Synthesis of isatin based N1-alkylated 3-β-C-glycoconjugated-oxopropylidene oxindoles as potent antiplasmodial agents

Article abstract of DOI:10.1016/j.ejmech.2018.11.008

In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated 3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and glucopyranosyl propanone via a well-known cross-aldol reaction followed by deh

Full text of DOI:10.1016/j.ejmech.2018.11.008

Accepted Manuscript
1
Synthesis of isatin based N -alkylated 3-β-C-glycoconjugated-oxopropylidene
oxindoles as potent antiplasmodial agents
Ravi Kumar Thakur, Prince Joshi, Kapil Upadhyaya, Kartikey Singh, Gaurav Sharma,
Sanjeev K. Shukla, Renu Tripathi, Rama Pati Tripathi
PII:
S0223-5234(18)30962-0
DOI:
https://doi.org/10.1016/j.ejmech.2018.11.008
EJMECH 10865
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 23 August 2018
Revised Date: 3 November 2018
Accepted Date: 5 November 2018
Please cite this article as: R.K. Thakur, P. Joshi, K. Upadhyaya, K. Singh, G. Sharma, S.K. Shukla, R.
1
Tripathi, R.P. Tripathi, Synthesis of isatin based N -alkylated 3-β-C-glycoconjugated-oxopropylidene
oxindoles as potent antiplasmodial agents, European Journal of Medicinal Chemistry (2018), doi: https://
doi.org/10.1016/j.ejmech.2018.11.008.
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ACCEPTED MANUSCRIPT
Synthesis of isatin based N1-alkylated 3-
oxindoles as potent antiplasmodial agents
β-C-glycoconjugated-oxopropylidene
Ravi Kumar Thakur,a,1,3 Prince Joshi,b,1 Kapil Upadhyaya,a Kartikey Singh,a Gaurav Sharma,c,d
Sanjeev K. Shukla,c,d Renu Tripathi, b,c,* and Rama Pati Tripathi a,c, 2,
*
aMedicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow-
226031, India.
bParasitology Division, CSIR-Central Drug Research Institute, Lucknow-226031, India.
cAcademy of Scientific and Innovative Research (AcSIR), New Delhi-110001, India.
dSophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow
226031, India.
1These authors contributed equally to this work
Current Addresses:
2Dean, National Institute of Pharmaceutical Education and Research Raebarely, New Transit
Campus, Bijnor Road, Sarojani Nagar Near CRPF Base Camp, Lucknow 226002, U.P., India
3Chandigarh University, NH-95 Chandigarh-Ludhiana Highway, Mohali, Punjab 140413, India.
*Corresponding Authors
E-mail addresses: rpt.cdri@gmail.com, (Rama Pati Tripathi), Mobile- 09415004443.
E-mail addresses: renu1113@rediffmail.com, renu_tripathi@cdri.res.in (Renu Tripathi), Tel:
+91-(522)-2772450. Fax: +91-(522)-2771941. Ext. 2453, Mobile- 09415349883.
Abstract
In an attempt to develop new antimalarial drugs, we have synthesized a new class of N-alkylated
3-glycoconjugated-oxopropylidene oxindoles starting from substituted isatins and
glucopyranosyl propanone via a well-known cross-aldol reaction followed by dehydration. The
newly synthesised compounds were screened for their in vitro antiplasmodial activity, and
among all the compounds 9g, 9f, 9b, 8d, 9d, 9c, and 9e displayed potent activity with the IC50
values in the range of 0.1-0.3 µM against Chloroquine (CQ) sensitive Pf3D7 strain, while
compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown promising activity having IC50 values in
0.1-0.4 µM range against CQ resistant PfK1 strain, which is even better than the standard drug
chloroquine with IC50 value of 0.5 µM.
Keywords: Isatin, Glucopyranosyl propanone, Cross aldol reaction, Antiplasmodial activity.

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Introduction
Malaria remains one of the most prevalent and deadliest parasitic diseases with persistent to the
global health problem. Among the five species of Plasmodium viz. Plasmodium ovale,
Plasmodium falciparum, Plasmodium malariae, Plasmodium vivax and, Plasmodium knowlesi,
the most virulent malarial parasite is Plasmodium falciparum, which is responsible for millions
of deaths per year[1]. Natural products such as quinine and artemisinin have contributed
immensely in the treatment of malaria and proved to be the lead compounds for the development
of antimalarials[2]. Despite the availability of various antimalarial drugs like quinine,
artemisinin, artemether, chloroquine, chlorproguanil, mefloquine, primaquine, sulfadoxine,
amodiaquine, and many others, the widespread emergence of multi-drug resistant strains of
Plasmodium falciparum to clinically approved drugs has realized the urgent need of highly
effective, safe, novel and fast-acting antimalarial agent[3].
Isatin (1H-Indole-2,3-dione) is a versatile heterocyclic scaffold endowed with various biological
activities and good tolerance in humans [4]. Isatin is present as a main component in many
alkaloids[5], drugs[6] as well as dyes[7], pesticides and analytical reagents. Besides, isatins, as
well as N-alkylated isatins have been used as synthetic building block for the preparation of
various important naturally occurring heterocyclic compounds[8], having significant biological
activities[9]. The C-3 carbonyl group of isatins is highly reactive and the nucleophilic attack at
this position leads to the formation of 2-oxindole derivatives. Oxindoles, basically isatin
derivatives are endowed with fascinating pharmacological[10] as well as biological activities
such as antimicrobial[11], antitumor[12], antitubercular[13], antimalarial[14], anti-HIV[15] and
antibacterial activities[16]. Some of them have been reported to exhibit significant antimalarial
activities[17] as shown below (Figure 1). It is known that glucose delivery is crucial for the
survival of the malarial parasites and in this context various glycoconjugates[18] and
glucosides[19] with potent antimalarial activities have also been reported (Figure 2). These
compounds inhibit the Plasmodium falciparum Hexose Transporter (PfHT) which plays an
important role in glucose uptake and survival of the malarial parasites. Therefore, glucose
consumption could be an excellent target for the development of novel antimalarial agents since
its elevated presence of glucose uptake and metabolism in infected erythrocytes in all stages of
the parasitic life cycle have been reported [19].

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Figure 1: Representative oxindole and chalcone based antimalarial agents and our proposed molecule.
In this context, development of glucose conjugated isatin derivatives as antimalarial agents
could be an effective strategy.
Figure 2: The structures of some carbohydrate-based antimalarials.
We report herein the synthesis of glycohybridised oxopropylidene oxindoles by utilizing the
most versatile cross-aldol reaction between substituted isatin and glucosyl propanone. Unlike
various reactions between an aldehyde and a ketone, the ketone–ketone cross-aldol reactions are
rare [20]. The enone functionality in target compounds have resemblance with chalcones, which
are considered as an important motif in medicinal chemistry, endowed with various biological
activities such as antimicrobial, anticancer, anti-inflammatory, antibacterial, and
antiproliferative[21]. A few of the chalcone derivatives including one of our sugar derived
chalcone, have demonstrated potent antimalarial activities [22], (Figure 1). Our recent work
showed that glycohybridised isatin hydrazones are potent antiplasmodial agents [23]. Thus,
keeping all these facts in mind and in continuation of our previous efforts in the development of

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novel antimalarials[22d, 24], we embarked upon a new series of isatin glycoconjugates and
evaluated them for their antiplasmodial activity.
Result and discussion
Chemistry
Synthesis of N1-alkylated-3-(3′-β-C-glucoconjugated-2′-oxo-propyl)-3-hydroxy-oxindoles:
Our synthetic strategy starts with the alkylation[25] of the commercially available isatin/5-
chloroisatin (1) with different alkyl bromides (2), in the presence of base K2CO3 and DMF as the
solvent to give the respective N1-alkylated isatin/5-chloroisatin derivatives (3 and 4) in 70-80%
yields (Scheme 1). The resulting N1-alkylated derivatives 3 or 4 on reaction with 1 equiv. of
acetylated β-C-glucopyranosyl-propanone (5) in the presence of Hunig’s base diethylamine (0.5
ml) in ethanol at room temperature, gave the aldol addition products N1-alkylated-3-(3′-β-C-
glucoconjugated-2′-oxo-propyl)-3-hydroxy-oxindoles (6 or 7) as diastereomeric mixtures[26].
The resulting diastereomeric mixtures thus formed were isolated in 70-85% yields in 53:47 to
63:37 ratios. (Scheme 2, Table 1) Ratios were determined by integration of the 1H NMR spectra
of the mixture of compounds. The structure elucidation of the diastereomeric mixtures was
carried out based on their spectroscopic data 1H, 13C, and mass.
Scheme 1: Synthesis of N1-alkylated-isatin/N1-alkylated-5-chloroisatin derivatives.

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Scheme 2: Synthesis of N1-alkylated-3-(3
′-β-C-glucoconjugated-2′-oxo-propyl)-3-hydroxy-oxindoles.
Table 1: Synthesis of N1-alkylated-3-(3′-β-C-glucoconjugated-2′-oxo-propyl)-3-hydroxy-
oxindoles (6 and 7) by the reaction of different N1-alkylated-isatin/N1-alkylated-5-chloroisatin
derivatives (3 or 4) and acetylated β-C-glucopyranosyl-propanone (5).
S.No.
1.
2.
3.
4.
5.
6.
7.
8.
Compound No.
R
X
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Yield (%)
78
Ratioa
60:40
63:37
61:39
59:41
62:38
61:39
61:39
61:39
53:47
56:44
61:39
63:37
59:41
60:40
61:39
60:40
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
7c
7d
7e
7f
Propyl-
Butyl-
PhCH2-
83
82
80
79
78
75
82
80
82
74
81
71
80
76
79
p-Br-C6H4CH2-
p-F-C6H4CH2-
m-Me-C6H4CH2-
PhCH2CH2-
H-
9.
Propyl-
Butyl-
PhCH2-
10.
11.
12.
13.
14.
15.
16.
p-Br-C6H4CH2-
p-F-C6H4CH2-
m-Me-C6H4CH2-
PhCH2CH2-
H-
7g
7h
aThe diastereomeric ratios were determined from 1H NMR.
Synthesis of N1-alkylated-3-β-C-glucoconjugated-oxopropylidene oxindoles:
The target compounds N1-alkylated-3-β-C-glucoconjugated-oxopropylidene oxindoles (8 & 9)
were accessed by dehydration of synthesized aldol addition products N1-alkylated-3-(3′-β-C-
glucoconjugated-2′-oxo-propyl)-3-hydroxy-oxindoles (6 & 7) with an appropriate dehydrating
agent. The screening of different acidic dehydrating agents such as 25% dil. HCl, acetic acid, and
p-TSA under various reaction conditions resulted into a complex mixture of compounds which
are difficult to isolate. Our base mediated dehydration methodology[27] resulted into a mixture

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of compounds albeit in poor yield of desired dehydrated product. Interestingly, the addition of a
well-known dehydrating agent P2O5 (5 equiv.)[28] to the stirring solution of N1-alkylated-3-(3′-
β-C-glucoconjugated-2′-oxo-propyl)-3-hydroxy-oxindoles (6 or 7,1 equiv.) in dichloromethane
at 0°C afforded a single stereoisomer of N1-alkylated-3-β-C-glucoconjugated-oxopropylidene
oxindoles 8 and 9 in 52-72% yields (Scheme 3, Table 2). The non-nucleophilic nature of the
P2O5 makes it an efficient dehydrating agent for the desired transformation.
Scheme 3: Synthesis of N1-alkylated-3-
β-C-glucoconjugated-oxopropylidene oxindoles.
Table 2: Synthesis of N1-alkylated-3-β-C-glucoconjugated-oxopropylidene oxindoles (8 & 9) by
treating the diastereomeric mixtures N1-alkylated-3-(3′-β-C-glucoconjugated-2′-oxo-propyl)-3-
hydroxy-oxindoles (6 & 7) with dehydrating agent P2O5.
S.No.
1.
2.
3.
4.
5.
6.
7.
8.
Compound No.
R
X
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Yield (%)
69
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
9c
9d
9e
9f
Propyl-
Butyl-
PhCH2-
65
55
88
52
60
58
64
72
70
60
62
57
64
63
68
p-Br-C6H4CH2-
p-F-C6H4CH2-
m-Me-C6H4CH2-
PhCH2CH2-
H-
9.
Propyl-
Butyl-
PhCH2-
10.
11.
12.
13.
14.
15.
16.
p-Br-C6H4CH2-
p-F-C6H4CH2-
m-Me-C6H4CH2-
PhCH2CH2-
H-
9g
9h
The structure elucidation of the target compounds (9 & 10) was done on the basis of their
1
spectroscopic data H, 13C, and HRMS. To confirm the configuration of the isolated single
1
13
isomer, detailed chemical shift assignment of H and C NMR signals was performed by using

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various 1D (1H, 13C, DEPT) and 2D (COSY, TOCSY, NOESY, HSQC, and HMBC) NMR
experiments for one of the above prototypes (9a). HMBC correlation of H-1' & H-4 with C-3 and
H-1' & H-8 with C-2 and H-1' & H-3' with C-2' showed their connectivity (Figure 3). It has been
reported in the literature that 3-substituted indolin-2-ones may exist as either the Z or E isomer
depending on the characteristics of the substituents at the C-3 position of the 3-substituted
indolin-2-one[29]. In the 1H, 1H - NOESY spectra, the missing correlation between H-1′ and H-4
strongly supported the formation of E configuration of the double bond between C-3 and C-1′ in
9a. Here, we observed only the nOe correlation between H-1′ and H-3′. Further, the
1
characteristic peaks (H-1′ and C-1′) in all the final compounds for H and 13C NMR spectra
appeared at around δ7.10-7.20 ppm and δ133 ppm, respectively.
Figure 3: Relevant nOe and HMBC correlations of 9a.
Use of Zemplén deacetylation reaction condition was found to be unsuitable for the deprotection
of the compounds 8 & 9[30] as well as methanolic-HCl proved to be inefficient. This may
probably be due to the retro-aldol reaction taking place leading to the formation of the
corresponding N1-alkylated isatin derivative and β-C-glucopyranosyl-propanone. Earlier, we
have reported acetyl protected phenyl butenonyl-C-glycosides[23d] as potent antimalarial agents
than their deacetylated counterpart. Apart from this, the literature survey revealed that acetyl-
protected glycosylated isoindigo, indirubin derivatives, and other glycoconjugates have shown
better antiproliferative activity than their deacetylated counterparts[31]. Screening of these

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acetylated analogues 8 & 9 has shown excellent in vitro antiplasmodial activity against P.
falciparum.
Biology
The synthesized N1-alkylated-3-β-C-glucoconjugated-oxopropylidene oxindoles (8 & 9) were
evaluated for their in vitro antiplasmodial activity against Chloroquine-sensitive (3D7) and
Chloroquine-resistant (K1) strains of P. falciparum as compared to the reference drug
chloroquine and the respective values for inhibitory concentration 50% (IC50 in µM), cytotoxic
concentrations 50% (CC50 in µM) and selectivity indices (SI) against both Pf strains are enlisted
in Table 3.
Table 3: In vitro antiplasmodial activity and cytotoxicity of targeted compounds (8 & 9) and
diastereomeric mixtures (6 & 7).
IC50 (µM)a,b
SI(µM)c
IC50 (µM)a,b
CC50 (µM)b,d
CC50 (µM)b,d
Entry
Entry
Pf3D7 PfK1
Pf3D7 PfK1
Pf3D7 PfK1
3.59
2.61
0.77
0.23
0.47
0.53
0.95
4.27
1.18
0.18
0.26
0.24
0.32
0.17
0.11
2.68
>5
124.74
125.56
71.18
76.54
119.07
72.46
64.69
127.20
95.55
88.90
91.21
93.33
107.26
90.96
92.97
121.94
>500
34.74
48.10
24.94
68.23
>5
>5
ND
8a
8b
8c
8d
8e
8f
6a
6b
6c
6d
6e
6f
1.84
0.29
0.80
1.19
0.30
0.75
>5
>5
>5
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
92.44 245.44
332.78 95.67
253.34 100.05
136.71 241.53
>5
>5
>5
>5
>5
>5
>5
>5
8g
8h
9a
9b
9c
9d
9e
9f
68.09
29.78
86.25
25.44
6g
6h
7a
7b
7c
7d
7e
7f
>5
>5
>5
>5
>5
>5
3.54
>5
>5
>5
>5
>5
80.97 238.87
493.88 404.09
350.80 294.22
388.87 622.20
335.18 429.04
535.05 87.46
845.18 98.90
0.40
0.22
0.31
0.15
0.25
1.04
0.94
2.52
0.5
>5
>5
>5
4.81
2.26
>5
9g
9h
7g
7h
>5
45.50
48.38
>5
>71428 >1000
CQ
0.007

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a50% Inhibitory concentration against chloroquine sensitive (3D7) and resistant (K1) strains of P. falciparum. bvalues are
represented as the average of at least duplicate determinations. cSelectivity index (SI) = CC50/IC50. d50% Cytotoxic
concentrations. ND = Not done.
The activity result shows that among all the synthesized targeted compounds 9g, 9f, 9b, 8d, 9d,
9c, and 9e have exhibited potent antiplasmodial activity having IC50 values in the range of 0.1-
0.3 µM as 0.11, 0.17, 0.18, 0.23, 0.24, 0.26 and 0.32 µM against chloroquine-sensitive Pf3D7
strain, respectively. Apart from this, compounds 9d, 9b, 9e, 8c, 8f, 9c, and 9a have shown
excellent promising activity having IC50 values in the range of 0.1-0.4 µM as 0.15, 0.22, 0.25,
0.29, 0.30, 0.31 and 0.40 µM, respectively against chloroquine-resistant PfK1 strain, which are
even better than the standard drug chloroquine showing IC50 value 0.5 µM. Moreover,
compounds 8e, 8f, 8c and 8g have also shown significant activity against Pf3D7 strain with IC50
values 0.47, 0.53, 0.77 and 0.95 µM, respectively while compounds 8g, 8d, and 9g displayed
very good activity against PfK1 strain with IC50 values 0.75, 0.80 and 0.94 µM, respectively. As
shown in Table 3 most of the compounds are active having IC50 values falling in the range of 0-1
µM, against both the strains. The most active series of compounds against both the strains is 9a-
h which is 5-chloroisatin derivative, while in the case of isatin derivatives 8a-h the
antiplasmodial activity comparatively reduced against both the strains. The latter indicates that
the in vitro antiplasmodial activity is highly enhanced by 5-chloro substitution at isatin core. The
effect of substitution at the N-1 position of isatin can also be studied in displaying the
antiplasmodial activity. The N-1 unsubstituted compounds such as 8h were found inactive at
higher concentration, while 9h being a 5-chloroisatin derivative showed moderate activity with
IC50 values 2.68 µM against Pf3D7 strain and 2.52 µM against the PfK1 strain. These
compounds showed the comparatively poor result as compared to other compounds with
substitution at N-1. In addition to this, the pure diastereomeric mixtures (6 & 7) have also been
evaluated for in vitro antiplasmodial activity against both Pf3D7 and PfK1 strains (Table 3). It
was found that almost all of these diastereomeric mixtures were inactive at a higher
concentration with IC50 >5 µM against any of the strains, except compound 7e which showed
moderate activity against PfK1 strain with IC50 value 2.26 µM. This clearly signifies the
importance of exocyclic double bond at the C-3 position of the isatin ring, for the antimalarial
activity. All the compounds having IC50 <5 µM against either of the Pf strains were evaluated for
their cytotoxicity against monkey kidney cell line (VERO) and these were found to be non-
cytotoxic with very good SI values. The most active compounds with IC50 values in 0.1-0.3 µM

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range against Pf3D7 strain have very good CC50 and SI values in 76.54-107.26 µM and 332.78-
845.18 µM range, respectively. Similarly, the compounds with IC50 values in 0.1-0.4 µM range
against PfK1 strain also have very good SI values in 238.87-622.20 µM. Therefore, these
compounds hold the potential to be developed as novel antimalarial drug candidates.
Conclusion
In conclusion, the present study describes the synthesis of a novel series of N1-alkylated-3-β-C-
glucoconjugated-oxopropylidene oxindoles 8 and 9 utilizing cross-aldol chemistry followed by
dehydration along with their antiplasmodial activity against 3D7 and K1 strains of P. falciparum.
Among all the synthesized targeted glucoconjugates, ten compounds have shown significantly
potent results with IC50 in the range of 0.11-0.77 µM against the chloroquine-sensitive Pf3D7
strain. Further, these compounds have also exhibited excellent promising results against
chloroquine-resistant PfK1 strain having IC50 values in 0.15-0.94 µM range. These compounds
were found to be more selective for plasmodial over mammalian cells. Our study reveals that the
exocyclic double bond at the C-3 position of isatin has played a crucial role in displaying the
antiplasmodial activity, as none of the diastereomeric mixtures (6 or 7) were active against
Plasmodium parasites. The preference for chloro substituent at C-5 position (9a-h) to exhibit
antiplasmodial activity is also evident.
Materials & Methods
In Vitro Cultivation of P. falciparum
The Chloroquine (CQ) sensitive (3D7) and resistant (K1) strains of P. falciparum were cultured
in vitro as per Trager and Jensen (1976) method with some modifications[32]. Cultures were
maintained in fresh human erythrocytes at 5% hematocrit in complete medium. RPMI-1640
(HEPES modified) medium (Sigma) supplemented with 0.5% AlbuMaxII, 0.2% glucose, sodium
bicarbonate and 15 µM hypoxanthine and incubated at 37 °C in a CO2 incubator. Parasite growth
rate and the stage were determined by the test of Giemsa’s stained thin smears of the RBCs. All
the above mentioned final compounds were tested over a concentration range of 150 nM to 10
µM. P. falciparum drug susceptibility test was carried out by determining fifty percent inhibitory
concentration (IC50) according to the method of Johnson et al. (2007) with some
modifications[33]. Briefly, two-fold serial dilutions of compounds and chloroquine were

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prepared in 96 well plates and then 50 µL asynchronous cultures of infected erythrocytes with
0.8-1% parasitaemia and 1% haematocrit was added to each well (100 µL-final volume). Eight
wells were treated as a positive control (without drug) and 4 wells as a negative control (without
parasite and drug). These plates were incubated in a CO2 incubator maintained at 37 °C for 72 h.
Then 100 µL lytic buffer containing SYBR Green 1x final concentration was added to each well
and incubated for 2 h at room temperature in dark place. Plates were read under fluorescence
reader at Ex. 485 nm, Em. 535 nm. Fifty percent inhibitory concentration (IC50) was determined
by quantifying DNA in treated and control cultures of parasites in human erythrocytes according
to the SYBR Green I (Sigma Aldrich) fluorescence-based method.
Cytotoxicity Assay
Cytotoxic level of compounds was determined according to O’Brien et. al. (2000) method with
few modifications[35]. The monkey kidney cell line (VERO) was maintained in vitro in MEM
medium (Sigma) supplied with 15% fetal bovine serum (FBS) and 5% CO2 at 37 °C. An
appropriate serial drug dilution was prepared in culture plates and the cells were exposed to the
concentrations of particular compounds for three days, 10% resazurin, a cell viability marker,
was added and read under fluorescent reader at excitation of 530 ± 25 nm and emission of 590 ±
25 nm wavelength for calculation of the median cytotoxic concentration (CC50).
Author contributions
The manuscript was written through contributions from all authors. All authors have given
approval to the final version of the manuscript. R.K.T. and P.J. contributed equally to this work.
Conflicts Of Interest
The authors declare that they have no conflicts of interest with the contents of this article.
Acknowledgments
RKT and PJ are thankful to UGC, New Delhi and DBT for providing fellowships. We thank
SAIF-CDRI for the analytical facilities and Mrs. Shashi Rastogi for technical assistance.
References

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Graphical Abstract

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Research highlights
‹ A series of glucoconjugated oxindoles were accessed from glucosyl propanone and
isatin.
‹ These compounds were accessed by simple cross-aldol reaction followed by
dehydration.
‹ 10 compounds showed potent activity with IC50 in 0.11-0.77 µM against Pf3D7 strain.
‹ 10 compounds showed promising activity with IC50 in 0.15-0.94 µM against PfK1
strain.
‹ Activity is enhanced in compounds having exocyclic double bond and 5-chloro
substituent.