with compound 7 which
5
0
has pyrrole, compound 16 showed better antimalarial activity which can be augmented to the
presence of more hydrophobic indole substituent as compared to pyrrole substituent in
compound 7. Further, the effects of pyrvinium pamoate (5a) and compound 14 on P.
falciparum 3D7 morphology were evaluated by treating the early ring stage parasites for 48
hours. The treatment caused growth arrest at the early trophozoite stage (figure 3), which
3
5
could be due to inhibition of mitochondrial function as has been previously proposed . To

find out if the inhibition was due to death or mere arrest of the parasite development, drug
was washed off after 48 hours of treatment with pyrvinium pamoate (5a) or compound 14,
and parasites were cultured in normal medium for the next 48 hours. The control parasites
(
DMSO-treated) grew normally and showed about 12-fold multiplication at the end of 2nd
cycle compared with the starting parasitemia (~2%). On the other hand, cultures of parasites
treated with pyrvinium pamoate or compound 14 did not have any parasites at the end of 2nd
cycle, indicating that these compounds exert parasiticidal effect. To investigate if these
compounds are effective against the drug resistant P. falciparum strain Dd2, compound 14,
1
6 and 5a were assessed for inhibition of the erythrocytic development of Dd2 (Table 2). P.
falciparum strain Dd2 is highly resistant to pyrimethamine and moderately resistant to
Chloroquine as compared to the 3D7 strain. As expected Dd2 and 3D7 showed similar IC50
for artemisinin but the IC50 concentrations of pyrimethamine and Chloroquine were
significantly higher for Dd2 than 3D7 (Table 1 and 2). All the three compounds tested had
comparable potency against 3D7 and Dd2 parasites. To assess safety, these analogs were
profiled against CHO-K1, HEK and NRK-49F cells (Table 1). The selectivity indices for
these compounds were calculated using IC of compounds against CHO-K1 cells divided by
5
0
IC of compounds against P. falciparum 3D7. All the compounds showed better selectivity
5
0
index than 5a. The potent antimalarial analogous 8, 13, 14, 15 and 16 showed more than 140
selectivity index, indicating their selective efficacy against the parasite. It is important to note
that compound 8 showed highest selectivity index of >500 while the most potent compound
1
4 showed selectivity index of >340.
Table 1: Antimalarial activity against P. falciparum and toxicity on CHO-K1, HEK and
NRK-49F cells
IC50 (HEK,
µM)
IC50
(NRK- SI
49F,
µM)
IC50
c
(CHO-
Comp. No.
Structure
IC50 (µM)a
(IC50b/
MIC )
K1 ,
µM)
d
a
b

0
.774 ± 0.06 10.90 ± 15.98 ± 0.96 20.15 ± 14.0
N
0
.06
2.4
5
N
N
I
O
O
OH
HO
0.342 ± 0.03 3.50 ±
0.69
2.99 ± 0.12
3.02 ±
0.39
10.2
N
O
N
N
5
a
2
0
.03
.228 ±
15.15 ± 14.56 ± 0.98 12.67 ± 66.2
.15 0.74
N
N
2
0
1
N
6
7
N
N
I
.54 ± 0.18
77.84 ± 66.89 ± 1.69 75.98 ± 50.5
.87 1.56
0
H
N
N
I
0
.094 ± 0.02 52.57 ± 62.12 ± 1.36 50.23 ± 553.1
.2 0.14
N
2
8
9
N
I
CN
0
0
.217 ± 0.01 87.62 ± 55.97 ± 1.02 59.45 ± 403.6
.62 1.09
N
1
CN
N
I
.441 ± 0.04 30.33 ± 15.26 ± 0.56 11.99 ± 68.7
0.54 0.56
N
OH
Cl
1
0
1
N
I
2
3
.47 ± 0.25
.60 ± 0.14
54.69 ± 50.12 ± 1.02 49.09 ± 22.1
3.68 1.99
N
OH
Cl
1
N
I
Cl
73.86 ± 66.66 ± 0.25 69.52 ± 20.5
N
1
.74
1.45
NO2
1
1
1
2
3
4
N
I
0
0
.087 ±
.006
12.44 ± 8.56 ± 0.12
.06
11.29 ± 142.5
0.36
N
0
Cl
Cl
N
I
0
0
.023 ±
.002
7.92 ±
0.42
5.62 ± 0.23
5.23 ±
0.12
344.3
N
Cl
N
I
Cl

0
.089 ± 0.01 41.64 ± 39.81 ± 1.2
.8
42.15 ± 467.4
0.18
N
N
1
1
1
5
6
N
I
0
.060±
11.36 ± 10.56 ± 0.12 11.29 ± 188.3
1
.6
0.54
0
.001
N
I
NH
0
0
.011 ±
.001
-
-
-
-
-
-
-
-
-
-
-
-
Pyrimethamine
Artemisinin
-
-
-
0
0
.025 ±
.001
0
0
.008 ±
.001
Chloroquine
aHalf maximal inhibitory concentration (IC50) of the indicated compounds against the P. falciparum 3D7
erythrocytic development. The data is mean of three independent experiments for pyrvinium pamoate (5a) and
b
its analogs (2 experiments for antimalarials), each done in duplicates. Cytotoxicity (IC50) of compounds against
c
d
CHO-K1 cells. Cytotoxicity (IC50) of compounds against HEK cells. Cytotoxicity (IC50) of compounds against
NRK-49F cells. Selectivity index (SI) is calculated by IC50 of compounds against CHO-K1 cells divided by IC50
of compounds against P. falciparum 3D7

Figure 2: IC50 graphs. The plots show inhibition of P. falciparum 3D7 erythrocytic development (% Growth)
at different concentrations of the compound 5a, 14 and 16 (x-axis).
Figure 3: Effect of inhibitor treatment on parasite morphology. Early ring stage P. falciparum 3D7 parasites
were treated with DMSO (Con, at 0.1%), 5a (at 3X IC50 concentration) or the compound 14 (at 3X IC50
concentration) for 48 hours. Giemsa-stained smears of cultures were prepared before the treatment (0 hour) and
at the indicated hours of post-treatment (hour-PT). The smears were observed under the 100x objective of a light
microscope and images were taken. The morphologies of treated parasites are shown.

Table 2: Antimalarial activity of 5a, 14 and 16 against P. falciparum Dd2. The data is mean
of three independent experiments for pyrvinium pamoate (5a) and its analogs (2 experiments
for antimalarials), each done in duplicates.
Compound/drug
IC (µM)
50
5
1
1
a
4
6
0.219 ± 0.022
0.053 ± 0.004
0.097 ± 0.006
85.0 ± 3.2
Pyrimethamine
Artemisinin
0.021 ± 0.001
0.0417 ± 0.004
Chloroquine
Furthermore, compounds were evaluated for inhibition of M. tuberculosis H37Rv (table 3).
The MABA assay (Microplate Alamar Blue Assay) was used for determining the MIC of
these pyrvinium-inspired analogous (supporting information). Compounds 10, 13, 14 and 16
showed equipotent inhibition of M. tuberculosis H37Rv to that of 5a with MIC of 3.12 µM.
The compounds 10, 13 and 14 have chlorophenyl substituent and indicate the possible role of
hydrophilicity in their antitubercular activity. This way, the pyrrole ring of pyrvinium
pamoate (5a) was successfully replaced by various chlorophenyl substituents. Compound 5
and 6 showed moderate antitubercular activity with MIC of 6.25µM against M. tuberculosis
H37Rv. The cyanophenyl-substituted analogs 8 and 9 showed weak antituberculosis activity.
Compound 15, which has unsubstituted phenyl ring, found to be inactive against the
tuberculosis bacteria. Further, the selectivity indices were measured for these compounds
(table 3). The selectivity index was in the rage of 1 to 9. This indicate the need for further
modifications of these compounds to generate more potent antitubercular compounds. Taking
together, this series should be further explored for development of next generation
pyrvinium-based chemotypes.

Table 3: Antitubercular activity of analogs and selectivity index
SI (IC50b/MICa)
Compound No.
MIC (µM)
6.25
3.12
6.25
25
5
1.73
1.12
2.42
3.11
1.05
3.50
9.72
2.18
1.47
3.98
2.53
<0.41
3.64
-
5
a
6
7
8
9
50
25
1
0
1
2
3
4
5
6
3.12
25
1
1
1
1
1
1
50
3.12
3.12
>100
3.12
0.24
Rifampicin
Minimum inhibitory concentration (MIC) of compounds against M. tuberculosis H37Rv was measured using
MABA assay. The MIC was defined as the lowest concentration of compound that prevented the growth of M.
b
tuberculosis H37Rv. The data is mean of two independent experiments, each done in duplicates. Cytotoxicity
(IC50) of compounds against CHO-K1 cells (please refer table 1)
In summary, we have demonstrated new pyrvinium analogs as antimalarial and antitubercular
agents. The study identified compound 14 and 16 with IC of 23 nM and 60 nM against P.
5
0
falciparum 3D7, respectively. Of note, these compounds also showed activity against drug-
resistant malaria parasite strain P. falciparum Dd2 with IC of 53 and 97 nM, respectively.
5
0
The selectivity index of compound 14 and 16 for antimalarial activity was found to be more
than 180 when compared with their toxicity against CHO-K1 cells. Importantly, these new
analogs are more selective and potent in their antimalarial activity than pyrvinium pamoate.
Furthermore, the analogs 10, 13, 14 and 16 were also found to be equipotent to that of
pyrvinium pamoate against M. tuberculosis H37Rv.

Acknowledgement
The financial support through a research grant GAP0584 from Department of Science and
Technology, Government of India is acknowledged. We thank Director, CSIR-IICT (Ms. No.
IICT/pubs./2019/296) for providing all the required facilities to carry out the work.
Gokulpriya Govindarajalu and Navin Adhikari have been supported by DBT, India through
the BT/COE/34/SP15138/2015 project. Vikas R. Gaikwad thanks National Institute of
Pharmaceutical Education and Research, Balanagar, Hyderabad-500 037, India for allowing
him to carry out his mater dissertation work at CSIR-IICT.
References
1
2
3
4
. World Health Organization (WHO). (Report 2018),
https://www.who.int/malaria/publications/world-malaria-report-2018/en/
. World Health Organization (WHO). (Report 2018),
https://www.who.int/tb/publications/global_report/en/
. Powles MA, Allocco J, Yeung L, Nare B, Liberator P, Schmatz D. MK-4815, a potential new
oral agent for treatment of malaria. Antimicrob Agents Chemother. 2012; 56: 2414−2419.
. Brunschwig C, Lawrence N, Taylor D, Abay E, Njoroge M, Basarab GS, Le Manach C,
Paquet T, Cabrera DG, Nchinda AT, de Kock C, Wiesner L, Denti P, Waterson D, Blasco B,
Leroy D, Witty MJ, Donini C, Duffy J, Wittlin S, White KL, Charman SA, Jiménez-Díaz
MB, Angulo-Barturen I, Herreros E, Gamo FJ, Rochford R, Mancama D, Coetzer TL, van der
Watt ME, Reader J, Birkholtz LM, Marsh KC, Solapure SM, Burke JE, McPhail JA,
Vanaerschot M, Fidock DA, Fish PV, Siegl P, Smith DA, Wirjanata G, Noviyanti R, Price
RN, Marfurt J, Silue KD, Street LJ, Chibale K. UCT943, a Next-generation Plasmodium
falciparum PI4K inhibitor preclinical candidate for the treatment of malaria. Antimicrob
Agents Chemother. 2018; 27: e00012−18
5
6
. Miley GP, Pou S, Winter R, Nilsen A, Li Y, Kelly JX, Stickles AM, Mather MW, Forquer IP,
Pershing AM, White K, Shackleford D, Saunders J, Chen G, Ting LM, Kim K, Zakharov LN,
Donini C, Burrows JN, Vaidya AB, Charman SA, Riscoe MK. ELQ-300 prodrugs for
enhanced delivery and single-dose cure of malaria. Antimicrob Agents Chemother. 2015; 59:
5
555−5560.
. Phyo AP, Jittamala P, Nosten FH, Pukrittayakamee S, Imwong M, White NJ, Duparc S,
Macintyre F, Baker M, Möhrle JJ. Antimalarial activity of artefenomel (OZ439), a novel

synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and
Plasmodium vivax malaria:an open-label phase 2 trial. Lancet Infect Dis. 2016; 16: 61−69
. White NJ, Pukrittayakamee S, Phyo AP, Rueangweerayut R, Nosten F, Jittamala P, Jeeyapant
A, Jain JP, Lefèvre G, Li R, Magnusson B, Diagana TT, Leong FJ. Spiroindolone KAE609
for falciparum and vivax malaria. N Engl J Med. 2014; 371: 403−410.
7
8
9
1
. Bélard S, Ramharter M. DSM265: a novel drug for single-dose cure of Plasmodium
falciparum malaria. Lancet Infect Dis. 2018; 18: 819−820.
. Okombo J, Chibale K. Recent updates in the discovery and development of novel antimalarial
drug candidates. MedChemComm, 2018; 9: 437−453.
0. Pethe K, Bifani P, Jang J, Kang S, Park S, Ahn S, Jiricek J, Jung J, Jeon HK, Cechetto J,
Christophe T, Lee H, Kempf M, Jackson M, Lenaerts AJ, Pham H, Jones V, Seo MJ, Kim
YM, Seo M, Seo JJ, Park D, Ko Y, Choi I, Kim R, Kim SY, Lim S, Yim SA, Nam J, Kang H,
Kwon H, Oh CT, Cho Y, Jang Y, Kim J, Chua A, Tan BH, Nanjundappa MB, Rao SP, Barnes
WS, Wintjens R, Walker JR, Alonso S, Lee S, Kim J, Oh S, Oh T, Nehrbass U, Han SJ, No Z,
Lee J, Brodin P, Cho SN, Nam K, Kim J. Discovery of Q203, a potent clinical candidate for
the treatment of tuberculosis. Nat Med. 2013; 19: 1157–1160.
1
1
1. H Sutherland HS, Tong AST, Choi PJ, Blaser A, Conole D, Franzblau SG, Lotlikar MU,
Cooper CB, Upton AM, Denny WA, Palmer BD. 3,5-Dialkoxypyridine analogues of
bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel.
Bioorg Med Chem. 2019; 27: 1292–1307.
2. TB Alliance, Institute of Materia Medica. Phase 1a began January 16, 2019. Placebo-
Controlled, Randomized, SAD Study to Evaluate the Safety, Tolerability, and PK of TBI-223
in Healthy NCT03758612. https://www.newtbdrugs.org/pipeline/compound/tbi-223.
Accessed on 27th September 2019.
1
1
1
1
3. Cox E, Laessig K. FDA approval of bedaquiline-the benefit-risk balance for drug-resistant
tuberculosis. N Engl J Med. 2014; 371: 689–691.
4. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-
resistant-forms-tuberculosis-affects-lungs. Accessed on 30th September 2019.
5. Turner JA, Johnson PE Jr. Pyrvinium pamoate in the treatment of pinworm infection
(
enterobiasis) in the home. J Pediatr. 1962; 60:243–251
6. Beck JW, Saavedra D, Antell GJ, Tejeiro B. The treatment of pinworm infections in humans
enterobiasis) with pyrvinium chloride and pyrvinium pamoate. Am J Trop Med Hyg. 1959;
:349–52.
(
8
1
7. Cho SY, Ahn YR, Ryang YS, Seo BS. Evaluation of anthelmintic treatment of Enterobius
vermicularis infection in highly endemic population by prolonged observation. Korean J
Parasitol. 1977; 15: 100–108.

1
1
2
2
2
8. Royer A, Berdnikoff K. Pinworm infestation in children: the problem and its treatment. Can
Med Assoc J. 1962; 86:60–65.
9. Desai AS. Single-dose treatment of oxyuriasis with pyrvinium embonate. Br Med J. 1962; 2:
1
583–1585
0. Sudigbia I, Notokarsono S, Darmawan S, Tjoen LW. Single-dose treatment of oxyuriasis with
pyrvinium pamoate (Vanquin). Paediatr Indones. 1970; 10: 125–130.
1. Lougheed KE, Taylor DL, Osborne SA, Bryans JS, Buxton RS. New anti-tuberculosis agents
amongst known drugs. Tuberculosis 2009; 89: 364–370.
2. Torres NS, Abercrombie JJ, Srinivasan A, Lopez-Ribot JL, Ramasubramanian AK, Leung
KP. Screening a commercial library of pharmacologically active small molecules against
Staphylococcus aureus biofilms. Antimicrob Agents Chemother. 2016; 60: 5663–5672.
3. Siles SA, Srinivasan A, Pierce CG, Lopez-Ribot JL, Ramasubramanian AK. High-throughput
screening of a collection of known pharmacologically active small compounds for
identification of Candida albicans biofilm inhibitors. Antimicrob Agents Chemother. 2013;
2
2
2
5
7: 3681–3687.
4. Esumi H, Lu J, Kurashima Y, Hanaoka T. Antitumor activity of pyrvinium pamoate, 6-
dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium
pamoate salt, showing preferential cytotoxicity during glucose starvation. Cancer Sci. 2004;
5: 685–690.
(
9
5. Downey AS, Graczyk TK, Sullivan DJ. In vitro activity of pyrvinium pamoate against
Entamoeba histolytica and Giardia intestinalis using radiolabelled thymidine incorporation
and an SYBR Green I-based fluorescence assay. J Antimicrob Chemother. 2009; 64:751-754.
6. Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ Jr. A clinical drug library screen identifies
astemizole as an antimalarial agent. Nat Chem Biol. 2006; 2: 415–416.
2
2
7. Makane VB, Krishna VS, Krishna EV, Shukla M, Mahizhaveni B, Misra S, Chopra S, Sriram
D, Dusthackeer VNA, Rode HB. Synthesis and evaluation of α-aminoacyl amides as
antitubercular agents effective on drug resistant tuberculosis. Eur J Med Chem. 2019; 164:
6
65–677.
2
2
3
8. Makane VB, Krishna VS, Krishna EV, Shukla M, Mahizhaveni B, Misra S, Chopra S, Sriram
D, Azger Dusthackeer VN, Rode. Novel 1,3,4-oxadiazoles as antitubercular agents with
limited activity against drug-resistant tuberculosis. Fut Med Chem. 2019; 11; 499–510.
9. Kotapalli SS, Nallam SS, Nadella L, Banerjee T, Rode HB, Mainkar PS, Ummanni R.
Identification of New Molecular Entities (NMEs) as Potential Leads against Tuberculosis
from Open Source Compound Repository. PLoS One 2015; 10: e0144018
0. Lade DM, Krishna VS, Sriram D, Rode HB. A Facile Synthesis and Antituberculosis
Properties of Almazole D and Its Enantiomer. ChemistrySelect 2017; 2: 1250–1252

3
1. Karale UB, Krishna VS, Krishna EV, Choudhari AS, Shukla M, Gaikwad VR, Mahizhaveni
B, Chopra S, Misra S, Sarkar D, Sriram D, Dusthackeer VNA, Rode HB. Synthesis and
biological evaluation of 2,4,5-trisubstituted thiazoles as antituberculosis agents effective
against drug-resistant tuberculosis. Eur J Med Chem. 2019; 178: 315–328.
2. Rode HB, Lade DM, Grée R, Mainkar PS, Chandrasekhar S. Strategies towards the synthesis
of anti-tuberculosis drugs. Org Biomol Chem. 2019; 17: 5428–5459.
3
3
3
3
3. Macdonald JE, Hysell MK, Yu D, Li H, Wong-Staal F. Novel quinolinium salts and
derivatives. WO2006/078754 A1, 2006
4. Mao Y, Lin N, Tian W, Huang Z, An J. New Synthesis of Pyrvinium That inhibits the β-
Catenin/Tcf4 Pathway. Heterocycles 2012; 85: 1179–1185.
5. Teguh SC, Klonis N, Duffy S, Lucantoni L, Avery VM, Hutton CA, Baell JB, Tilley L. Novel
conjugated quinoline-indoles compromise Plasmodium falciparum mitochondrial function
and show promising antimalarial activity. J Med Chem. 2013; 56: 6200–6215.