Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents

Article abstract of DOI:10.1016/j.bmcl.2011.10.057

In the present investigation, a series of 1,5-dimethyl-2-phenyl-4-{[(5- aryl-1,3,4-oxadiazol-2-yl)methyl]amino}-1,2-dihydro-3H-pyrazol-3-one were subjected to molecular properties prediction, drug-likeness by Molinspiration (Molinspiration, 2008) and MolSoft (MolSoft, 2007) software, lipophilicity and solubility parameters using ALOGPS 2.1 program. The compounds followed the Lipinski 'Rule of five' were synthesized for antimicrobial and antitubercular screening as oral bioavailable drugs/leads. Maximum drug-likeness model score (0.95) was found for compound, 4a. All the synthesized compounds were characterized by IR, NMR and mass spectral analysis followed by antimicrobial and antimycobacterial screening. Among the title compounds, compound 4d showed pronounced activity against Mycobacterium tuberculosis H₃₇Rv and isoniazid resistant M. tuberculosis (INHR-TB) with minimum inhibitory concentrations (MICs) 0.78 μM and 1.52 μM, respectively. The compound, 4a showed maximum activity against all bacterial strains with MIC 4-8 μg/mL comparable to standard drug ciprofloxacin, while the compounds, 4e and 4k showed maximum antifungal activity with MIC 8-16 μg/mL less active than standard drug fluconazole.

Full text of DOI:10.1016/j.bmcl.2011.10.057

Bioorganic & Medicinal Chemistry Letters 21 (2011) 7246–7250
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole
analogues as potent antimicrobial and antitubercular agents
Mohamed Jawed Ahsan a,b, , Jeyabalan Govinda Samy a, Habibullah Khalilullah a, Md. Shivli Nomani a,
⇑
Pankaj Saraswat a, Ramakant Gaur a, Abhimanyu Singh a
a New Drug Discovery Research, Department of Medicinal Chemistry, Alwar Pharmacy College, Alwar, Rajasthan 301 030, India
b Department of Pharmaceutical Sciences, National Institute of Medical Sciences University, Jaipur 303 121, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 July 2011
Revised 14 September 2011
Accepted 17 October 2011
Available online 20 October 2011
In the present investigation, a series of 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl)methy-
l]amino}-1,2-dihydro-3H-pyrazol-3-one were subjected to molecular properties prediction, drug-
likeness by Molinspiration (Molinspiration, 2008) and MolSoft (MolSoft, 2007) software, lipophilicity
and solubility parameters using ALOGPS 2.1 program. The compounds followed the Lipinski ‘Rule of five’
were synthesized for antimicrobial and antitubercular screening as oral bioavailable drugs/leads.
Maximum drug-likeness model score (0.95) was found for compound, 4a. All the synthesized compounds
were characterized by IR, NMR and mass spectral analysis followed by antimicrobial and antimycobacte-
rial screening. Among the title compounds, compound 4d showed pronounced activity against Mycobac-
terium tuberculosis H37Rv and isoniazid resistant M. tuberculosis (INHR-TB) with minimum inhibitory
Keywords:
Oxadiazoles
Antimicrobial agents
Antitubercular agents
Molecular properties prediction
Lipinski ‘Rule of five’
concentrations (MICs) 0.78
lM and 1.52
l
M, respectively. The compound, 4a showed maximum activity
g/mL comparable to standard drug ciprofloxacin, while the
against all bacterial strains with MIC 4–8
l
compounds, 4e and 4k showed maximum antifungal activity with MIC 8–16 lg/mL less active than
standard drug fluconazole.
Ó 2011 Elsevier Ltd. All rights reserved.
The pathogenic agent of tuberculosis (TB), Mycobacterium
tuberculosis (MTB) is responsible for death of 2–3 million people
annually.1 There are estimated 1.3 million multi/extensively drug
resistant TB (M/XDR-TB) cases will need to be treated between
2010 and 2015.2 Antibacterial resistance is a cause of increased
mortality.3 Fungal infections like Candidiasis, Crytococcosis and
Aspergillosis are more common in immuno-compromised
patients.4 Life threatening infectious disease caused by multi-
drug-resistant pathogenic bacteria (Gram-positive/Gram-negative)
increased an alarming level around the world. Owing to this
increased microbial resistance, new classes of antimicrobial agents
with novel mechanisms are today’s need to fight against the
multidrug-resistant infections.
Oxadiazoles are important classes of compounds which have
long attracted attention, owing to their remarkable biological and
pharmacological properties, such as antitubercular, antibacterial,
antiviral, anti-inflammatory, antifungal and insecticidal activi-
ties.5–13 Also the azole group of heterocyclic compounds possess
significant pharmacokinetic property, lipophilicity that influence
the ability of drug to reach the target by transmembrane diffusion
and show promising activity against resistant TB by inhibiting the
biosynthesis of lipids.14,15 Most of the antitubercular drugs
(isoniazid, pyrazinamide, etc.) are inhibitors of mycobacterial cell
wall synthesis by inhibiting fatty acid synthetase. In the present
investigation it has been tried to design and synthesized such no-
vel compounds which include both the advantage of pyrazole and
oxadiazole nucleus in the single molecule. All the title compounds
(4a–4n) were subjected to molecular properties prediction by
Molinspiration and MolSoft (MolSoft, 2007) software in order to
filter the drugs for synthesis and biological screening and to reduce
enormous wastage of expensive chemicals and precious time.
Earlier we have reported the antimycobacterial activity of
diketones and pyrazoline.16,17
A good bioavailability can be achieved with an appropriate bal-
ance between solubility and partitioning properties. The computed
logP values (P is the partition coefficient of the molecule in the
water/octanol system) are shown in Table 1. The ALOGPS method
is part of the ALOGPS 2.1 program used to predict lipophilicity
and aqueous solubility of compounds. The lipophilicity calcula-
tions within this program are based on the associative neural net-
work approach and the efficient partition algorithm. The Log Kow
(Kow-WIN) program estimates the log octanol/water partition
coefficient (logP) of organic chemicals and drugs using an atom/
fragment contribution method developed at Syracuse Research
Corporation. The XLOGP2 is an atom additive method applying cor-
rections. Computed partition coefficients for drugs studied varied
⇑
Corresponding author. Tel.: +91 9694087786; fax: +91 144 5121120.
E-mail address: jawedpharma@gmail.com (M.J. Ahsan).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.10.057

M. J. Ahsan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7246–7250
7247
Table 1
Physical constants and calculated partition coefficients, solubilities and drug likeness model score of the synthesized compounds
N
Ar
N
NH
N
O
N
O
4a-n
Compound
Ar
Yield (%)
Mp (°C)
ALOGPS
KoW-WIN
XLOP2
Drug-likeness model score
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
2-Chlorophenyl-
4-Chlorophenyl-
4-Aminophenyl-
4-Pyridinyl-
2-Hydroxyphenyl-
2-Phenylacetate-
Phenyl-
4-Methoxyphenyl-
2-Methylphenyl-
3-Methylphenyl-
4-Methylphenyl-
Benzyl-
65
78
82
78
67
62
82
85
89
69
77
80
84
89
154
132
124
186
114
108
98
118
164
198
212
112
116
102
À4.48 (12.99 mg/L)
À4.48 (12.99 mg/L)
À3.82 (56.46 mg/L)
À3.08 (0.30 g/L)
1.09
1.09
À0.47
À0.74
À0.03
0.05
0.45
0.53
1.00
1.00
1.00
0.94
0.47
0.27
4.70
4.70
3.26
2.83
3.68
3.87
4.08
4.00
4.52
4.52
4.52
3.89
3.76
3.11
0.95
0.79
0.61
0.60
0.47
0.17
0.44
0.37
0.93
0.82
0.69
0.56
0.85
0.86
À3.03 (0.35 g/L)
À4.05 (37.56 mg/L)
À3.75 (64.57 mg/L)
À3.77 (67.10 mg/L)
À4.09 (30.38 mg/L)
À4.09 (30.38 mg/L)
À4.09 (30.38 mg/L)
À3.31 (0.19 g/L)
Phenoxymethyl-
2-Thiophenyl-
À3.22 (0.22 g/L)
À3.67 (78.74 mg/L)
between 2.83 and 4.70 (XLOGP2 method) and between À0.74 and
1.09 (KoW-WIN method) is presented in Table 1. Both the XLOGP2
method and KoW-WIN best supported for most of the compounds
on the basis of lipophilicity (65) to consider an oral drug/lead. Also
the absorption of a drug is usually very low if the calculated solu-
bility is <0.0001 mg/L.18 As per the criterion compounds of the ser-
ies (4a–4n) almost fulfil the requirement of solubility (ALOGPS).
Good intestinal absorption, reduced molecular flexibility (mea-
sured by the number of rotatable bonds), low polar surface area
or total hydrogen bond count (sum of donors and acceptors), are
important predictors of good oral bioavailability.19,20 Membrane
permeability and bioavailability is always associated with some
basic molecular descriptors such as logP (partition coefficient),
molecular weight (MW), or hydrogen bond acceptors and donors
counts in a molecule. Number of rotatable bonds is important for
conformational changes of molecules under study and ultimately
for the binding with receptors or channels. It is revealed that for
passing oral bioavailability criteria, number of rotatable bond
should be 610.19 The compounds in this series (4a–4n) in general
possess high number of rotatable bonds (5–7) and therefore, exhi-
bit large conformational flexibility. Drug-likeness model score (a
combined effect of physico-chemical properties, pharmacokinetics
and pharmacodynamics of a compound and is represented by a
numerical value) was computed by MolSoft (MolSoft, 2007) soft-
ware for the entire compounds under study. Maximum drug-like-
ness score was found out to be 0.95 for compound, 4a. Molecular
polar surface area (TPSA) is a very useful parameter for the predic-
tion of drug transport properties. TPSA is a sum of surfaces of polar
atoms (usually oxygen, nitrogen and attached hydrogen) in a mol-
ecule. TPSA and volume is inversely proportional to %ABS. Topolog-
ical polar surface area (TPSA), that is, surface belonging to polar
atoms, is a descriptor that was shown to correlate well with pas-
sive molecular transport through membranes and, therefore, al-
lows prediction of transport properties of drugs in the intestines
and blood–brain barrier crossing.18 TPSA was used to calculate
the percentage of absorption (%ABS) according to the equation:
%ABS = 109 0.345 Â TPSA, as reported.21 From all these parame-
ters, it can be observed that all the title compounds exhibited a
great %ABS ranging from 80.43 to 87.71% and that of standard drug
isoniazid has %ABS of 88.78 calculated by MolSoft software. A com-
putational study for prediction of ADME properties of all molecules
performed is presented in Table 2. The number of rotatable bonds
(NROTB) and Lipinski’s rule of five were also calculated.22 The rule
states that most molecules with good membrane permeability
have logP 6 5, molecular weight 6500, number of hydrogen bond
acceptors 610, and number of hydrogen bond donors 65. This rule
is widely used as a filter for drug-like properties. Furthermore,
none of the compounds violated Lipinski’s parameters, making
them potentially promising agents for antitubercular and antimi-
crobial therapy.
The 1,5-dimethyl-2-phenyl-4-{[(5-aryl-1,3,4-oxadiazol-2-yl)-
methyl]amino}-1,2-dihydro-3H-pyrazol-3-one analogues (4a–n)
described in this study are shown in Table 1 and the reaction se-
quence for the synthesis is summarised in Scheme 1. In the initial
step 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-
one (1) (0.1 mol) and chloroacetic acid (2) (0.1 mol) in dry acetone
and potassium carbonate refluxed for 8 h giving [(1,5-dimethyl-3-
oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]acetic acid (3).
In the subsequent step [(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihy-
dro-1H-pyrazol-4-yl)amino]acetic acid (3) was treated with appro-
priate hydrazides in 5 ml phosphorus oxychloride furnished the
titled compounds (4a–4n). The yields of the title compounds were
ranging from 62% to 89% after recrystallization with absolute eth-
anol. The purity of the compounds was checked by TLC using elu-
ants toluene/ethyl acetate/formic acid (5:4:1) and petroleum
ether/toluene/ethyl acetate (5:4:1) and elemental analyses. The
spots were located under iodine vapour/UV light. Both the analyt-
ical and spectral data (IR, 1H NMR) of all the synthesized com-
pounds were in full harmony with the proposed structures. In
general, the IR spectra of the compounds afforded absorption at
1531–1567 cmÀ1 due to C@N group, band at 1153–1174 cmÀ1
due to stretching of oxadiazole ring. In the Nuclear Magnetic Res-
onance spectra (1H NMR) the signals of the respective protons of
the synthesized titled compounds were verified on the basis of
their chemical shift, multiplicities and coupling constants in
DMSO-d6. The spectra showed a singlet at d 1.91–2.23 ppm
corresponding to CH3 group (pyrazolone ring); a singlet at d
2.27–2.39 ppm corresponding to CH3 (aromatic); a singlet at d
2.49–2.61 ppm corresponding to CH3 group (N–CH3); a doublet
at
d
3.93–4.07 ppm corresponding to CH2; a singlet at d

7248
M. J. Ahsan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7246–7250
Table 2
Pharmacokinetic parameters important for good oral bioavailability of title compounds (4a–n)
Compound
%ABS
Volume (A3)
TPSA (A2)
NROTB
HBA
HBD
LogP
MW
Lipinski’s violations
Rule
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
—
—
—
—
5
5
5
5
5
7
5
6
5
5
5
6
7
5
<10
4
4
4
5
5
5
4
5
4
4
4
4
5
5
<5
1
1
3
1
2
1
1
1
1
1
1
1
1
1
65
<500
61
0
0
0
0
0
0
0
0
0
0
0
0
0
0
87.27
87.71
80.43
84.01
81.76
84.96
87.71
84.82
87.71
87.71
87.71
87.92
85.04
87.36
381.64
381.18
371.49
361.70
375.09
395.09
363.99
395.84
383.59
385.01
384.93
380.68
394.25
358.87
63.00
61.71
82.80
72.43
78.95
69.68
61.71
70.10
61.71
61.71
61.71
61.11
69.45
62.73
2.72
2.70
1.13
0.80
1.71
1.98
2.02
2.07
2.38
2.39
2.48
1.64
0.98
1.90
395.11
395.11
376.16
362.15
377.15
391.16
361.15
391.16
375.17
375.17
375.17
375.17
391.16
367.11
%ABS, percentage of absorption; TPSA, topological polar surface area; NROTB, number of rotatable bonds; MW, molecular weight; LogP, logarithm of compound partition
coefficient between n-octanol and water; HBA, number of hydrogen bond donors; HBD, number of hydrogen bond acceptors.
NH
NH
2
N
N
COOH
N
Dry Acetone
K CO
N
ClCH COOH
2
O
+
O
2
3
3
2
1
POCl
ArCONHNH
3
2
N
O
Ar
N
NH
N
N
O
4a-4n
Scheme 1. Protocol for the synthesis of oxadiazoles.
4.9–5.2 ppm corresponding to NH; a multiplet at d 6.58–7.89 ppm
corresponding to aromatic protons. The elemental analysis results
were within 0.4% of the theoretical values.
(4a–4n) were screened for antifungal activity against Aspergillus ni-
ger (NCIM 1196) and Candida albicans (NCIM 3471) in DMSO by
agar diffusion method26,27 All the fungal strains were procured
from National Chemical Laboratory, Pune, India. The lowest con-
centration (highest dilution) required to arrest the growth of fun-
gus was regarded as minimum inhibitory concentration (MIC).
The MIC of compounds was reported in Table 3 with standard
drugs ciprofloxacin and fluconazole for comparison.
All the synthesized compounds (4a–r) were tested for their
in vitro antimycobacterial activity against MTB and INHR-MTB
by agar dilution method using double dilution technique
recommended by the National Committee for Clinical Laboratory
Standards.23 The MTB and INHR-TB clinical isolate were obtained
from Tuberculosis Research Centre, Alwar, India. The MIC was
defined as the minimum concentration of compound required to
inhibit 90% of bacterial growth and MIC of the compounds were re-
ported in Table 3 with standard drug isoniazid for comparison. The
synthesized title compounds (4a–4n) were screened for antibacte-
rial activity against Staphylococcus aureus (NCIM 2079), Bacillus
subtilis (NCIM 2439), Escherichia coli (NCIM 5051) and Pseudomonas
aeruginosa (ATCC 10145) bacterial strains by disc-diffusion meth-
od.24,25 All the bacterial strains were procured from National
Chemical Laboratory, Pune and American Type Culture Collection
(ATCC) and Gene Bank, Institute of Microbial Technology, Chandi-
garh, India. Ciprofloxacin was used as a standard drug. Minimum
inhibitory concentrations (MICs) were determined by broth
dilution technique. The lowest concentration (highest dilution) re-
quired to arrest the growth of bacteria was regarded as minimum
inhibitory concentration (MIC). The synthesized title compounds
Among the fourteen synthesized compounds, five compounds
were found to be active with minimum inhibitory concentration
of 0.78–6.81
be active against MTB and INHR-TB with MICs of 0.78
1.52 M, respectively. The antimycobacterial activity of com-
lM against MTB. The compound, 4d was found to
l
M and
l
pound, 4d was comparable to isoniazid (INH) against MTB while
7.6-folds more active than INH against INHR-TB. The compound
4a, 4b, 4c and 4n showed good to moderate inhibitory activity
against MTB with MICs 1.97–6.81 lM. The compound, 4c was
found to be 1.4-fold more active than INH against INHR-TB. The
N-aryl with electronegative group substitution showed maximum
activity, in which 4-pyridinyl group had maximum inhibition
when compare to 2-chlorophenyl, 4-chlorophenyl and 4-amino-
phenyl group substitution. The electron releasing group such as
4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methyl-
phenyl etc. showed less inhibition. All the compounds showed

M. J. Ahsan et al. / Bioorg. Med. Chem. Lett. 21 (2011) 7246–7250
7249
Table 3
Antimicrobial and antitubercular screening of the title compounds (4a–n)
Compound
Minimum inhibitory concentration (
Antibacterial
B. subtilis E. coli
l
g/mL)
MIC (
Antitubercular
MTBa MTBb
lM)
Antifugal
C. albicans
S. aureus
P. aeruginosa
A. niger
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4
8
16
16
4
8
32
16
4
4
8
8
64
32
256
256
128
256
8
512
512
16
8
128
4
512
>512
128
—
256
128
128
256
16
512
512
32
16
256
4
512
512
256
—
1.97
3.94
4.15
0.78
>13.25
>12.78
10
>12.78
>13.31
>13.31
10
12.65
12.65
8.29
1.52
NT
NT
13.8
NT
16
16
128
256
512
256
256
512
256
256
64
8
128
512
512
>512
256
>512
512
256
128
8
64
128
512
512
>512
512
>512
512
256
128
8
256
512
>512
256
>512
512
256
128
16
NT
NT
13.31
>13.31
12.78
13.62
—
10
4m
4n
Ciprofloxacin
Fluconazole
Isoniazid
12.78
6.81
—
—
0.78
4
—
—
4
—
—
4
—
—
4
—
—
2
—
1
—
—
11.58
NT = not tested.
a
Mycobacterium tuberculosis H37Rv.
INHR-TB.
b
low to high antibacterial activity. The compound 4a showed good
antibacterial activity while compounds 4c, 4d and 4n showed
facilities. The authors are also thankful to Dr. K. P. Singh and Dr.
(Mrs.) Shobha Tomar, National Institute of Medical Sciences Uni-
versity, Jaipur, Rajasthan, India for their guidance.
moderate activity with MICs 8–64
strains. The activity of compound, 4a (MIC 4
eus, B. subtiltis and E. coli and the activity of compound, 4b (MIC
g/mL) against E. coli was found to be comparable with that of
lg/mL against various bacterial
lg/mL) against S. aur-
Supplementary data
4
l
the standard drug ciprofloxacin. The N-aryl with electronegative
group substitution such as 2-chlorophenyl, 4-chlorophenyl and
2-thiophenyl group showed maximum antibacterial activity. The
antifungal activity of the title compound was found to be low to
moderate. The compounds, 4e, 4i and 4k showed moderate anti-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.10.057.
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and MDR are in progress in our laboratory. The oxadiazole deriva-
tives discovered in this study may provide valuable therapeutic
intervention for the treatment of tubercular disease.
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