Synthesis, antimicrobial activities and QSAR studies of heterocyclic Schiff base ligands with organosilicon(IV) halides

Article abstract of DOI:10.1007/s00044-015-1478-6

A series of heterocyclic Schiff base ligands 4-hydroxy-3-[1-{(2-hydroxy-aryl) imino}-ethyl]-6-methyl-pyran-2-one; aryl = phenyl, 4-methylphenyl, 4-chlorophenyl or 4-nitrophenyl (1-4) and their organosilicon(IV) complexes R₂Si(L) (R = Et, Bu or

Full text of DOI:10.1007/s00044-015-1478-6

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-015-1478-6
ORIGINAL RESEARCH
Synthesis, antimicrobial activities and QSAR studies
of heterocyclic Schiff base ligands with organosilicon(IV) halides
Jai Devi1 Suman Kumari1 Nisha Batra1 Pradeep Kumar2
•
•
•
•
Balasubramanian Narasimhan2 Rajesh Malhotra1
•
Received: 26 February 2015 / Accepted: 1 November 2015
Ó Springer Science+Business Media New York 2015
Abstract A series of heterocyclic Schiff base ligands
4-hydroxy-3-[1-{(2-hydroxy-aryl) imino}-ethyl]-6-methyl-
pyran-2-one; aryl = phenyl, 4-methylphenyl, 4-chlor-
ophenyl or 4-nitrophenyl (1–4) and their organosilicon(IV)
complexes R2Si(L) (R = Et, Bu or Ph) (5–16) were syn-
thesized and characterized. The elemental analyses, molar
conductance and spectral (IR, 1H, 13C and 29Si NMR) data
suggested pentacoordinated environment around the silicon
atom, where tridentate ligands coordinate through the
azomethine nitrogen and oxygen of hydroxyl groups. The
ligands and their organosilicon complexes were tested
in vitro against pathogenic bacteria and fungi to assess their
antimicrobial properties. The activity of the ligands
improved against most of the strains of the tested
microorganisms on complexation to the organosilicon
groups. The antimicrobial activities were correlated with
QSAR studies using the linear free energy relationship
model which indicate the importance of topological
parameters, third-order and valence first-order molecular
Keywords Organosilicon complexes Á
Dehydroacetic acid Á Antimicrobial activity Á
Heterocyclic ligand Á QSAR
Introduction
The Schiff base complexes are of particular interest to
inorganic chemists for their structural, spectral and chem-
ical behaviour (Raman et al., 2007; Malhotra et al., 2007;
Devi et al., 2012a). Many of these complexes provide
biological models for understanding the structure of bio-
molecules and biological processes which are of special
interest to bioinorganic chemists (Bharti et al., 2010).
Schiff bases and their silicon complexes exhibit a broad
spectrum of biological activity such as antibacterial, anti-
fungal, antitumor, antiviral, anti-inflammatory, insecticidal
and antinematodal because of their specific structures (Jain
et al., 2004; Belwal and Singh, 2000; Singh and Dharam-
pal, 2009; Abad et al., 2004). It is, however, noteworthy
that the biological activity is enhanced on complexation to
silicon atoms (Devi et al., 2012b). It has been reported that
some microorganisms have already become resistant to
many of the commonly used organic drugs. Therefore,
today’s requirement for researchers is to develop novel
antibacterial and antifungal drugs which would target the
lipid layer of microorganisms. Earlier we have reported
that when biological active molecule is attached to the
metal atom, the lipophilic nature is increased which
favours its permeation through the lipid layer of the cell
membrane of the microorganisms thus interfering the cell
process (Devi et al., 2012c; Devi and Batra, 2013; Yousef
et al., 2012).
1
connectivity indices (3vv and vv), to explain the antibac-
terial and antifungal activities of all synthesized
compounds.
Electronic supplementary material The online version of this
article (doi:10.1007/s00044-015-1478-6) contains supplementary
material, which is available to authorized users.
& Rajesh Malhotra
malhotra_ksrk@yahoo.co.in
1
Department of Chemistry, Guru Jambheshwar University of
Science and Technology, Hisar, Haryana 125001, India
2
Quantitative structure–activity relationship (QSAR)
models are effective in describing structural basis of
Faculty of Pharmaceutical Sciences, Maharishi Dayanand
University, Rohtak, Haryana 124001, India
123

Med Chem Res
biological activity of chemical compounds by using com-
puter-aided models. Previous studies in the field of QSAR
(Judge et al., 2012; Kumar et al., 2012) indicated that the
multi-target QSAR (mt-QSAR) models are better than one-
target QSAR (ot-QSAR) models in describing the antimi-
crobial activity. So, in the present study, we have devel-
oped multi-target QSAR models to describe the
antimicrobial activity of synthesized compounds. In the
present work, dehydroacetic acid is used as one component
for the synthesis of Schiff base ligands which were
reported to act as fungicides and bactericides (Munde et al.,
2010). So, we hereby report synthesis, characterization,
antimicrobial evaluation and QSAR studies of Schiff base
ligands and their organosilicon(IV) complexes.
dehydroacetic acid and substituted 2-aminophenol yielded
the other Schiff base ligands (H2LI–IV).
H2LI (1): brown (EtOH); yield: 80 %; IR (KBr) v max
3380, 1605 cm-1
;
1H NMR (CDCl3, 300 MHz,):
d = 10.57 (1H, C4–OH), 15.23 (1H, C9–OH), 5.59 (1H,
C5–H), 7.44 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 7.02 (d,
J = 8.5 Hz, 1H); 13C NMR (CDCl3, 300 MHz): d = 163.4
(C, C2), 96.2 (C, C3), 182.3 (C, C4), 105.1 (C, C5), 162.9
(C, C6), 176.1 (C, C7), 19.5, 19.0 (C–CH3), 149.1, 130.4,
126.9, 125.2, 123.7 117.1 (Ar–C); MS m/z: 260.0
C14H13NO4 (calcd. 259.2); Anal. Calcd: C, 64.86; H, 5.05;
N, 5.40. Found: C, 64.98; H, 5.35; N, 5.64.
H2LII (2): light brown (EtOH); yield: 81 %; IR (KBr)
1
v max 3390, 1620 cm-1; H NMR (CDCl3, 300 MHz,):
d = 8.32 (1H, C4–OH), 14.98 (1H, C9–OH), 5.70 (1H, C5–
H), 7.10 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H),
6.85 (s 1H); 13C NMR (CDCl3, 300 MHz): d = 163.8 (C,
C2), 96.5 (C, C3), 183.8 (C, C4), 106.4 (C, C5), 162.1 (C,
C6), 175.5 (C, C7), 19.7, 19.1 (C–CH3), 150.2, 128.8,
126.3, 124.4, 122.3 117.6 (Ar–C); MS m/z: 274.4
C15H15NO4 (calcd. 273.2); Anal. Calcd: C, 65.92; H, 5.53;
N, 5.13. Found: C, 66.12; H, 5.82; N, 5.35.
Materials and methods
Analytical grade dichlorodiorganosilane and 2-aminophe-
nol derivatives were purchased from Aldrich. Solvents
were purified according to standard procedures (Vogel,
1999). Anhydrous conditions were maintained throughout
during the synthesis of the complexes, since the dichloro-
diorganosilane and their product complexes are highly
moisture sensitive. Molar conductances were measured in
dry DMSO with a conductivity bridge model-306 Sys-
tronics. Silicon was estimated gravimetrically as SiO2. The
IR spectra were recorded using a Spectrum BX Series FT-
IR spectrophotometer using KBr pellets. Multinuclear
magnetic resonance spectra (1H, 13C, 29Si) were recorded
on a Bruker Avance II 300-MHz NMR Spectrometer, and
all chemical shifts d were reported in ppm relative to
tetramethylsilane (TMS) as an internal standard in CDCl3
and DMSO-d6. Elemental analyses were carried out on a
Perkin Elmer 2400. Mass spectra were recorded on an API
2000 (Applied Biosystems) mass spectrometer equipped
with an electrospray source and a Shimadzu prominence
LC. All the bacterial strains were procured from Microbial
Type Culture Collection (MTCC), IMTECH, Chandigarh.
H2LIII (3): dark brown (EtOH); yield: 78 %; IR (KBr)
1
v max 3385, 1619 cm-1; H NMR (CDCl3, 300 MHz,):
d = 9.99 (1H, C4–OH), 15.38 (1H, C9–OH), 5.81 (1H, C5–
H), 7.06 (d, J = 9.6 Hz, 1H), 7.03 (s, 1H), 6.90 (d,
J = 9.6 Hz, 1H); 13C NMR (CDCl3, 300 MHz): d = 163.7
(C, C2), 96.5 (C, C3), 183.9 (C, C4), 106.8 (C, C5), 162.7
(C, C6), 176.3 (C, C7), 19.6, 18.9 (C–CH3), 151.2, 128.1,
127.1, 123.9, 121.9 118.1 (Ar–C); MS m/z: 305.2
C14H12N2O6 (calcd. 304.2); Anal. Calcd: C, 55. 27; H,
3.98; N, 9.21. Found: C, 55.45; H, 4.13; N, 9.43.
H2LIV (4): brownish (EtOH); yield: 80 %; IR (KBr)
1
v max 3398, 1613 cm-1; H NMR (CDCl3, 300 MHz,):
d = 9.72 (1H, C4–OH), 15.40 (1H, C9–OH), 5.59 (1H, C5–
H), 7.01 (d, J = 8.7 Hz, 1H), 6.93 (s, 1H), 6.85 (d,
J = 8.7 Hz, 1H); 13C NMR (CDCl3, 300 MHz): d = 163.8
(C, C2), 95.9 (C, C3), 183.3 (C, C4), 105.9 (C, C5), 163.3
(C, C6), 175.9 (C, C7), 19.2, 19.9 (C–CH3), 151.4, 129.2,
125.9, 124.0, 123.7 119.9 (Ar–C); MS m/z: 294.2 C14H12-
ClNO4 (calcd. 293.7); Anal. Calcd: C, 57. 25; H, 4.12; N,
4.77. Found: C, 57.50; H, 4.36; N, 4.98.
Experimental
General procedure for the synthesis of ligands (1–4)
General procedure for the synthesis of organosilicon
The synthesis of the ligand, 4-hydroxy-3-[1-(2-hydroxy-
phenylimino)-ethyl]-6-methyl-pyran-2-one (H2LI), was
carried out by dissolving 1.68 g dehydroacetic acid
(10 mmol) in 20 mL of ethanol and 1.23 g 4-methyl-2-
aminophenol (10 mmol) in 10 mL of the ethanol sepa-
rately. The solutions were mixed together and refluxed for
30 min. After cooling, a brownish precipitate formed at
room temperature was recrystallized from ethanol to give
the pure compound. Similarly, the reactions between
complexes (5–16)
Disodium salts of the ligands were prepared by stirring the
respective ligand (10 mmol) and sodium metal (20 mmol)
in 30 mL dry ethanol in an inert dry nitrogen atmosphere.
For the synthesis of the complexes, calculated amount of
Et2SiCl2, Bu2SiCl2 or Ph2SiCl2 was slowly added to the
requisite amount of the disodium salt of the corresponding
ligands (Na2L) in a 1:1 molar ratio in the dry ethanol with
123

Med Chem Res
continuous stirring. The mixture was then refluxed for
3–4 h, the precipitated sodium chloride was filtered off,
and excess solvent was removed under vacuum. The sep-
arated solid was washed with dry n-hexane and recrystal-
lized from the mixture of dry ethanol and n-hexane (50:50
v/v) to ensure the purity of the product.
d = 5.71 (1H, C5–H), 7.25 (d, J = 9.3 Hz, 1H), 7.18 (d,
J = 9.3 Hz, 1H), 7.05 (s, 1H), 1.50 (t, J = 2.3 Hz, 4H),
0.99 (t, J = 4.3 Hz, 6H), 0.95–0.90 (m, 8H); 13C NMR
(CDCl3, 300 MHz): d = 163.8 (C, C2), d = 96.7 (C, C3),
188.5 (C, C4), 105.9 (C, C5), 162.0 (C, C6), 181.9 (C, C7),
19.5, 19.1 (C–CH3), 149.4, 126.9, 121.7, 118.9, 117.6,
117.2 (Ar–C), 13.3, 15.3, 20.6, 21.5 (Si–Bu); MS m/z:
414.9 C23H32NO4Si (calcd. 414.5); Anal. Calcd: C, 66.63;
H, 7.78; N, 3.38; Si, 6.77. Found: C, 66.95; H, 7.43; N,
3.26; Si, 6.66.
Et2Si(LI) (5): dark brown (EtOH); yield: 76 %; IR (KBr)
v max 1592, 600, 520 cm-1; 1H NMR (CDCl3, 300 MHz,):
d = 5.57 (1H, C5–H), 7.56 (d, J = 8.5 Hz, 1H), 7.11 (s,
1H), 6.98 (d, J = 8.5 Hz, 1H), 1.18 (t, J = 4.5 Hz, 6H),
1.01 (q, J = 4.5 Hz, 4H), 13C NMR (CDCl3, 300 MHz):
d = 163.8 (C, C2), 96.8 (C, C3), 188.1 (C, C4), 105.3 (C,
C5), 162.7 (C, C6), 183.0 (C, C7), 19.8, 19.3 (C–CH3),
151.0, 128.9, 126.8, 124.5, 121.9 118.5 (Ar–C), d = 9.2,
11.2 (Si–Et); MS m/z: 343.8 C18H22NO4Si (calcd. 344.4);
Anal. Calcd: C, 62.76; H, 6.82; N, 4.15; Si, 8.15. Found: C,
62.42; H, 6.44; N, 4.07; Si, 8.23.
Ph2Si(LII) (10): dark brown (EtOH): yield: 72 %; IR
(KBr) v max 1603, 636, 558 cm-1 1H NMR (CDCl3,
;
300 MHz,): d = 5.73 (1H, C5–H), 7.61 (d, J = 8.8 Hz,
1H), 7.01 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.45–7.33 (m,
4H), 7.29–7.14 (m, 6H); 13C NMR (CDCl3, 300 MHz):
d = 163.9 (C, C2), 96.4 (C, C3), 189.8 (C, C4), 106.8 (C,
C5), 162.5 (C, C6), 182.7 (C, C7), 18.8, 18.6 (C–CH3),
150.1, 127.4, 122.6, 118.5, 117.8, 117.1 (Ar–C), 148.8,
138.1, 130.9, 121.8 (Si–Ph); MS m/z: 453.9 C27H24NO4Si
(calcd. 454.5); Anal. Calcd: C, 71.34; H, 5.32; N, 3.08; Si,
6.18. Found: C, 71.62; H, 5.61; N, 3.16; Si, 5.45.
Bu2Si(LI) (6): dark brown (EtOH); yield: 74 %; IR
(KBr) v max 1591, 630, 529 cm-1 1H NMR (CDCl3,
;
300 MHz,): d = 5.58 (1H, C5–H), 7.58 (d, J = 9.1 Hz,
1H), 7.19 (s, 1H), 7.05 (d, J = 9.1 Hz, 1H), 1.53
(J = 3.2 Hz, t, 4H), 1.09 (J = 5.1 Hz, t, 6H), 0.97–0.91(m,
8H); 13C NMR (CDCl3, 300 MHz): d = 163.9 (C, C2),
96.3 (C, C3), 188.5 (C, C4), 106.1 (C, C5), 163.1 (C, C6),
182.5 (C, C7), 19.9, 19.2 (C–CH3), 150.3, 129.6, 127.2,
124.9, 122.7, 118.9 (Ar–C), 13.6, 15.7, 20.5, 21.6 (Si–Bu);
MS m/z: 401.6 C22H30NO4Si (calcd. 400.5); Anal. Calcd:
C, 65.97; H, 7.55; N, 3.50; Si, 7.01. Found: C, 66.13; H,
7.83; N, 3.58; Si, 6.92.
Et2Si(LIII) (11): dark brown (EtOH); yield: 73 %; IR
(KBr) v max 1600, 636, 548 cm-1 1H NMR (CDCl3,
;
300 MHz,): d = 5.80 (1H, C5–H), 7.55 (d, J = 8.0 Hz,
1H), 7.13 (s, 1H), 7.11 (d, J = 8.0 Hz, 1H), 1.17 (J = 2.9,
t, 6H), 0.99 (q, J = 2.9, 4H); 13C NMR (CDCl3,
300 MHz): d = 163.9 (C, C2), 96.8 (C, C3), 188.7 (C, C4),
107.0 (C, C5), 162.8 (C, C6), 183.7 (C, C7), 19.9, 19.4 (C–
CH3), 150.3, 128.7, 128.0, 124.5, 122.7, 119.4 (Ar–C), 9.3,
11.1 (Si–Et); MS m/z: 390.1 C18H21N2O6Si (calcd. 389.4);
Anal. Calcd: C, 55.51; H, 5.43; N, 7.19; Si, 7.21. Found: C,
55.83; H, 5.89; N, 7.08; Si, 6.94.
Ph2Si(LI) (7): brown (EtOH); yield: 78 %; IR (KBr)
v max 1593, 650, 540 cm-1; 1H NMR (CDCl3, 300 MHz,):
d = 5.58 (1H, C5–H), 7.64 (d, J = 7.8 Hz, 1H), 7.20 (s,
1H), 7.10 (d, J = 7.8 Hz, 1H), 7.53–7.46 (m, 4H),
7.30–7.24 (m, 6H); 13C NMR (CDCl3, 300 MHz):
d = 163.3 (C, C2), 97.7 (C, C3), 189.3 (C, C4), 106.5 (C,
C5), 163.3 (C, C6), 183.8 (C, C7), 19.6, 19.0 (C–CH3),
150.8, 130.7, 127.8, 124.7, 123.4, 119.3 (Ar–C), 147.3,
137.5, 133.6, 128.2 (Si–Ph); MS m/z: 441.6 C26H22NO4Si
(calcd. 440.5); Anal. Calcd: C, 70.88; H, 5.03; N, 3.18; Si,
6.38. Found: C, 71.03; H, 5.32; N, 2.50; Si, 5.67.
Bu2Si(LIII) (12): dark brown (EtOH); yield: 74 %; IR
(KBr) v max 1599, 647, 538 cm-1 1H NMR (CDCl3,
;
300 MHz,): d = 5.81 (1H, C5–H), 7.56 (d, J = 8.9 Hz,
1H), 7.18 (s, 1H), 6.99 (d, J = 8.9 Hz, 1H), 1.60 (t,
J = 4.1 Hz, 4H), 1.19 (t, J = 3.8 Hz, 6H), 0.98–0.92 (m,
8H); 13C NMR (CDCl3, 300 MHz): d = 163.7 (C, C2),
96.5 (C, C3), 189.6 (C, C4), 106.9 (C, C5), 162.6 (C, C6),
184.2 (C, C7), 20.1, 19.6 (C–CH3), 152.1, 129.2, 128.7,
125.1, 123.1, 119.6 (Ar–C), 14.1, 15.0, 20.2, 21.9 (Si–Bu);
MS m/z: 445.9 C22H29NO6Si (calcd. 445.0); Anal. Calcd:
C, 59.30; H, 6.56; N, 6.29; Si, 6.30. Found: C, 59.63; H,
6.82; N, 6.15; Si, 5.83.
Et2Si(LII) (8): brown (EtOH); yield: 74 %; IR (KBr)
v max 1599, 656, 556 cm-1;1H NMR (CDCl3, 300 MHz,):
d = 5.72 (1H, C5–H), 7.20 (d, J = 8.9 Hz, 1H), 7.08 (d,
J = 8.9 Hz, 1H), 6.95 (s, 1H), 1.12 (J = 4.6 Hz, t, 6H),
0.98 (J = 4.6 Hz, q, 4H); 13C NMR (CDCl3, 300 MHz):
d = 163.5 (C, C2), 96.9 (C, C3), 188.9 (C, C4), 106.1 (C,
C5), 162.3 (C, C6), 182.0 (C, C7), 19.9, 19.2 (C–CH3),
151.9, 127.8, 123.1, 119.2, 118.1 117.5 (Ar–C), 9.1, 10.9
(Si–Et); MS m/z: 357.8 C19H24NO4Si (calcd. 358.4); Anal.
Calcd: C, 63.66; H, 6.75; N, 3.91; Si, 7.83. Found: C,
63.92; H, 6.53; N, 3.40; Si, 7.70.
Ph2Si(LIII) (13): brown (EtOH); yield: 76 %; IR (KBr)
v max 1601, 650, 528 cm-1; 1H NMR (CDCl3, 300 MHz,):
d = 5.82 (1H, C5–H), 7.67 (d, J = 9.0 Hz, 1H), 7.21 (s,
1H), 7.19 (d, J = 9.0 Hz, 1H), 7.56–7.46 (m, 4H),
7.27–7.22 (m, 6H); 13C NMR (CDCl3, 300 MHz):
d = 163.8 (C, C2), 96.9 (C, C3), 190.1 (C, C4), 107.2 (C,
C5), 162.8 (C, C6), 184.9 (C,C7), 20.4, 19.5 (C–CH3),
151.9, 129.6, 128.9, 125.2, 123.4, 119.9 (Ar–C), 149.5,
139.7, 133.2, 130.6 (Si–Ph); MS m/z: 485.9 C26H21NO6Si
Bu2Si(LII) (9): brown (EtOH); yield: 77 %; IR (KBr)
v max 1600, 639, 560 cm-1; 1H NMR (CDCl3, 300 MHz,):
123

Med Chem Res
(calcd. 485.5); Anal. Calcd: C, 64.32; H, 4.36; N, 5.77; Si,
5.78. Found: C, 64.63; H, 4.65; N, 5.71; Si, 5.25.
Et2Si(LIV) (14): dark brown (EtOH); yield: 68 %; IR
;
(KBr) v max 1593, 630, 560 cm-1 1H NMR (CDCl3,
dry DMSO with concentration of 100 lg/mL. Norfloxacin
and fluconazole were used as standards for comparing the
activity of 1–16 compounds. Each sample was assayed in
triplicate and the mean values were calculated.
300 MHz,): d = 5.57 (1H, C5–H), 7.51 (d, J = 8.3 Hz,
1H), 6.99 (d, J = 8.3 Hz, 1H), 7.23 (s, 1H), 1.19 (t,
J = 3.1 Hz, 6H), 1.08 (q, J = 2.6 Hz, 4H); 13C NMR
(CDCl3, 300 MHz): d = 164.0 (C, C2), 96.7 (C, C3), 190.5
(C, C4), 106.2 (C, C5), 163.8 (C, C6), 185.6 (C, C7), 19.9,
19.3 (C, C–CH3), 151.9, 129.7, 126.2, 124.3, 123.8 120.2
(Ar–C), 9.5, 11.6 (Si-Et); MS m/z: 378.3 C18H21ClNO4Si
(calcd. 378.9); Anal. Calcd: C, 57.06; H, 5.59; N, 3.70; Si,
7.41. Found: C, 57.32; H, 5.82; N, 3.67; Si, 6.66.
QSAR studies
Pre-optimization of structure of (1–16) was done with the
Molecular Mechanics Force Field (MM?) procedure
included in Hyperchem 6.03 (1993) and the consequential
geometries were further refined by means of the semiem-
pirical method PM3 (Parametric Method-3). A gradient
˚
norm limit of 0.01 kcal/A was chosen for the geometry
Bu2Si(LIV) (15): dark brown (EtOH); yield: 73 %; IR
(KBr) v max 1598, 626, 550 cm-1 1H NMR (CDCl3,
;
optimization. To calculate physicochemical properties,
lowest energy structure was used for each molecule using
TSAR 3.3 (2000) software for Windows. Further, the
regression analysis was performed using the SPSS (1999)
software package.
300 MHz,): d = 5.58 (1H, C5–H), 7.58 (d, J = 8.2 Hz,
1H), 7.19 (s, 1H), 7.17 (d, J = 8.2 Hz, 1H), 1.65 (t,
J = 3.4, 4H), 1.21 (t, J = 4.1, 6H), 0.97–0.92 (m, 8H); 13
C
NMR (CDCl3, 300 MHz): d = 163.7 (C, C2), 96.5 (C, C3),
191.3 (C, C4), 106.5 (C, C5), 164.1 (C, C6), 186.2 (C, C7),
19.7, 19.1 (C–CH3), 152.2, 130.3, 126.5, 124.7, 124.3
120.2 (Ar–C), 4.5, 15.9, 20.7, 21.3 (Si–Bu); MS m/z: 435.8
C22H29ClNO4Si (calcd. 435.0); Anal. Calcd: C, 60.74; H,
6.72; N, 3.22; Si, 6.46. Found: C, 60.96; H, 6.93; N, 3.28;
Si, 5.96.1
Results and discussion
Chemistry
The ligands and their organosilicon complexes were syn-
thesized using the synthetic procedure described in
Scheme 1. The ligands (1–4) were prepared by the con-
densation of dehydroacetic acid and p-substituted
2-aminophenol. The homogeneity of the compounds was
regularly monitored through TLC. Dichlorodiorganosilane
was reacted with the disodium salt of the Schiff base in dry
ethanol in 1:1 molar ratio. The elemental analyses data of
the compounds 1–16 are well in agreement with the cor-
responding molecular formulae with small deviation from
actual values for each element. The low molar conductance
values for the complexes in the range of 8.0–12.0 X-1
cm2 mol-1 in dry dimethyl sulfoxide indicate the non-
electrolytic nature of complexes. Single crystals of the
complexes could not be obtained as powdery substance got
precipitated from the solution upon each attempt of
crystallization.
Ph2Si(LIV) (16): brown (EtOH); yield: 76 %; IR (KBr)
v max 1595, 639, 560 cm-1; 1H NMR (CDCl3, 300 MHz,):
d = 5.60 (1H, C5–H), 7.61 (d, J = 7.9 Hz, 1H), 7.25 (s,
1H), 7.18 (d, J = 7.9 Hz, 1H), 7.66–7.65 (m, 4H),
7.39–7.31 (m, 6H); 13C NMR (CDCl3, 300 MHz):
d = 163.9 (C, C2), 96.8 (C, C3), 191.7 (C, C4), 106.8 (C,
C5), 164.3 (C, C6), 186.5 (C, C7), 20.2, 19.5 (C–CH3),
152.5, 130.7, 126.8, 125.2, 124.6 120.7 (Ar–C), 149.9,
139.7, 134.2, 131.8 (Si–Ph); MS m/z: 474.2 C26H21
ClNO4Si (calcd. 474.9); Anal. Calcd: C, 65.74; H, 4.46; N,
2.95; Si, 5.91. Found: C, 65.45; H, 4.71; N, 2.83; Si, 5.35.
Antimicrobial activity
For determination of in vitro antimicrobial activity, the
ligands and their organosilicon complexes were screened
against Gram-positive bacteria viz. Bacillus subtilis
(MTCC no. 2063) and Staphylococcus aureus (MTCC no.
2901) and the Gram-negative bacteria viz. Escherichia coli
(MTCC no. 1652), as well as in vitro antifungal activity
against Candida albicans (MTCC no. 183) and Aspergillus
niger (MTCC no. 1344), using two fold serial dilution
technique in double-strength nutrient broth and Sabouraud
dextrose broth, respectively (Cappucino and Sherman,
1999). The incubation period of A. niger and C. albicans
was 7 days at 25 1 °C and 48 h at 37 1 °C, respec-
tively, whereas for bacteria it was 24 h at 37 1 °C. Stock
solutions were prepared by dissolving the compounds in
Spectral studies
All the synthesized compounds were well characterized by
IR, NMR (1H, 13C and 29Si) and mass spectral studies in
addition to elemental analyses which were in full agree-
ment with their molecular structures. The infrared spectra
recorded using KBr pellets of the complexes were com-
pared with that of the Schiff base ligands to ascertain the
coordination sites of the ligand on the basis of shifts in the
frequency of various groups and the absence of certain
absorptions, which may be due to changes in the electronic
123

Med Chem Res
HO
NH2
OH
O
O
OH
N
O
R1
OH
Ethanol
CH3
+
CH3
H3C
O
H3C
O
R1
R2SiCl2
Ethanol
EtONa
R1
11
12
10
9
Ligand
H2LI
H2LII
H2LIII
H2LIV
R1
H
CH3
NO2
Cl
O
Si
O
13
8
R
R
N
CH3
7
3
2
R=ethyl, butyl or phenyl
O
4
5
O
1
6
H3C
Scheme 1 Synthesis of Schiff base ligands and their organosilicon complexes
environment of the ligands after the formation of silicon
ligand bond. In the spectra of the ligands, a broad band
centre at 3380–3398 cm-1 was due to m(OH), and the
broadness of this band suggested the presence of a
hydrogen bond between the OH group and the azomethine
nitrogen of the ligand. In addition, a weak band in the
region 2780–2800 cm-1 was attributed to an intramolecu-
lar hydrogen bond due to an OH group. The absorption
band due to m(OH) was found to be completely absent in
the complexes, thereby suggesting the involvement of both
phenolic hydroxyl groups after deprotonation in coordina-
tion. Moreover, the phenolic m(C–O) stretching and bend-
coordination indeed had taken place through the nitrogen
atom (Nejo et al., 2010). New bands also appeared in the
range of 600–650 cm-1 which were assigned to m(Si–N).
1
The H, 13C and 29Si NMR spectra of the ligands and
their corresponding organosilicon(IV) complexes were
1
recorded in CDCl3 using TMS as the internal standard. H
NMR spectra of the free ligands have broad singlets at d
8.35 ppm and d 15.0 ppm due to the OH protons attached
to C4 and C9, respectively, which completely disappeared
from the spectra of the corresponding complexes indicating
deprotonation with the formation of the covalent bond
between the oxygen and silicon atom. Sharp singlets at d
5.70 ppm and d 2.54 ppm due to the CH proton and methyl
protons attached to carbon C6 of the pyran-2-one ring
remained almost unchanged on complexation, while a
downfield shift of d *0.1 was observed in the methyl
protons attached to C7 which appeared as a singlet. Aro-
matic protons appeared as a singlet and a doublet at d 6.85,
and d 6.96–7.10 ppm, respectively, and shifted slightly
downfield in the complexes. A new triplet at d 0.9 ppm and
a quartet at d 1.1 ppm due to the ethyl protons attached to
ing vibrations, at 1500–1520 and 1270–1290 cm-1
respectively, as expected for an uncoordinated phenol were
found to be shifted to higher frequencies by 20–30 cm-1
,
.
Coordination of the oxygen to the silicon atom was further
confirmed by the appearance of bands in the region of
520–560 cm-1 which were assigned to m(Si–O). The shift
in the absorption bands due to m(C=N) which earlier
appeared at 1605–1620 cm-1 in the ligands to a lower
frequencies by 10–20 cm-1 in the complexes indicated that
123

Med Chem Res
the silicon atom or a multiplet at d 7.1–7.4 ppm due to the
phenyl group attached to the silicon atom appeared in the
spectra of the complexes. A singlet and a multiplet at d
1.5 ppm and d 0.9 ppm were assigned to the n-butyl group
attached to the silicon atom.
standard drugs (positive control) for antibacterial and
antifungal activity, respectively, whereas DMSO was used
as the negative control which produces no visible effect on
activity.
Studies have shown that the nitrogen of azomethine
group with lone pair of electron has considerable biological
importance (Dholakiya and Patel, 2004). The activity of the
ligands therefore may be reorganized due to the presence of
[C=N group. The ligands H2LIII (3) and H2LIV (4), having
nitro- and chloro-substituted phenyl groups, showed better
activity towards all microorganisms than the ligand H2LII
(2) with a methyl substituted phenyl group. Organosilicon
complexes were more active towards the bacteria and fungi
than their corresponding ligands under identical experi-
mental conditions. This increase in the activity on com-
plexation is explained on the basis of chelation theory
(Devi and Batra, 2015). According to this theory, when
biological active molecule is attached to the silicon atom,
the lipophilic nature is increased which favours their per-
meation through lipid layer of the cell membrane of
microorganisms, thus interfering the cell process which
further restrict the growth of organism. None of the com-
pounds showed better inhibition than the conventional
fungicides and bactericides used. Among all the complexes
Ph2Si(LI–IV) [7, 10, 13, 16] were found to be more potent
than Bu2Si(LI–IV) or Et2Si(LI–IV) which is in agreement
with our previous work (Devi et al., 2012b, c).
In the 13C NMR spectra of the ligands, the signal at d
175.5 ppm due to the azomethine carbon was shifted
towards a lower value by d 10–15 ppm in the complexes.
This observed downfield change in chemical shift indicates
the coordination of the azomethine nitrogen to the silicon
atom upon the complexation. Signals due to C4 and C9
were shifted towards a higher chemical shift value in the
organosilicon complexes. The signal for the methyl carbon
appeared at d 19.1–19.8 ppm in the spectra of the ligands
and remained almost same in the complexes. The signal
due to the carbons of the ethyl and n-butyl groups attached
to the silicon atom appeared in the range of d 9.1–12.9 ppm
and d 13.3–26.5 ppm. The resonances due to the carbons of
phenyl ring attached to the silicon atom appeared in the
range of d 128.8–148.8 ppm. The signals for the aromatic
carbons appeared in the range of d 117.6–126.8 ppm.
Shifts in the positions of other carbon atoms involved in
complex formation indicate a bonding pattern in the
complexes.
The pentacoordinated silicon atom in all the complexes
showed a sharp singlet at d -95.6 to -110.9 ppm in the
29Si NMR spectra of the complexes. On the basis of above
spectral data, it may be concluded that the complexes are
five-coordinated and probably possess trigonal bipyramidal
geometry around silicon atom.
QSAR studies
LC-MS of the ligands and their corresponding
organosilicon complexes were recorded and the mass
spectrum of H2LII (2) showed a well-defined molecular ion
peak at m/z = 274.4 The corresponding silicon complex
Et2Si(LII) showed a base peak at m/z = 357.8. The
molecular ion peaks in spectra of the other ligands and their
organosilicon complexes are summarized in experimental
part.
In order to understand the experimental antimicrobial data
on theoretical basis, quantitative structure activity rela-
tionship (QSAR) studies were undertaken between in vitro
antimicrobial activity of synthesized compounds and
descriptors coding for lipophilic, electronic, steric and
topological properties of the molecules being discussed,
using the linear free energy relationship (LFER) model
(Hansch and Fujita, 1964). Data set of all 1–16 was used
for the regression analysis, and no outlier was found. The
standard drugs were not included in the model develop-
ment as they belong to a different structural series.
Antimicrobial activity
All the newly synthesized compounds were subjected to
in vitro antibacterial activity against the Gram-positive
bacteria viz. B. subtilis and S. aureus and the Gram-neg-
ative bacteria viz. E. coli, as well as in vitro antifungal
activity against C. albicans and A. niger. Minimum inhi-
bitory concentrations (MICs) were determined by means of
twofold serial dilution technique. As evident from antimi-
crobial activity output, most of the compounds exhibited
excellent activity. Results indicated clear concentration-
dependent activity, as growth of bacteria and fungus
decreases with increase in concentration of the tested
compounds. Norfloxacin and fluconazole were used as
The biological activity data determined as MIC values
were first transformed into pMIC values (i.e. –log MIC)
and used as dependent variables in QSAR study (Table 1).
Molecular descriptors (independent variables) like log of
octanol–water partition coefficient (log P), molar refrac-
tivity (MR), Kier’s molecular connectivity (0v, 0vv, 1v, 1vv,
2
2v, vv) and shape (j1, ja1, ja2, ja3) topological indices,
Randic topological index (R), Balaban topological index
(J), Wiener topological index (W), total energy (Te),
energies of highest occupied molecular orbital (HOMO)
and lowest unoccupied molecular orbital (LUMO), dipole
moment (l) and electronic energy (Ee) (Hansch et al.,
123

Med Chem Res
Table 1 Antimicrobial activity (pMIC)
S. No.
Ligand/complexes
pMICsa
pMICbs
pMICec
pMICan
pMICca
pMICab
pMICaf
pMICam
1
H2LI
0.41
0.44
0.48
0.47
1.14
1.51
1.85
1.46
1.22
1.56
1.19
1.25
1.59
1.48
1.24
1.58
[2.15
[2.01
–
0.41
0.44
0.48
0.77
1.44
1.20
1.25
1.46
1.22
1.56
1.79
1.55
1.29
1.48
1.24
1.58
[2.15
[2.01
–
0.41
0.44
0.78
0.47
1.14
1.20
1.55
1.15
1.22
1.86
1.49
1.25
1.59
1.76
1.84
1.58
[2.15
[2.01
–
0.71
0.44
0.48
0.77
1.44
1.51
1.85
1.15
1.52
1.86
1.19
1.55
1.29
1.78
1.54
2.18
–
0.41
0.44
0.78
0.47
1.44
1.81
1.25
1.76
1.52
1.56
1.19
1.85
2.19
1.48
1.84
1.88
–
0.41
0.44
0.58
0.57
1.24
1.30
1.55
1.36
1.22
1.66
1.49
1.35
1.49
1.58
1.44
1.58
[2.15
[2.01
–
0.56
0.44
0.63
0.62
1.44
1.66
1.55
1.46
1.52
1.71
1.19
1.70
1.74
1.63
1.69
2.03
–
0.47
0.44
0.60
0.59
1.32
1.44
1.55
1.40
1.34
1.68
1.37
1.49
1.59
1.60
1.54
1.76
2
H2LII
3
H2LIII
4
H2LIV
5
Et2Si(LI)
Bu2Si(LI)
Ph2Si(LI)
Et2Si(LII)
Bu2Si(LII)
Ph2Si(LII)
6
7
8
9
10
11
Et2Si(LIII
Bu2Si(LIII
Ph2Si(LIII
Et2Si(LIV
Bu2Si(LIV
Ph2Si(LIV
)
12
)
13
)
14
)
15
)
16
)
Tetracyclin
Chloramphenicol
Cycloheximide
Fluconazole
–
–
–
–
–
–
[1.95
[1.99
[1.95
[1.99
[1.95
[1.99
–
–
–
–
1973; Kier and Hall, 1976; Randic, 1975; Balaban, 1982;
Randic, 1993), were calculated for synthesized ligands and
their complexes and used as independent variables. Values
of selected molecular descriptors are presented in Table 2.
Since multi-target QSAR (mt-QSAR) models are better
in describing the antimicrobial activity, and therefore in
order to develop mt-QSAR models, initially we calculated
the average antibacterial, antifungal and antimicrobial
Table 2 Values of selected molecular descriptors used in QSAR study
S. No.
MR
1v
1vv
3v
3vv
j1
W
LUMO
HOMO
l
1
71.66
76.70
78.99
76.47
9.31
8.99
5.66
1.51
1.80
2.01
1.80
2.08
2.08
2.18
2.37
2.37
2.47
2.58
2.58
2.68
2.37
2.37
2.47
0.53
0.69
0.64
0.73
1.53
1.53
1.63
1.70
1.70
1.80
1.65
1.65
1.74
1.73
1.73
1.83
15.39
16.37
18.34
16.37
18.78
22.68
23.73
19.75
23.66
24.68
21.70
25.62
26.60
19.75
23.66
24.68
708.00
-0.88
-0.87
-1.19
-0.97
-0.86
-0.86
-0.76
-0.84
-0.85
-0.82
-1.50
-1.50
-1.44
-0.99
-0.99
-0.83
-8.60
-8.46
-9.29
-8.67
-8.52
-8.51
-8.70
-8.43
-8.43
-8.40
-9.08
-9.07
-9.03
-8.62
-8.61
-8.75
4.97
2
9.38
10.29
9.38
6.07
6.16
814.00
1068.00
814.00
4.56
10.90
6.29
2.55
2.64
8.03
2.42
2.53
7.56
7.79
7.82
7.83
3.25
3.36
8.01
3
4
6.17
5
11.48
13.48
15.57
11.87
13.87
15.96
12.78
14.78
16.87
11.87
13.87
15.96
10.56
12.56
12.32
10.97
12.97
12.73
11.06
13.06
12.82
11.07
13.07
12.82
1132.00
1766.00
2368.00
1273.00
1941.00
2573.00
1607.00
2351.00
3051.00
1273.00
1941.00
2573.00
6
11.17
12.48
9.78
7
8
9
11.63
12.95
12.95
12.95
13.09
9.81
10
11
12
13
14
15
16
11.66
12.97
123

Med Chem Res
Table 3 Correlation matrix for antibacterial activity
pMICab
MR
1v
1vv
3v
3vv
j1
W
LUMO
HOMO
l
pMICab
MR
1v
1vv
3v
1.000
-0.945
0.842
1.000
-0.762
-0.946
-0.791
-0.975
-0.760
-0.665
0.046
1.000
0.927
0.894
0.815
1.000
0.860
0.837
0.962
1.000
3vv
0.974
0.827
0.873
0.856
1.000
j1
0.813
0.975
0.913
0.822
0.745
1.000
W
0.760
0.987
0.830
0.788
0.968
-0.282
-0.183
0.224
1.000
LUMO
HOMO
l
-0.091
0.042
-0.159
-0.107
0.248
-0.090
0.085
-0.463
-0.267
0.177
-0.069
0.127
-0.231
-0.181
0.336
1.000
0.821
-0.164
0.273
1.000
-0.033
-0.126
-0.170
-0.474
-0.771
1.000
Table 4 Correlation of antibacterial, antifungal and antimicrobial
activity of the synthesized compounds with calculated molecular
descriptors
activity values of dehydroacetic acid-derived Schiff base
ligands and their organosilicon(IV) complexes which are
presented in Table 1. The correlation matrix for antibac-
terial activity is presented in Table 3. In general, high
colinearity (r [ 0.5) was observed between different
parameters. The high interrelationship was observed
between topological parameters, such as first-order
molecular connectivity index (1v) and Wiener index
(W) (r = 0.987), and low interrelationship was observed
for electronic parameter, energy of lowest unoccupied
molecular orbital (LUMO) and molar refractivity (MR)
(r = 0.046). Correlation of antibacterial, antifungal and
antimicrobial activities of 1–16 compounds with their
molecular descriptors is given in Table 4.
Descriptors
pMICab
pMICaf
pMICam
Cos E
MR
0v
0.563
-0.945
0.841
0.605
-0.927
0.872
0.591
-0.953
0.869
0vv
1v
0.911
0.952
0.945
0.842
0.873
0.870
1vv
2v
0.927
0.960
0.957
0.836
0.853
0.858
2vv
3v
0.951
0.957
0.970
0.860
0.800
0.849
3vv
0.974
0.949
0.980
Correlation matrix (Table 3) indicated that valence
third-order molecular connectivity index (3vv) was the most
dominating descriptor in describing the antibacterial
activity of synthesized ligands and their complexes. So,
QSAR model for antibacterial activity (Eq. 1) was devel-
j1
0.813
0.862
0.848
j2
0.730
0.821
0.782
j3
0.509
0.644
0.577
ja1
ja2
ja3
R
0.836
0.894
0.876
3
0.751
0.853
0.808
oped using vv.
0.531
0.668
0.600
0.842
0.873
0.870
LR-mt-QSAR model for antibacterial activity
J
-0.642
0.760
-0.591
0.806
-0.631
0.794
pMICab ¼ 0:9053vv À 0:086
ð1Þ
W
Te
-0.808
-0.852
0.853
-0.832
-0.893
0.896
-0.832
-0.884
0.887
n ¼ 16 r ¼ 0:974 q2 ¼ 0:936 s ¼ 0:103
Ee
F ¼ 259:85
Ne
Here and thereafter, n—number of data points, r—corre-
lation coefficient, q2—cross-validated r2 obtained by leave
one out method, s—standard error of the estimate and F—
Fischer statistics.
SA
IP
0.846
0.915
0.891
-0.042
-0.091
0.042
-0.092
-0.015
0.092
-0.064
-0.059
0.064
LUMO
HOMO
l
The coefficient of third-order molecular connectivity
index (3vv) was found to be high in QSAR model devel-
oped to describe the antibacterial activity (1), which indi-
-0.033
-0.111
-0.067
increase with increase in their vv values and vice versa.
The organosilicon complexes Ph2Si(LI–IV) have highest 3vv
values (1.63, 1.80, 1.74 and 1.83, Table 2) for ligands LI,
3
3
cated that there is a positive correlation between vv and
antibacterial activity of the compounds which means that
antibacterial activity values of synthesized compounds will
123

Med Chem Res
Table 5 Observed, predicted and residual antimicrobial activities
Comp.
pMICab
Obs.
pMICaf
Obs.
pMICam
Obs.
Pre.
Res.
0.02
Pre.
Res.
0.05
Pre.
Res.
0.06
1
0.41
0.44
0.58
0.57
1.24
1.30
1.55
1.36
1.22
1.66
1.49
1.35
1.49
1.58
1.44
1.58
0.39
0.54
0.49
0.57
1.30
1.30
1.39
1.45
1.45
1.54
1.40
1.40
1.49
1.48
1.48
1.57
0.56
0.44
0.63
0.62
1.44
1.66
1.55
1.46
1.52
1.71
1.19
1.70
1.74
1.63
1.69
2.03
0.52
0.59
0.60
0.60
1.34
1.68
1.64
1.41
1.75
1.70
1.42
1.76
1.72
1.43
1.76
1.72
0.47
0.44
0.60
0.59
1.32
1.44
1.55
1.40
1.34
1.68
1.37
1.49
1.59
1.60
1.54
1.76
0.41
0.57
0.52
0.60
1.36
1.36
1.45
1.52
1.52
1.61
1.47
1.47
1.56
1.55
1.55
1.64
2
-0.11
0.09
-0.15
0.03
-0.13
0.09
3
4
0.00
0.02
-0.01
-0.05
0.08
5
-0.06
0.00
0.10
6
-0.02
-0.09
0.05
7
0.16
0.09
8
-0.10
-0.23
0.12
-0.13
-0.18
0.07
9
-0.23
0.01
10
11
12
13
14
15
16
0.09
-0.23
-0.06
0.02
-0.10
0.02
-0.05
0.00
0.03
0.09
0.20
0.04
-0.04
0.01
-0.07
0.31
-0.01
0.12
1.6
1.4
1.2
1.0
.8
.3
.2
.1
-.0
-.1
.6
-.2
-.3
.4
.2
.4
.6
.8
1.0
1.2
1.4
1.6
1.8
.4
.6
.8
1.0
1.2
1.4
1.6
1.8
Observed pMICab
Observed pMICab
Fig. 1 Plot of observed pMICab against predicted pMICab by Eq. 1
Fig. 2 Plot of observed pMICab against residual pMICab by Eq. 1
LII, LIII and LIV, respectively, as compared to their coun-
terparts Bu2Si(LI–IV) and Et2Si(LI–IV), thereby indicating
Ph2Si(LI–IV) [7, 10, 13, 16] complexes have better
antibacterial activity.
and Tropsha, 2002). Developed model for antibacterial
activity expressed by this equation is also favoured by the
plot of predicted pMICab against observed pMICab (Fig. 1).
Further, the plot of observed pMICab versus residual pMICab
(Fig. 2) indicated that there was no systemic error in model
development as the propagation of error was observed on
both sides of zero (Kumar et al., 2007).
The developed QSAR model (1) was cross-validated by
q2 = 0.936 obtained by leave one out (LOO) method. The
value of q2 higher than 0.5 indicated that the model devel-
oped is a valid one also justified by closeness of observed
and predicted values (Table 5), the mt-QSAR model for
antibacterial activity given by (1) is a valid one (Golbraikh
Topological parameter, valence first-order molecular
connectivity index (1vv), was found to be the dominating
descriptor for the antifungal activity of 1–16 (Table 4).
123

Med Chem Res
n
LR-mt-QSAR model for antifungal activity
X
À
ÁÀ1=2
v ¼
ViVj
i ¼ 1
pMICaf ¼ 0:1681vv À 0:434
ð2Þ
i
n ¼ 16 r ¼ 0:960 q2 ¼ 0:902 s ¼ 0:146
where Vi and Vj are the degrees of adjacent vertices i and j,
and n is the number of vertices in a hydrogen suppressed
molecular structure (Lather and Madan, 2005). The topo-
logical index v signifies the degree of branching, connec-
tivity of atoms and unsaturation in the molecule, which
accounts for variation in activity (Mahiwal et al., 2012).
High value of q2 (0.948) as well as the low residual
values (Table 5) favoured the validity of QSAR model for
antimicrobial activity (3). Developed model expressed by
Eq. 3 also favoured by plot of predicted pMICam against
observed pMICam (Fig. 3). The plot of observed pMICam
vs residual pMICam (Fig. 4) indicated that there was no
systemic error in model development as the propagation of
error was observed on both sides of zero (Kumar et al.,
2007).
F ¼ 164:12
As in case of antibacterial activity, antifungal activity of 1–
1
16 is also positively correlated with their vv values which
means that the antifungal activity of 1–16 will increase
1
with increase in their vv values (Tables 2 and 3).
QSAR model for antifungal activity, i.e. Equation (2)
was cross-validated by q2 value (q2 = 0.902) obtained by
leave one out (LOO) method. Further, as the observed and
predicted values are close to each other (Table 5), the mt-
QSAR model for antifungal activity (Eq. 2) is a valid one
(Golbraikh and Tropsha, 2002).
Topological parameter valence third-order molecular
connectivity index (3vv) was found to be most effective in
describing antimicrobial activity of the synthesized com-
pounds (Table 4).
It was observed from the mt-QSAR models [Eq. 1–3]
that the antibacterial, antifungal and the overall antimi-
crobial activities of 1–16 were governed by topological
parameters, valence first- and third-order molecular con-
LR-mt-QSAR model for antimicrobial activity
nectivity indices (1vv and vv).
3
pMICam ¼ 0:9463vv À 0:0871
ð3Þ
Generally for QSAR studies, the biological activities of
compounds should span two to three orders of magnitude.
But in the present study, the range of antimicrobial activ-
ities of the synthesized compounds is within one order of
magnitude. This is in accordance with results (Bajaj et al.,
2005) where it is stated that the reliability of the QSAR
model lies in its predictive ability, even though the activity
data are in the narrow range. When biological activity data
lie in the narrow range, the presence of minimum standard
deviation of the biological activity justifies its use in QSAR
studies (Narasimhan et al., 2007). The minimum standard
n ¼ 16 r ¼ 0:980 q2 ¼ 0:948 s ¼ 0:094
F ¼ 338:52
Antimicrobial activity of 1–16 is positively correlated with
valence third-order molecular connectivity index (3vv)
which means that antimicrobial activity of the
synthesized compounds will increase with increase in
3
their vv values (Tables 1, 2). The molecular connectivity
index, and adjacency-based topological index proposed by
Randic, is denoted by v and is defined as sum over all the
edges (ij) as per following
1.8
1.6
1.4
1.2
1.0
.8
.2
.1
0.0
-.1
-.2
.6
.4
.4
.6
.8
1.0
1.2
1.4
1.6
1.8
.4
.6
.8
1.0
1.2
1.4
1.6
1.8
Observed pMICam
Observed pMICam
Fig. 3 Plot of observed pMICam against predicted pMICam by Eq. 3
Fig. 4 Plot of observed pMICam against residual pMICam by Eq. 3
123

Med Chem Res
Devi J, Batra N, Malhotra R (2012a) Ligational behavior of Schiff
bases towards transition metal ion and metalation effect on their
antibacterial activity. Spectrochim Acta A 97:397–405
deviation (Table 2) observed in the antimicrobial activity
data justifies its use in QSAR studies.
Devi J, Kumari S, Asijaa S, Malhotra
R (2012b) Synthetic,
spectroscopic, and biological aspects of triorganosilicon(IV)
complexes of tridentate Schiff bases. Phosphorus, Sulfur Silicon
Relat Elem 187(11):1409–1417
Conclusion
Devi J, Kumari S, Malhotra R (2012c) Synthesis, spectroscopic
studies, and biological activity of organosilicon(IV) complexes
of ligands derived from 2-aminobenzothiazole derivatives and
2-hydroxy-3-methoxy benzaldehyde. Phosphorus, Sulfur Silicon
Relat Elem 187(5):587–597
Dholakiya PP, Patel MN (2004) Metal Complexes: preparation,
magnetic, spectral, and biocidal studies of some mixed-ligand
complexes with Schiff bases containing NO and NN donor
atoms. Synth React Inorg Met-Org Chem 34:553–563
Golbraikh A, Tropsha A (2002) Beware of q2! J Mol Graph Model
20:269–276
Hansch C, Fujita T (1964) p–r–p analysis: a method for the
correlation of biological activity and chemical structure. J Am
Chem Soc 86:1616–1626
Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ (1973)
‘‘Aromatic’’ substituent constants for structure-activity correla-
tions. J Med Chem 16:1207–1216
In the present study, a series of 4-hydroxy-3-[1-{(2-hy-
droxy-aryl) imino}-ethyl]-6-methyl-pyran-2-one (1–4) and
their organosilicon(IV) complexes (5–16) was synthesized,
characterized and screened for its in vitro antimicrobial
activity and performed QSAR studies. Antimicrobial
studies showed that organosilicon(IV) complexes were
found to be more potent than their respective ligands, thus
exhibiting their broad spectrum nature and can become a
novel antimicrobial agent after further biological studies.
The QSAR studies of 1–16 reveal the importance of
topological parameters, valence first- and third-order
3
molecular connectivity indices (1vv and vv) in describing
the antibacterial and antifungal activity.
Hyperchem 6.0 (1993) Hypercube, Inc., Florida
Compliance with ethical standards
Jain M, Gaur S, Diwedi SC, Joshi SC, Singh RV, Bansal A (2004)
Nematicidal, insecticidal, antifertility, antifungal and antibacte-
rial activities of salicylanilide sulphathiazole and its manganese,
silicon and tin complexes. Phosphorus, Sulfur Silicon Relat Elem
179(8):1517–1537
Conflict of interest The authors declare that they have no conflict
of interest.
Human and animal rights statement This article does not contain
any studies with human participants or animals performed by any of
the authors.
Judge V, Narasimhan B, Ahuja M, Sriram D, Yogeeswari P, Clercq
ED, Pannecouque C, Balzarini J (2012) Isonicotinic acid
hydrazide derivatives: synthesis, antimicrobial activity and
QSAR studies. Med Chem Res 21:1451–1470
Informed consent Informed consent was obtained from all indi-
vidual participants included in the study.
Kier LB, Hall LH (1976) Molecular connectivity in chemistry and
drug research. Academic Press, NewYork
Kumar A, Narasimhan B, Kumar D (2007) Synthesis, antimicrobial,
and QSAR studies of substituted benzamides. Bioorgan Med
Chem 15:4113–4124
Kumar R, Kumar P, Kumar M, Narasimhan B (2012) Synthesis, anti-
microbial evaluation, and QSAR studies of 4-amino-3-hydroxy-
naphthalene-1-sulfonic acid derivatives. Med Chem Res
21:4301–4310
Lather V, Madan AK (2005) Topological models for the prediction of
anti-HIV activity of dihydro(alkylthio) (naphthylmethyl)oxopy-
rimidines. Bioorgan Med Chem 13:1599–1604
Mahiwal K, Kumar P, Narasimhan B (2012) Synthesis, antimicrobial
evaluation, ot-QSAR and mt-QSAR studies of 2-amino benzoic
acid derivatives. Med Chem Res 21:293–307
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