Antimicrobial evaluation of 4-methylsulfanyl benzylidene/3-hydroxy benzylidene hydrazides and QSAR studies

Article abstract of DOI:10.1007/s00044-010-9543-7

A series of 4-methylsulfanyl benzylidene/3-hydroxy benzylidene hydrazides (1-20) was synthesized and tested for in vitro antimicrobial activity against S. aureus, B. subtilis, E. coli, C. albicans and A. niger. The results of antimicrobial studies indicated that 3-phenylacrylic acid-(3-hydroxybenzylidene) -hydrazide, 16, was the most effective as it showed both bactericidal and fungicidal properties and other compounds possessed bacteriostatic/fungistatic activity. The multi-target QSAR model demonstrated that the topological parameter, Balaban topological index (J) is effective in describing the antimicrobial activity of synthesized substituted hydrazides. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9543-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:382–394
DOI 10.1007/s00044-010-9543-7
ORIGINAL RESEARCH
Antimicrobial evaluation of 4-methylsulfanyl benzylidene/
3-hydroxy benzylidene hydrazides and QSAR studies
•
Davinder Kumar Rakesh Narang
•
•
•
Vikramjeet Judge Devinder Kumar
Balasubramanian Narasimhan
Received: 21 August 2010 / Accepted: 14 December 2010 / Published online: 7 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 4-methylsulfanyl benzylidene/3-
hydroxy benzylidene hydrazides (1–20) was synthesized
and tested for in vitro antimicrobial activity against S.
aureus, B. subtilis, E. coli, C. albicans and A. niger. The
results of antimicrobial studies indicated that 3-phenylac-
rylic acid-(3-hydroxybenzylidene)-hydrazide, 16, was the
most effective as it showed both bactericidal and fungicidal
properties and other compounds possessed bacteriostatic/
fungistatic activity. The multi-target QSAR model dem-
onstrated that the topological parameter, Balaban topo-
logical index (J) is effective in describing the antimicrobial
activity of synthesized substituted hydrazides.
Introduction
Almost all the major classes of antibiotics have encoun-
tered resistance in clinical applications. The emergence of
bacterial resistance to b-lactam antibiotics, macroliodes,
quinolones and vancomycin is becoming a major world-
wide health problem (Metwally et al., 2006). The
increasing incidence of bacterial resistance to established
antibiotic classes is driving researchers to search for newer
antibacterial agents (Tanitame et al., 2004).
Hydrazones are well known class of compounds,
possess various activities like antimicrobial (Vittorio
et al., 1995), antimycobacterial (Nayyar et al., 2007),
antitumour (Sztanke et al., 2007), anti-inflammatory
(Kalsi et al., 1990), trypanocidal (Leite et al., 2006),
anti-HIV (Al-Mawsawi et al., 2007), antimalarial
(Gemma et al., 2006) and antidiabetic activities (Smalley
et al., 2006).
Keywords Hydrazides derivatives ꢀ Antimicrobial ꢀ
QSAR ꢀ MBC ꢀ MFC
During the last 20 years quantitative structure activity
relationship (QSAR) models have gained an extensive
recognition in physical, organic, analytical, pharmaceu-
tical and medicinal chemistry. The success of the QSAR
approach can be explained by the insight offered based
on the structural determination of chemical properties,
and the possibility to estimate the properties of new
chemical compounds without the need to synthesize and
test them among the homologous series (Ivanciuc et al.,
2002).
D. Kumar
Swami Devi Dyal Institute of Pharmacy, Barwala,
Panchkula 134009, India
R. Narang ꢀ V. Judge
Department of Pharmaceutical Sciences,
Guru Jambheshwar University of Science and Technology,
Hisar 125001, India
D. Kumar
Department of Chemistry, Guru Jambheshwar
University of Science and Technology,
Hisar 125001, India
Inspired by the above facts and in continuation of
our work in describing biological activity and QSAR
study (Kumar et al., 2008, 2009; Narasimhan et al.,
2003, 2004, 2006a, b, 2007a, b, c, d), we hereby report
the synthesis, antimicrobial evaluation and QSAR studies
of 4-methylsulfanyl benzylidene/3-hydroxy benzylidene
hydrazides.
B. Narasimhan (&)
Faculty of Pharmaceutical Sciences,
Maharshi Dayanand University,
Rohtak 124001, India
e-mail: naru2000us@yahoo.com
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Med Chem Res (2012) 21:382–394
383
Compound 3
Experimental
1
Mp (°C) 103–107; Yield—43.10%; H NMR (400 MHz,
CDCl3) ppm: 0.86–0.89 (t, 3H, CH3 of CH2CH3), 1.23–1.28
(m, 24H, C4–C15 of palmitic acid), 7.59 (s, 1H, N=CH),
1.59–1.63 (m, 2H, terminal CH2 of CH2CH2CONH),
2.26–2.30 (t, 2H, CH2 of CH2CONH), 2.48–2.53 (s, 3H, CH3
of S-CH3), 7.81–8.27 (m, 4H, ArH), 9.91–9.92 (s, 1H, NH).
IR (KBr pellets) cm-1: 3235.57 (NH str., amide), 3043.10
(CH str., aromatic), 2925.96 (CH str., aliphatic), 1702.40
(C=O str.), 720.01 (C–S str.).
Melting points were determined in open capillary tubes
using Sonar melting point apparatus and are uncorrected.
Reaction progress was monitored by thin layer chroma-
tography on silica gel sheets (Merck silica gel G) and
purity of compound was ascertained by single spot TLC.
1H nuclear magnetic resonance (1H NMR) spectra were
recorded on Bruker Avance II 400 NMR spectrometer
using appropriate deuterated solvents and are expressed in
parts per million (d, ppm) downfield from tetramethyl-
silane (internal standard). Infrared (IR) spectra were
recorded on Perkin Elmer FTIR spectrometer using KBr
pellets.
Compound 11
Mp (°C) 87–91; Yield—69.40%; 1H NMR (400 MHz,
CDCl3) ppm: 0.77–0.80 (t, 3H, terminal CH3), 7.76 (s, 1H,
N=CH), 1.17–1.22 (m, 14H, C4–C10 of lauric acid),
1.26–1.30 (m, 2H, CH2 of CH2CH3), 1.56–1.64 (m, 2H,
terminal CH2 of CH2CH2CONH), 2.60–2.63 (t, 2H, CH2 of
CH2CONH), 2.84 (s, 1H, OH), 6.99–7.17 (m, 4H, ArH),
10.42 (s, 1H, NH). IR (KBr pellets) cm-1: 3307.46 (NH
str., amide), 3040.15 (CH str., aromatic), 2916.47 (CH str.,
aliphatic), 1706.26 (C=O str.).
General procedure for synthesis of esters
The mixture of corresponding acid (0.08 mol) and ethanol
(0.74 mol) was heated under reflux in the presence of
sulphuric acid till the completion of reaction. When the
reaction completed, the mixture was added to 200 ml ice-
water and the produced ester was extracted with ether
(50 ml). The ether layer was separated and after evapora-
tion yielded the related ethyl esters.
Compound 12
General procedure for synthesis of acid hydrazides
Mp (°C) 90–94; Yield—65.02%; 1H NMR (400 MHz,
CDCl3) ppm: 0.91–0.94 (t, 3H, terminal CH3), 1.26–1.36
(m, 20H, CH2 of CH3(CH2)10), 2.73–2.76 (t, 2H,
CH2CONH), 1.70–1.71 (m, 2H terminal CH2 of
CH2CH2CONH), 6.88–7.25 (m, 4H, ArH), 10.69 (s, 1H,
NH), 8.59 (s, 1H, N=CH). IR (KBr pellets) cm-1: 3193.09
(NH str., amide), 3037.25 (CH str., aromatic), 2958.79 (CH
str., aliphatic), 1731.82 (C=O str.).
The ethanolic solution of ester (0.01 mol) and hydrazine
hydrate (99%) (0.015 mol) was refluxed for 5 h. The
reaction mixture was then cooled, filtered and the precip-
itated solid was washed with water, dried and recrystallized
in ethanol.
General procedure for synthesis of hydrazones (1–20)
Compound 13
A solution of 0.01 mol of acid hydrazide and appropriate
aldehyde (0.01 mol) in ethanol was heated under reflux for
4–5 h. The precipitates obtained was filtered off, washed
with water and recrystallized with ethanol.
1
Mp (°C) 107–111; Yield—52.01%; H NMR (400 MHz,
CDCl3) ppm: 0.85–0.89 (t, 3H, terminal CH3), 1.22–1.27
(m, 24H, C4–C15 of palmitic acid), 1.57–1.67 (m, 2H ter-
minal CH2 of CH2CH2CONH), 2.25–2.29 (t, 2H, CH2 of
CH2CONH), 7.10–7.37 (m, 4H, ArH), 7.5 (s, 1H, N=CH),
9.91 (s, 1H, NH). IR (KBr pellets) cm-1: 3301.83 (NH str.,
amide), 3043.10 (CH str., aromatic), 2925.96 (CH str.,
aliphatic), 1739.70 (C=O str.).
Compound 1
Mp (°C) 79–83; Yield—63.20%; 1H NMR (400 MHz,
CDCl3) ppm: 0.85–0.89 (t, 3H, terminal CH3 of CH2CH3),
1.25–1.38 (m, 16H, C4–C10 of lauric acid), 2.72–2.76 (t,
2H, CH2 of CH2CONH), 8.06 (s, 1H, N=CH), 2.49–2.53(s,
3H, CH3 of S-CH3), 1.68–1.76 (m, 2H terminal CH2 of
CH2CH2CONH), 7.22–7.58 (m, 4H, ArH), 9.80 (s, 1H,
NH). IR (KBr pellets) cm-1: 3193.09 (NH str., amide),
3037.25 (CH str., aromatic), 2955.23 (CH str., aliphatic),
1737.98 (C=O str.), 720.45 (C–S str.).
Compound 20
1
Mp (°C) 270–274; Yield—71.10%; H NMR (400 MHz,
CDCl3) ppm: 7.32–7.56 (m, 4H, ArH of ArOH), 9.12–9.26
(s, 3H, ArH of Ar(NO2)2), 8.06 (s, 1H, N=CH), 9.9 (s, 1H,
NH). IR (KBr pellets) cm-1: 3334.69 (NH str., amide),
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Med Chem Res (2012) 21:382–394
3095.76 (CH str., aromatic), 2988.94 (CH str., aliphatic),
1725.14 (C=O str.), 1343 cm-1 (symmetric NO2 stretch-
ing), 1538 cm-1 (asymmetric NO2 stretching).
Kier and Hall, 1976; Randic, 1975, 1993; Balaban, 1982;
Wiener, 1947).
The structure of 4-methylsulfanyl benzylidene/3-hydroxy
benzylidene hydrazides was optimized by energy minimi-
zation. The physicochemical properties of each molecule was
calculated in TSAR 3.3 software (TSAR 3D for Windows,
Version 3.3, 2000) for the geometrically optimized structures
and the values of selected descriptors are presented in
Table 4. Further, theregressionanalysiswasperformedusing
the SPSS software package (SPSS for windows, version
10.05, 1999). The predictive powers of the equations were
validated by leave one out (LOO) cross-validation method
(Schaper, 1999), where a model is built with N - 1 com-
pounds and Nth compound is predicted. Each compound is
left out of the model derivation and predicted in turn.
Evaluation of antimicrobial activity
Determination of MIC
The antimicrobial activity was performed against Gram-
positive bacteria: S. aureus MTCC 2901, B. sublitis MTCC
2063, Gram-negative bacterium: E. coli MTCC 1652 and
fungal strains: C. albicans MTCC 227 and A. niger MTCC
8189 by tube dilution method (Cappucino and Sherman,
1999). Dilutions of test and standard compounds [cipro-
floxacin (antibacterial) and fluconazole (antifungal)] were
prepared in double strength nutrient broth—I.P. (bacteria)
and Sabouraud dextrose broth—I.P (fungi) (Pharmacopoeia
of India, 2007). The samples were incubated at 37°C for
24 h (bacteria), at 25°C for 7 days (A. niger) and at 37°C
for 48 h (C. albicans), respectively, and the results
(Table 2) were recorded in terms of MIC (the lowest
concentration of test substance which inhibited the growth
of microorganisms).
Results and discussion
Chemistry
The synthesis of target compounds was carried out as
outlined in Scheme 1. The ethyl esters of different car-
boxylic acids were prepared by their reaction with ethanol
in the presence of sulphuric acid. The ethyl ester
(0.01 mol) on reaction with hydrazine hydrate (0.015 mol)
yielded the corresponding hydrazides which on treatment
with corresponding aromatic aldehydes resulted the acid
hydrazones (1–20). The products so obtained were purified
by recrystallization from ethanol. The target compounds
were obtained in appreciable yield and their physico-
chemical characteristics are presented in Table 1.
Determination of MBC/MFC
The minimum bactericidal concentration (MBC) and fun-
gicidal concentration (MFC) were determined by subcul-
turing 100 ll of culture from each tube that remained clear
in the MIC determination into fresh medium. MBC and
MFC values represent the lowest concentration of com-
pound that produces a 99.9% end point reduction (Rodri-
guez-Arguelles et al., 2005).
The structures of the synthesized compounds (1–20)
were ascertained on the basis of their consistent IR and
NMR spectral characteristics. The presence of C=O func-
tional group was marked by the appearance of stretching
band around 1700 cm-1, which is a characteristic of amide
linkage. The appearance of stretching band around
3200 cm-1 indicates the presence of NH linkage in the
synthesized hydrazide derivatives. The presence of peaks
slightly above and below 3000 cm-1 indicates the presence
of aromatic and aliphatic portion in synthesized com-
pounds, respectively. The aromatic nitro stretching around
1343 cm-1 (symmetric NO2 stretching) and 1538 cm-1
(asymmetric NO2 stretching) depicts the presence of nitro
functional group in compound 20. The appearance of
stretching band around 720 cm-1 indicates the presence of
C–S linkage in the synthesized hydrazide derivatives
(compounds 1 and 3). The appearance of singlet around d
7–8 ppm of N=CH indicated the formation of title com-
pounds. The appearance of singlet signal ranging from d
9.8 to 10.69 in synthesized compounds confirms the pres-
ence of NH of hydrazide. The display of singlet signal in
QSAR studies
In an attempt to determine the role of structural features
which appears to influence the observed activity of
4-methylsulfanyl benzylidene/3-hydroxy benzylidene
hydrazide derivatives (1–20), QSAR studies were under-
taken using linear free energy relationship (LFER) model
of Hansch and Fujita (1964). The pMIC value of the bio-
logical activity data was used as dependent variable in
QSAR study. These were correlated with different molec-
ular descriptors like log of octanol–water partition coeffi-
cient (log P), molar refractivity (MR), Kier’s molecular
connectivity (0vv), shape (j1, ja1) topological indices,
Randic topological index (R), Balaban topological index
(J), Total energy (Te), energies of highest occupied
molecular orbital (HOMO) and lowest unoccupied molec-
ular orbital (LUMO), dipole moment (l), electronic energy
(Ele.E) and nuclear energy (Nu.E) (Hansch et al., 1973;
123

Med Chem Res (2012) 21:382–394
385
X1
Table 1 Physicochemical characteristics of substituted benzylidene
hydrazides
O
O
X2
Y
OH
M. wt. M.p./B.p.? (°C) Rf value % Yield
R
OH
Comp. M. formula
1
C20H32 N2OS 348
79–83
0.65
63.20
58.20
43.10
62.08
72.08
70.20
39.80
52.20
60.10
77.70
69.40
65.02
52.01
76.60
71.80
65.70
39.01
45.30
63.20
71.10
X3
X1
EtOH
H2SO4
2
C22H36 N2OS 376
C24H40 N2OS 404
C26H44 N2OS 432
C14H16 N2OS 260
C17H16 N2OS 296
C16H16 N2OS 284
C16H16 N2OS 284
C17H18N2O3S 330
C15H12N4O5S 360
C19H30 N2O2 318
C21H34 N2O2 346
C23H38 N2O2 374
C25H42 N2O2 402
C13H14 N2O2 230
C16H14 N2O2 266
C15H14 N2O2 254
C15H14 N2O2 254
C16H16 N2O4 300
C14H10N4O6 330
97–101
0.57
3
103–107
129–133
127–131?
Semisolid
143–147
150–154
198–202?
249–253
87–91
0.78
O
O
4
0.82
R
OEt
X2
Y
OEt
5
0.61a
0.44a
0.75a
0.63a
0.89a
0.82
6
X3
X1
NH2NH2.H2O
7
8
O
O
9
R
NHNH2
X2
Y
NHNH2
10
11
12
13
14
15
16
17
18
19
20
0.86
H
O
X3
90–94
0.66
107–111
113–117
121–125
Semisolid
157–161
187–191
213–217
270–274
0.82
R2
0.68
R1
0.59a
0.62a
0.59a
0.73a
0.62a
0.72a
X1
O
O
X2
Y
NHN
R
NHN
X3
R2
R2
R1
Mobile phase—toluene:chloroform (7:3)
a
Ethyl acetate:hexane (6:4)
R1
6-10, 16-20
R
1-5, 11-15
the presence of proton of aromatic nucleus containing of
NO2 group.
Comp.
R1
H
R2
Y
-
X1
X2
X3
1
2
CH3(CH2)9CH2-
SCH3
SCH3
SCH3
SCH3
SCH3
-
-
-
-
CH3(CH2)11CH2-
H
-
-
-
-
3
CH3(CH2)13CH2-
H
-
-
-
Antimicrobial activity
4
CH3(CH2)15CH2-
H
-
-
-
-
5
CH3(CH=CH)2-
H
-
-
-
-
For antifungal activity against A. niger compounds 10, 16,
19 and 20 were found to be highly active having high
pMIC value of 2.06, 1.93, 1.98 and 2.02 (Table 2),
respectively, as compared to other synthesized derivatives.
Further, in case of C. albicans compounds 8, 16 and 19
have shown good antifungal potential at pMIC values of
1.96, 1.93 and 1.98 (Table 2), respectively.
6
-
H
SCH3 CH=CH
H
CH3
H
H
H
H
H
H
NO2
-
7
-
H
SCH3
SCH3
SCH3
SCH3
H
-
H
8
-
H
-
CH3
9
-
H
-
OCH3
OCH3
10
11
12
13
14
15
16
17
18
19
20
-
H
-
NO2
H
CH3(CH2)9CH2-
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
-
-
-
CH3(CH2)11CH2-
H
-
-
-
-
CH3(CH2)13CH2-
H
-
-
-
-
-
In case of B. subtilis compounds 2, 3, 10 and 12 have
shown marked antibacterial capability at pMIC value
greater than 2.03 as compared to other synthesized
substituted benzylidene hydrazide derivatives. For anti-
bacterial activity against S. aureus compounds 18 and 19
have shown better antibacterial potential as compared to
other synthesized derivatives. Compounds 3, 8, 10 and 18
have shown appreciable antibacterial activity against
E. coli with pMIC value of 1.81 1.96, 2.06 and 1.77
(Table 2), respectively. In general, synthesized benzyli-
dene hydrazide derivatives have shown higher antifungal
and antibacterial potential against A. niger and B. subtilis,
respectively.
CH3(CH2)15CH2-
H
-
-
-
-
CH3(CH=CH)2-
H
-
-
-
-
-
-
-
-
H
CH=CH
H
H
H
H
H
H
NO2
H
-
-
-
-
CH3
H
H
H
CH3
OCH3
H
H
OCH3
NO2
H
Scheme 1 Synthetic route followed to obtain target compounds from
aliphatic acids
the range of d 2.48–2.53 in compounds 1 and 3 reveals the
presence of thiomethyl group. The appearance of multiplet
signal in the range of d 9.12–9.26 (compound 20) reveals
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Med Chem Res (2012) 21:382–394
Table 2 Antimicrobial activity (lM/ml) of substituted benzylidene hydrazides
Comp.
pMICsa
pMICbs
pMICec
pMICca
pMICan
pMICam
pMICb
pMICf
1
1.30
0.58
1.21
0.94
1.02
1.68
1.55
1.66
1.72
1.46
0.98
0.94
0.99
1.10
0.96
1.70
1.31
1.91
1.98
1.12
0.14
2.61a
1.45
2.08
2.11
0.64
0.72
1.68
1.06
1.96
1.42
2.06
0.80
2.04
1.78
1.51
1.27
1.93
1.31
1.91
1.38
1.42
0.29
2.61a
1.30
1.48
1.81
1.65
1.32
1.68
1.66
1.96
1.70
2.06
0.98
0.94
1.13
1.30
1.27
1.32
1.77
1.77
1.38
1.42
0.26
2.61a
1.66
0.58
0.61
0.70
1.32
1.37
1.67
1.96
1.42
0.86
1.10
0.54
0.57
0.60
1.41
1.93
1.31
1.31
1.98
1.42
0.23
2.64b
1.25
1.70
0.61
0.70
1.32
1.37
1.70
1.66
1.59
2.06
1.71
1.20
1.20
1.51
1.27
1.93
1.31
1.61
1.98
2.02
0.28
2.64b
1.39
1.28
1.27
0.93
1.14
1.56
1.53
1.84
1.57
1.70
1.11
1.13
1.13
1.20
1.24
1.76
1.40
1.70
1.74
1.48
0.17
2.62
1.35
1.38
1.71
1.08
1.02
1.68
1.42
1.86
1.61
1.86
0.92
1.31
1.30
1.30
1.17
1.65
1.46
1.86
1.58
1.32
0.18
2.61
1.46
1.14
0.61
0.70
1.32
1.37
1.69
1.81
1.51
1.46
1.41
0.87
0.89
1.06
1.34
1.93
1.31
1.46
1.98
1.72
0.20
2.64
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
S.D.
Std.
S.D. standard deviation
a
Ciprofloxacin
b
Fluconazole
In general, the results of MBC/MFC (Table 3) revealed
that the synthesized compounds were bacteriostatic and
fungistatic in action as their MBC and MFC values were
threefold higher than their MIC values (a drug is consid-
ered to be bacteriostatic/fungistatic when its MBC and
MFC values are threefold higher than its MIC value)
(Rodriguez-Arguelles et al., 2005). Particularly compounds
9 and 16 were bactericidal for S. aureus, compounds 16
and 18 were bactericidal against B. subtilis, compounds 4,
10 and 16 were bactericidal for E. coli and compounds 16,
19 and 20 were found to fungicidal in case of A. niger.
Compound 16 was found to be active fungicidal agent
against C. albicans. 3-Phenylacrylic acid-(3-hydroxyben-
zylidene)-hydrazide, 16, was found to be bactericidal as
well as fungicidal.
high interrelationship was observed between ja3 and j3
(r = 0.999), and low interrelationship was observed
between HOMO and J (r = -0.008) (Table 5).
The correlation of calculated molecular descriptors with
antimicrobial activity is presented in Table 6 which
depicted the importance of valence third order molecular
connectivity index (3vv, r = 0.825) in describing the anti-
microbial activity of benzylidene hydrazides against
E. coli.
ot-QSAR model for antibacterial activity against E. coli
pMICec ¼ 1:8593vv þ 0:725
ð1Þ
when n = 20, r = 0.825, q2 = 0.589, s = 0.180, F =
38.36; where, n number of data points, r correlation coef-
ficient, q2 cross-validated r2 obtained by leave one out
methods, s standard error of the estimate and F Fischer
statistics.
Development of one-target QSAR model
In this work, a data set of 20 benzylidene hydrazide
derivatives was used for linear regression model genera-
tion. The values of selected descriptors are presented in
Table 4. The correlation matrix constructed for antibacte-
rial activity against E. coli is presented in Table 5. The
The topological index, 3vv, signifies the degree of
branching, connectivity of atoms and the unsaturation in
the molecule which accounts for variation in activity
3
(Wiener, 1947). The positive coefficient of vv in Eq. 1
indicates that there is a positive correlation between the
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Med Chem Res (2012) 21:382–394
387
Table 3 MBC/MFC values of
substituted benzylidene
hydrazides
Comp.
MBC/MFC (lM/ml)
S. aureus
B. subtilis
E. coli
C. albicans
A. niger
1
[0.142
[0.132
[0.122
[0.115
0.192
[0.142
0.033
[0.142
[0.132
0.061
[0.142
[0.132
[0.122
[0.115
[0.192
0.084
0.071
[0.132
[0.122
0.115
2
3
0.061
4
[0.115
[0.192
[0.168
[0.176
0.044
0.028
5
[0.192
0.168
0.096
6
[0.168
[0.176
[0.176
0.037
[0.168
0.088
7
0.176
0.176
8
0.088
0.088
0.088
9
[0.151
0.069
[0.151
0.008
[0.151
[0.138
0.157
[0.151
0.069
10
11
12
13
14
15
16
17
18
19
20
Std.
0.069
[0.157
[0.144
[0.133
[0.124
[0.217
0.046
0.157
0.157
0.078
0.144
[0.144
[0.133
[0.124
[0.217
0.046
[0.144
[0.133
[0.124
0.217
[0.144
[0.133
[0.124
0.217
0.133
0.124
0.217
0.046
0.093
0.093
[0.196
0.098
[0.196
0.012
0.098
0.098
0.098
0.098
0.098
[0.196
0.041
0.083
[0.166
[0.151
0.019
[0.166
[0.151
0.019
0.083
[0.151
0.019
[0.151
0.040
0.037
0.040
Table 4 Values of selected descriptors used in the regression analysis
Comp.
log P
3v
3vv
j1
j2
j3
ja1
ja2
J
HOMO
1
5.798
6.591
7.384
8.176
3.240
3.924
3.984
3.984
3.011
3.424
5.423
6.216
7.009
7.801
2.865
3.549
3.609
3.609
2.636
3.049
0.697
0.697
0.697
0.697
0.697
0.901
1.099
1.099
1.219
1.811
0.781
0.781
0.781
0.781
0.781
0.986
1.184
1.184
1.303
1.895
0.384
0.384
0.384
0.384
0.370
0.467
0.612
0.612
0.582
0.669
0.243
0.243
0.243
0.243
0.230
0.326
0.472
0.472
0.441
0.529
22.042
24.039
26.036
28.033
16.056
17.355
16.372
16.372
19.326
21.302
21.044
23.040
25.037
27.035
15.059
16.372
15.390
15.390
18.340
20.314
15.270
17.123
18.993
20.878
9.868
12.086
13.786
15.519
17.280
7.259
6.743
5.379
5.379
6.094
6.585
12.071
13.812
15.584
17.381
7.111
6.549
5.120
5.120
5.864
6.353
21.313
23.310
25.307
27.304
14.810
15.616
14.890
14.890
17.759
18.942
19.926
21.922
23.919
25.916
13.425
14.253
13.530
13.530
16.392
17.572
14.599
16.444
18.308
20.188
8.785
8.502
7.320
7.320
8.890
8.632
13.331
15.160
17.011
18.880
7.604
7.434
6.320
6.320
7.867
7.663
1.801
1.774
1.750
1.729
1.897
1.401
1.462
1.467
1.523
1.581
1.778
1.760
1.737
1.717
1.886
1.404
1.472
1.477
1.535
1.597
-8.007
-8.007
-8.007
-8.143
-7.958
-7.977
-8.002
-7.998
-7.979
-8.292
-8.857
-8.991
-8.992
-8.991
-8.775
-8.803
-8.846
-8.839
-8.821
-9.266
2
3
4
5
6
9.904
7
8.444
8
8.444
9
10.096
10.364
14.352
16.194
18.056
19.934
9.000
10
11
12
13
14
15
16
17
18
19
20
9.107
7.695
7.695
9.333
9.630
123

388
Med Chem Res (2012) 21:382–394
Table 5 Correlation matrix for pMICec with molecular descriptors
pMICec
0vv
2v
3v
3vv
j3
ja1
ja2
ja3
J
HOMO
pMICec
0vv
2v
3v
3vv
1.000
-0.103
0.076
1.000
0.781
-0.437
-0.285
0.915
1.000
0.444
0.181
0.025
0.629
0.816
0.664
0.618
0.071
-0.133
1.000
0.825
0.702
-0.615
-0.394
-0.596
-0.632
-0.539
-0.264
1.000
j3
-0.402
-0.214
-0.320
-0.386
-0.544
0.508
-0.630
-0.383
-0.541
-0.616
-0.634
0.442
1.000
ja1
ja2
ja3
J
0.981
0.947
0.991
1.000
0.970
0.948
0.502
0.042
0.957
1.000
0.994
0.589
0.058
0.923
0.999
1.000
0.424
0.617
0.618
1.000
-0.008
HOMO
0.203
-0.045
-0.010
1.000
Table 6 Correlation of molecular descriptors with antimicrobial activity
Molecular
descriptor
pMICsa
pMICbs
pMICec
pMICca
pMICan
pMICb
pMICf
pMICam
log P
MR
0v
0vv
1v
1vv
2v
2vv
3v
-0.586
-0.499
-0.448
-0.493
-0.437
-0.517
-0.243
-0.490
0.454
0.069
0.081
0.134
0.071
0.137
0.066
0.224
0.089
0.165
0.124
0.089
0.025
0.011
0.067
0.015
0.005
0.137
-0.270
0.055
-0.156
-0.149
-0.048
0.062
-0.236
-0.089
-0.094
-0.103
-0.102
-0.095
0.076
-0.751
-0.728
-0.727
-0.721
-0.724
-0.714
-0.599
-0.712
0.321
-0.623
-0.542
-0.335
-0.530
-0.380
-0.575
-0.102
-0.549
0.685
-0.315
-0.214
-0.163
-0.222
-0.160
-0.233
0.042
-0.803
-0.746
-0.639
-0.735
-0.661
-0.754
-0.437
-0.740
0.558
-0.676
-0.577
-0.482
-0.576
-0.493
-0.594
-0.232
-0.560
0.624
-0.056
0.444
-0.193
0.461
3vv
0.564
0.825
0.411
0.407
0.628
0.474
0.684
j1
-0.545
-0.635
-0.672
-0.568
-0.635
-0.667
-0.437
-0.800
-0.519
0.368
-0.195
-0.326
-0.402
-0.214
-0.320
-0.386
-0.102
-0.544
-0.145
0.073
-0.770
-0.778
-0.783
-0.771
-0.768
-0.776
-0.724
-0.523
-0.763
0.650
-0.435
-0.584
-0.596
-0.490
-0.604
-0.610
-0.380
-0.458
-0.522
0.130
-0.269
-0.394
-0.447
-0.299
-0.398
-0.442
-0.160
-0.713
-0.258
0.107
-0.718
-0.800
-0.809
-0.747
-0.804
-0.812
-0.661
-0.572
-0.759
0.484
-0.597
-0.725
-0.764
-0.633
-0.730
-0.763
-0.493
-0.794
-0.613
0.356
j2
j3
ja1
ja2
ja3
R
J
W
Te
LUMO
HOMO
l
-0.072
0.087
-0.262
0.508
-0.043
0.102
-0.502
-0.267
0.590
-0.213
0.201
-0.284
-0.072
0.562
-0.305
0.090
0.493
0.332
0.402
0.380
0.575
antibacterial activity of substituted hydrazides and 3vv.
This is evidenced by the antibacterial activity data of
substituted hydrazides (Table 2) and their 3vv values
Table 4) value have minimum antibacterial activity (pMI-
Cec 0.94 and 1.27; Table 2). The cross-validation of Eq. 1
was subsequently checked by employing ‘‘leave one out’’
(LOO) method. The q2 value of Eq. 1 (q2 [ 0.5) justifies it
to be a valid model according to the recommendations of
Golbraikh and Tropsha (2002). The predictability of Eq. 1
is evidenced by the low residual values observed in Table 7
as well by the plot of predicted pMICec against observed
3
(Table 4). Compounds 8 and 10 with maximum vv values
of 0.612 and 0.669 (Table 4) have maximum antibacte-
rial activity against E. coli (compound 8, pMICec
1.96; compound 10, pMICec 2.06; Table 2). Similarly, the
compounds 12 and 15 with minimum 3vv (0.243 and 0.230;
123

Med Chem Res (2012) 21:382–394
389
Table 7 Comparison of observed and predicted antimicrobial activity obtained by ot-QSAR models
Comp.
pMICec (Eq. 1)
pMICsa (Eq. 2)
pMICca (Eq. 3)
pMICan (Eq. 4)
Obs.
Pre.
Res.
Obs.
Pre.
Res.
0.30
Obs.
Pre.
Res.
0.66
Obs.
Pre.
Res.
1
1.30
1.48
1.81
1.65
1.32
1.68
1.66
1.96
1.70
2.06
0.98
0.94
1.13
1.30
1.27
1.32
1.77
1.77
1.38
1.42
1.44
1.44
1.44
1.44
1.41
1.59
1.86
1.86
1.81
1.97
1.18
1.18
1.18
1.18
1.15
1.33
1.60
1.60
1.54
1.71
-0.14
0.04
1.30
0.58
1.21
0.94
1.02
1.68
1.55
1.66
1.72
1.46
0.98
0.94
0.99
1.10
0.96
1.70
1.31
1.91
1.98
1.12
1.00
1.05
1.09
1.13
0.82
1.75
1.64
1.63
1.52
1.41
1.04
1.07
1.12
1.16
0.84
1.75
1.62
1.61
1.50
1.38
1.66
0.58
0.61
0.70
1.32
1.37
1.67
1.96
1.42
0.86
1.10
0.54
0.57
0.60
1.41
1.93
1.31
1.31
1.98
1.42
1.00
0.85
0.70
0.55
1.41
1.46
1.57
1.57
1.51
1.47
1.00
0.85
0.70
0.55
1.43
1.47
1.60
1.60
1.53
1.49
1.25
1.70
0.61
0.70
1.32
1.37
1.70
1.66
1.59
2.06
1.71
1.20
1.20
1.51
1.27
1.93
1.31
1.61
1.98
2.02
1.25
1.25
1.25
1.25
1.25
1.41
1.56
1.56
1.65
2.10
1.32
1.32
1.32
1.32
1.32
1.47
1.62
1.62
1.71
2.17
0.00
0.45
2
-0.47
0.12
-0.27
-0.09
0.15
3
0.37
-0.64
-0.55
0.07
4
0.21
-0.19
0.20
5
-0.09
0.09
-0.09
-0.09
0.10
6
-0.07
-0.09
0.03
-0.04
0.14
7
-0.20
0.10
8
0.39
0.10
9
-0.11
0.09
0.20
-0.09
-0.61
0.10
-0.06
-0.04
0.39
10
11
12
13
14
15
16
17
18
19
20
0.05
-0.20
-0.24
-0.05
0.12
-0.06
-0.13
-0.13
-0.06
0.12
-0.31
-0.13
0.05
-0.12
-0.12
0.19
0.12
-0.02
0.46
-0.05
0.46
-0.01
0.17
-0.05
-0.31
0.30
-0.29
-0.29
0.45
-0.31
-0.01
0.27
0.17
-0.16
-0.29
0.48
-0.26
-0.07
-0.15
2.0
.4
.3
1.8
1.6
1.4
.2
.1
-.0
-.1
1.2
1.0
-.2
-.3
.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
.8
1.0
1.2
1.4
1.6
1.8
2.0
2.2
Observed pMICec
Observed pMICec
Fig. 1 Plot of predicted pMICec against the experimental pMICec for
the linear regression model developed by Eq. 1
Fig. 2 Plot of residual pMICec against the experimental pMICec for
the linear regression model developed by Eq. 1
different substituted benzylidene hydrazides against S.
aureus, C. albicans and A. niger.
pMICec (Fig. 1). Further, the plot of observed pMICec vs.
residual pMICec (Fig. 2) indicated that there was no sys-
temic error in model development as the propagation of
error was observed on both sides of zero (Kumar et al.,
2007).
ot-QSAR model for antibacterial activity against S. aureus
pMICsa ¼ ꢁ1:889 J þ 4:398
ð2Þ
when n = 20, r = 0.800, q2 = 0.603, s = 0.236, F =
31.93.
Similarly, monoparametric QSAR models (Eqs. 2–4)
were developed to predict the antimicrobial potential of
123

390
Med Chem Res (2012) 21:382–394
ot-QSAR model for antifungal activity against C. albicans
compounds are within one order of magnitude. But it is
important to note that the predictability of the QSAR
models developed in this study is high evidenced by the
low residual values. This is in accordance with results
suggested by the Bajaj et al. (2005), who stated that the
reliability of the QSAR model lies in its predictive ability
even though the activity data are in the narrow range.
Further, recent literature reveals that the QSAR have been
applied to describe the relationship between narrow range
of biological activity and physicochemical properties of the
molecules (Narasimhan et al., 2006b; Sharma et al., 2006;
Hatya et al., 2006; Kumar et al., 2006). When biological
activity data lies in the narrow range, the presence of
minimum standard deviation of the biological activity
justifies its use in QSAR studies (Narasimhan et al., 2007a;
Kumar et al., 2007; Kim et al., 2007). The minimum
standard deviation (Table 2) observed in the antimicrobial
activity data justifies its use in QSAR studies.
pMICca ¼ ꢁ0:086 j3 þ 2:034
ð3Þ
when n = 20, r = 0.783, q2 = 0.584, s = 0.316,
F = 28.51.
ot-QSAR model for antifungal activity against A. niger
pMICan ¼ 0:7643v þ 0:718
ð4Þ
when n = 20, r = 0.685, q2 = 0.427, s = 0.296,
F = 15.91.
The model described in Eq. 2 indicated the importance
of topological parameter, Balaban topological index,
J (r = 0.800) in demonstrating antibacterial activity of
substituted hydrazide derivatives against S. aureus. In case
of B. subtilis the regression analysis did not yield valid
QSAR model. For the antifungal activity of C. albicans the
statistically significant relationship was observed with
Kier’s third order shape index (j3) (Table 6).
For the antifungal activity of A. niger the coefficient of
third order molecular connectivity index, 3v, is positive
indicating that as the value of v increases, the antifungal
Development of multi-target QSAR model
3
According to the above ot-QSAR models one should use
five different equations with different errors to predict the
activity of a new compound against the five microbial
species. The ot-QSAR models, which are almost in all the
literature, become unpractical or at less complicated to use
when we have to predict to each compound results for more
than one target. In these cases we have to develop one ot-
QSAR for each target. However, very recently the interest
has been increased in development of multi-target QSAR
(mt-QSAR) models. In opposition to ot-QSAR, the mt-
QSAR model is a single equation that considers the nature
of molecular descriptors which are common and essential
for describing the antimicrobial activity (Prado-Prado
et al., 2008; Gonzalez-Diaz et al., 2007, 2008; Gonzalez-
Diaz and Prado-Prado 2008; Cruz-Monteagudo et al.,
2007).
activity of synthesized derivatives also increases. This is
evidenced by the high 3v values of compounds 9, 10, 18, 19
and 20 (3v = 1.219, 1.811, 1.184, 1.303, 1.895; Table 4)
which make them highly active with pMICan value of 1.59,
2.06, 1.61, 1.98 and 2.02 (Table 2), respectively. The
predictability of Eqs. 2–4 was evidenced by the low
residual values (Table 7).
Topological descriptors (3v) contain information about
degree of branching and size of molecules. The topological
descriptor characterizes the flexibility of alkyl chain and is
connected closely with rearrangement of compounds. For
molecule with more than one branched chain or with
quaternary carbon atom in alkyl chain, the freedom of
molecular skeleton decreases, where as the value of 3v
increase. The 3v value for molecules having only one
branch is smaller than those with many side chains. The
In this study we have attempted to develop three dif-
ferent types of mt-QSAR models viz. mt-QSAR model for
describing antibacterial activity of synthesized compounds
against S. aureus, B. subtilis and E. coli, mt-QSAR model
for describing antifungal activity of synthesized com-
pounds against C. albicans and A. niger as well a common
mt-QSAR model for describing the antimicrobial activity
of substituted hydrazide derivatives against all the afore-
mentioned microorganisms.
3
positive coefficient in the models for v means that mole-
cule having higher degree of branching will have increased
relative retention time (Fragkaki et al., 2004). As the
topological descriptor characterizes the shape of molecules
so they play an important role in binding with receptor site.
As per ‘rule of thumb’ (Narasimhan et al., 2006b) one
can select one parameter for a five-compound data set in
developing QSAR model. Even though the sample size and
the ‘Rule of Thumb’ allowed us to go for development of
tetra-parametric model in multiple linear regression anal-
ysis, the multi-colinearity among the parameters restricted
us to mono-parametric models only.
In order to develop mt-QSAR models initially we have
calculated the average antibacterial activity [pMICb =
(pMICsa ? pMICbs ? pMICec)/3], antifungal activity
[pMICf = (pMICca ? pMICan)/2] and antimicrobial activ-
In most of the QSAR studies, the biological activities of
compounds span 2–3 orders of magnitude but in this study
the range of antimicrobial activities of the synthesized
ity values [pMICam = (pMICsa ? pMICbs ? pMICec
?
pMICca ? pMICan)/5] of substituted benzylidene hydra-
zide derivatives which are presented in Table 2. These
123

Med Chem Res (2012) 21:382–394
391
mt-QSAR model for antifungal activity
average activity values were correlated with the molecular
descriptors of synthesized compounds (Table 6). The data
depicted in Table 6 indicated that the pMICb, pMICf
and pMICam are equally correlated with the molecular
descriptors as compared to ot-MIC values, i.e., pMICsa,
pMICbs, pMICec, pMICca and pMICan.
pMICf ¼ ꢁ0:067ja3 þ 1:926
ð6Þ
when n = 20, r = 0.812, q2 = 0.609, s = 0.230, F =
34.88.
Further, model depicted in Eq. 6 describes the statisti-
cally significant relationship between Kier’s alpha third
order shape index (ja3) and antifungal activity of substi-
tuted hydrazide derivative. In this case also negative rela-
tionship was observed between ja3 and antifungal activity
of synthesized substituted hydrazide derivatives. The above
fact can be proved by antifungal activity values (Table 2)
and their respective ja3 values (Table 4).
mt-QSAR model for antibacterial activity
pMICb ¼ ꢁ1:230 J þ 3:45
ð5Þ
when n = 20, r = 0.713, q2 = 0.488, s = 0.201, F =
18.56.
In case of antibacterial mt-QSAR studies the developed
model (Eq. 5) reveals the importance of Balaban topolog-
ical index (J) in describing antibacterial activity of syn-
thesized benzylidene hydrazide derivatives. The negative
coefficient of Balaban topological index in Eq. 5 indicates
that there is negative correlation between antibacterial
activity of substituted hydrazides and Balaban topological
index. This is evidence by low antibacterial activity values
(1.08, 1.02, 0.92 and 1.17, Table 2) and their high J (1.729,
1.897, 1.778 and 1.886, Table 4) values of compounds 4, 5,
11 and 15, respectively.
mt-QSAR model for antimicrobial activity
pMICam ¼ 1:287 J þ 3:51
ð7Þ
when n = 20, r = 0.794, q2 = 0.614, s = 0.164, F = 36.65.
Similarly, in case of antimicrobial studies, the developed
mt-QSAR model Eq. 7 signifies the importance of Balaban
topological index (J) in demonstrating the antimicrobial
activity of synthesized derivatives. This is evidenced by
antimicrobial activity data (Table 2) and their J values
(Table 4).
Table 8 Comparison of observed and predicted antimicrobial activity obtained by mt-QSAR models
Comp.
pMICb (Eq. 5)
Obs.
pMICf (Eq. 6)
Obs.
pMICam (Eq. 7)
Pre.
Res.
0.11
Pre.
Res.
0.30
Obs.
Pre.
Res.
0.20
1
1.35
1.38
1.71
1.08
1.02
1.68
1.42
1.86
1.61
1.86
0.92
1.31
1.30
1.30
1.17
1.65
1.46
1.86
1.58
1.32
1.24
1.27
1.30
1.33
1.12
1.73
1.66
1.65
1.58
1.51
1.27
1.29
1.32
1.34
1.14
1.73
1.65
1.64
1.57
1.49
1.46
1.14
0.61
0.70
1.32
1.37
1.69
1.81
1.51
1.46
1.41
0.87
0.89
1.06
1.34
1.93
1.31
1.46
1.98
1.72
1.16
1.04
0.93
0.81
1.50
1.55
1.62
1.62
1.58
1.57
1.18
1.07
0.95
0.83
1.53
1.58
1.65
1.65
1.61
1.60
1.39
1.28
1.27
0.93
1.14
1.56
1.53
1.84
1.57
1.70
1.11
1.13
1.13
1.20
1.24
1.76
1.40
1.70
1.74
1.48
1.19
1.23
1.26
1.29
1.07
1.71
1.63
1.62
1.55
1.48
1.22
1.25
1.28
1.30
1.08
1.71
1.62
1.61
1.54
1.46
2
0.11
0.41
0.10
-0.32
-0.11
-0.18
-0.18
0.07
0.05
0.01
3
4
-0.25
-0.10
-0.05
-0.24
0.21
-0.36
0.07
5
6
-0.15
-0.10
0.22
7
8
0.19
9
0.03
-0.07
-0.11
0.23
0.02
10
11
12
13
14
15
16
17
18
19
20
0.35
0.22
-0.35
0.02
-0.11
-0.12
-0.15
-0.10
0.16
-0.20
-0.06
0.23
-0.02
-0.04
0.03
-0.19
0.35
-0.08
-0.19
0.22
0.05
-0.34
-0.19
0.37
-0.22
0.09
0.01
0.20
-0.17
0.12
0.02
123

392
Med Chem Res (2012) 21:382–394
Fig. 3 Structural requirements
for the antimicrobial activity of
substituted benzylidene
hydrazides
NO2
[Antimicrobial activity]
OCH3
[Antifungal activity]
OH
Aromatic Nucleus
[Antimicrobial Activity]
H
[Antifungal]
N
O
N
SCH3
[Antibacterial]
In order to confirm our results we have predicted the
antibacterial, antimicrobial and antifungal activity values
using mt-QSAR Eqs. 5–7, respectively. The comparison of
observed and predicted values (Table 8) demonstrated that
they are close to each other, evidenced by their low
residual values.
and tested for antimicrobial activity against S. aureus,
B. subtilis, E. coli, C. albicans and A. niger The results of
antimicrobial activity indicated that compounds having
dinitro, methoxy, and methyl substituents were the most
active ones. The results of MBC/MFC revealed that most
of the synthesized compounds were bacteriostatic and
fungistatic in nature except that compounds 9 and 16 were
bactericidal for S. aureus, compounds 16 and 18 were
bactericidal against B. subtilis, compounds 4, 10 and 16
were bactericidal for E. coli and compounds 16, 19 and 20
were found to fungicidal in case of A. niger and compound
16 was found to be active fungicidal agent against
C. albicans. 3-Phenylacrylic acid-(3-hydroxybenzylidene)-
hydrazide, 16, was found to be bactericidal as well as
fungicidal. The QSAR studies showed the importance of
Balaban topological index (J), valence third order molec-
ular connectivity index, 3vv, and third order molecular
connectivity index, 3v, in governing the antimicrobial
activity of these synthesized compounds.
Structure activity relationship (SAR) studies
1. The results of antimicrobial activity depicted that the
presence of electron donating group, OCH3, in com-
pound 9 and 19, increase the antifungal activity of
benzylidene hydrazides. This is supported by results of
Emami et al. (2008).
2. The presence of electron withdrawing group (NO2) in
compounds 10 and 20 made them highly active
antimicrobial agents. The role of electron withdrawing
group in increasing the antimicrobial activity is similar
to the results of Sharma et al. (2006).
3. The synthesized compounds derived from 4-thiometh-
ylbenzaldehyde have shown higher antibacterial activ-
ity (1–10) as compared to compounds derived from
3-hydroxybenzaldehyde (11–20).
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