Synthesis, antileishmanial activity and docking study of N′-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl) acetohydrazides

Article abstract of DOI:10.1016/j.bmcl.2014.01.035

A series of N′-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c] pyridin-5(4H)-yl)acetohydrazide derivatives is synthesized and evaluated for antileishmanial activity against Leishmania donovani promastigotes. Compounds 9a and 9i were shown significant antileishmanial when compared with standard sodium stilbogluconate. Antimicrobial study revealed that compound 9b has potent as well as broad spectrum antibacterial activity when compared with ampicillin and compound 9e showed promising antifungal activity when compared with miconazole. Also, none of the synthesized compounds showed cytotoxicity up to tested concentration. Further, docking study against pteridine reductase 1 enzyme of L. donovani showed good binding interactions. ADME properties of synthesized compounds were also analyzed and showed potential to develop as good oral drug candidates.

Full text of DOI:10.1016/j.bmcl.2014.01.035

Bioorganic & Medicinal Chemistry Letters 24 (2014) 1605–1610
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, antileishmanial activity and docking study
of N0-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]
pyridin-5(4H)-yl)acetohydrazides
a
a
b
Jaiprakash N. Sangshetti a, , Rehan I. Shaikh , Firoz A. Kalam Khan , Rajendra H. Patil ,
⇑
Sayali D. Marathe b, Wasudev N. Gade b, Devanand B. Shinde c
a Dr. Rafiq Zakaria Campus, Y.B. Chavan College of Pharmacy, Aurangabad 431001 (M.S.), India
b Department of Biotechnology, University of Pune, Pune 411007 (M.S.), India
c Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad 431004 (M.S.), India
a r t i c l e i n f o
a b s t r a c t
A
series of N0-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide
Article history:
Received 3 September 2013
Revised 28 December 2013
Accepted 16 January 2014
Available online 28 January 2014
derivatives is synthesized and evaluated for antileishmanial activity against Leishmania donovani prom-
astigotes. Compounds 9a and 9i were shown significant antileishmanial when compared with standard
sodium stilbogluconate. Antimicrobial study revealed that compound 9b has potent as well as broad
spectrum antibacterial activity when compared with ampicillin and compound 9e showed promising
antifungal activity when compared with miconazole. Also, none of the synthesized compounds showed
cytotoxicity up to tested concentration. Further, docking study against pteridine reductase 1 enzyme
of L. donovani showed good binding interactions. ADME properties of synthesized compounds were also
analyzed and showed potential to develop as good oral drug candidates.
Keywords:
Thieno[3,2-c]pyridine
Antileishmanial activity
L. donovani promastigotes
Antimicrobial activity
Docking study
Ó 2014 Elsevier Ltd. All rights reserved.
ADME properties
Leishmaniasis is a group of diseases caused by infection with
intracellular species of the parasitic protozoan of the genus Leish-
mania with different clinical forms ranging from cutaneous leish-
maniasis (CL) with skin lesions to visceral leishmaniasis (VL)
with enlargement of liver, spleen, and bone marrow dysfunctions.
According to the World Health Organization, leishmaniasis is an
uncontrolled tropical disease with high morbidity and mortality
rates in Africa, Asia, and the America.1 The drugs currently in use
are expensive, require long term treatment,2 display high liver
and heart toxicities, develop clinical resistance after few weeks of
treatment and currently contribute to increase leishmaniasis-AIDS
co-infections in some countries3,4 and hence there is a need for
new antileishmanials with improved efficacy and less side effects.
Also, there are several classes of antimicrobial agents are available
and used for clinical treatment, their advances in medical care are
threatened by a natural phenomenon known as ‘drug resistance’.5,6
This has created an urgent need to devote our continuous efforts
for the discovery and development of new antimicrobials with
broader spectrum of activity and lower toxicity.7,8
Thieno[3,2-c]pyridine compounds are known to possess diverse
range of pharmacological activities such as antimicrobials,9–13 anti-
arrhythmic activity,14 antiplatelet agent15 and antidiabetic activ-
ity.16 Compounds containing acetohydrazide group are reported to
posses various pharmacological activities like antimicrobial,17–21
anticancer,22,23 anticonvulsant24,25 and antileishmanial.26 To reduce
the economical burden of developing new antileishmanial drugs
from scratch and limited understanding of leishmanial biology, a
current strategy is to study drugs known to possess anti-infective
activity.27,28 Many leishmanicidal drugs in distinct phases of devel-
opment are derived from this approach, including some in current
clinical use such as the amphotericin B29 (antifungal) and paromo-
mycin30 and sitamaquine31 (antibacterial). Structures of some
anti-infective agents bearing thieno[3,2-c]pyridine ring and acet-
ohydrazide chain reported in literature are presented in Figure 1.
Taking into account all of the aforementioned and due to the urgent
need for innovative drugs based on new molecular scaffolds, and as an
extension of our earlier work on thieno[3,2-c]pyridine derivatives9,10
and the increased interest on new antileishmanial agents due to the
lack of effective drugs, we decided to synthesize and test the efficiency
of
0N0-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-
5(4H)-yl)acetohydrazides 9(a–j) for antimicrobial and antileishmanial
activity. The computational parameters like docking study for
⇑
Corresponding author. Tel./fax: +91 240 2381129.
E-mail address: jnsangshetti@rediffmail.com (J.N. Sangshetti).
http://dx.doi.org/10.1016/j.bmcl.2014.01.035
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

1606
J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1605–1610
7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)acetate (7) was obtained
via reaction of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochlo-
ride (5) with ethyl-2-bromoacetate (6) using triethyl amine as
catalyst. Ethyl-2(6,7-dihydrothieno[3,2-c]pyridine-5(4H)-yl)ace-
tate (7) was reacted with hydrazine hydrate to give the com-
pound 2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide
(8).9
N
S
F
N
O
HN
Further, to expand the series, N0-substitutedbenzylidene-2-(6,7-
dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazides 9(a–j) were
prepared reacting the compound (8) with various substituted aro-
matic aldehydes in ethanol using glacial acetic acid as catalyst. The
physical data of the synthesized compounds are presented in
Table 1. All the reactions proceeded well in 6–8 h to give products
in very good yields (74–90%). The purity of the synthesized com-
pounds was checked by TLC and melting points were determined
in open capillary tubes on a Buchi 530 melting point apparatus
and are uncorrected. All synthesized derivatives 9(a–j) were char-
acterized using IR, 1H NMR, 13C NMR and Mass spectra.
O
N
1
O
O
N
H
S
F
2
O
O
N
The title compounds 9(a–j) were tested for their in vitro antile-
ishmanial activity against a culture of Leishmania donovani prom-
astigotes (NHOM/IN/80/DD8). Parasite viability was evaluated
using a modified 3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyl tetra-
zolium bromide (MTT) assay wherein the amount of formazan pro-
duced is directly proportional to the number of metabolically
active cells.32 The concentration that decreased cell growth by
50% (IC50) was determined by graphic interpolation and data ob-
tained depicted in Table 2. Sodium stibogluconate and pentami-
dine were used as standard drugs. Compounds 9(a–j) showed
varying degrees of antileishmanial activities with IC50 ranging be-
N
N
H
N
N
S
N
O
3
N
N
H
N
N
N
S
N
tween 93.75 and 265
9i were found to be most promising compounds showing IC50 va-
lue of 98.75 g/mL and 93.75 g/mL, respectively when compared
lg/mL. Amongst all tested compounds 9a and
O
l
l
F
with sodium stilbogluconate. All the synthesized compounds
4
showed better activity than standard sodium stibogluconate
(IC50 = 490 lg/mL) against L. donovani promastigotes. Structure
Figure 1. Structures of some anti-infective agents reported in literatures 1–4.
activity relationship revealed that the activity mainly depends
upon the presence of substituent on phenyl ring. If we compare
the activity of most active member of the series, compounds with
2-chloro 9a and 4-N,N-dimethylamino substituted phenyl ring 9i
showed significant antileishmanial activity against L. donovani
promastigotes. Introduction of 4-chloro 9b or 2,6-dichloro 9c on
phenyl ring showed decrease in activity. Substitution of methoxyl
group on various position of phenyl ring contributed no significant
antileishmanial and ADME prediction of synthesized compounds were
also performed. The results suggest that the compound could be
exploited as an antileishmanial drug.
The synthetic protocols employed for the synthesis of N0-substi-
tutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acet-
ohydrazides 9(a–j) are presented in Scheme 1. The ethyl-2(6,
O
O
N
NH
. HCl
Br
CH3CN
TEA, (4-5 h)
+
O
O
S
S
7
6
5
n-butanol
(15-17 h)
NH2NH2.H2O
AcOH
H
H
N
N
Ar-CHO
EtOH,
AcOH,
N
N
NH
2
N
Ar
(6-8 h)
O
O
S
S
8
9(a-j)
Where Ar =
R
R= Cl, OH, NH2, OCH3, N(CH3)2, CN
Scheme 1. Synthetic protocol for title compounds.

J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1605–1610
1607
Table 1
Physical data for N0-substitutedbenzylidene-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives 9(a–j)
Entry
Ar
Molecular formula
Yield (%)
Rf value
Mp (°C)
9a
9b
9c
9d
9e
9f
9g
9h
9i
2-Chlorophenyl
4-Chlorophenyl
C
C
C
C
16H16ClN3OS
16H16ClN3OS
16H15Cl2N3OS
16H17N3O3S
88
80
76
86
82
86
88
90
82
74
0.62
0.74
0.59
0.64
0.44
0.49
0.68
0.56
0.65
0.73
138–140
158–160
220–222
148–150
200–202
160–162
208–210
146–148
158–160
168–170
2,6-Dichlorophenyl
3,4-Dihydroxyphenyl
2,4-Dimethoxyphenyl
2,5-Dimethoxyphenyl
3,4-Dimethoxyphenyl
2-Amino-6-methoxy phenyl
4-N,N-Dimethylaminophenyl
4-Cyanophenyl
C18H21N3O3S
C
C
C
C
C
18H21N3O3S
18H21N3O3S
17H20N4O2S
18H22N4OS
17H16N4OS
9j
Solvent of recrystallization was ethanol; eluants used in TLC were petroleum ethyl acetate/n-hexane (8:2) for all compounds.
Table 2
In vitro antileishmanial evaluation and molecular docking statistics of synthesized compounds 9(a–j)
Entry
L. donovani (IC50
)
Docking result against L. donovani (Pteridine reductase 1)
l
g/mL
lM
H-bond
Binding energy (kcal/mol)
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
98.75
246.25
237.50
223.75
265.00
247.50
222.50
248.75
93.75
295.80
737.62
644.88
672.16
737.25
688.57
619.01
722.20
273.75
693.58
537.92
16.15
SER185-NH; SER185N@CH
ꢀ67.16
ꢀ53.75
ꢀ50.58
ꢀ52.13
ꢀ53.32
ꢀ54.11
ꢀ51.62
ꢀ46.95
ꢀ70.76
ꢀ51.55
ND
SER185-NH
*
VAL180-OH; ASP181-OH
*
*
LYS16-OCH3
*
LYS16-N(CH3)2; SER185O@C
LEU18-NH
ND
225.00
490.00
5.5
STD1
STD2
ND
ND
IC50 represents the mean values of three replicates; standard errors were all within 10% of the mean.
*
Denotes no hydrogen bond interaction of ligands with protein; STD1: sodium stibogluconate; STD2: pentamidine; ND: not done.
activity. A representation of the effect of compounds on the L.
donovani was as shown in Figure 2. In presence of compound, the
organism loses its viability as seen by irregular shape morphology
of the same. Cytotoxicity study on HeLa cell line was evaluated as
per reported procedure33 for synthesized compounds and none of
the compounds showed cytotoxicity at concentration up to
(MIC = 50 lg/mL). Compounds 9a, 9b and 9c revealed broad spec-
trum activity comparable to ampicillin. Compound 9d had shown
selectivity for Gram-negative bacteria. Modification of the parent
compounds with various substituents such as halogen, hydroxyl,
methoxyl, amino and cyano were performed to explore the struc-
ture–activity relationships (SAR) of theses thieno[3,2-c]pyridine
derivatives containing acetohydrazide linkage. As observed from
activity data, compounds 9a, 9b, 9c and 9j with electron withdraw-
ing substituents at phenyl ring are more effective than compounds
9d, 9e, 9f, 9g, 9h and 9i with electron donating substituents against
Gram-negative bacteria. Replacement 2-Cl 9a with 4-Cl 9b at phe-
nyl ring increases the antibacterial activity. Introduction of 2,6-di-
chloro group 9c decreases the activity.
300 lg/mL (Fig. 2).
The antibacterial activity was evaluated against two Gram-neg-
ative bacteria namely, Escherichia coli (NCIM-2256) and Pseudomo-
nas aeruginosa (NCIM-2036) and two Gram-positive bacteria
namely, Staphylococcus aureus (NCIM-2901) and Bacillus subtilis
(NCIM-2063) using ampicillin and ciprofloxacin as standard drugs.
The antifungal activity was evaluated against two fungal strains
Candida albicans (NCIM-3471) and Aspergillus niger (NCIM-1196)
using miconazole and fluconazole as standard drugs. Minimum
inhibitory concentration (MIC) values for antibacterial and anti-
fungal were determined using standard agar method.34–36
Dimethyl sulfoxide was used as solvent control. MIC values of
the tested compounds are presented in Table 3.
The results of in vitro antifungal activities (Table 3) showed that
synthesized compounds 9(a–j) have moderate to good activity.
Comparison of antifungal activity of compounds with that of anti-
fungal drug miconazole (MIC = 25
9e and 9f (MIC = 25 g/mL) had same antifungal profile against C.
albicans. Compound 9g (MIC = 12.5 g/mL) had shown equipotent
activity against A. niger when compared with miconazole
(MIC = 12.5 g/mL). Compounds 9g (MIC = 37.5 g/mL) and 9i
(MIC = 40 g/mL) had shown moderate activity against C. albicans
lg/mL), showed that compound
l
l
From the antibacterial activity data, comparison of antibacterial
activity of synthesized compounds with that of ampicillin
l
l
(MIC = 100
(MIC range = 25–50
9b (MIC = 50 g/mL) against P. aeruginosa strain were most active.
Compound 9j (MIC = 100 g/mL) was equipotent with ampicillin
against E. coli. On comparison of compounds with ciprofloxacin
(MIC = 25 g/mL), compounds 9a and 9b (MIC = 25 g/mL) showed
equipotent activity against E. coli. The compounds 9a, 9b, 9e, 9f
and 9g (MIC range = 50–100 g/mL) were found to be most
active when compared with ampicillin (MIC = 250 g/mL) against
l
g/mL), showed that compounds 9a, 9b, 9c, 9d and 9i
l
lg/mL) against E. coli strain and compound
when compared with miconazole. All the synthesized compounds
were found less active against C. albicans and A. niger when
compared with fluconazole. Structure–activity relationship of
compounds 9(a–j) revealed that scaffold containing 4,5,6,7-tetra-
hydrothieno[3,2-c]pyridine and acetohydrazide shows consider-
able antifungal activity. As observed through data analysis, the
compounds 9d, 9e, 9f, 9g, 9h and 9i with electron donating groups
on phenyl ring are more effective than compounds 9a, 9b, 9c and 9j
with electron withdrawing groups except for the compound 9f
where activity has reduced against A. niger organism. Introduction
l
l
l
l
l
l
S. aureus and B. subtilis strains. Compound 9b showed equipotent
activity against S. aureus when compared with ciprofloxacin

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J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1605–1610
Figure 2. Antileishmanial activity (upper panel) and cytotoxic study on HeLa cell line (lower panel) of compound 9i.
Table 3
In vitro antimicrobial evaluation of synthesized compounds 9(a–j)
Entry
Antibacterial activity (MIC values in
lg/mL)
Antifungal activity (MIC values in lg/mL)
E. coli
P. aeruginosa
S. aureus
B. subtilis
C. albicans
A. niger
9a
9b
9c
9d
9e
9f
9g
9h
25
25
50
125
50
150
150
250
250
100
50
100
100
60
100
80
75
25
25
37.5
60
40
80
—
120
100
160
75
250
250
*
*
50
125
125
150
175
50
100
100
25
75
75
100
100
50
150
12.5
140
100
140
—
—
12.5
10
200
150
275
100
250
250
50
150
*
*
*
*
*
9i
9j
150
100
25
—
Ampicillin
Ciprofloxacin
Miconazole
Fluconazole
250
50
—
—
25
5
—
—
—
—
—
—
*
No activity found up to 300 lg/mL; — denotes not tested; the data represents the mean values of three replicates; standard errors were all within 10% of the mean.
of 2,4-dimethoxy 9e and 2,5-dimethoxy 9f against C. albicans and
3,4-dimethoxy 9g against A. niger on phenyl ring lead to potent
compounds. Replacement of 3,4-dihydroxy 9d with 3,4-dimethoxy
9g of phenyl ring increases the activity.
lowest interaction energy that is ꢀ67.16 kcal/mol and
ꢀ70.76 kcal/mol, respectively. The docking results indicated that
the thienopyridine acetohydrazide core of these compounds
9(a–j) held in the active pocket by combination of hydrophobic
and van der Waals interactions with the protein. Major hydropho-
bic contacts occurred between the thienopyridine acetohydrazide
core with the side chain of THR12, GLY13, ARG17, LEU18, LEU66,
ASP181, ALA182, and SER185. The hydrophilic substituents (–OH,
and –OCH3) at phenyl ring did not form any interactions with
active hydrophobic pocket of enzyme. The hydrophobic groups
(–Cl, and –N(CH3)2 at phenyl ring were more favorable for hydro-
phobic interactions. The 4-N(CH3)2 substituent at phenyl ring of
most active compound 9i fitted well into the hydrophobic pocket
and formed hydrophobic interactions with amino acid residues like
Molecular docking study of the synthesized compounds 9(a–j)
was performed against pteridine reductase 1 enzyme of L. donovani
(PDB ID: 2XOX)37 to understand the binding interactions using
VLife MDS 4.3 package following standard procedure38 and dock-
ing calculation and hydrogen bond interactions are shown in
Table 2. Pteridine reductase 1 (PTR1), a Leishmania enzyme
responsible for salvage of pteridines is potential target for chemo-
therapeutic intervention.39 The interaction energy of the
compounds 9(a–j) and their antileishmanial activity showed the
corresponding results. The active compounds 9a and 9i showed

J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1605–1610
1609
ARG17, LEU18, ASP181, and SER185. Thus, suggesting that the
replacement of hydrophilic group with bulky hydrophobic group
at phenyl ring would show good interactions with pteridine reduc-
tase 1 enzyme. The interactions of most active compound 9i with
enzyme is shown in Figure 3 and revealed that amino acids
LYS16 (2.499 Å) and SER185 (2.249 Å) had formed hydrogen bond
with nitrogen of –N(CH3)2 and oxygen of AC@O group, respec-
tively. On the basis of activity data and docking result, it was found
the compound 9i had potential to inhibit pteridine reductase 1
enzyme.
A computational study of titled compounds 9(a–j) was per-
formed for prediction of ADME, molecular volume, molecular
weight, miLog P, number of hydrogen acceptors, number proper-
ties and value obtained depicted in Table 4. Polar surface area
(TPSA),40 number of rotatable bonds of hydrogen donors and Lipin-
ski’s rule of five41 were calculated using Molinspiration online
property calculation toolkit.42 Absorption (% ABS) was calculated
by: % ABS = 109 ꢀ (0.345 ꢁ TPSA).43 From all these parameters, it
can be observed that all titled compounds exhibited a good %
ABS (79.62–93.57%). Furthermore, none of the compounds violated
Lipinski’s rule of five and thus showing possible utility of series for
developing the compound with drug like properties. A molecule
likely to be developed as an orally active drug candidate should
show no more than one violation of the following four criteria:
logP (octanol–water partition coefficient) 65, molecular weight
6500, number of hydrogen bond acceptors 610 and number of
hydrogen bond donors 65.40 All the synthesized compounds fol-
lowed the criteria for orally active drug and therefore, these com-
pounds can be further developed as oral drug candidates.
In conclusion, synthesis of N0-substitutedbenzylidene-2-(6,7-
dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetohydrazide derivatives
9(a–j) has been presented and newly synthesized compounds
investigated for antileishmanial, antibacterial and antifungal
activities. Compounds 9a with 2-Cl substituent and 9i with 4-
N,N-dimethylamino substituent on phenyl ring were most active
for antileishmanial activity among the tested compounds. Com-
pounds 9b with 4-Chloro substituent on phenyl ring showed po-
tent as well broad spectrum antibacterial activity. Compound 9e
with 2,4-dimethoxy substituent on phenyl ring showed promising
antifungal activity. Molecular docking study showed good binding
of these compounds to the active site of pteridine reductase 1 en-
zyme of L. donovani. Also none of the synthesized compounds were
cytotoxic to HeLa cell line up to the concentration 300
lg/mL.
Furthermore, analysis of the ADME parameters for synthesized
Figure 3. Docking study of compounds 9i with pteridine reductase 1 (PDB ID: 2XOX). Ligands are shown in red color. Hydrogen bonds are shown in green color. Hydrophobic
bonds are shown in sky blue color.
Table 4
Pharmacokinetic parameters important for good oral bioavailability of synthesized compounds 9(a–j)
Entry
% ABS
TPSA (A2)
n-ROTB
MV
MW
milogP
n-ON acceptors
n-OHNH donors
Lipinski’s violations
Rule
9a
9b
9c
9d
9e
9f
9g
9h
9i
—
—
—
4
4
4
4
6
6
6
5
5
4
—
<500
65
<10
4
4
4
6
6
6
6
6
<5
1
1
1
3
1
1
1
3
1
1
61
0
0
0
0
0
0
0
0
93.57
93.57
93.57
79.62
87.20
87.20
87.20
81.41
92.46
85.37
44.70
44.70
44.70
85.15
63.16
63.16
63.16
79.95
47.93
68.49
283.49
283.49
297.03
285.99
321.05
321.05
321.05
306.79
315.86
286.81
333.84
333.84
368.28
331.39
359.44
359.44
359.44
344.43
342.46
324.40
3.31
3.36
3.96
1.71
2.72
2.33
2.72
2.12
2.78
2.43
5
5
0
0
9j
% ABS: percentage absorption, TPSA: topological polar surface area, n-ROTB: number of rotatable bonds, MV: molecular volume, MW: molecular weight, milogP: logarithm of
partition coefficient of compound between n-octanol and water, n-ON acceptors: number of hydrogen bond acceptors, n-OHNH donors: number of hydrogen bonds donors.

1610
J. N. Sangshetti et al. / Bioorg. Med. Chem. Lett. 24 (2014) 1605–1610
11. (a) Kawade, D. P.; Khedekar, P. B. Der Pharma. Chemica. 2012, 5, 1856;
(b) Modi, V. P.; Patel, P. N.; Patel, S. H. Der Pharmacia Lett. 2011, 3, 120.
12. Srivastava, B. K.; Solanki, M.; Mishra, B.; Soni, R.; Jayadev, S.; Valani, D.; Jain,
M.; Patel, P. R. Bioorg. Med. Chem. Lett. 2007, 17, 1924.
13. Lohray, B. B.; Lohray, V. B.; Srivastava, B. K.; Kapadnis, P. B.; Pandya, P. Bioorg.
Med. Chem. 2004, 12, 4557.
compounds showed good drug like properties and can be devel-
oped as oral drug candidate. Thus, suggesting that compounds
from the present series 9a and 9i (antileishmanial activity), 9b
(antibacterial activity) and 9e (antifungal activity) can be further
optimized and developed as a lead molecule.
14. Amr, A. E.; Abdel-Hafez, N. A.; Mohamed, S. F.; Abdalla, M. M. Turk. J. Chem.
2009, 33, 421.
15. Yina, L.; Shana, W.; Jia, X.; Li, X.; Chana, A. S. C. J. Organomet. Chem. 2009, 694,
2092.
Acknowledgments
16. Madsen, P.; Lundbeck, J. M.; Jakobsen, P.; Varmingb, A. R.; Westergaard, N.
Bioorg. Med. Chem. 2007, 8, 277.
17. Bayrak, H.; Demirbas, A.; Karaoglu, S. A.; Demirbas, N. Eur. J. Med. Chem. 2009,
44, 1057.
18. Altıntop, M. D.; Ozdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atli, O.; Iscan, G.;
Kaplancıkl, Z. A. Eur. J. Med. Chem. 2012, 58, 299.
19. Bonde, C. G.; Gaikwad, N. J. Bioorg. Med. Chem. 2004, 12, 2151.
20. Li, Y.; Zhao, C.; Ma, H.; Zhao, M.; Xue, Y.; Wang, X.; Zhu, H. Bioorg. Med. Chem.
2013, 21, 3120.
The authors are thankful to the Mrs. Fatima Rafiq Zakaria Chair-
man Maulana Azad Educational Trust and Dr. M.H.G. Dehghan,
Principal, Y.B. Chavan College of Pharmacy, Dr. Rafiq Zakaria Cam-
pus, Aurangabad 431 001 (M.S.), India for providing the laboratory
facility. The authors are also thankful to Bar C. (Department of
Zoology, University of Pune) for providing L. donovani culture.
21. Cheng, K.; Qing-Zhong, Z.; Qian, Y.; Shi, L.; Zhao, J.; Hai-Liang, Z. Bioorg. Med.
Chem. 2009, 17, 7861.
22. Liu, T.; Sun, C.; Xing, X.; Jing, L.; Tan, R.; Luo, Y.; Huang, W.; Song, H.; Li, Z.;
Zhao, Y. Bioorg. Med. Chem. Lett. 2012, 22, 3122.
23. Arafa, R. K.; Hegazy, G. H.; Piazza, G. A.; Abadi, A. H. Eur. J. Med. Chem. 2013, 63,
826.
24. Botros, S.; Khalil, N. A.; Naguib, B. H.; El-Dash, Y. Eur. J. Med. Chem. 2013, 60, 57.
25. Kaushik, D.; Khan, S. A.; Chawla, G.; Kumar, S. Eur. J. Med. Chem. 2010, 45, 3943.
26. Taha, M.; Baharudin, M. S.; Ismail, N. H.; Khan, K. M.; Jaafar, F. M.; Samreen,
Siddiqui S.; Choudhary, M. I. Bioorg. Med. Chem. Lett. 2013, 23, 3463.
27. Cruz, L. J.; Luque-Ortega, J. R.; Rivas, L.; Albericio, F. Mol. Pharm. 2009, 6, 813.
28. Tipparaju, S. K.; Joyasawal, S.; Pieroni, M.; Kaiser, M.; Brun, R.; Kozikowski, A. P.
J. Med. Chem. 2008, 51, 7344.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2014.01.
035.
References and notes
1. World Health Organization, Leishmaniases Fact Sheet No. 116, 2000, http://
www.who.int/ mediacentre/factsheets/fs116/en/.
29. Golenser, J.; Domb, A. Mini Rev. Med. Chem. 2006, 6, 153.
30. Boer, M. D.; Davidson, R. N. Expert Rev. Anti-Infect. Ther. 2006, 4, 187.
31. Jha, T. K.; Sundar, S.; Thakur, C. P.; Felton, J. M.; Sabin, A. J.; Horton, J. A. Am. J.
Trop. Med. Hyg. 2005, 73, 1005.
32. Dutta, A.; Bandyopadhyay, S.; Mandal, C.; Chatterjee, M. Parasitol. Int. 2005, 54,
119.
33. Denizlt, F.; Lang, R. J. Immunol. Methods 1986, 89, 271.
34. Collins, A. H. Microbiological Methods, 2nd ed.; Butterworth: London, 1976.
35. Khan, Z. K. In vitro and in vivo screening techniques for bioactivity screening
and evaluation, Proc. Int. Workshop UNIDO-CDRI, 1997, 210.
36. Duraiswamy, B.; Mishra, S. K.; Subhashini, V.; Dhanraj, S. A.; Suresh, B. Indian J.
Pharm. Sci. 2006, 68, 389.
37. Barrack, K. L.; Tulloch, L. B.; Burke, L. A.; Fyfe, P. K.; Hunter, W. N. Acta Cryst.
2011, F67, 33.
38. VLife Molecular Design Suite 4.3, VLife Sciences Technologies Pvt. Ltd;
www.Vlifesciences.com.
39. Nare, B.; Luba, J.; Hardy, L. W.; Beverley, S. Parasitology 1997, 114, S101.
40. Ertl, P.; Rohde, B.; Selzer, P. J. Med. Chem. 2000, 43, 3714.
41. Lipinski, C. A.; Lombardo, L.; Dominy, B. W.; Feeney, P. J. Adv. Drug Deliv. Rev.
2001, 46, 3.
42. Molinspiration Chemoinformatics, Brastislava, Slovak Republic, Available from:
http://www.molinspiration.com/cgi-bin/properties, 2013.
43. Zhao, Y.; Abraham, M. H.; Lee, J.; Hersey, A.; Luscombe, N. C.; Beck, G.;
Sherborne, B.; Cooper, I. Pharm. Res. 2002, 19, 1446.
2. Murray, H. W. Am. J. Trop. Med. Hyg. 2004, 71, 787.
3. Croft, S. L. Trends Pharmacol. Sci. 1988, 9, 376.
4. Berman, J. D. Rev. Infect. Dis. 1988, 10, 560.
5. Otvos, L. J.; Wade, J. D.; Lin, F.; Condie, B. A.; Hanrieder, J.; Hoffmann, R. J. Med.
Chem. 2005, 48, 5349.
6. Li, Z. L.; Li, Q. S.; Zhang, H. J.; Hu, Y.; Zhu, D. D.; Zhu, H. L. Bioorg. Med. Chem.
2011, 19, 4413.
7. (a) Sangshetti, J. N.; Chabukswar, A. R.; Shinde, D. B. Bioorg. Med. Chem. Lett.
2011, 21, 444; (b) Sangshetti, J. N.; Chouthe R. S.; Jadhav, M. R.; Sakle, N. S.;
Chabukswar, A.; Gonjari, I.; Darande, Sunil.; Shinde, D. B. Arabian J. Chem. 2013,
in Press. http://dx.doi.org/10.1016/j.arabjc.2013.04.004.; (c) Sangshetti, J. N.;
Dharmadhikari, P. P.; Chouthe R. S.; Fatema, B. Arabian J. Chem. 2012, in Press.
http://dx.doi.org/10.1016/j.arabjc.2012.06.005.; (d) Sangshetti, J. N.; D. B Eur. J.
Med. Chem. 2011, 46, 1040.
8. (a) Sangshetti, J. N.; Kokare, N. D.; Kotharkar, S. A.; Shinde, D. B. Chin. Chem. Lett.
2008, 19, 762; (b) Zambre, S. S.; Darandale, S. S.; Sangshetti, J. N. Arabian J.
Chem. 2012, in Press. http://dx.doi.org/10.1016/j.arabjc.2012.03.006.; (c)
Sangshetti, J. N.; Nagawade, R. R.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2009,
19, 3564; (d) Sangshetti, J. N.; D. B Bioorg. Med. Chem. Lett. 2010, 20, 742.
9. Sangshetti, J. N.; Dharmadhikari, P. P.; Chouthe, R. S.; Fatema, B.; Lad, V.;
Karande, V.; Darandale, S. N.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2013, 23,
2250.
10. Darandale, S. N.; Mulla, N. A.; Pansare, D. N.; Sangshetti, J. N.; Shinde, D. B. Eur.
J. Med. Chem. 2013, 65, 527.