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Anti-Infective Agents, 2019, 17, 000-000 1

RESEARCH ARTICLE

Biological Evaluation of 2-aminothiazole Hybrid as Antimalarial and

Antitrypanosomal Agents: Design and Synthesis

Surender Singh Jadava, Vishnu Nayak Badavathb,*, Ramesh Ganesana, Narayana Murthy Gantaa,c,
Dominique Bessond,*, Venkatesan Jayaprakasha,*

a
Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jhar-
khand, India; bDepartment of Chemistry, Indian Institute of Technology (Banaras Hindu University), Varanasi, 221005,
India; cVishnu Institution of Pharmaceutical Education and Technology, Narsapur, Medak, Telangana, India; dSpecial
Programme for Research and Training in Tropical Diseases, World Health Organization, Geneva, Switzerland

Abstract: Introduction: A series of 2-aminothiazole schiff’s bases (1-24) were synthesized and
screened against a few neglected tropical disorders (NTDs). Compounds 12 and 14 were found to
have antitrypanosidal activity, whereas compound 14 was found to be more effective than standard
benznidazole. The antiplasmodial assay provided three specific and effective compounds (9, 12 and
24) than standard chloroquine. Compound (21) inhibited Leishmania infantum, almost comparable
to Miltefosine.
ARTICLE HISTORY

Received: June 22, 2018 Methods: All the compounds were subjected to cytotoxicity assay and none of the compounds
Revised: October 22, 2018 were found to have cytotoxicity. Molecular docking simulations revealed that four compounds (1,
Accepted: October 11, 2018
9, 12 and 21) were found to similarly occupy the hydrophobic active site of trans-2-enoyl acyl car-
DOI: rier protein reductase of P. falciparum (PfENR) as triclosan and outcomes were closely related to
10.2174/2211352516666181016122537
their anti-malarial potencies.
Results: The screening results against T. cruzi, T. brucei, L. donovani, L. infantum, P. falciferum
and cytotoxicity assays provided a few significant to most potent compounds; two variant class of
NTDs.
Keywords: 2-aminothiazole hybrid, antimalarial activity, anti-trypanosomal activity, anti leishmanial activity, cytotoxicity
studies, molecular docking simulatin.

1. INTRODUCTION carbaxoamide was observed as the most potent with noticea-

ble bioavailability. Another scaffold i.e, thiosemicarbazones
The NTDs are known to be caused by the few protozoal,
and semicarbazones exhibited the significant antimalarial
parasitic, bacterial and viral infections; which greatly affect
activity along with other NTDs [7]. The Schiff’s bases of
the poorest countries across the world [1, 2]. The difficulty aminothiazoles are the products of thiosemicarbazones, ex-
in identification of the mechanism of actions of the drugs
hibiting potent envelope protein inhibitory activity against
obtained through the rational process still exist. The huge
various mosquito borne dengue strains and became the lead
effort is ongoing to find the potential leads against NTDs for
molecules in the arena of the viral NTDs [8]. Recently, 2-
the therapeutic applications. In this scenario, the aminothia-
amino-4-(2-pyridyl) thiazole scaffold was synthesized and
zole compounds have brought a new hope for the prevention
tested for in vitro antiplasmodial activity against the
of the few NTDs. The aminothiazoles are becoming leads for chloroquine sensitive NF54 Plasmodium falciparum strain
the inhibition of a variety of complications like antimicrobi-
[9]. The history of the aminothiazole derivatives clearly
al, antifungal, anticancer, anti-tubercular, anti proliferative,
demonstrated that they can inhibit the few more NTDs, in
sedatives [3-5]. The high throughput phenotypic whole-cell
this aspect, we have synthesized the Schiff’s bases of the
assay of a Soft Focus library provided the antimalarial ami-
aminothiazole (Scheme 1) and further proceeded for the
nothiazole and aminopyrimidine scaffolds could be featured
screening against the T. cruzi, T. brucei, L.donovani, L. in-
scaffolds in the design of drug-resistant antiplasmodial drugs fantum, P. falciferum and cytotoxicity assays. The relation-
6
. The SAR findings of aminothiazoles library presented the
ship between antimalarial thiosemicarbazones and
positive features which are essential for the antimalarial effi-
aminomethylthiazole pyrazole carbaxoamide derivatives
cacy. Among them, the aminomethylthiazole pyrazole
with our compounds were represented in Fig. (1). A putative
target trans-2-enoyl acyl carrier protein reductase of P. falci-
*
Address Correspondence to this author at the Department of Chemistry, parum (PfENR) was studied along with anti-malarial poten-
Indian Institute of Technology (Banaras Hindu University), Varanasi, tials of hydrazinyl aminothiazole derivatives [10-12]. While
221005, India; Tel.: +91-9430316423; E-mail: [email protected] hindrances in the anti-malarial potency of most effective

2211-3525/19 $58.00+.00 ©2019 Bentham Science Publishers

2 Anti-Infective Agents, 2019, Vol. 17, No. 1 Jadavet al.

Cl H2 N N
CH3 NH NH N
N N
H 3C N N N N
H H H
Biguanide Cl O
Cycloguanil OH Cl
Proguanil
Chloroguanide Cyclized form Triclosan Pf ENR inhibitor
Anti-malarial drugs

Essential pharmacophoric
properties for antimalarial
efficacy

S H N
N N
N N
N NH 2
H H 2N S O
R

Thiosemicarbazone Aminomethylthiazole
pyrazole carbaxoamide

O
N
N S O
HN S
N
N R1 R1 = Cl, Ph
O N N
N H
N S R
HN
N Aminothiazole schiff's bases comprising
Pf ENR inhibitors of both pharmacophoric features

Fig. (1). Design strategy adopted for designing aminothiazole schiffs bases against neglected tropical diseases.

Scheme 1. Reagents and conditions: (a) MeOH, NH2-CS-NH-NH2, AcOH, rt, 2 hrs; (b) MeOH, R2-C6H4-CO-CH2Br, rt, 30-60 min.

compounds among the Schiff’s bases of the aminothiazole quine for P. falciparum, miltefosine for L. infantum, benzni-
through molecular docking simulations employing the trans- dazole for T. cruzi and Sermon for T. b. brucei. All reference
2-enoyl acyl carrier protein reductase of P. falciparum drugs were either obtained from the fine chemical supplier
(PfENR) (PDB: 2OP0) were solved by analyzing binding Sigma-Aldrich (tamoxifen, suramin) or from WHO-TDR
modes. (chloroquine, miltefosine, benznidazole) [13].
2.2.1. Cytotoxicity Studies
2. RESULTS AND DISCUSSION
The cytotoxicity activity of all the compounds was car-
2.1. Chemistry ried out against MRC-5 cell lines, none of the compounds
All the final compounds were synthesized by Scheme 1. were found to have cytotoxicity. The three compounds (6, 15
Hydrazinecarbothioamide were synthesized by reaction of and 18) were found to have aspecificity and selectivity to-
acetophenone/ benzaldehyde and thiosemicarbazide in meth- wards the cytotoxicity and all other protozoans (Table 2).
anol, by using glacial acetic acid in a catalytic amount. The 2.2.2. Antitrypanosomial Activity
final compounds were synthesized by the reaction between
hydrazinecarbothioamide and phenacyl bromide in methanol Compounds, two compounds (12 and 14) exhibited po-
to provided compounds 1-24. The proton NMR exhibited a tent and specific inhibition of T. cruzi. Compound 14 was
broad peak due to NH at δ 3.50-5.80 and a singlet for =C-H found to have higher potency and selectivity (IC50 0.244
at 7.97-8.80. Mass spectra of all of the synthesized com- µg/mL; SI > 104.8) than the standard drug benznidazole.
pounds displayed the presence of [M]+ and [M+1]+ peaks for Whereas, compound 12 exhibited selectivity (IC50 0.634
almost all the compounds (Supplimentary information). µg/mL; SI > 31.8) slightly higher than the standard drug and
less than compound 14. It has also shown lower potency
2.2 Biological Screening against T. brucei (IC50 1.296 µg/mL; SI > 15.5), when com-
pared to its standard drug suramin it may be regarded as less
For the different tests, appropriate reference drugs were effective (Table 3).
used as a positive control: tamoxifen for MRC-5, chloro-
Biological Evaluation of 2-aminothiazole Hybrid as Antimalarial Anti-Infective Agents, 2019, Vol. 17, No. 1 3

Table 1. Structural formulas of compounds (1-24).

Compound X R R1 R2 Compound X R R1 R2

1 CH -CH3 -H -Cl 13 CH -CH3 -H -C6H5

2 CH -CH3 -Cl -Cl 14 CH -CH3 -Cl -C6H5

3 CH -CH3 -OH -Cl 15 CH -CH3 -OH -C6H5

4 CH -CH3 -OCH3 -Cl 16 CH -CH3 -OCH3 -C6H5

5 CH -CH3 -NO2 -Cl 17 CH -CH3 -NO2 -C6H5

6 N -CH3 -H -Cl 18 N -CH3 -H -C6H5

7 CH -H -H -Cl 19 CH -H -H -C6H5

8 CH -H -Cl -Cl 20 CH -H -Cl -C6H5

9 CH -H -OH -Cl 21 CH -H -OH -C6H5

10 CH -H -OCH3 -Cl 22 CH -H -OCH3 -C6H5

11 CH -H -NO2 -Cl 23 CH -H -NO2 -C6H5

12 N -H -H -Cl 24 N -H -H -C6H5

Table 2. Cytotoxicity studies against human MRC-5hum cell lines.

Compound IC50 (ug/ml) Compound IC50 (ug/ml)

1 >20.98 13 >23.64

2 >23.18 14 >25.85

3 - 15 3.38

4 >22.90 16 >25.56

5 >23.86 17 >26.52

6 0.16 18 1.17

7 >20.08 19 >24.95

8 >22.28 20 0

9 >21.10 21 >23.77

10 >22.00 22 >24.67

11 >22.96 23 >25.62

12 >20.14 24 >22.81

Benznidazole >64.0 Miltefosine >64.0

Suramin >64.0 Chloroquine >64.0

Table 3. Antitrypanosomial activity of compounds (1-24).

Chagas Disease (American trypanosomiasis) Sleeping Sickness (Human African trypanosomiasis)

Compound T. cruzi T. brucei Remarks

IC50 (ug/ml) SI IC50 (ug/ml) SI

1 > 20.982 0 >20.98 0 Inactive

2 > 23.186 0 >23.18 0 Inactive

3 > 22.006 0 >22.00 0 Inactive

(Table 3) Contd…
4 Anti-Infective Agents, 2019, Vol. 17, No. 1 Jadavet al.

Chagas Disease (American trypanosomiasis) Sleeping Sickness (Human African trypanosomiasis)

Compound T. cruzi T. brucei Remarks

IC50 (ug/ml) SI IC50 (ug/ml) SI

4 > 22.903 0 >22.90 0 Inactive

5 16.46 1.4 12.57 1.9 Inactive

6 0.1455 1.2 0.66 0.3 Aspecific

7 > 20.084 0 >20.08 0 Inactive

8 > 22.289 0 >22.28 0 Inactive

9 19.923 >1.1 >21.10 0 Inactive

10 >22.006 0 >22.00 0 Inactive

11 > 22.964 0 >22.96 0 Inactive

12 0.6341 >31.8 1.29 15.5 Chagas +ve

13 11.698 >2 >23.64 0 Inactive

14 0.2466 >104.8 >25.85 0 Chagas +ve

15 2.4115 1.4 2.99 1.1 Aspecific

16 > 25.569 0 >25.56 0 Inactive

17 18.299 >1.4 >26.52 0 Inactive

18 0.0572 20.6 0.74 1.6 Aspecific

19 > 22.749 0 >24.95 0 Inactive

20 > 24.954 0 >24.95 0 Inactive

21 > 23.773 0 >23.77 0 Inactive

22 > 24.671 0 >24.67 0 Inactive

23 > 25.629 0 >25.62 0 Inactive

24 14.691 >1.6 >22.81 0 Inactive

Benznidazole 2.2 ± 0.5 >29 - - Chagas +ve

Suramin - - 0.03±0.02 >2133 HAT +ve

2.2.3. Antileishmanial Activity SI > 380.4) than Chloroquine and also exhibited the antipro-
tozoal activity as discussed earlier. Whereas, compound 1
The antileishmanial screening against L.infantum provid-
was found to be less active (IC50 0.804 µg/mL; SI > 26.1)
ed that none of the tested compounds found to have enough
among the specific antiplasmodial active compounds (Table
efficacy and conclude as selective inhibitors. Compound 21
5).
exhibited the slightest inhibition of L. infantum with less
selectivity (IC50 1.485 µg/ml; SI > 16) when com- 2.3. Molecular Docking Studies
pared to its standard drug miltefosine (Table 4).
The Glide 5.0 of Schrodinger LLC was utilized for pre-
2.2.4. Antiplasmodial Activity
sent binding mode analysis, X-ray three dimensional struc-
Four compounds (1, 9, 14 and 21) exhibited remarkable ture of trans-2-enoyl acyl carrier protein reductase of P. fal-
potency and specificity against P. falciferum. Compound 21 ciparum (PfENR) (PDB: 2OP0) in complex with Triclosan
was found to have four folds higher selectivity and specifici- was retrived from protein data bank. The receptor grid by
ty (IC50 0.029 µg/mL; SI > 801.8) than the standard drug picking triclosan as reference ligand was built and this site
Chloroquine, it can also be regarded as most potent com- was employed for Xtra precision docking studies. The hy-
pound among others. Compound 9 was found to be the se- drophobic tricloson active site consists of several hydropho-
cond highest potent derivative among the series, showing bic residues include Tyr277, Tyr267, Ala269, Ala372,
potency and specificity IC50 0.040 µg/mL; SI > 517.5 than Pro314, Phe368, Ile369, Ile323, Ala219 and hydrophilic res-
chloroquine. The next compound, i.e., 12 also exhibited an- idues like Ser317, Lys285 and Asn218. The biphenyl ring of
timalarial potency with higher selectivity (IC50 0.053 µg/ml; triclosan was observed to be occupied into the hydrophobic
Biological Evaluation of 2-aminothiazole Hybrid as Antimalarial Anti-Infective Agents, 2019, Vol. 17, No. 1 5

Table 4. Anti leishmaniasis activity (L.infantum) of compounds (1-24).

Compound IC50 (ug/ml) SI Remarks Copound IC50 (ug/ml) SI Remarks

1 >20.982 0 Inactive 13 >23.647 0 Inactive

2 >23.186 0 Inactive 14 >25.852 0 Inactive

3 >22.006 0 Inactive 15 2.3182 1.5 Aspecific

4 11.452 >2 Inactive 16 >25.569 0 Inactive

5 >23.862 0 Inactive 17 >26.527 0 Inactive

6 1.7356 0.1 Aspecific 18 12.024 0.1 Aspecific

7 >20.084 0 Inactive 19 >24.954 0 Inactive

8 >22.289 0 Inactive 20 >14.838 >1.7 Inactive

9 >21.108 0 Inactive 21 1.4858 16 Leishmania +ve

10 >22.006 0 Inactive 22 >24.671 0 Inactive

11 >22.964 0 Inactive 23 >25.629 0 Inactive

12 11.572 >1.7 Inactive 24 >22.813 0 Inactive

Miltefosine 3.32 ± 0.7 >19 Leishmania +ve - - - -

Table 5. Anti malarial activity (P.falciferum) of compounds (1-24)

Copound IC50 (ug/ml) SI Remarks Copound IC50 (ug/ml) SI Remarks

1 0.804 >26.1 Malaria +ve 13 >23.647 0 Inactive

2 >23.186 0 Inactive 14 >25.852 0 Inactive

3 >22.006 >22.0 Inactive 15 0.9574 3.5 Aspecific

4 >22.903 0 Inactive 16 >25.569 0 Inactive

5 5.6557 >4.2 Inactive 17 >26.527 0 Inactive

6 0.1163 1.5 Aspecific 18 0.1325 8.9 Aspecific

7 >20.084 0 Inactive 19 4.5141 >5 Inactive

8 >22.289 0 Inactive 20 >24.954 >24.95 Inactive

9 0.0408 517.5 Malaria +ve 21 0.0297 801.8 Malaria +ve

10 >22.006 0 Inactive 22 >24.671 0 Inactive

11 >22.964 0 Inactive 23 >25.629 0 Inactive

12 0.053 >380.4 Malaria +ve 24 >22.813 0 Inactive

Chloroquine 0.3 ± 0.1 >213 Malaria +ve - - - -

cavity by establishing two π-π bond with Tyr277, Phe similar binding recognition. Whereas, heteroaryl ring of
368 and hbond with Tyr277. The hbond of free hydroxyl compound 12 displayed hbond with Ala219 and remaining
group with NAD ligand was noticed. However, the best four interactions were found to be similar. On the other aspect,
anti-malarial compounds i.e., compound 21, 12, 9 & 1 were compound 1 was found to be bounded in active site com-
selected for the docking analysis to find out the binding pat- pletely opposite to that of compound 21, 12 & 9. Binding of
tern in the biological active site of trans-2-enoyl acyl carrier compound 1 at the active site of trans-2-enoyl acyl carrier
protein reductase of P. falciparum (PfENR). The biphenyl protein reductase of P. falciparum (PfENR) clearly indicated
ring compound 21 and chlorophenyl ring of compound 9 on its lower anti-malarial potency as compared to compound
were completely occupied in the hydrophobic active site as 21, 12 and 9. The glide energy and glide evdw of above four
triclosan, hydroxyl phenyl ring of both compounds exhibited ligands were presented in Fig. (2).
6 Anti-Infective Agents, 2019, Vol. 17, No. 1 Jadavet al.

A)

Fig. (2). A) Glide energy and Glide evdw score, PfENR (PDB: 20P0) complexed with Triclosan. B) Superpose of active compounds (indi-
cated by red and blue thick sticks) at the active site, Triclosan and NAD indicated by green sticks. C) Compound 21 (green thick stick) at the
active site.

benzylidene part is essential for the specific inhibition and

2.4. Structural Activity Relationship
potency towards the antiplasmodial activity. The substitution
Compound 12 and 14 were found to inhibit T. cruzi, in of a methyl group at benzylidene (compound 15) part makes
case of compound 14 the two substitutions i.e., methyl group it aspecific. Incase of compound 9, the substitution of the
on aralkydene or benzylidene part and the presence of the mono halo aryl ring on the aminothiazole nucleus also makes
biaryl group in the aminothiazole nucleus were found to play it active, but it reduces its antiplasmodial efficacy to half of
a role in the amtiprotozoal activity. The presence of mono compound 21. In addition to this, the presence of hydroxyl
halo aryl ring on the aminothiazole and removal of the me- group on the benzylidene phenyl ring (compound 21 and 9)
thyl group is responsible for reducing the antiprotozoal effi- might be responsible for the effective inhibition and selectiv-
cacy or making them inactive. Incase of compound 12, it ity. Simultaneously, for example, the presence of the methyl
lacks the methyl group at benzylidene and has the mono halo group on benzylidene part on either compound (compound 4
aryl ring on aminothiazole making it less active than com- and 15) makes them aspecific or inactive. Incase of com-
pound 14. The substitution of a methyl group (compound 6) pound 12, the presence of a heteroaryl ring on penzylidene
and biaryl group (compound 18) on aminothiazole nucleus part also makes them active, but it was found to be less ef-
makes them aspecific. From the obtained reults, we can say fective than compound 21 and 9. The presence of methyl
that the presence of methyl group at benzylidene part and group and biaryl ring on aminothiazole (compound 6, 16 and
biaryl ring on aminothiazole nucleus is essential for impart- 24) makes it aspecific and inactive.
ing the specificity towards the antiprotozoal activity, where-
as, four compounds (1, 9, 12 and 21) possessed the very best
CONCLUSION
antimalarial efficacy with potent specificity than standard
drug. Incase of compound 21, the presence of birayl ring on The twenty-four aminothiazole schiff bases with different
the aminothiazole nucleus and absence of methyl ring on substitution were synthesized and biological screening
Biological Evaluation of 2-aminothiazole Hybrid as Antimalarial Anti-Infective Agents, 2019, Vol. 17, No. 1 7

Fig. (3). Findings of antimalarial aminothiazoles.

against few NTDs comprising of trypanosomal like T.cruzi, CONSENT FOR PUBLICATION
T. brucei,and protozoal like L. donovani, L. infantum, P.
falciferum along with cytotoxicity assays were carried out. Not applicable.
The two compounds (14 and 12) were found to have the
specificity to inhibit the T. Cruzi, among them compound 14 CONFLICT OF INTEREST
exhibited higher potency than standard benznidazole. The authors declare no conflict of interest, financial or
Whereas, compounds 21, 9 and 12 were found to be the most otherwise.
potent compounds than standard Chloroquine against P. fal-
ciferum amongst the series. The contemporary results clearly ACKNOWLEDGEMENTS
stated that amintothiazoles might have specificity towards
the inhibition of the P. falciferum. Later on it was found that The authors acknowledge UGC, GoI, India for RGNF-
the present series of compounds comprises of the antimalari- SRF for providing fellowship. Central Instrumentation Facil-
al thiosemicarbazone and aminothiazole skeletons, which are ity, BIT, Mesra and Dr. Reddy’s Institute of Life Sciences,
essential for the specificity towards antiplasmodial efficacy. Hyderabad were acknowledged for Spectral Characteriza-
Binding mode analysis of compounds 21, 9, 12 and 1 against tion. This investigation received support from the
trans-2-enoyl acyl carrier protein reductase of P. falciparum UNICEF/UNDP/World Bank/WHO Special Programme for
(PfENR) enzyme was successfully achieved to clear the Research and Training in Tropical Diseases (TDR).
hindrances in their anti-malarial potentials.
SUPPLEMENTARY MATERIAL
ETHICS APPROVAL AND CONSENT TO PARTICI- Supplementary material is available on the publisher’s
PATE
web site along with the published article.
Not applicable.
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