Synthesis, antimicrobial evaluation, and QSAR analysis of 2-isopropyl-5-methylcyclohexanol derivatives

Article abstract of DOI:10.1007/s00044-011-9550-3

A series of 2-isopropyl-5-methylcyclohexanol derivatives were synthesized and evaluated for their antibacterial activity against Gram-positive Staphylococcus aureus and Bacillus subtilis and Gram-negative Escherichia coli and in vitro antifungal activity against Candida albicans and Aspergillus niger. The results of antimicrobial activity demonstrated that the compounds 10, 20, and 21 were the most active ones among the synthesized compounds. The QSAR studies revealed the importance of dipole moment (μ), total energy (Te), and topological parameters (κ1 and κ3) in describing the antimicrobial activity of 2-isopropyl-5-methylcyclohexanol derivatives. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9550-3

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:511–522
DOI 10.1007/s00044-011-9550-3
ORIGINAL RESEARCH
Synthesis, antimicrobial evaluation, and QSAR analysis
of 2-isopropyl-5-methylcyclohexanol derivatives
•
Manjeet Singh Sunil Kumar Ashwani Kumar
•
•
•
Pradeep Kumar Balasubramanian Narasimhan
Received: 21 August 2010 / Accepted: 4 January 2011 / Published online: 22 January 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of 2-isopropyl-5-methylcyclohexanol
derivatives were synthesized and evaluated for their anti-
bacterial activity against Gram-positive Staphylococcus
aureus and Bacillus subtilis and Gram-negative Esche-
richia coli and in vitro antifungal activity against Candida
albicans and Aspergillus niger. The results of antimicrobial
activity demonstrated that the compounds 10, 20, and 21
were the most active ones among the synthesized com-
pounds. The QSAR studies revealed the importance of
dipole moment (l), total energy (Te), and topological
parameters (j1 and j3) in describing the antimicrobial
activity of 2-isopropyl-5-methylcyclohexanol derivatives.
Pneumocystis carinii pneumonia is the leading cause of
death in AIDS patients in North America and Europe
(Garcia-Domenech et al., 2003).
The number of cases of multidrug resistant bacterial
infections is increasing at an alarming rate. Clinicians have
to become reliant on few antimicrobial drugs available in
the market but that is not sufficient as microbial species are
getting resistant very fastly. In order to meet these chal-
lenges, there is need for the development of novel anti-
microbial drugs to which the microbes have never been
presented before (Emami et al., 2008).
2-Isopropyl-5-methylcyclohexanol (menthol) is obtained
from the dried leaves of Mentha piperata (peppermint) and
Mentha arvensis (Family-Labiatae) and by extraction from
other natural sources such as citronella java oil, spanish
pennyroyal oil, eucalyptus oil as well as from other plant
sources (Galeotti et al., 2002).
Keywords 2-Isopropyl-5-methylcyclohexanol esters ꢀ
Antimicrobial activity ꢀ QSAR
Introduction
2-Isopropyl-5-methylcyclohexanol has been reported to
possess wide variety of biological activities viz. Acaricidal
(Kim et al., 2008), acetyl cholinesterase inhibitor (Miyaz-
awa et al., 1997), anesthetic (Haeseler et al., 2002), anal-
gesic (Macpherson et al., 2006), antiacne (Miyazawa et al.,
1997), antiallergenic (Miyazawa et al., 1997), antiasth-
matic (Tamaoki et al., 1995), antibacterial (Kotan et al.,
2007), anticancer (Beck et al., 2007), antiepileptic (Garcia
et al., 2006), antifungal (Dambolena et al., 2008), anti-
inflammatory (Juergens et al., 1998), antimicrobial
(Trombetta et al., 2005), antioxidant (Mimica-Dukic et al.,
2003), antiplasmid (Schelz et al., 2006), antispasmodic
(Hawthorn et al., 1988), central nervous system stimulant
(Silva et al., 2007), hepatoprotective (Janbaz and Gilani
2002), immunomodulator (Sidell et al., 1991), and sedative
(Desousa et al., 2007) activities.
During the past two decades, the frequency of systemic
infection has increased dramatically along with the number
of invasive, mostly opportunistic, microbial species carry-
ing infectious diseases. Fungal infections are the important
cause of morbidity and mortality in hospitalized patients:
candidiasis is the fourth most common blood culture iso-
lates at US hospitals, pulmonary aspergillosis is the leading
cause of death in bone marrow transplant recipients, and
M. Singh ꢀ S. Kumar ꢀ A. Kumar
Department of Pharmaceutical Sciences, Guru Jambheswar
University of Science and Technology, Hisar 125001, India
P. Kumar ꢀ B. Narasimhan (&)
Faculty of Pharmaceutical Sciences,
Maharshi Dayanand University, Rohtak 124001, India
e-mail: naru2000us@yahoo.com
QSAR analysis applies statistical methods to describe
relationship between chemical structure and biological
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Med Chem Res (2012) 21:511–522
activities of a series of analogs quantitatively (Wang et al.,
2006). Quantitative structure–activity relationship has been
traditionally perceived as means of establishing correlation
between trends in chemical structure modification and the
respective changes of biological activity (Yao et al., 2004).
Thus, QSAR studies have a predictive ability and simul-
taneously provide deeper insight into the mechanism of
drug receptor interaction (Vasanthanthan et al., 2006).
In view of above and in continuation of our studies in
development of antimicrobial agents (Narasimhan et al.,
2003, 2004, 2006a, b, c, 2007a, b, c; Kumar et al., 2007;
Ohlan et al., 2007), we hereby report the synthesis, anti-
microbial activity, and QSAR studies of esters of 2-iso-
propyl-5-methylcyclohexanol (1–26).
into a separating funnel containing hexane (100 ml) and
was shaken vigorously. The hexane solution was washed
with aq. NaHCO3 solution and then water. After that the
mixture was dried over anhydrous MgSO4, filtered and the
solvent was removed under reduced pressure to yield the
esters.
Compound 1: IR (KBr pellets): cm-1 3050.00 (CH str.,
aromatic), 2955.77 (CH str., aliphatic), 1692.52 (CO str.,
ester), 1584.94 (COO- asymmetric str.), 1384.16 (COO-
1
symmetric str.); H NMR(CDCI3): d 7.40–7.53 (m, 5H,
Ar–H), 4.93–4.94 (m, 1H, C1 of 2-isopropyl-5-methylcy-
clohexanol), 2.15 (m, 1H, C2 of 2-isopropyl-5-methylcy-
clohexanol), 1.53–1.74 (m, 7H, C3–C6 of 2-isopropyl-5-
methylcyclohexanol), 1.01–1.05 (d, 9H, terminal CH3);
compound 7: IR (KBr pellets): cm-1 3080.00 (CH str.,
aromatic), 2956.83 (CH str., aliphatic), 1721.60 (CO str.,
a,b-unsaturated acid), 1591.59 (COO- asymmetric str.),
1384.06 (COO- symmetric str.), 743.46 (C–Cl str., Ar.-Cl);
1H NMR (DMSO): d 7.38–7.54 (m, 4H, Ar–Cl), 4.32–4.36
(m, 1H, C1 of 2-isopropyl-5-methylcyclohexanol), 2.17 (m,
1H, C2 of 2-isopropyl-5-methylcyclohexanol), 1.57–1.73
(m, 7H, C3–C6 of 2-isopropyl-5-methylcyclohexanol),
1.00–1.08 (d, 9H, terminal CH3); compound 10: IR (KBr
pellets): cm-1 3084.91 (CH str., aromatic), 2958.34 (CH str.,
aliphatic), 1735.44 (CO str., ester), 1592.61 (COO- asym-
metric str.), 1535.83 (NO2 asymmetric str., aromatic nitro
group), 1351.29 (COO- symmetric str.), 719.47 (C–C out of
plane bending, monosubstituted benzene); 1H NMR
(CDCI3): d 8.49–8.97 (m, 4H, Ar NO2), 4.44–4.46 (m, 1H,
C1 of 2-isopropyl-5-methylcyclohexanol), 2.18 (m, 1H, C2
of 2-isopropyl-5-methylcyclohexanol), 1.42–1.72 (m, 7H,
C6–C6 of 2-isopropyl-5-methylcyclohexanol), 1.01–1.09
(d, 9H, terminal CH3); compound 14: IR (KBr pellets): cm-1
3050.00 (CH str., aromatic), 2920.00 (CH str., aliphatic),
1670.00 (CO str., ester), 1521.35 (COO- asymmetric str.),
1384.03 (COO- symmetric str.), 1257.27 (COC str., Ara-
alkyl ether); 1H NMR(CDCI3): d 7.26–7.50 (m, 4H,
ArOCH3), 3.80 (s, 3H, OCH3), 1.23–2.29 (m, 8H, C2–C6 of
2-isopropyl-5-methylcyclohexanol), 1.01–1.09 (d, 9H, ter-
minal CH3); compound 15: IR (KBr pellets): cm-1 3095.30
(CH str., aromatic), 2956.66 (CH str., aliphatic), 1721.59
(CO str., ester), 1591.35 (COO- asymmetric str.), 1365.57
(COO- symmetric str.), 1226.44 (COC str., Araalkyl ether);
1H NMR(CDCI3): d 6.90–7.98 (m, 4H, ArOCH3), 3.88 (m,
1H, C1 of 2-isopropyl-5-methylcyclohexanol), 3.85 (s, 3H,
OCH3 of ArOCH3), 2.17 (m, 1H, C2 of 2-isopropyl-
5-methylcyclohexanol), 1.45–1.97 (m, 7H, C3–C6 of 2-iso-
propyl-5-methylcyclohexanol), 0.96–1.09 (d, 9H, terminal
CH3); compound 17: IR (KBr pellets): cm-1 3040.00 (CH
str., aromatic), 2956.46 (CH str., aliphatic), 1692.88 (CO str.,
ester), 1540.00 (COO- asymmetric str.), 1384.10 (COO-
symmetric str.), 695.52 (C–C out of plane bending, mono-
substituted benzene); 1H NMR(CDCI3): d 7.24–7.90 (m, 4H,
Experimental
Melting points (°C) were determined using Elico melting
point apparatus and are uncorrected. The FTIR spectra
were recorded in KBr pellets on Perkin Elmer IR spec-
trophotometer. 1H NMR was recorded on Bruker Avance II
400 NMR spectrophotometer using CDCl3 as a solvent and
TMS as an internal standard (chemical shift in d, ppm). The
purity of compounds was checked by thin layer chroma-
tography (TLC) on silica gel G plates. The spots were
detected by exposure to iodine vapors.
General procedure for synthesis of acid chloride
0.25 mol of acid with 0.35 mol of thionyl chloride were
taken in a 500-ml round-bottomed flask equipped with a
stir bar. Bubbles evolved out from the light yellow solution
immediately. The mixture was stirred at room temperature
for 10 min and then heated under reflux for 30 min, during
which time the mixture turned brown. Then the solution
was heated up to 80°C and stirred for 3 h. The excess
thionyl chloride was removed by distillation.
General procedure for synthesis of esters
of (1R,2S,5R)-2-isopropyl-5 methylcyclohexanol
(1–26)
0.25 mol of (-)-2-isopropyl-5-methylcyclohexanol dis-
solved in 90 ml of tetrahydrofuran and 2 ml of pyridine
were stirred to dissolve completely. Then acid chloride was
slowly dropped into the solution. The mixture was refluxed
for appropriate time and temperature until evolution of HCl
ceased. Reaction progress was monitored by TLC using a
9:1 hexane/acetone mobile phase solution, and visualiza-
tion of TLC plate was accomplished in iodine chamber. On
completion of reaction, the mixture leaving the pyridine
hydrochloride in the reaction vessel itself was transferred
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Med Chem Res (2012) 21:511–522
513
ArCH3), 2.39–2.41 (s, 3H, CH3 of ArCH3), 1.33–2.41
(m, 8H, C2–C6 of 2-isopropyl-5-methylcyclohexanol).
software for Windows (TSAR 3D Version 3.3, 2000).
Further, the regression analysis was performed using the
SPSS software package (SPSS for windows, Version 10.05,
1999).
Antimicrobial evaluation
Antibacterial assay
Cross-validation
A 24-h fresh culture was obtained by inoculation of
respective bacteria in double strength nutrient broth—IP,
followed by incubation at 37 1°C The stock solution of
synthesized 2-isopropyl-5-methylcyclohexanol derivatives
was serially diluted in tube containing 1 ml of sterile
double strength nutrient broth—IP (Pharmacopoeia of
India, 1996) to get a concentration of 50–0.78 lg/ml and
then inoculated with 100 ll of suspension (with a count of
105 cfu/ml) of respective microorganisms (Gram-positive
S. aureus MTCC 1430, B. subtilis MTCC 2423, Gram-
negative E. coli MTCC 739) in sterile saline. The inocu-
lated tubes were incubated at 37 1°C for 24 h, and
minimum inhibitory concentrations (MICs) were deter-
mined. From the observed MIC values, the exact MIC
values were determined by making suitable dilution of the
stock solution.
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 compounds and
Nth compound is predicted. Each compound is left out of
the model derivation and predicted in turn. An indication of
the performance is obtained from cross-validated (or pre-
dictive q2) method which is defined as
P
2
ðYpredicted ꢁ Yactual
Þ
q2 ¼ 1 ꢁ
;
P
2
ðYactual ꢁ Ymean
Þ
where Ypredicted, Yactual, and Ymean are the predicted, actual,
and mean values of target property (pMIC), respectively.
R(Ypredicted - Yactual)2 is the predictive residual error sum
of squares.
Results and discussion
Antifungal assay
The esters of 2-isopropyl-5-methylcyclohexanol were pre-
pared by the refluxing various aliphatic and aromatic
acid chlorides with 2-isopropyl-5-methylcyclohexanol as
depicted in the Scheme 1. The acid chlorides, in turn, were
prepared by the reaction of different acids with thionyl
chloride. The physicochemical properties and the elemen-
tal analyses for the synthesized compounds are presented in
Table 1. The purity of compounds was ascertained by
single spot TLC on silica gel G. The spectral character-
ization (IR and NMR) were found in agreement with the
assigned molecular structure.
The antifungal activity of synthesized 2-isopropyl-5-
methylcyclohexanol derivatives against the fungal species
C. albicans MTCC 227 and A. niger MTCC 2425 was
determined by serial dilution method similar to antibacte-
rial assay using Sabouraud dextrose broth—IP. The inoc-
ulated tubes were incubated at 37 1°C and 25 1°C for
a period of 2 and 7 days in case of C. albicans and A. niger,
respectively.
QSAR studies
The synthesized esters derivative of 2-isopropyl-5-
methylcyclohexanol have shown characteristic peaks in the
region 1721–1670 cm-1 corresponding to the C=O group
of ester. The IR bands corresponding to COO- asymmetric
stretching were present around 1592–1521 cm-1 and COO-
Data set is the set of molecules whose biological activity is
regressed with its molecular descriptor values. In the
present study, the synthesized 2-isopropyl-5-methylcyclo-
hexanol derivatives (1–26) are selected as data set.
Descriptor is any molecular property which is character-
istic of a molecule and can be utilized to determine new
QSAR. The number of descriptors selected for the present
study fell into four categories, viz. electronic, steric, lipo-
philic, and topological (Sharma et al., 2004; Randic, 1975;
Balaban, 1982; Wiener, 1947; Sortino et al., 2007)
(Table 3). The structure of 2-isopropyl-5-methylcyclohex-
anol derivatives was optimized by energy minimization.
The lowest energy structure was used for each molecule to
calculate the physicochemical parameters using TSAR 3.3
symmetric stretching were present at 1384–1351 cm-1
,
which confirmed the formation of ester linkage. The
presence of CH stretching at 2958–2920 cm-1 depicts the
existence of aliphatic alkyl groups in the synthesized
compounds, and IR bands at 3040–3095 cm-1 confirm the
existence of aromatic group in the synthesized compounds.
The IR band at 743.46 cm-1 corresponding to C–Cl
stretching confirms the presence of monochlorinated ben-
zene nucleus in compound 7. The presence of IR band at
1226.44 and 1257.27 cm-1 supports the existence of
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Med Chem Res (2012) 21:511–522
Scheme 1 General procedure
for synthesis of esters of
(1R,2S,5R)-2-isopropyl-5-
methyl cyclohexanol (1–26)
RCOOH
SOCl2
THF, Pyridine
RCOCl
+
O
OH
O
R
(1 - 26)
Comp.
Comp.
R
Comp.
R
R
NO2
1.
10.
19.
20.
21.
C
C
H
H
O2N
Br
2.
11.
NO2
C
H
C
H
O2N
Br
NO2
3.
4.
5.
12.
13.
14.
NO2
C
C
H
H
H3CO
Br
C
C
NO2
22.
23.
H
H
OCH3
Cl
CH3
Cl
6.
7.
15.
16.
24.
25.
26
CH2Cl
OCH3
H3C
CH2CH3
Cl
Cl
CH3
8.
9.
17.
18.
CHClCH3
Cl
O2N
CH3
methoxy group in compounds 15 and 14. The asymmetric
stretching band at 1535.83 cm-1 depicts the presence of
aromatic nitro group in compound 10 which was not seen
in all other synthesized compounds.
17 which confirms the attachment of aromatic acid with
2-isopropyl-5-methylcyclohexanol via an ester linkage.
These NMR and IR spectral characterization supports
the fact that acid groups were attached to the 2-isopropyl-
5-methylcyclohexanol through an ester linkage. Moreover,
the absence of signals at d 11.0 and 4.0 ppm confirms the
absence of any residual acid or 2-isopropyl-5-methylcy-
clohexanol in the synthesized compounds thus confirming
the completion of reaction.
The presence of signals at d 0.96–1.09 ppm reveals the
presence of terminal CH3 group in the synthesized 2-iso-
propyl-5-methylcyclohexanol derivatives. The multiplet
signals at d 7.24–7.90 ppm depict the presence of aromatic
phenyl nucleus in the synthesized derivatives. The presence
of singlet at d 3.80 and 3.85 ppm in compounds 14 and 15
depicts the presence of OCH3 group in the synthesized
compounds. A singlet at d 2.39–2.41 ppm supports the
presence of CH3 group on aromatic nucleus in compound
The synthesized esters were evaluated for their in vitro
antibacterial activity against Gram-positive Staphylococcus
aureus, Bacillus subtilis and Gram-negative Escherichia
coli and in vitro antifungal activity against Candida
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Med Chem Res (2012) 21:511–522
515
Table 1 Physicochemical characteristics of synthesized 2-isopropyl-5-methylcyclohexanol derivatives
Comp. Mol. formula M. Wt. MP/BP* (°C) Ref. value % Yield Elemental analyses
C (found)
H (found)
N (found)
O (found)
1
C17H24O2
260
339
339
339
295
295
295
330
305
305
305
350
290
290
290
274
274
274
286
331
331
331
198
233
212
247
54–56
0.34e
0.41c
0.38d
0.60a
0.51b
0.44c
0.47c
0.40d
0.52b
0.38e
0.42c
0.48a
0.30e
0.34d
0.42b
0.35c
0.36d
0.44a
0.52b
0.40e
0.45a
0.57a
0.27a
0.31a
0.38b
0.44a
65.3
54.2
56.3
57.8
57.6
61.6
64.4
47.8
68.8
59.6
70.8
50.2
51.7
46.8
48.9
53.2
54.7
56.9
57.3
53.7
51.3
56.7
58.5
50.6
46.2
38.8
78.42 (78.45) 9.29 (9.25)
60.18 (60.21) 6.83 (6.79)
–
–
–
–
–
–
–
–
12.29 (12.30)
9.43 (9.45)
2
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
17H23BrO2
17H23BrO2
17H23BrO2
17H23ClO2
17H23ClO2
17H23ClO2
17H22Cl2O2
17H23NO4
17H23NO4
17H23NO4
17H22N2O6
18H26O3
78–80
3
83–85
60.18 (6.22)
6.83 (6.80)
9.43 (9.43)
4
80–82
60.18 (60.14) 6.83 (6.85)
69.26 (69.29) 7.86 (7.83)
69.26 (69.27) 7.86 (7.85)
69.26 (69.24) 7.86 (7.88)
62.01 (61.05) 6.73 (6.79)
66.86 (66.82) 7.59 (7.64)
66.86 (66.89) 7.59 (7.64)
66.86 (66.82) 7.59 (7.57)
58.28 (58.32) 6.33 (6.36)
74.45 (74.41) 9.02 (9.05)
74.45 (74.43) 9.02 (8.97)
74.45 (74.39) 9.02 (9.07)
78.48 (78.52) 9.55 (9.57)
78.48 (78.46) 9.55 (9.53)
78.48 (78.50) 9.55 (9.49)
79.68 (79.64) 9.15 (9.11)
68.86 (68.81) 7.60 (7.63)
68.86 (68.82) 7.60 (7.56)
68.86 (68.81) 7.60 (7.62)
72.68 (72.61) 11.18 (11.15)
61.93 (61.96) 9.09 (9.07)
73.54 (73.54) 11.39 (11.36)
63.27 (63.29) 9.39 (9.42)
d
9.43 (9.40)
5
90–92
10.85 (10.82)
10.85 (10.84)
10.85 (10.87)
9.72 (9.69)
6
95–97
7
92–94
8
101–103
68–70
9
4.59 (4.56) 20.96 (20.91)
4.59 (4.62) 20.96 (20.91)
4.59 (4.55) 20.96 (20.92)
8.00 (7.95) 27.40 (27.35)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
63–65
62–64
66–68
78–80
–
–
–
–
–
–
–
16.53 (16.56)
16.53 (16.59)
16.53 (16.51)
11.66 (11.71)
11.66 (11.61)
11.66 (11.61)
11.17 (11.12)
18H26O3
81–83
18H26O3
76–78
18H26O2
73–75
18H26O2
68–70
18H26O2
65–67
19H26O2
37–39
19H25NO4
19H25NO4
19H25NO4
12H22O2
49–51
4.23 (4.26) 19.31 (19.27)
4.23 (4.25) 19.31 (19.36)
4.23 (4.21) 19.31 (19.28)
84–86
92–94
102–104*
106–108*
104–106*
113–115*
–
–
–
–
16.14 (16.10)
13.75 (13.80)
15.07 (15.06)
12.97 (12.94)
e
12H21ClO2
13H24O2
13H23ClO2
a
b
c
TLC mobile phase: hexane:ethyl acetate (9:1); hexane:acetone (9:1); chloroform:acetone (8.5:1.5); hexane:ethyl acetate (4:1); tolu-
ene:chloroform (7:3)
1. The presence of electron withdrawing group like nitro
increases the antimicrobial potential of synthesized
compounds which is clearly evident from the high-
antimicrobial activity of compounds 10, 11, 12, 20, 21,
and 22. The importance of electron withdrawing group
in the increasing antimicrobial activity is similar to the
results obtained by Sharma et al. (2004).
albicans and Aspergillus niger. MIC was determined by
serial dilution method (Shadomy and Espinel, 1980).
The results of antimicrobial study are presented in
Table 2. The compounds 10, 11, 12, 20, and 21 showed
significant activity against S. aureus with pMICsa values
2.29, 2.29, 2.35, 2.33, and 2.33, respectively. Further the
compounds 18, 19, and 22 were found to be more active
against B. subtilis having pMICbs values more than 2.09 in
comparison to other synthesized derivatives. Compounds 9,
10, 20, and 22 were found to be highly active against
E. coli with pMICec value more than 2.28. Further in case
of C. albicans, compounds 10, 20, 21, and 22 showed
highest pMIC value (pMICca = 2.33) in comparison to
other synthesized derivatives. Compounds 10, 20, and 21
were found to be more active against A. niger having
pMICan more than 2.28.
2. The 2-isopropyl-5-methylcyclohexanol esters derived
from aromatic carboxylic acids were found to be more
active than derivatives obtained from aliphatic car-
boxylic acids which can be evidenced from low pMIC
values of aliphatic esters (23, 24, 25, and 26) Table 2.
This may be probably due to the involvement of
aromatic nucleus with the target binding site which is
similar to the results of our previous study (Narasim-
han et al., 2007a).
3. The derivative obtained by esterification of cinnamic
acid were found to be more active as compared to
From the above results the following structure–activity
relationship can be deduced:
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Med Chem Res (2012) 21:511–522
synthesized compounds, QSAR studies were undertaken
using linear free energy relationship (LFER) model of
Hansch and Fujita 1964). Biological activity data deter-
mined as MIC value were first transformed to pMIC on
molar basis, which was used as dependent variable in
QSAR studies. These were correlated with different
molecular descriptor like log of octanol–water partition
coefficient (log P), molar refractivity(MR), Kier’s molec-
ular connectivity (v) and shape (j1, ja1) topological indi-
ces, Randic topological index (R), Balaban topological
index (J), Wiener topological index (W), Total energy (Te),
energy of highest occupied molecular orbital (HOMO) and
lowest unoccupied molecular orbital (LUMO), and dipole
moment (l) (Hansch et al., 1973; Kier and Hall, 1976;
Randic, 1975, 1993; Balaban, 1982; Wiener, 1947). The
values of selected descriptors used in regression analysis
are presented in Table 3.
Table 2 Antimicrobial activity of synthesized 2-isopropyl-5-
methylcyclohexanol derivatives
Comp.
pMICsa
pMICbs
pMICec
pMICca
pMICan
1
1.92
2.04
1.96
1.98
1.97
1.97
1.88
2.02
1.99
2.29
2.29
2.35
2.06
1.97
2.01
1.94
2.05
1.85
1.96
2.33
2.33
2.03
1.50
2.00
1.75
1.60
0.22
2.61*
2.01
2.04
1.96
2.04
1.91
1.97
1.97
1.96
2.03
1.99
2.02
2.05
1.98
1.99
2.01
1.94
2.02
2.10
2.26
2.03
2.03
2.33
1.80
1.86
1.88
1.90
0.11
2.61*
2.01
1.98
1.88
2.02
2.10
1.88
1.67
2.02
2.29
2.29
1.99
2.35
1.97
1.97
1.98
2.01
1.93
1.90
1.96
2.33
2.14
2.33
1.50
1.79
1.75
1.90
0.21
2.61*
1.92
2.04
2.04
1.85
1.97
1.97
1.67
1.72
2.29
2.33
2.29
2.05
1.97
1.97
1.67
1.64
1.94
1.94
1.96
2.33
2.33
2.33
1.80
1.87
1.83
1.90
0.22
2.64**
1.92
2.04
2.04
2.04
2.10
1.97
2.05
1.95
2.17
2.29
2.18
2.05
2.07
2.11
2.04
1.94
2.03
2.04
2.01
2.33
2.33
2.18
1.98
2.17
2.13
1.90
0.12
2.64**
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
SD
Std.
In the present study, a set of 2-isopropyl-5-methylcy-
clohexanol derivatives (1–26) were used for linear regres-
sion model generation. The reference drugs were not
included in model generation as they belong to different
structural series. Preliminary analysis was carried out in
terms of correlation analysis.
A correlation matrix constructed for antifungal activity
of synthesized 2-isopropyl-5-methylcyclohexanol deriva-
tives against C. albicans is presented in Table 4. In general,
the parameters showed high colinearity (r [ 0.700). The
data presented in Table 5 demonstrated the correlation of
molecular descriptors of different substituted esters with
their corresponding antimicrobial activity. Generally, good
correlation was observed with dipole moment (l) in case of
C. albicans (Eq. 1).
SD standard deviation
* Norfloxacin, ** Fluconazole
QSAR model for antifungal activity against C. Albicans
pMICca ¼ 0:121l þ 1:609
ð1Þ
derivative obtained by esterification with benzoic acid
which may be due to the presence of an extra
unsaturation in the molecule containing cinnamic acid
derivatives. The above results are summarized in
Fig. 1.
n = 26, r = 0.906, r2 = 0.820, q2 = 0.788, F = 109.85,
s = 0.093.
Here and thereafter n is the number of data points,
r correlation coefficient, r2 squared correlation, q2 cross-
validated r2 obtained by LOO method, s standard error of
estimation, and F Fischer ratio.
In an attempt to determine the role of structural features
which appear to influence the antimicrobial activity of
The antifungal activity of synthesized 2-isopropyl-5-
methylcyclohexanol ester against C. albicans is positively
correlated to the dipole moment (l). The coefficient of
dipole moment in Eq. 1 is positive which signifies that the
activity of synthesized compounds will increase with
increase in value of dipole moment. This is evidenced by
the antifungal activity data of 2-isopropyl-5-methylcyclo-
hexanol esters (Table 2.) and their l values (Table 3).
Compounds 20 and 21 have highest l values 6.54 and 6.30
(Table 3.), respectively, and have maximum antifungal
Essential for antimicrobial activity
R = Aliphatic - Low antimicrobial activity
R
O
R = Aromatic - Appreciable antimicrobial
activity
O
R = Ar-NO - High antimicrobial activity
2
Fig. 1 SAR for antimicrobial activity of synthesized 2-isopropyl
methylcyclohexanol derivatives
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Med Chem Res (2012) 21:511–522
517
Table 3 Values of selected molecular descriptors used in regression analysis
Comp.
log P
MR
j1
j2
j3
ja1
ja2
ja3
Te
l
1
4.82
5.61
5.61
5.61
5.34
5.34
5.34
5.86
4.78
4.78
4.78
4.73
4.57
4.57
4.57
5.29
5.29
5.29
5.23
5.18
5.18
5.18
2.91
3.50
3.54
4.04
76.77
84.39
84.39
84.39
81.57
81.57
81.57
86.38
84.09
84.09
84.09
91.42
83.23
83.23
83.23
81.81
81.81
81.81
87.01
94.34
94.34
94.34
56.60
61.35
61.22
65.84
15.39
16.37
16.37
16.37
16.37
16.37
16.37
17.36
18.34
18.34
18.34
21.30
17.36
17.36
17.36
16.37
16.37
16.37
17.36
20.31
20.31
20.31
12.07
13.07
13.07
14.06
7.14
7.32
7.32
7.32
7.32
7.32
7.32
7.51
8.20
8.20
8.20
9.27
8.02
8.02
8.02
7.32
7.32
7.32
8.59
9.63
9.63
9.63
5.19
5.92
5.92
6.07
4.23
4.25
4.50
4.50
4.25
4.50
4.50
4.49
4.75
5.00
5.00
5.49
4.49
4.73
4.73
4.25
4.50
4.50
5.61
6.05
6.35
6.35
3.59
3.81
3.81
4.08
14.26
15.71
15.71
15.71
15.53
15.53
15.53
16.79
16.77
16.77
16.77
19.30
16.19
16.19
16.19
15.24
15.24
15.24
15.97
18.49
18.49
18.49
11.70
12.99
12.70
13.98
6.33
6.86
6.86
6.86
6.73
6.73
6.73
7.13
7.11
7.11
7.11
7.90
7.19
7.19
7.19
6.53
6.53
6.53
7.56
8.31
8.31
8.31
4.92
5.86
5.64
6.02
3.66
3.93
4.16
4.16
3.84
4.07
4.07
4.21
4.00
4.22
4.22
4.53
3.92
4.14
4.14
3.71
3.93
3.93
4.82
5.07
5.34
5.34
3.38
3.76
3.60
4.03
-3149.45
-3488.84
-3489.03
-3489.03
-3509.37
-3509.52
-3509.54
-3869.44
-3980.03
-3980.24
-3980.23
-4810.65
-3625.15
-3625.27
-3625.34
-3305.25
-3305.32
-3305.33
-3432.64
-4263.30
-4263.45
-4263.46
-2482.54
-2842.52
-2638.34
-2998.24
2.16
2.47
2.70
1.65
2.73
2.78
1.63
2.21
4.73
6.74
4.93
4.33
2.69
3.40
1.72
1.68
2.08
2.63
2.02
6.54
6.30
4.94
1.84
2.07
1.65
2.15
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Table 4 Correlation matrix for antifungal activity of 2-isopropyl-5-methylcyclohexanol derivatives against C. albicans
pMICca
log P
MR
j1
j2
j3
ja1
ja2
ja3
Te
l
pMICca
log P
MR
j1
1.000
0.128
0.488
0.624
0.638
0.676
0.592
0.593
0.614
-0.611
0.906
1.000
0.793
0.548
0.520
0.397
0.590
0.580
0.397
-0.513
0.123
1.000
0.931
0.925
0.815
0.938
0.936
0.752
-0.881
0.553
1.000
j2
0.976
0.890
0.991
0.958
0.802
-0.977
0.732
1.000
j3
0.943
0.958
1.000
ja1
ja2
ja3
Te
0.870
0.929
1.000
0.982
0.963
0.809
1.000
0.863
0.966
0.892
-0.913
0.670
1.000
-0.919
0.720
-0.819
0.736
-0.983
0.702
-0.746
1.000
-0.735
l
0.658
1.000
activity against C. albicans having pMICca value of 2.33
and 2.33, respectively. Compounds 7 and 16 have mini-
mum l values 1.63 and 1.68, respectively, and have min-
imum antifungal activity with pMICca 1.67 and 1.64,
respectively, which supports the positive correlation of
dipole moment (l) with antifungal activity of synthe-
sized 2-isopropyl-5-methylcyclohexanol esters against
C. albicans.
The importance of dipole moment (l) in the modulating
antifungal activity against C. albicans may be due to the
123

518
Med Chem Res (2012) 21:511–522
2.5
2.4
2.3
2.2
2.1
2.0
1.9
1.8
Table 5 Correlation of molecular descriptors with antimicrobial
activity of 2-isopropyl-5-methylcyclohexanol derivatives
Parameter
pMICsa
pMICbs
pMICec
pMICca
pMICan
log P
MR
0v
0vv
1v
1vv
2v
2vv
3v
0.415
0.736
0.811
0.712
0.790
0.698
0.790
0.573
0.731
0.192
0.816
0.782
0.689
0.821
0.782
0.628
0.790
-0.531
0.791
-0.833
-0.797
-0.047
0.716
0.502
0.707
0.650
0.625
0.675
0.650
0.649
0.546
0.464
0.156
0.659
0.725
0.756
0.642
0.722
0.731
0.675
-0.635
0.697
-0.560
-0.617
0.283
0.324
0.419
0.754
0.844
0.707
0.817
0.697
0.820
0.588
0.752
0.218
0.855
0.821
0.725
0.851
0.807
0.647
0.817
-0.492
0.823
-0.854
-0.820
-0.110
0.742
0.128
0.488
0.595
0.395
0.567
0.395
0.576
0.279
0.553
-0.027
0.624
0.638
0.676
0.592
0.593
0.614
0.567
-0.318
0.643
-0.611
-0.642
-0.340
0.906
-0.034
0.355
0.466
0.265
0.442
0.262
0.422
0.089
0.383
-0.250
0.506
0.549
0.592
0.478
0.520
0.553
0.442
-0.204
0.540
-0.491
-0.452
-0.281
0.821
1.7
1.6
3vv
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
j1
Observed pMICca
j2
Fig. 2 Plot of predicted pMICca activity values against the experi-
mental pMICca values for the linear regression developed model by
Eq. 1
j3
ja1
ja2
ja3
R
.2
.1
B
W
Te
LUMO
HOMO
l
0.0
-.1
-.2
presence of carbonyl group (C?–O-) where permanent
polarization is seen due to electro negativity difference
between the atoms. The carbonyl oxygen of 2-isopropyl-
5-methylcyclohexanol esters may involve in making fruit-
ful binding interaction with amino acid present at the target
site, through hydrogen bonding. The molecular property
dipole moment (l) thus plays an important role in modu-
lating antifungal profile of synthesized 2-isopropyl-
5-methylcyclohexanol esters (Pillai et al., 2005).
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
Observed pMICca
Fig. 3 Plot of residual pMICca values against the experimental
pMICca values
To determine the existence of systemic error in the
model development, we have plotted pMICca observed
against pMICca residual values (Fig. 3). The propagation of
residuals on both sides of zero indicated that there is
no systemic error in development of QSAR models
(Heravi and Kyani, 2005). The QSAR models presented in
Eqs. 2–5 are developed to predict the antimicrobial activ-
ity of 2-isopropyl-5-methylcyclohexanol esters against
A. niger, S. aureus, B. subtilis, and E. coli, respectively.
The QSAR model expressed by Eq. 1 was cross vali-
dated by its high q2 value (q2 = 0.788) obtained by LOO
method (Tetko et al., 2001). It is noteworthy to mention
here that the entire data set (n = 26) was used for the
generation of QSAR models as no outliers were seen in the
study. The q2 value of Eq. 1 (q2 = 0.788; q2 [ 0.5) qual-
ifies it to be a valid model according to the recommenda-
tion of Golbraikh and Trophsa (2002). In order to confirm
our results, we have predicted antifungal activity of syn-
thesized 2-isopropyl-5-methylcyclohexanol esters against
C. albicans using Eq. 1. The comparison of the observed
and predicted values (Table 7; Fig. 2) demonstrated that
they are close to each other which is evident from their
low-residual values.
QSAR model for antifungal activity against A. Niger
pMICan ¼ 0:059l þ 1:894
ð2Þ
n = 26, r = 0.821, r2 = 0.674, q2 = 0.625, F = 49.69,
s = 0.068.
123

Med Chem Res (2012) 21:511–522
519
QSAR model for antifungal activity against S. Aureus
pMICsa ¼ ꢁ0:003Te þ 0:764
Table 6 Observed and predicted antibacterial activities of synthe-
sized 2-isopropyl-5-methylcyclohexanol derivatives using best QSAR
models
ð3Þ
n = 26, r = -0.833, r2 = 0.693, q2 = 0.627, F = 54.23,
s = 0.123.
Comp. pMICsa
Obs. Pre. Res.
pMICbs
pMICec
Obs. Pre. Res.
Obs. Pre. Res.
1
1.92 1.85
2.04 1.96
1.96 1.96
1.98 1.96
1.97 1.97
1.97 1.97
0.07 2.01 1.95 -0.06 2.01 1.88
0.08 2.04 1.95 0.09 1.98 1.95
0.13
0.03
QSAR model for antifungal activity against B. Subtilis
2
pMICbs ¼ 0:114j3 þ 1:461
ð4Þ
3
0.00 1.96 1.98 -0.02 1.88 1.95 -0.07
n = 26, r = 0.756, r2 = 0.572, q2 = 0.398, F = 32.07,
s = 0.073.
4
0.02 2.04 1.98
0.06 2.02 1.95
0.07
0.15
5
0.00 1.91 1.95 -0.04 2.10 1.95
6
0.00 1.97 1.98 -0.01 1.88 1.95 -0.07
7
1.88 1.97 -0.09 1.97 1.98 -0.01 1.67 1.95 -0.28
2.02 2.09 -0.07 1.96 1.97 -0.01 2.02 2.03 -0.01
QSAR model for antifungal activity against E. Coli
8
pMICec ¼ 0:114j1 þ 0:671
ð5Þ
9
1.99 2.13 -0.14 2.03 2.00
0.03 2.29 2.11
0.18
0.18
n = 26, r = 0.855, r2 = 0.730, q2 = 0.686, F = 65.07,
s = 0.109.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2.29 2.13
2.29 2.13
0.16 1.99 2.03 -0.04 2.29 2.11
0.16 2.02 2.03 -0.01 1.99 2.11 -0.12
0.01
0.01 1.97 2.03 -0.06
1.97 2.01 -0.04 1.99 2.00 -0.01 1.97 2.03 -0.06
The antifungal activity of synthesized 2-isopropyl-5-
methylcyclohexanol esters against A. niger was correlated
with the dipole moment (l). As in case of C. albicans, here
also a positive correlation was observed between the
molecular descriptor (l) and antifungal activity against
A. niger (Eq. 2). In case of antibacterial activity against
S. aureus, an inverse relationship was observed between
antibacterial activity of synthesized 2-isopropyl-5-methyl-
cyclohexanol esters and total energy (Te) of the molecule
(Eq. 3). This is evidenced by low Te values (-4263.30 and
-4263.45) of compounds 20 and 21 and high pMICsa
values (2.33 and 2.33), respectively.
2.35 2.42 -0.07 2.05 2.09 -0.04 2.35 2.34
2.06 2.01 0.05 1.98 1.97
2.01 2.01
1.94 1.90
2.05 1.90
0.00 2.01 2.00
0.01 1.98 2.03 -0.05
0.06
0.04 1.94 1.95 -0.01 2.01 1.95
0.15 2.02 1.98
0.04 1.93 1.95 -0.02
0.12 1.90 1.95 -0.05
0.16 1.96 2.03 -0.07
1.85 1.90 -0.05 2.10 1.98
1.96 1.94
2.33 2.23
2.33 2.23
0.02 2.26 2.10
0.10 2.03 2.15 -0.12 2.33 2.26
0.10 2.03 2.19 -0.16 2.14 2.26 -0.12
0.14 2.33 2.26 0.07
1.50 1.62 -0.12 1.80 1.87 -0.07 1.50 1.62 -0.12
0.07
2.03 2.23 -0.20 2.33 2.19
The total energy calculated by semiempirical methods
can be used as a measure of non-specific interaction of drug
with its target site, i.e., the total energies of the protonated
and neutral forms of molecule can be considered as good
measure of the strength of hydrogen bonds (the higher the
energy, the stronger the bond) and can be used to determine
correct localization of most favorable hydrogen bond
acceptor site (Karelson et al., 1996).
2.00 1.74
1.75 1.67
0.26 1.86 1.90 -0.04 1.79 1.70
0.08 1.88 1.90 -0.02 1.75 1.70
0.10
0.06
0.13
1.60 1.79 -0.19 1.90 1.93 -0.03 1.90 1.77
Trophsa (2002) who have recently reported that the only
way to estimate the true predictive power of model is to
test their ability to predict accurately the biological activ-
ities of compound. As the observed and predicted values
are close to each other, the QSAR model for B. subtilis
(Eq. 4) is valid one. In order to confirm the validity of all
the developed QSAR models, we have predicted the anti-
microbial activity of all the synthesized compounds using
the models expressed by Eqs. 2 to 5 and compared them
with observed values (Tables 6, 7; Figs. 4, 5, 6, 7).
The negative correlation of total energy of molecule
with antibacterial activity against S. aureus indicated that
the increase in the total energy of the molecule will
decrease the antibacterial activity against S. aureus of
the synthesized 2-isopropyl-5-methylcyclohexanol esters
which is evidenced by antibacterial activity (Table 2) and
total energy values (Table 3).
The antibacterial activity against B. subtilis and E. coli
was best correlated with topological parameter j (Table 5).
The positive correlation of j with antibacterial activity
indicated that the antibacterial potential will increase with
increase in j values. The antibacterial model against
B. subtilis has the q2 value less than 0.5 (q2 = 0.398)
which indicated that the developed model is invalid one as
it fails to meet the requirement of q2 [ 0.5. However, one
should not forget the recommendation of Golbraikh and
Even though the sample size and the ‘‘Rule of Thumb’’
(Narasimhan et al., 2006c) allowed us to go for the
development of penta-parametric model in multiple linear
regression analysis, the high interrelationship among the
parameters restricted us for mono-parametric model. The
multi-colinearity occurs when two independent variables
are correlated with each other. One should note that the
change in signs of the coefficients, a change in the values
123

520
Med Chem Res (2012) 21:511–522
2.6
2.4
2.2
2.0
Table 7 Observed and predicted antifungal activities of synthesized
2-isopropyl-5-methylcyclohexanol derivatives using best QSAR
models
Comp.
pMICca
Obs.
pMICan
Obs.
Pre.
Res.
0.05
Pre.
Res.
1
1.92
2.04
2.04
1.85
1.97
1.97
1.67
1.72
2.29
2.33
2.29
2.05
1.97
1.97
1.67
1.64
1.94
1.94
1.96
2.33
2.33
2.33
1.80
1.87
1.83
1.90
1.87
1.91
1.94
1.81
1.94
1.95
1.81
1.88
2.18
2.43
2.21
2.13
1.94
2.02
1.82
1.81
1.86
1.93
1.85
2.40
2.37
2.21
1.83
1.86
1.81
1.87
1.92
2.04
2.04
2.04
2.10
1.97
2.05
1.95
2.17
2.29
2.18
2.05
2.07
2.11
2.04
1.94
2.03
2.04
2.01
2.33
2.33
2.18
1.98
2.17
2.13
1.90
2.02
2.04
2.06
1.99
2.06
2.06
1.99
2.03
2.18
2.30
2.19
2.15
2.05
2.10
2.00
1.99
2.02
2.05
2.01
2.28
2.27
2.19
2.00
2.02
1.99
2.02
-0.10
0.00
2
0.13
0.10
3
-0.02
0.05
4
0.04
5
0.03
0.04
1.8
1.6
6
0.02
-0.09
0.06
7
-0.14
-0.16
0.11
8
-0.08
-0.01
-0.01
-0.01
-0.10
0.02
1.5
1.6
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
Observed pMICsa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
-0.10
0.08
Fig. 5 Plot of predicted pMICsa activity values against the experi-
mental pMICsa values for the linear regression developed model by
Eq. 3
-0.08
0.03
-0.05
-0.15
-0.17
0.08
0.01
0.04
2.2
2.1
2.0
1.9
1.8
-0.05
0.01
0.01
-0.01
0.00
0.11
-0.07
-0.04
0.12
0.05
0.06
-0.01
-0.02
0.15
-0.03
0.01
0.02
0.14
0.03
-0.12
1.7
1.8
1.9
2.0
2.1
2.2
2.3
2.4
2.4
Observed pMICbs
Fig. 6 Plot of predicted pMICbs activity values against the experi-
mental pMICbs values for the linear regression developed model by
Eq. 4
2.3
2.2
2.1
2.0
1.9
of previous coefficient, change of significant variable into
insignificant one or an increase in standard error of the
estimate on addition of an additional parameter to the
model are indications of high interrelationship among
descriptors (Narasimhan et al., 2006c).
Generally for QSAR studies, the biological activities of
compounds should span 2–3 orders of magnitude. How-
ever, in the present study, the range of antimicrobial
activities of the synthesized compounds is within one
order of magnitude. However, it is important to note that
the predictability of the QSAR models developed in the
1.8
1.9
2.0
2.1
2.2
2.3
2.4
Observed pMICan
Fig. 4 Plot of predicted pMICan activity values against the experi-
mental pMICan values for the linear regression developed model by
Eq. 2
123

Med Chem Res (2012) 21:511–522
521
2.4
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