Synthesis, characterization, antimicrobial activity, and QSAR studies on substituted oxadiazaboroles

Article abstract of DOI:10.1007/s00044-016-1603-1

This paper presents the synthesis and in vitro antimicrobial activity studies of 3,4,5-trisubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4) and 3,5-disubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (7). The antimicrobial activities of the compounds were

Full text of DOI:10.1007/s00044-016-1603-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1603-1
ORIGINAL RESEARCH
Synthesis, characterization, antimicrobial activity, and QSAR studies
on substituted oxadiazaboroles
Meryem Pir1 Hikmet Agirbas1 Fatma Budak2 Merve Ilter1
●
●
●
Received: 24 February 2016 / Accepted: 28 May 2016
© Springer Science+Business Media New York 2016
●
Abstract This paper presents the synthesis and in vitro
antimicrobial activity studies of 3,4,5-trisubstituted 4,5-
dihydro-1,2,4,5-oxadiazaboroles (4) and 3,5-disubstituted
4,5-dihydro-1,2,4,5-oxadiazaboroles (7). The antimicrobial
activities of the compounds were assessed against a panel
of microorganisms including Staphylococcus aureus,
Enterococcus faecalis, Pseudomonas aeruginosa, Escher-
ichia coli, Streptococcus mutans, and Candida albicans.
Some of the oxadiazaboroles exhibited fair activities against
these microorganisms. The pMIC values of the compounds
were first correlated with Hammett polar substituent con-
stant (σ) and lipophilic constant (π) and statistically sig-
nificant correlations were obtained. Additionally, the pMIC
values of the compounds were correlated with σ, π, and
some theoretical descriptors and fair 2D-quantitative
structure–activity relationship models with clogP, surface
area approx, ELUMO, µ, and EHOMO as independent vari-
ables were obtained. Application of training and test sets to
quantitative structure–activity relationship models gave
good results. Squared correlation matrix of the theoretical
descriptors used in the quantitative structure–activity rela-
tionship study showed no correlation between the
descriptors.
Keywords Oxadiazaborole derivatives Antimicrobial
activity QSAR
●
Introduction
Drug resistance is a natural response that is caused by
antibiotic use. Hence, new drugs are needed to struggle with
this resistance. Boron compounds are underexploited in
medicinal chemistry and have tremendous potential in drug
discovery. In the literature, boron-containing compounds
have been identified as the agents that have potential bio-
logical activities (Ciaravino et al., 2013). Among these, it is
worth mentioning the activities of the following com-
pounds: heterocyclic aminoboron compounds (anti-
tuberculosis agents) (Campbell-Verduyn et al., 2014),
boron-containing GSK2251052 (antimicrobial agent) (Ross
et al., 2013), oxaborole compounds (antibacterial proto-
types) (Li et al., 2013), α-amino cyclic boronates (inhibitors
of HCV NS3 protease) (Li et al., 2010), benzoxaborole
compounds (anti-inflammatory agents) (Akama et al.,
2009), and boronic acid esters (antibacterial agent with anti-
inflammatory activity) (Baker et al., 2006).
Some heterocyclic boron compounds that contain B–N
bonds also show biological activity (Das et al., 2012;
Jabbour et al., 2004). Oxadiazaboroles possess a B–N bond
and are readily obtained from an amidoxime and a boronic
acid. On the basis of the biological activity displayed by other
heterocyclic systems that contain B–N bonds, oxadiazaboroles
should be interesting candidates for biological activity. Con-
sidering the structural characteristics of the 1,2,4,5-oxadiaza-
boroles, and the existence of the oxygen-, nitrogen-, and
boron-containing five-membered nonaromatic heterocycles
Electronic supplementary material The online version of this article
(doi:10.1007/s00044-016-1603-1) contains supplementary material,
which is available to authorized users.
* Hikmet Agirbas
agirbash@yahoo.com
1
Department of Chemistry, Kocaeli University, Umuttepe 41300
Izmit, Turkey
2
Department of Microbiology, Kocaeli University, Umuttepe
41300 Izmit, Turkey

Med Chem Res
Scheme 1 Synthesis of
compounds (4a–r)
O
H
N
H
OH
X
X
Na2CO3
rt
+ NH2OH.HCl
(1a-r)
(2a-r)
Chloroform
Cl2(g)
N
OH
X
Y
N
OH
NH2
X
NH
Benzene, rt
Cl
Y
(3a-r)
HO
OH
Toluene,
reflux
B
X
Y
a: p-Cl
b: p-Cl
c: p-Cl
d: p-Cl
e: p-Cl
f: p-Cl
g: p-Cl
h: p-Cl
i: p-Cl
j: H
k: p-F
l: p-Br
m:m-Cl
n: m-Br
o: p-CF3
p-N(CH3)2
p-OCH3
m-CH3
H
m-OCH3
p-Br
-2H2O
N
X
O
p-Cl
m-Cl
m-CF3
m-CH3
m-CH3
m-CH3
m-CH3
m-CH3
m-CH3
B
N
p: m-NO2 m-CH3
r: p-NO2 m-CH3
Y
(4a-r)
system, it is reasonable to expect physiological activities from
these compounds. Therefore, the study of substituent
effects on the antimicrobial activity of the oxadiazaboroles
was thought to give a better understanding of their
structure–antimicrobial activity relationships.
(QSAR) and 2D-QSAR analysis to observe the relations of the
molecular descriptors with the activities.
Synthesis
Some oxadiazaboroles were synthesized from amidoximes
and phenylboronic acid (Yale, 1971; Dürüst et al., 2007).
However, to our knowledge, no antimicrobial activity data of
3,4,5-trisubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4)
and 3,5-disubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (7)
was reported. We synthesized some series of new oxadiaza-
borole derivatives (Schemes 1 and 2) and determined their
antimicrobial activities against some bacteria and fungi. We
also applied 1D-quantitative structure–activity relationship
Synthesis of compounds (2–4, Scheme 1) starts with
p-chlorobenzaldehyde, which was reacted with hydroxylamine
hydrochloride to give p-chlorobenzaldehyde oxime (2a–i).
Then, chlorination was followed: p-chlorobenzaldehyde oxime
was reacted with chlorine gas in anhydrous chloroform at
0 °C, until a certain weight increase was obtained, to have
4-chloro-N-hydroxybenzimidoyl chloride. The solution was
kept in the fridge overnight. Then the solvent was evaporated.

Med Chem Res
Scheme 2 Synthesis of
compounds (7a–s)
The residue, 4-chloro-N-hydroxybenzimidoyl chloride, was
reacted with substituted anilines in benzene at room tem-
perature to give N-substituted-p-chlorobenzamidoximes
(3a–i). N-(m-tolyl)-substituted benzamidoximes (3j–r) were
synthesized by the literature method (Sümengen and Pelter,
1983). Then the compounds (3a–r) were reacted with phe-
nylboronic acid in toluene to yield the corresponding 3,4,5-
trisubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4a–r).
Synthesis of compounds 6 and 7, outlined in Scheme 2,
started with benzonitrile (5), which was reacted with
hydroxylamine hydrochloride to afford benzamidoxime (6).
This was followed by cyclodehydration reaction: benzami-
doxime (6) was reacted with boronic acid derivatives in
benzene to yield the corresponding 3,5-disubstituted 4,5-
dihydro-1,2,4,5-oxadiazaboroles (7a–s).
All the synthesized compounds were analyzed by their
infrared radiation (IR), 1H and 13C nuclear magnetic
resonance spectroscopy (NMR) spectra and the purity of
compounds 4a–r and 7a–s was checked by elemental
analysis.
Benzamidoxime was synthesized according to the literature
methods A (Krüger, 1885) and B (Gosenca et al., 2013).
Method B gives less amide impurity and high yield.
(S. aureus, E. faecalis, and S. mutans), two gram-negative
bacteria (P. aeruginosa and E. coli) and one fungi (C.
albicans) by their minimal inhibitory concentrations
(MIC) via broth microdilution susceptibility tests (CLSI,
2002, 2005, 2006). The biological activities of all the
compounds are given in Table 1 and shown graphically in
Figs. 1 and 2. Compounds 7k, 7l, and 7o have been found
to be the most active derivatives against fungi (C. albicans)
at MIC value of 25 µg/mL among the tested compounds. All
the compounds exhibited antimicrobial activity with MIC
values between 25−800 µg/mL against C. albicans. 4i is the
most active compound against S. aureus (MIC 25 µg/mL).
Additionally, compounds 4f, 4g, 4h, 4i, 4o, and 7n showed
activity (MIC 25 µg/mL) against S. mutans. The results
show that 3,5-disubstituted 4,5-dihydro-1,2,4,5-oxadiaza-
boroles (7) are the most active derivatives against P. aeru-
ginosa among the tested compounds (MIC 12.5−25 µg/mL).
All compounds exhibited antibacterial activity with
MIC values between 25−800 µg/mL against S. aureus,
with MIC values between 50−800 µg/mL against E. coli;
with MIC values between 12.5−200 µg/mL against P. aeru-
ginosa; with MIC values between 50−800 µg/mL against E.
faecalis; and with MIC values between 25−100 µg/mL against
S. mutans.
Biological activity
QSAR analysis
The synthesized compounds (4 and 7) have been evaluated
for their in vitro antimicrobial activity against a panel of
microorganisms, including three gram-positive bacteria
We have carried out linear regression studies of molecular
descriptors against the antimicrobial activity of compounds

Med Chem Res
Table 1 Antimicrobial activities of compounds (4a–r) and (7a–s)
Compound
Antibacterial and antifungal activities, µg/mL (µmol/mL)
(substituents: X, Y)
S. aureus
E. faecalis
P. aeruginosa
E. coli
S. mutans
C. albicans
ATCC 25983
ATCC 29212
ATCC 27853
ATCC 25922
ATCC 25175
ATCC 90028
Ampicillin
0.78
0.78
−
6.25
≤0.25
−
Ciprofloxacin
0.25
0.25
0.25
0.04
−
−
4a (p-Cl, p-N(CH3)2)
4b (p-Cl, p-OCH3)
4c (p-Cl, m-CH3)
4d (p-Cl, H)
800 (2.13)
800 (2.21)
100 (0.29)
100 (0.30)
100 (0.28)
200 (0.49)
200 (0.54)
50 (0.14)
25 (0.06)
200 (0.64)
200 (0.61)
50 (0.13)
50 (0.14)
50 (0.13)
50 (0.13)
200 (0.56)
200 (0.56)
100 (0.38)
100 (0.42)
100 (0.39)
100 (0.42)
100 (0.38)
100 (0.42)
100 (0.45)
100 (0.39)
50 (0.17)
50 (0.19)
100 (0.38)
50 (0.17)
50 (0.19)
50 (0.20)
50 (0.19)
100 (0.33)
50 (0.19)
100 (0.50)
−
100 (0.27)
800 (2.21)
100 (0.29)
200 (0.60)
400 (1.10)
200 (0.49)
200 (0.54)
50 (0.14)
50 (0.12)
100 (0.32)
100 (0.30)
50 (0.13)
50 (0.14)
50 (0.13)
50 (0.13)
200 (0.56)
200 (0.56)
50 (0.19)
100 (0.42)
100 (0.39)
100 (0.42)
100 (0.38)
200 (0.84)
100 (0.45)
100 (0.39)
100 (0.33)
100 (0.38)
100 (0.38)
100 (0.33)
100 (0.38)
100 (0.40)
50 (0.19)
100 (0.33)
100 (0.37)
100 (0.50)
−
100 (0.27)
200 (0.55)
50 (0.14)
800 (2.13)
800 (2.21)
200 (0.58)
200 (0.60)
400 (1.10)
200 (0.49)
200 (0.54)
100 (0.27)
200 (0.50)
100 (0.32)
100 (0.30)
400 (1.02)
100 (0.29)
100 (0.26)
100 (0.26)
100 (0.28)
200 (0.56)
50 (0.19)
50 (0.21)
50 (0.20)
100 (0.42)
50 (0.19)
50 (0.21)
50 (0.23)
100 (0.39)
50 (0.17)
50 (0.19)
50 (0.19)
100 (0.33)
50 (0.19)
50 (0.20)
100 (0.37)
100 (0.33)
50 (0.19)
50 (0.25)
−
50 (0.13)
50 (0.14)
50 (0.14)
50 (0.15)
50 (0.14)
25 (0.06)
25 (0.07)
25 (0.07)
25 (0.06)
50 (0.16)
50 (0.15)
50 (0.13)
50 (0.14)
50 (0.13)
25 (0.07)
100 (0.28)
50 (0.14)
100 (0.38)
100 (0.42)
100 (0.39)
100 (0.42)
50 (0.19)
50 (0.21)
100 (0.45)
50 (0.20)
50 (0.17)
50 (0.19)
50 (0.19)
50 (0.17)
50 (0.19)
25 (0.10)
50 (0.19)
50 (0.17)
50 (0.19)
50 (0.25)
−
800 (2.13)
800 (2.21)
100 (0.29)
100 (0.30)
100 (0.28)
400 (0.97)
800 (2.18)
50 (0.14)
400 (1.00)
200 (0.64)
200 (0.61)
100 (0.26)
100 (0.29)
100 (0.26)
100 (0.26)
200 (0.56)
200 (0.56)
200 (0.75)
200 (0.84)
200 (0.79)
200 (0.84)
200 (0.75)
200 (0.84)
200 (0.90)
200 (0.79)
200 (0.66)
100 (0.38)
25 (0.09)
25 (0.08)
200 (0.75)
100 (0.40)
25 (0.09)
200 (0.66)
100 (0.37)
200 (0.98)
0.25
50 (0.15)
4e (p-Cl, m-OCH3)
4f (p-Cl, p-Br)
50 (0.14)
100 (0.24)
50 (0.14)
4g (p-Cl, p-Cl)
4h (p-Cl, m-Cl)
4i (p-Cl, m-CF3)
4j (H, m-CH3)
50 (0.14)
50 (0.12)
50 (0.16)
4k (p-F, m-CH3)
4l (p-Br, m-CH3)
4m (m-Cl, m-CH3)
4n (m-Br, m-CH3)
4o (p-CF3, m-CH3)
4p (m-NO2, m-CH3)
4r (p-NO2, m-CH3)
7a (p-(CH3)2NC6H4)
7b (p-HOC6H4)
7c (p-CH3OC6H4)
7d (p-CH3C6H4)
7e (m-(CH3)2NC6H4)
7f (m-CH3C6H4)
7g (C6H5)
50 (0.15)
50 (0.13)
50 (0.14)
50 (0.13)
50 (0.13)
100 (0.28)
100 (0.28)
12.5 (0.047)
12.5 (0.052)
12.5 (0.050)
12.5 (0.052)
12.5 (0.047)
12.5 (0.052)
12.5 (0.057)
12.5 (0.048)
12.5 (0.042)
12.5 (0.047)
12.5 (0.047)
12.5 (0.041)
12.5 (0.047)
12.5 (0.050)
12.5 (0.046)
25 (0.082)
12.5 (0.047)
12.5 (0.062)
−
7h (m-CH3OC6H4)
7i (p-BrC6H4)
7j (p-ClC6H4)
7k (m-ClC6H4)
7l (m-BrC6H4)
7m (p-CH3COC6H4)
7n (m-NCC6H4)
7o (m-O2NC6H4)
7p (p-CH3SO2C6H4)
7r (p-O2NC6H4)
7s (n-Bu)
Fluconazole
4a–r and 7a–s. The results of the biological activities,
reported as MIC values (Table 1), were converted to
pMIC (− logMIC) on a molar basis and used as dependent
variables to obtain the linear relationship. The pMIC values
of compounds were first correlated with Hammett polar
substituent constant (σ) (Hansch et al., 1991) or lipophilic
constant (π) (Hansch et al., 1973), and statistically sig-
nificant correlations were obtained (Table 2; Eqs. 2, 4, 5, 8,
14, 16, and 18). However, by application of the 2D statis-
tical method, the correlation of pMIC values against σ and π
independent variables gave two statistically significant 2D-
QSAR models (Table 2; Eqs. 1 and 17).

Med Chem Res
Fig. 1 Comparable chart for
MIC values (µg/mL) of all
compounds against bacterias
850
800
750
700
650
600
550
500
450
400
350
300
250
200
150
100
50
S. aureus
E. faecalis
P. aeruginosa
E. coli
S. mutans
0
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4r 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7r 7s
Fig. 2 Comparable chart for
MIC values (µg/mL) of all
compounds against fungi
850
800
750
700
650
600
550
500
450
400
350
300
250
200
150
100
50
C. albicans
0
4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4r 7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p 7r 7s
Computer aid ranges from molecular design to archi-
tectural design (Agirbas, 2015) and also helps to check the
experimental data. In order to add theoretical descriptors to
the structure–antimicrobial activity relationship study, the
geometrical optimization of all the compounds (4a–r, 7a–s)
was done by the ab initio (RHF/3-21G) method incorporated
in the Hyperchem package (HyperChem, 2002). Theoretical
descriptors, namely, surface area approx (SAA), molecular
volume (MV), molar refractivity (MR), polarizability (polar),
magnitude of dipolar moment (µ), and the calculated log of
octanol–water partition coefficient (clogP) of the compounds
were also computed by the Hyperchem software (RHF/3-
21G) method (Table 3). EHOMO (energies of the highest
occupied molecular orbital) and ELUMO (lowest unoccupied
molecular orbital) were calculated by Gaussian 03W software
(Frisch et al., 2004), using the DFT (B3LYP) method with

Med Chem Res
Table 2 Significant 2D−QSAR models obtained for antimicrobial activity of 3,4,5-trisubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4a–r) and
3,5-disubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (7a–s)
Microorganisms Equations Regression equation
Statistic parameter
r2
n
r
r2
s
P
F
adj.
S. aureus
1
2
3
pMICs.a. = 0.26( 0.07)σ + 0.08( 0.05)π + 0.48( 0.03)
pMICs.a. = 0.63( 0.08)π + 0.32( 0.05)
17a 0.733 0.537 0.471 0.123 0.0045
8b 0.948 0.899 0.882 0.119 0.0003
35 0.542 0.294 0.250 0.279 0.0038
8.131
53.639
6.673
pMICs.a. = 0.09( 0.05)clogP − 8.70( 2.70)ELUMO
−
1.52( 0.59)
E. faecalis
4
5
6
7
pMICE.f. = 0.54( 0.02)π + 0.43( 0.01)
pMICP.a. = 0.24( 0.05)π + 0.69( 0.03)
pMICP.a. = −0.005( 0.0005)SAA + 2.68( 0.16)
8b 0.992 0.985 0.983 0.036 o0.0001 418.108
P. aeruginosa
8b 0.884 0.782 0.746 0.072 0.0035
21.594
35 0.873 0.763 0.756 0.151 o0.0001 106.614
35 0.879 0.773 0.759 0.150 o0.0001 54.522
pMICP.a. = 2.01( 1.74)EHOMO − 0.006( 0.0006)SAA +
3.53( 0.75)
8
pMICP.a. = 0.08( 0.02)π + 1.29( 0.01)
17a 0.793 0.628 0.604 0.041 0.0001
25.360
E. coli
9
pMICE.c. = −0.004( 0.0008)SAA + 1.60( 0.24)
35 0.645 0.416 0.398 0.223 o0.0001 23.544
35 0.682 0.465 0.432 0.216 o0.0001 13.925
10
pMICE.c. = − 0.003( 0.0008)SAA − 3.75( 2.19)ELUMO +
0.68( 0.59)
S. mutans
11
pMICS.m. = 0.56( 0.15)σ + 6.76( 3.54)ELUMO
+
17a 0.791 0.627 0.573 0.121 0.0010
11.763
2.01( 0.74)
12
13
pMICS.m. = 0.33( 0.07)σ − 0.03( 0.02)µ + 0.74( 0.10)
17a 0.774 0.599 0.542 0.125 0.0017
10.471
pMICS.m. = 0.004( 0.0006)SAA − 4.72( 1.65)ELUMO
1.31( 0.44)
−
35 0.732 0.536 0.507 0.163 o0.0001 18.498
9c 0.898 0.806 0.778 0.084 0.0010
14
15
pMICS.m. = 0.41( 0.07)π + 0.83( 0.04)
29.016
35 0.677 0.459 0.425 0.176 o0.0001 13.593
pMICS.m. = −3.22( 2.04)EHOMO + 0.003( 0.0007)SAA −
1.49( 0.88)
16
17
18
pMICS.m. = 0.31( 0.07)σ + 0.59( 0.03)
17a 0.728 0.530 0.498 0.132 0.0009
17a 0.734 0.540 0.474 0.267 0.0043
8b 0.936 0.877 0.857 0.070 0.0006
16.897
8.222
C. albicans
pMICc.a. = 0.47( 0.15)σ + 0.28( 0.10)π + 0.21( 0.07)
pMICc.a. = 0.33( 0.05)π + 0.27( 0.03)
42.955
a
Compounds (7a–r)
Compounds (4j–r)
Compounds (4a–i)
b
c
3-21G basis set (Table 3). Several descriptors (Ferreira et al.,
2009) were also calculated as shown below:
values was obtained (Table 2; Eqs. 3, 6, 7, 9, 10, 13,
and 15). However, with the application of the 2D statistical
method, the correlation of pMIC values against the theo-
retical descriptors (ELUMO and µ) and σ gave two statisti-
cally significant 2D-QSAR models (Table 2; Eqs. 11
and 12). The overall quality of 2D-QSAR models was
shown by r and r2 (correlation coefficients), s (standard
deviations) of the regression equations, F value (F-statis-
tical analysis; Fischer test), P (probability value), and n
(number of data points). The predictability of each model
was assessed by using the cross-validated correlation
coefficient (r2 adj). A value of r2 adj 40.25 was considered
for the structure–reactivity models.
To evaluate the predictive power of the model equations,
MIC values were split into the training and test sets. The
regression equations of the training sets gave fair internal
cross-validation (r2 adj) values and good coefficient of
determination (r2) values (Table 4). Good predicted values
of the test sets were also obtained. The plot of the observed
SA
À
Á
OðovalityÞ¼
3MV
4π
4π
2=3
EHOMOꢀELUMO
χðelectronegativityÞ¼
2
ELUMOꢀEHOMO
ηðhardnessÞ¼
2
χ2
ωðelectrophilicityÞ¼
2η
1
ηꢀ1ðsoftnessÞ¼
η
When these theoretical descriptors were used as inde-
pendent variables, seven significant correlation with pMIC

Med Chem Res
Table 3 Theoretical descriptors of 3,4,5-trisubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4a–r) and 3,5-disubstituted 4,5-dihydro-1,2,4,5-
oxadiazaboroles (7a–s) used for the regression analyses
Compound
clogP
SAA
(Ǻ2)
MV
(Ǻ3)
MR
(Ǻ3)
Polar
(Ǻ3)
EHOMO
ELUMO
µ
η
η−1
ω
χ
O
(au)
(au)
(D)
4a
4b
4c
4d
4e
4f
1.19
1.15
2.29
2.14
1.15
2.19
1.92
1.92
2.71
2.52
1.91
2.57
2.29
2.57
3.08
− 0.23
− 0.23
1.01
0.93
0.96
2.11
1.01
2.11
1.96
0.96
2.01
1.73
1.73
2.01
1.89
1.68
− 0.79
0.36
− 0.79
2.67
394.4
366.3
353.5
330.0
363.1
351.8
347.4
347.3
388.7
336.1
341.3
357.9
353.5
357.8
372.4
364.0
366.1
298.9
243.7
271.1
258.6
298.9
258.6
235.0
271.1
256.8
252.4
252.3
256.7
280.1
263.7
264.9
309.4
265.0
247.4
340.8
319.6
312.0
295.5
320.1
317.4
310.5
310.4
327.5
296.9
299.4
318.9
311.9
318.9
320.7
316.0
315.9
251.2
212.8
230.7
222.9
251.3
222.9
206.1
230.8
228.3
221.3
221.3
228.2
240.6
224.3
225.2
254.4
225.0
199.9
118.69
111.44
109.35
105.07
111.44
112.60
109.78
109.78
110.28
104.63
104.76
112.17
109.35
112.17
109.85
110.35
110.35
84.49
42.35
39.80
39.17
37.33
39.80
39.96
39.26
39.26
38.89
37.24
37.15
39.87
39.17
39.87
38.80
39.08
39.08
30.76
26.38
28.22
27.58
30.76
27.58
25.74
28.22
28.37
27.67
27.67
28.37
29.50
27.60
27.58
28.72
27.58
23.42
− 0.3455
− 0.3596
− 0.3753
− 0.3812
− 0.3494
− 0.3609
− 0.3800
− 0.3807
− 0.3854
− 0.3733
− 0.3748
− 0.3710
− 0.3771
− 0.3653
− 0.3786
− 0.3820
− 0.3817
− 0.3479
− 0.3781
− 0.3718
− 0.3830
− 0.3401
− 0.3796
− 0.3920
− 0.3784
− 0.3808
− 0.3853
− 0.3788
− 0.3740
− 0.3648
− 0.3931
− 0.4035
− 0.3889
− 0.4042
− 0.4201
− 0.1678
− 0.1801
− 0.2144
− 0.2160
− 0.2076
− 0.2179
− 0.2199
− 0.2197
− 0.2206
− 0.2102
− 0.2116
− 0.2097
− 0.2165
− 0.2126
− 0.2203
− 0.2225
− 0.2345
− 0.1748
− 0.2045
− 0.1955
− 0.2136
− 0.1890
− 0.2193
− 0.2241
− 0.1967
− 0.2152
− 0.2191
− 0.2260
− 0.2214
− 0.2273
− 0.2370
− 0.2393
− 0.2347
− 0.2416
− 0.2439
6.82
5.67
5.27
5.14
3.91
3.46
2.77
4.62
4.68
5.70
5.23
5.25
4.08
4.49
5.63
3.58
6.40
5.33
6.29
6.36
4.67
6.30
5.00
4.72
4.41
5.24
5.69
3.04
3.38
7.59
2.98
9.84
7.87
7.76
4.95
0.177
0.179
0.160
0.165
0.141
0.143
0.160
0.161
0.164
0.163
0.163
0.161
0.160
0.152
0.158
0.159
0.147
0.086
0.086
0.088
0.084
0.075
0.080
0.083
0.090
0.082
0.083
0.076
0.076
0.068
0.078
0.082
0.077
0.081
0.088
5.65
0.088
0.089
0.080
0.082
0.070
0.071
0.080
0.080
0.082
0.081
0.081
0.080
0.080
0.076
0.079
0.079
0.073
0.043
0.043
0.044
0.042
0.037
0.040
0.041
0.045
0.041
0.041
0.038
0.038
0.034
0.039
0.041
0.038
0.040
0.044
− 0.177
1.6718
1.6206
1.5893
1.5383
1.6048
1.5636
1.5669
1.5667
1.6919
1.5618
1.5772
1.5857
1.5896
1.5853
1.6438
1.6226
1.6323
1.5525
1.4137
1.4910
1.4549
1.5522
1.4550
1.3928
1.4899
1.4218
1.4268
1.4264
1.4221
1.4978
1.4773
1.4804
1.5940
1.4814
1.4965
5.58
6.25
− 0.179
− 0.160
− 0.165
− 0.141
− 0.143
− 0.160
− 0.161
− 0.164
− 0.163
− 0.163
− 0.161
− 0.160
− 0.152
− 0.158
− 0.159
− 0.147
− 0.086
− 0.086
− 0.088
− 0.084
− 0.075
− 0.080
− 0.083
− 0.090
− 0.082
− 0.083
− 0.076
− 0.076
− 0.068
− 0.078
− 0.082
− 0.077
− 0.081
− 0.088
6.06
7.09
6.99
4g
4h
4i
6.25
6.21
6.09
4j
6.13
4k
4l
6.13
6.21
4m
4n
4o
4p
4r
7a
7b
7c
7d
7e
7f
6.25
6.58
6.33
6.29
6.80
11.55
11.52
11.34
11.80
13.24
12.48
11.91
11.00
12.07
12.03
13.08
13.10
14.54
12.81
12.18
12.96
12.30
11.35
72.47
77.24
75.15
84.49
75.15
7g
7h
7i
70.87
77.24
78.40
7j
75.58
7k
7l
75.58
78.40
7m
7n
7o
7p
7r
7s
80.42
75.85
76.58
84.53
76.58
60.15
pMICs.a values against predicted ones, using regression
equation of the training set (Table 4, Eq. 1), is shown in
Fig. 3. This QSAR model has a squared correlation coeffi-
cient (r2) of ~ 0.68. The predicted pMICs.a. values (deter-
mined from Eq. 1) with residuals are given in Table 5.
The correlation matrix for the descriptors is given in
Table 6 and, as seen, cross-relations between the descri
ptors are not observed. Therefore, the values of the
descriptors allow its safe use in the multilinear regression
relationship (Myers, 1987; Draper and Smith, 1981).
The statistical calculations were performed by SigmaPlot
program package.
Conclusion
A series of eighteen 3,5-disubstituted 4,5-dihydro-1,2,4,5-
oxadiazaboroles (7) were synthesized from the reactions of
benzamidoxime (6) with boronic acid derivatives. Seventeen
3,4-disubstituted 4,5-dihydro-1,2,4,5-oxadiazaboroles (4)

Med Chem Res
Table 4 The results of the application of training and test sets to 2D−QSAR models (Eqs. 1–18 in Table 2)
Eq. Training set
Regression equation of training set
Test set
(MIC)
Predicted
value
(MIC)
Statistic parameter
r2
r2
s
adj.
1
7a, 7b, 7d, 7e, 7f, 7h, 7i, 7j, 7l, 7m, 7o, 7r pMICs.a. = 0.28σ + 0.10π + 0.50
7c (100)
7g (100)
7k (100)
7n (50)
96
0.685 0.615 0.111
70
51
59
7p (100)
4k (200)
4n (50)
86
2
3
4j, 4l, 4m, 4o, 4p, 4r
pMICs.a. = 0.60π + 0.36
119
52
0.936 0.921 0.099
0.492 0.436 0.249
4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l,
4m, 4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l,
7m, 7n
pMICs.a. = 0.42clogP − 11.70ELUMO
− 2.80
4a (800)
816
4j (200)
4o (50)
60
32
4p (200)
4r (200)
7a (100)
7b (100)
7c (100)
7e (100)
7h (100)
7o (50)
700
507
567
247
324
387
314
573
240
539
14
7p (100)
7r (50)
7s (100)
4k (100)
4n (50)
4k (50)
4n (50)
4a (100)
4
5
6
4j, 4l, 4m, 4o, 4p, 4r
4j, 4l, 4m, 4o, 4p, 4r
pMICE.f. = 0.54π + 0.43
pMICP.a. = 0.26π + 0.67
103
50
0.984 0.980 0.043
0.843 0.804 0.070
0.742 0.728 0.157
65
50
4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l, 4m, pMICP.a. = −0.005SAA + 2.60
88
4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l, 7m, 7n
4j (50)
38
69
59
61
21
10
14
21
14
14
26.5
14
9
4o (50)
4p (100)
4r (100)
7a (12.5)
7b (12.5)
7c (12.5)
7e (12.5)
7h (12.5)
7o (12.5)
7p (25)
7r (12.5)
7s (12.5)

Med Chem Res
Table 4 continued
Eq. Training set
Regression equation of training set
Test set
(MIC)
Predicted
value
(MIC)
Statistic parameter
r2
r2
s
adj.
7
4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l,
4m, 4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l,
7m, 7n
pMICP.a. = − 3.34EHOMO
0.005SAA + 1.23
−
4a (100)
4j (50)
145
50
0.753 0.725 0.158
4o (50)
89
4p (100)
4r (100)
7a (12.5)
7b (12.5)
7c (12.5)
7e (12.5)
7h (12.5)
7o (12.5)
7p (25)
74
76
34
13
19
36
18
15
31
7r (12.5)
7s (12.5)
7c (12.5)
7f (12.5)
7g (12.5)
7i (12.5)
7j (12.5)
4a (800)
4j (100)
4o (100)
4p (100)
4r (200)
7a (50)
15
8
8
9
7a, 7b, 7d, 7e, 7h, 7k, 7l, 7m, 7n, 7o,
7p, 7r
pMICP.a. = 0.08π + 1.30
13
0.662 0.628 0.045
0.450 0.420 0.226
11
11
12.5
11
4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l, 4m, 4n, pMICE.c. = − 0.004SAA + 1.64
7d, 7f, 7g, 7i, 7j, 7k, 7l, 7m, 7n
325
158
269
234
239
95
7b (50)
51
7c (50)
70
7e (50)
95
7h (100)
7o (100)
7p (100)
7r (50)
70
70
119
70
7s (50)
45
10 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l,
4m, 4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l,
7m, 7n
pMICE.c. = − 0.002SAA − 16.02ELUMO
− 2.34
4a (800)
4j (100)
4o (100)
4p (100)
4r (200)
7a (50)
1000
137
136
114
75
0.698 0.665 0.172
364
85
7b (50)
7c (50)
142
216
136
29
7e (50)
7h (100)
7o (100)
7p (100)
47

Med Chem Res
Table 4 continued
Eq. Training set
Regression equation of training set
Test set
(MIC)
Predicted
value
(MIC)
Statistic parameter
r2
r2
s
adj.
7r (50)
7s (50)
7c (100)
7f (50)
7g (100)
7i (50)
27
17
88
94
87
76
70
82
61
53
57
25
87
47
32
31
23
126
95
96
91
93
39
32
37
31
40
45
45
20
24
27
22
22
21
40
45
39
43
37
33
28
33
25
11 7a, 7b, 7d, 7e, 7h, 7k, 7l, 7m, 7n, 7o, 7p, 7r pMICS.m. = 0.56σ + 7.16ELUMO + 2.01
0.683 0.613 0.115
0.679 0.609 0.116
0.637 0.597 0.146
7j (50)
7c (100)
7f (50)
7g (100)
7i (50)
12 7a, 7b, 7d, 7e, 7h, 7k, 7l, 7m, 7n, 7o, 7p, 7r pMICS.m. = 0.31σ − 0.03µ + 0.76
7j (50)
4a (50)
4j (50)
4o (25)
4p (100)
4r (50)
7a (100)
7b (100)
7c (100)
7e (50)
7h (50)
7o (50)
7p (50)
7r (50)
7s (50)
4a (50)
4b (50)
4e (50)
4g (25)
4a (50)
4j (50)
4o (25)
4p (100)
4r (50)
7a (100)
7b (100)
7c (100)
7e (50)
7h (50)
7o (50)
7p (50)
7r (50)
7s (50)
13 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l,
pMICS.m. = 0.004SAA − 10.05
4m, 4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l, 7m, 7n ELUMO − 2.63
14 4c, 4d, 4f, 4h, 4i
pMICS.m. = 0.48π + 0.77
0.741 0.654 0.118
0.502 0.446 0.171
15 4b, 4c, 4d, 4e, 4f, 4g, 4h, 4i, 4k, 4l,
pMICS.m. = − 4.09EHOMO + 0.004SAA −
4m, 4n, 7d, 7f, 7g, 7i, 7j, 7k, 7l, 7m, 7n 1.80

Med Chem Res
Table 4 continued
Eq. Training set
Regression equation of training set
Test set
(MIC)
Predicted
value
(MIC)
Statistic parameter
r2
r2
s
adj.
16 7a, 7b, 7d, 7e, 7h, 7k, 7l, 7m, 7n,
pMICS.m. = 0.28σ + 0.61
7c (100)
7f (50)
74
0.577 0.535 0.126
0.679 0.608 0.259
0.914 0.892 0.061
7o, 7p, 7r
61
7g (100)
7i (50)
55
64
7j (50)
54
17 7a, 7b, 7d, 7e, 7h, 7k, 7l, 7m, 7n,
pMICc.a. = 0.46σ + 0.37π + 0.28
7c (200)
7f (200)
7g (200)
7i (200)
7j (100)
4k (200)
4n (100)
182
86
7o, 7p, 7r
117
52
58
18 4j, 4l, 4m, 4o, 4p, 4r
pMICc.a. = 0.31π + 0.30
150
106
r2 coefficient of determination, r2 adj internal cross-validation, s standard deviation
Fig. 3 The plot of observed
versus predicted pMICs.a. using
the QSAR model (Table 4;
Eq. 1)
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
Pre.pMICs.a.=0.245(Obs.pMICs.a.) + 0.409
R=0.630 R2=0.397
0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8
Observed pMICs.a.
were also synthesized from the reactions of substituted ben-
zamidoximes (3) with phenylboronic acid. The antimicrobial
activity studies of these oxadiazaboroles are not present in the
literature. Antibacterial and antifungal activities of oxadia-
zaborole derivatives have been screened against three
gram-positive bacteria, two gram-negative bacteria,
and one fungi. Interestingly, all the compounds exhibited
better results against P. aeruginosa (MIC of
12.5−200 µg/mL) than S. aureus, E. faecalis, E. coli,
S. mutans, and C. albicans. These bacteria show the most
dramatic resistance problems related to nosocomial infections
and multiresistant strains (Kiska and Gilligan, 1999).
Additionally, quantitative structure–activity relationship stu-
dies were carried out and this allowed us to draw the fol-
lowing conclusions about the antimicrobial activities of these
synthesized oxadiazaboroles: (i) all oxadiazaboroles showed
fair 2D correlations with some theoretical descriptors
(clogP, SAA, ELUMO, and EHOMO) against S. aureus,
P. aeruginosa, E. coli, and S. mutans; (ii) 3,5-disubstituted
4,5-dihydro-1,2,4,5-oxadiazaboroles (7a–r) showed fair 2D
correlations with the electronic (σ) and lipophilic (π)
descriptors against S. aureus and C. albicans; (iii) all oxa-
diazaboroles gave fair 1D correlations with the theoretical
descriptor (SAA) against P. aeruginosa and E. coli; (iv)

Med Chem Res
compounds (4a–i, 4j–r, and 7a–r) showed fair 1D correla-
tions with the electronic (σ) or lipophilic (π) descriptors
against S. aureus, E. faecalis, P. aeruginosa, S. mutans, and
C. albicans.
Me4Si as an internal standard. Silica gel (Fluka or Merck)
was used for column chromatography. Bands for the oxime
NOH and C=N groups were followed in IR spectrum.
The QSAR study has given key information regarding
the structural properties of 3,4,5-trisubstituted 4,5-dihydro-
1,2,4,5-oxadiazaboroles and 3,5-disubstituted 4,5-dihydro-
1,2,4,5-oxadiazaboroles, and may help to design more
potent antimicrobial compounds in the future studies.
Synthesis of p-chlorobenzaldehyde oxime (2a–i)
A solution of hydroxylamine hydrochloride (53 mmol, 3.7 g)
in water (10 mL) and a solution of anhydrous sodium
carbonate (27 mmol, 2.8 g) in water (15 mL) were mixed
and stirred. p-Chlorobenzaldehyde (53 mmol, 7.5 g) in
chloroform (20 mL) was added to this mixture. The reaction
was stirred at room temperature for 24 h. After the reaction
was complete, the chloroform phase was taken, the water
phase was extracted with chloroform (15 mL) three times,
and then the chloroform phase was collected and dried with
anhydrous CaCl2 overnight. The solvent was evaporated
under vacuum. The precipitate was crystallized from
ethyl acetate–petroleum ether (1:4) mixture to give
p-chlorobenzaldehyde oxime (2a–i) (5.76 g, 70 %). Mp:
107.2–109.3 °C, Lit. (Liu et al., 1980): 105.5–108 °C; IR
(ATR), υ (cm−1): 3255 (NOH), 1594 (C=N).
Experimental
Melting points were determined on the Electrothermal 9200
apparatus and are uncorrected. The FT IR spectra were
recorded on the Bruker Alpha-P spectrometer in the region of
1
4000–400 cm−1. H and 13C NMR spectra were recorded on
the Bruker DPX-400 (400 MHz) High Performance Digital
FT-NMR Spectrometer using CDCl3 and DMSO-d6 with
Table 5 Comparison of observed and predicted antibacterial activity
obtained by equation (1)
Synthesis of N-phenyl-p-chlorobenzamidoxime (3d)
(general procedure for 3a–i)
Compound
pMICs.a. (Eq. 1)
Observed
Predicted
Residuals
p-Chlorobenzaldehyde oxime (2a–i) (39 mmol, 6.08 g) was
dissolved in anhydrous chloroform (100 mL). After cooling
the solution in an ice bath, chlorine gas was passed through
the solution until the determination of the 3.20-g weight
increase. The solution was refrigerated for one night. Then
the solution was evaporated under reduced pressure at 40 °C.
The formed p-chloro-N-hydroxybenzimidoyl chloride was
dissolved in dry benzene (30 mL), and to the solution aniline
(78 mmol, 7.28 g) was added dropwise in dry benzene (20
mL) with constant stirring at room temperature for 24 h. After
this the mixture was refrigerated for 1 h. The salt precipitated
was removed by filtration. The residual solid was subjected to
flash column chromatography (eluant:ethyl acetate:petroleum
ether). The crude product was crystallized from ethyl acetate:
petroleum ether (1:6) mixture to give N-phenyl-p-chlor-
obenzamidoxime (3d) (5.24 g, 54 %). Mp: 127–130 °C. IR
(ATR), υ (cm−1): 3390 (N–H), 3141 (NOH), 1611 (C=N);
1H NMR (DMSO-d6), δ (ppm): 10.67 (s, 1H, NOH); 8.36
7a
7b
7c
7d
7e
7f
0.420
0.370
0.400
0.370
0.420
0.370
0.340
0.400
1.470
0.720
0.420
1.470
0.720
0.690
0.720
0.480
0.720
0.280
0.340
0.420
0.500
0.470
0.540
0.490
0.520
0.680
0.640
0.700
0.740
0.600
0.620
0.720
0.540
0.740
0.140
0.030
−0.020
−0.130
−0.050
−0.170
−0.150
−0.120
0.790
7g
7h
7i
7j
0.080
7k
7l
−0.280
0.730
7m
7n
7o
7p
7r
0.120
0.070
0.000
−0.060
−0.020
Table 6 Correlation
clogP
1.000
0.147
0.057
−0.508
0.087
clogP
coefficients (r2) of squared
correlation matrix of the
theoretical descriptors used in
the QSAR study
SAA
1.000
ELUMO
µ
0.289
−0.116
0.432
SAA
1.000
−0.220
0.808
1.000
−0.103
µ
EHOMO
Variables
1.000
ELUMO
EHOMO

Med Chem Res
(s, 1H, N–H); 7.35 (d, J = 15.5 Hz, aromatic, 4H); 7.05 (d, J
= 17.2 Hz, aromatic, 2H); 6.78 (t, J = 7.0 Hz, aromatic, 1H);
6.62 (d, J = 7.9 Hz, aromatic, 2H).
(m, aromatic, 4H); 7.07–7.01 (m, aromatic, 1H); 6.81–6.74
(m, aromatic, 2H); 6.44 (d, J = 7.9 Hz, aromatic, 1H).
N-(m-trifluoromethylphenyl)-p-chlorobenzamidoxime (3i)
yield: 36 %; mp: 160 °C; IR (ATR), υ (cm−1): 3387 (N–H),
3087 (NOH), 1633 (C=N); H NMR (DMSO-d6), δ (ppm):
Spectroscopic and analytical data of compounds (3)
1
10.91 (s, 1H, NOH); 8.80 (s, 1H, N–H); 7.40–7.26
(m, aromatic, 5H); 7.08–6.99 (m, aromatic, 2H); 6.79–6.77
(m, aromatic, 1H).
N-(p-dimethylaminophenyl)-p-chlorobenzamidoxime (3a)
yield: 55 %; mp: 205–208 °C; IR (ATR), υ (cm−1): 3369
(N–H), 3198 (NOH), 1636 (C=N); H NMR (DMSO-d6),
1
δ (ppm): 10.32 (s, 1H, NOH); 7.89 (s, 1H, N–H); 7.30 (d, J
= 19.6 Hz, aromatic, 4H); 6.56–6.46 (m, aromatic, 4H);
2.74 (s, 6H, N(CH3)2).
Synthesis of 3-(p-chlorophenyl)-4,5-diphenyl-4,5-
dihydro-1,2,4,5-oxadiazaborole (4d) (general procedure
for 4a–i)
N-(p-methoxyphenyl)-p-chlorobenzamidoxime (3b) yield:
47 %; mp: 185–186 °C; IR (ATR), υ (cm−1): 3408 (N–H),
3137 (NOH), 1632 (C=N); H NMR (DMSO-d6), δ (ppm):
10.45 (s, 1H, NOH); 8.11 (s, 1H, N–H); 7.32 (d, J = 19.6
Hz, aromatic, 4H); 6.68–6.58 (dd, J = 20.5 Hz, 12.3 Hz,
aromatic, 4H); 3.61 (s, 3H, OCH3).
N-phenyl-p-chlorobenzamidoxime
(3d)
(1.21 mmol,
0.300 g) and phenylboronic acid (1.36 mmol, 0.165 g)
were dissolved in toluene (20 mL) and the solution was
refluxed for 30 h in the presence of molecular sieves (4 Ǻ).
After extracting with acetone and filtering, the solvent was
evaporated under reduced pressure. The residual was
crystallized from ethyl acetate–petroleum ether (1:4)
mixture to give 3-(p-chlorophenyl)-4,5-diphenyl-4,5-
dihydro-1,2,4,5-oxadiazaborole (4d) (0.240 g, 59 %).
Mp: 201–202.8 °C. IR (ATR), υ (cm−1): 1599 (C=N),
1
N-(m-tolyl)-p-chlorobenzamidoxime (3c): 38 %; mp:
110–113 °C; IR (ATR), υ (cm−1): 3383 (N–H), 3194
(NOH), 1632 (C=N); 1H NMR (CDCl3), δ (ppm):
7.38–6.37 (m, aromatic, 8H); 2.20 (s, 3H, CH3).
1
1371 (B–N), 1125 (B–O); H NMR (CDCl3), δ (ppm):
7.55 (d, J = 7.9 Hz, aromatic, 2H); 7.45–7.38 (m, aro-
matic, 4H); 7.33–7.26 (m, aromatic, 6H); 7.17–7.13
(m, aromatic, 2H); 13C NMR (CDCl3), δ (ppm): 160.0
(C=N); 137.2; 136.7; 134.3; 131.3; 130.5; 129.9; 128.9;
128.3; 128.2; 128.0; 124.7. Anal. calcd. for
C19H14BClN2O: C, 68.61; H, 4.24; N, 8.42; found: C,
68.39; H, 4.32; N, 8.35.
N-(m-methoxyphenyl)-p-chlorobenzamidoxime (3e) yield:
42 %; mp: 66–69 °C; IR (ATR), υ (cm−1): 3301 (N–H),
3169 (NOH), 1631 (C=N); H NMR (DMSO-d6), δ (ppm):
10.68 (s, 1H, NOH); 8.34 (s, 1H, N–H); 7.40–7.33
(m, aromatic, 4H); 6.96–6.91 (m, aromatic, 1H); 6.35
(d, J = 8.2 Hz, aromatic, 1H); 6.23 (s, aromatic, 1H); 6.15
(d, J = 7.6 Hz, aromatic, 1H); 3.54 (s, 3H, OCH3).
1
Synthesis of 3,5-diphenyl-4-(m-tolyl)-4,5-dihydro-
1,2,4,5-oxadiazaborole (4j) (general procedure for 4j–r)
N-(p-bromophenyl)-p-chlorobenzamidoxime (3f) yield:
37 %; mp: 186–187 °C; IR (ATR), υ (cm−1): 3395 (N–H),
3085 (NOH), 1632 (C=N); H NMR (DMSO-d6), δ (ppm):
10.78 (s, 1H, NOH); 8.55 (s, 1H, N–H); 7.40–7.34
(m, aromatic, 4H); 7.22 (d, J = 6.1 Hz, aromatic, 2H); 6.56
(d, J = 6.7 Hz, aromatic, 2H).
1
N-(m-tolyl)-benzamidoxime (3j) (1.33 mmol, 0.300 g) and
phenylboronic acid (1.49 mmol, 0.181 g) were dissolved in
toluene (20 mL) and the solution was refluxed for 30 h in
the presence of molecular sieves (4 Ǻ). After extracting with
acetone and filtering, the solvent was evaporated under
reduced pressure. The residual was crystallized from pet-
roleum ether to give 3,5-diphenyl-4-(m-tolyl)-4,5-dihydro-
1,2,4,5-oxadiazaborole (4j) (0.30 g, 72 %). Mp: 191–194 °C.
IR (ATR), υ (cm−1): 1601 (C=N), 1370 (B–N), 1125
N-(p-chlorophenyl)-p-chlorobenzamidoxime (3g) yield:
41 %; mp: 170–172 °C; IR (ATR), υ (cm−1): 3394 (N–H),
1
3083 (NOH), 1629 (C=N); H NMR (DMSO-d6), δ (ppm):
10.76 (s, 1H, NOH); 8.55 (s, 1H, N–H); 7.40–7.36
(m, aromatic, 4H); 7.10 (d, J = 8.7 Hz, aromatic, 2H); 6.61
(d, J = 8.7 Hz, aromatic, 2H).
1
(B–O); H NMR (CDCl3), δ (ppm): 7.57 (d, J = 7.9 Hz,
aromatic, 2H); 7.44–7.22 (m, aromatic, 9H); 7.17 (d, J =
7.6 Hz, aromatic, 1H); 6.96 (d, J = 7.0 Hz, aromatic, 2H);
2.30 (s, 3H, CH3); 13C NMR (CDCl3), δ (ppm): 160.9
(C=N); 139.8; 137.4; 134.4; 131.1; 130.3; 129.5; 129.2;
128.9; 128.5; 128.5; 128.2; 126.3; 125.1; 21.5 (CH3). Anal.
calcd. for C20H17BN2O: C, 76.95; H, 5.49; N, 8.97; found:
C, 76.53; H, 5.37; N, 9.16.
N-(m-chlorophenyl)-p-chlorobenzamidoxime (3h) yield:
44 %; mp: 135–137 °C; IR (ATR), υ (cm−1): 3379 (N–H),
1
3193 (NOH), 1636 (C=N); H NMR (CDCl3), δ (ppm):
10.85 (s, 1H, NOH); 8.63 (s, 1H, N–H); 7.51–7.39

Med Chem Res
Spectroscopic and analytical data of compounds (4)
3-(p-chlorophenyl)-4-(p-bromophenyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4f) yield: 59 %; mp: 199–201 °C;
IR (ATR), υ (cm−1): 1598 (C=N), 1367 (B–N), 1123
(B–O); 1H NMR (CDCl3), δ (ppm): 7.56–7.42 (m, aromatic,
4H); 7.34–7.23 (m, aromatic, 5H); 7.04–7.0 (m, aromatic,
4H); 13C NMR (CDCl3), δ (ppm): 159.7 (C=N); 137.0;
136.3; 134.3; 133.1; 131.5; 130.5; 129.5; 129.1; 128.3;
124.3; 122.1.11B NMR (CDCl3), δ (ppm): 32.3. Anal. calcd.
for C19H13BBrClN2O: C, 55.46; H, 3.18; N, 6.81; found: C,
55.44; H, 3.34; N, 6.96.
3-(p-chlorophenyl)-4-(p-N,N-dimethylaminophenyl)-5-phe-
nyl-4,5-dihydro-1,2,4,5-oxadiazaborole (4a) yield: 75 %;
mp: 208 –210 °C; IR (ATR), υ (cm−1): 1601 (C=N), 1371
(B–N), 1126 (B–O); 1H NMR (CDCl3), δ (ppm): 7.59 (d, J
= 7.3 Hz, aromatic, 2H); 7.43–7.26 (m, aromatic, 7H); 6.99
(d, J = 8.5 Hz, aromatic, 2H); 6.64 (d, J = 8.5 Hz, aromatic,
2H); 2.99 (s, 6H, N(CH3)2); 13C NMR (CDCl3), δ (ppm):
160.5 (C=N); 149.9; 136.4; 134.4; 131.1; 130.5; 128.8;
128.5; 128.1; 125.6; 125.1; 112.8; 40.6 (CH3). Anal. calcd.
for C21H19BClN3O: C, 67.14; H, 5.10; N, 11.19; found: C,
66.48; H, 5.28; N, 11.04.
3-(p-chlorophenyl)-4-(p-chlorophenyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4g) yield: 59 %; mp: 187–190 °C;
IR (ATR), υ (cm−1): 1597 (C=N), 1368 (B–N), 1122
(B–O); 1H NMR (CDCl3), δ (ppm): 7.56–7.52 (m, aromatic,
4H); 7.46–7.24 (m, aromatic, 5H); 7.10–7.07 (m, aromatic,
3-(p-chlorophenyl)-4-(p-methoxyphenyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4b) yield: 61 %; mp: 197–199 °C;
IR (ATR), υ (cm−1): 1599 (C=N), 1369 (B–N), 1124
4H); 13C NMR (CDCl3),
δ (ppm): 159.8 (C=N);
1
(B–O); H NMR (CDCl3), δ (ppm): 7.55 (d, J = 7.0 Hz,
136.9; 135.8; 134.3; 134.1; 131.4; 130.5; 130.2; 129.2;
129.1; 128.3; 124.3. Anal. calcd. for C19H13BCl2N2O:
C, 62.17; H, 3.57; N, 7.63; found: C, 62.26; H, 3.68;
N, 7.66.
aromatic, 2H); 7.44–7.25 (m, aromatic, 7H); 7.05
(d, J = 8.7 Hz, aromatic, 2H); 6.88 (d, J = 8.7 Hz, aromatic,
2H); 3.84 (s, 3H, OCH3); 13C NMR (CDCl3), δ (ppm):
160.2 (C=N); 159.2; 136.6; 134.3; 131.2; 130.5; 129.9;
129.0; 128.9; 128.2; 124.8; 115.0; 55.7 (OCH3). HRMS:
m/z (M + H)+ calcd. for C20H17BClN2O2: 363.1072;
found: 363.1081 (M + H)+. Anal. calcd. for C20H16BClN2O2:
C, 66.24; H, 4.45; N, 7.73; found: C, 65.56; H, 4.76;
N, 7.68.
3-(p-chlorophenyl)-4-(m-chlorophenyl)-5-phenyl-4,5-dihy-
dro-1,2,4,5-oxadiazaborole (4h) yield: 60 %; mp:
177.7–179 °C; IR (ATR), υ (cm−1): 1599 (C=N), 1367
1
(B–N), 1124 (B–O); H NMR (CDCl3), δ (ppm): 7.54 (d,
J = 8.2 Hz, aromatic, 2H); 7.47–7.25 (m, aromatic, 10H);
7.18 (t, J = 1.7 Hz, aromatic, 1H); 7.04 (m, aromatic, 1H);
13C NMR (CDCl3), δ (ppm): 159.7 (C=N); 138.5; 137.0;
135.5; 134.3; 131.5; 130.9; 130.5; 129.1; 128.7; 128.4;
128.1; 126.3; 124.2. Anal. calcd. for C19H13BCl2N2O: C,
62.17; H, 3.57; N, 7.63; found: C, 62.24; H, 3.52; N, 7.63.
3-(p-chlorophenyl)-4-(m-trifluoromethylphenyl)-5-phenyl-
4,5-dihydro-1,2,4,5-oxadiazaborole (4i) yield: 46 %; mp:
165–167 °C; IR (ATR), υ (cm−1): 1598 (C=N), 1368
3-(p-chlorophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4c) yield: 57 %; mp: 182–184 °C;
IR (ATR), υ (cm−1): 1599 (C=N), 1369 (B–N), 1124
1
(B–O); H NMR (CDCl3), δ (ppm): 7.55 (d, J = 9.3 Hz,
aromatic, 2H); 7.42–7.39 (m, aromatic, 1H); 7.32–7.18 (m,
aromatic, 8H); 6.96 (d, J = 6.1 Hz, aromatic, 2H); 2.32 (s,
3H, CH3); 13C NMR (CDCl3), δ (ppm): 160.0 (C=N);
140.0; 137.1; 136.6; 134.4; 131.2; 130.5; 129.7; 129.1;
128.9; 128.5; 128.2; 125.0; 124.8; 21.5 (CH3). Anal. calcd.
for C20H16BClN2O: C, 69.30; H, 4.65; N, 8.08; found: C,
68.78; H, 4.58; N, 7.92.
1
(B–N), 1119 (B–O); H NMR (CDCl3), δ (ppm): 7.66 (d,
J = 7.9 Hz, aromatic, 1H); 7.55–7.42 (m, aromatic, 5H);
7.34–7.21 (m, aromatic, 7H); 13C NMR (CDCl3), δ (ppm):
159.6 (C=N); 137.9; 137.1; 134.2; 132.6; 132.2; 131.6;
131.3; 130.6; 130.5; 129.2; 128.4; 125.2; 125.1; 125.0;
124.8; 124.0. Anal. calcd. for C20H13BClF3N2O: C, 59.97;
H, 3.27; N, 6.99; found: C, 59.81; H, 3.23; N, 6.96.
3-(p-chlorophenyl)-4-(m-methoxyphenyl)-5-phenyl-4,5-
dihydro-1,2,4,5-oxadiazaborole (4e) yield: 60 %; mp:
170–172 °C; IR (ATR), υ (cm−1): 1601 (C=N), 1367
(B–N), 1123 (B–O); 1H NMR (CDCl3), δ (ppm):
7.58 (d, J = 7.9 Hz, aromatic, 2H); 7.45–7.25 (m, aro-
matic, 8H); 6.92 (d, J = 10.8 Hz, aromatic, 1H);
6.75 (d, J = 9.6 Hz, aromatic, 1H); 6.67 (t, J = 2.0 Hz,
aromatic, 1H); 3.73 (s, 3H, OCH3); 13C NMR (CDCl3),
δ (ppm): 159.9 (C=N); 160.6; 138.3; 136.7; 134.3;
131.3; 130.6; 130.4; 128.9; 128.2; 124.7; 120.2; 113.8;
113.8; 55.6 (OCH3). Anal. calcd. for C20H16BClN2O2:
C, 66.24; H, 4.45; N, 7.73; found: C, 65.67; H, 4.53;
N, 7.63.
3-(p-fluorophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4k) yield: 62 %; mp: 188–190 °C;
IR (ATR), υ (cm−1): 1598 (C=N), 1370 (B–N), 1123
1
(B–O); H NMR (CDCl3), δ (ppm): 7.55 (d, J = 8.2 Hz,
aromatic, 2H); 7.44–7.39 (t, J = 7.3 Hz, aromatic, 1H);
7.36–7.24 (m, aromatic, 5H); 7.18–6.94 (m, aromatic, 5H);
2.31 (s, 3H, CH3); 13C NMR (CDCl3), δ (ppm): 160.1
(C=N); 165.6; 162.2; 140.0; 137.2; 134.3; 131.4; 131.2;
131.2; 129.6; 129.0; 128.5; 128.2; 125.1; 122.4; 122.4;
115.9; 115.6; 21.5 (s, 3H, CH3). Anal. calcd. for

Med Chem Res
C20H16BFN2O: C, 72.76; H, 4.88; N, 8.48; found: C, 72.88;
H, 5.02; N, 8.48.
IR (ATR), υ
(cm−1): 1599 (C=N), 1349 (B–N),
1138 (B–O); 1H NMR (CDCl3), δ (ppm): 8.24–
8.21 (m, aromatic, 2H); 7.71 (d, J = 8.7 Hz, aromatic,
1H); 7.59–7.41 (m, aromatic, 4H); 7.33–7.21 (m, aro-
matic, 4H); 7.01 (d, J = 7.0 Hz, aromatic, 2H); 2.33
(s, 3H, CH3); 13C NMR (CDCl3), δ (ppm): 159.0
(C=N); 148.1; 140.4; 136.7; 134.9; 134.4; 131.5; 130.0;
129.7; 129.6; 128.4; 128.3; 128.1; 125.1; 125.0; 124.2;
21.5 (s, 3H, CH3). Anal. calcd. for C20H16BN3O3: C,
67.25; H, 4.52; N, 11.76; found: C, 67.55; H, 4.60;
N, 11.83.
3-(p-bromophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4l) yield: 60 %; mp: 192–193 °C;
IR (ATR), υ (cm−1): 1598 (C=N), 1367 (B–N), 1122
1
(B–O); H NMR (CDCl3), δ (ppm): 7.55 (d, J = 7.0 Hz,
aromatic, 2H); 7.43–7.41 (m, aromatic, 3H); 7.32–7.18 (m,
aromatic, 6H); 6.95 (d, J = 6.7 Hz, aromatic, 2H); 2.32 (s,
3H, CH3); 13C NMR (CDCl3), δ (ppm): 160.1 (C=N);
140.1; 137.1; 134.4; 131.8; 131.2; 130.7; 129.7; 129.1;
128.5; 128.2; 125.2; 125.0; 21.5 (s, 3H, CH3). Anal. calcd.
for C20H16BBrN2O: C, 61.42; H, 4.12; N, 7.16; found: C,
61.28; H, 4.22; N, 7.12.
3-(p-nitrophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-1,2,4,5-
oxadiazaborole (4r) yield: 76 %; mp: 190–192 °C; IR
(ATR), υ (cm−1): 1598 (C=N), 1340 (B–N), 1122
1
(B–O); H NMR (CDCl3), δ (ppm): 8.13 (d, J = 10.8 Hz,
3-(m-chlorophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4m) yield: 75 %; mp: 130–133 °C;
IR (ATR), υ (cm−1): 1600 (C=N), 1370 (B–N), 1134
aromatic, 2H); 7.57–7.53 (m, aromatic, 4H); 7.46–7.41
(m, aromatic, 1H); 7.33–7.21 (m, aromatic, 4H); 6.98
(d, J = 5.8 Hz, aromatic, 2H); 2.33 (s, 3H, CH3); 13C NMR
(CDCl3), δ (ppm): 159.2 (C=N); 148.8; 140.4; 136.7;
134.4; 132.6; 131.5; 130.1; 129.9; 129.5; 128.3; 128.3;
124.9; 123.7; 21.5 (s, 3H, CH3). Anal. calcd. for
C20H16BN3O3: C, 67.25; H, 4.52; N, 11.76; found: C,
67.48; H, 4.51; N, 11.84.
1
(B–O); H NMR (CDCl3), δ (ppm): 7.57 (d, J = 9.3 Hz,
aromatic, 2H); 7.44–7.13 (m, aromatic, 9H); 6.96 (d, J =
5.5 Hz, aromatic, 2H); 2.32 (s, 3H, CH3); 13C NMR
(CDCl3), δ (ppm): 159.8 (C=N); 140.0; 137.0; 134.5;
134.4; 131.3; 130.5; 129.8; 129.7; 129.4; 129.2; 128.4;
128.2; 128.0; 127.3; 125.0; 21.5 (s, 3H, CH3). Anal. calcd.
for C20H16BClN2O: C, 69.30; H, 4.65; N, 8.08; found: C,
69.31; H, 4.46; N, 8.07.
Synthesis of benzamidoxime (6) (general procedure)
Method A: A solution of hydroxylamine hydrochloride
(200 mmol, 13.89 g) in ethanol (100 mL) and a solution
of anhydrous sodium carbonate (100 mmol, 10.59 g)
in boiling water (25 mL) were mixed and stirred.
Benzonitrile (200 mmol, 20.62 g) in ethanol (25 mL) was
added to this mixture. The reaction was refluxed at
80 °C for 21 h. The solvent was evaporated under reduced
pressure. The residue was washed with water and
extracted with chloroform. The solution was dried with
anhydrous CaCl2 and the solvent was evaporated under
vacuum. The precipitate was crystallized from ethyl
acetate–petroleum ether to give benzamidoxime (6)
(11.88 g, 43 %). Mp: 75–77.5 °C, Lit. (Krüger, 1885):
79–80 °C; IR (ATR), υ (cm−1): 3450, 3358 (NH2), 3181
(N–OH), 1645 (C=N).
3-(m-bromophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4n) yield: 56 %; mp: 139–141 °C;
IR (ATR), υ (cm−1): 1600 (C=N), 1371 (B–N), 1131
(B–O); 1H NMR (CDCl3), δ (ppm): 7.61–7.55 (m, aromatic,
3H); 7.49–7.41 (dd, J = 18.1 Hz, 10.8 Hz, aromatic, 2H);
7.32–7.09 (m, aromatic, 6H); 6.96 (d, J = 5.5 Hz, aromatic,
2H); 2.32 (s, 3H, CH3); 13C NMR (CDCl3), δ (ppm): 159.6
(C=N); 140.0; 137.0; 134.4; 133.4; 132.2; 131.3; 130.0;
129.7; 129.2; 128.4; 128.2; 127.7; 125.0; 122.5; 21.5
(s, 3H, CH3). Anal. calcd. for C20H16BBrN2O: C, 61.42; H,
4.12; N, 7.16; found: C, 61.37; H, 4.16; N, 7.15.
3-(p-trifluoromethylphenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4o) yield: 36 %; mp: 123–127 °C;
IR (ATR),
υ
(cm−1): 1601 (C=N), 1372 (B–N),
1
1126 (B–O); H NMR (CDCl3), δ (ppm): 7.58–7.40 (m,
aromatic, 7H); 7.33–7.19 (m, aromatic, 4H); 6.97 (d, J =
6.7 Hz, aromatic, 2H); 2.32 (s, 3H, CH3); 13C NMR
(CDCl3), δ (ppm): 159.8 (C=N); 140.2; 137.0; 134.4;
131.3; 129.8; 129.5; 129.3; 128.4; 128.2; 125.5; 125.5;
125.0; 21.5 (s, 3H, CH3). Anal. calcd. for C21H16BF3N2O:
C, 66.35; H, 4.24; N, 7.37; found: C, 66.28; H, 4.32;
N, 7.39.
Method B (Gosenca et al., 2013): A solution of
benzonitrile (3.6 mmol, 0.371 g), hydroxylamine hydro-
chloride (7.2 mmol, 0.50 g), and potassium carbonate
(7.25 mmol, 1.0 g) were suspended in anhydrous ethanol
(50 mL). The mixture was refluxed for 8 h. The pre-
cipitate was rapidly filtered off before cooling and the
solvent was evaporated under vacuum. The crude pro
duct was recrystallized from dichloromethane–petroleum
ether to give benzamidoxime (6) (0.325 g, 66 %). Mp:
63–65 °C. IR (ATR), υ (cm−1): 3450, 3357 (NH2), 3181
(N–OH), 1642 (C=N).
3-(m-nitrophenyl)-4-(m-tolyl)-5-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (4p) yield: 70 %; mp: 125–127 °C;

Med Chem Res
Synthesis of 3,5-diphenyl-4,5-dihydro-1,2,4,5-
oxadiazaborole (7g) (general procedure for 7a–s)
5-(4-tolyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole
(7d) yield 91 %; mp: 149–149.5 °C; IR (ATR), υ (cm−1):
1
3377 (N–H), 1614 (C=N), 1416 (B–N), 1211 (B–O); H
Benzamidoxime (6) (22 mmol, 3.0 g) and phenylboronic acid
(22 mmol, 2.86 g) were dissolved in benzene (150 mL) and
the solution was refluxed overnight, then the solvent was
evaporated under reduced pressure. The residual was crystal-
lized from hexane to give 3,5-diphenyl-4,5-dihydro-1,2,4,5-
oxadiazaborole (7g) (4.57 g, 94 %). Mp: 164–164.5 °C, Lit.
(Akcan, 2007): 154–156 °C; IR (ATR), υ (cm−1): 3418,
NMR (DMSO-d6), δ (ppm): 10.39 (s, 1H, NH); 8.00–7.97
(m, aromatic, 2H); 7.86 (d, J = 7.6 Hz, aromatic, 2H);
7.58–7.56 (t, J = 3.8 Hz, aromatic, 3H); 7.34 (d, J = 7.6 Hz,
aromatic, 2H); 2.37 (s, 3H, ArCH3); 13C NMR (DMSO-d6), δ
(ppm): 159.8 (C=N); 141.5; 134.6; 131.4; 129.6; 129.6;
127.4; 126.9; 21.9 (CH3). Anal. calcd. for C14H13BN2O: C,
71.23; H, 5.55; N, 11.87; found: C, 71.43; H, 5.57; N, 11.90.
1
3379 (N–H), 1601 (C=N), 1415 (B–N), 1200 (B–O); H
5-(3-N,N-dimetylaminophenyl)-3-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (7e) yield 82 %; mp: 95–96 °C; IR
(ATR), υ (cm−1): 3237 (N–H), 1599 (C=N), 1416 (B–N),
NMR (DMSO-d6), δ (ppm): 10.46 (s, 1H, NH); 8.02–7.49
(m, aromatic, 10H); 13C NMR (DMSO-d6), δ (ppm): 159.9
(C=N); 134.6; 131.8; 131.4; 129.6; 128.9; 127.4; 126.9.
Anal. calcd. for C13H11BN2O: C, 70.32; H, 4.99; N, 12.62;
found: C, 70.26; H, 5.28; N, 12.53.
1
1234 (B–O); H NMR (DMSO-d6), δ (ppm): 10.35 (s, 1H,
NH); 7.99–7.94 (m, aromatic, 2H); 7.58–7.56 (t, J = 3.5 Hz,
aromatic, 3H); 7.39–7.24 (m, aromatic, 3H); 6.91–6.88 (m,
aromatic, 1H); 2.96 (s, 6H, N(CH3)2); 13C NMR (DMSO-
d6), δ (ppm): 159.9 (C=N); 150.8; 131.4; 129.6; 129.5;
127.4; 126.9; 126.0; 122.3; 118.2; 115.8; 40.4 (CH3). Anal.
calcd. for C15H16BN3O: C, 67.95; H, 6.08; N, 15.85; found:
C, 67.20; H, 6.34; N, 15.43.
Spectroscopic and analytical data of compounds (7)
5-(4-N,N-dimethylaminophenyl)-3-phenyl-4,5-dihydro-
1,2,4,5-oxadiazaborole (7a) yield: 91 %; mp: 198–200 °C;
IR (ATR), υ (cm−1): 3329 (N–H), 1608 (C=N), 1418
1
(B–N), 1234 (B–O); H NMR (DMSO-d6), δ (ppm): 10.13
5-(3-tolyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole
(7f) yield 93 %; mp: 158–160 °C; IR (ATR), υ (cm−1):
(s, 1H, NH); 7.99–7.96 (m, aromatic, 2H); 7.78 (d, J = 8.7
Hz, aromatic, 2H); 7.58–7.55 (m, aromatic, 3H); 6.81 (d, J
= 8.7 Hz, aromatic, 2H); 2.97 (s, 6H, N(CH3)2); 13C NMR
(DMSO-d6), δ (ppm): 159.6 (C=N); 152.8; 135.8; 131.2;
129.6; 127.7; 126.9; 112.1; 40.2 (CH3). Anal. calcd. for
C15H16BN3O: C, 67.95; H, 6.08; N, 15.85; found: C, 68.27;
H, 6.28; N, 15.90.
1
3239 (N–H), 1591 (C=N), 1422 (B–N), 1200 (B–O); H
NMR (DMSO-d6), δ (ppm): 10.40 (s, 1H, NH); 7.99–7.94
(m, aromatic, 2H); 7.74–7.70 (t, J = 7.0 Hz, aromatic, 2H);
7.56–7.53 (m, aromatic, 3H); 7.39–7.33 (m, aromatic, 2H);
2.35 (s, 3H, ArCH3); 13C NMR (DMSO-d6), δ (ppm): 159.9
(C=N); 137.8; 135.1; 132.4; 131.6; 131.4; 129.6; 128.8;
128.7; 127.4; 126.9; 21.7 (CH3). Anal. calcd. for
C14H13BN2O: C, 71.23; H, 5.55; N, 11.87; found: C, 71.71;
H, 5.80; N, 11.94.
5-(4-hydroxyphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadia-
zaborole (7b) yield 82 %; mp: 197–198 °C; IR (ATR), υ
(cm−1): 3385 (N–H), 1608 (C=N), 1425 (B–N), 1204
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.23 (s, 1H, NH);
5-(3-methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadia-
zaborole (7h) yield 27 %; mp: 115–117 °C; IR (ATR), υ
(cm−1): 3228 (N–H), 1604 (C=N), 1423 (B–N), 1233
7.98–7.95 (m, aromatic, 2H); 7.80–7.76 (m, aromatic, 2H);
7.58–7.55 (m, aromatic, 3H); 6.92–6.89 (m, aromatic, 2H);
13C NMR (DMSO-d6), δ (ppm): 160.8 (Ar–O); 159.7
(C=N); 136.4; 131.3; 129.6; 127.5; 126.9; 118.6; 116.1.
Anal. calcd. for C13H11BN2O2: C, 65.59; H, 4.66; N, 11.77;
found: C, 65.18; H, 5.20; N, 11.41.
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.45 (s, 1H, NH);
8.00–7.97 (m, aromatic, 2H); 7.59–7.41 (m, aromatic, 7H);
3.84 (s, 3H, ArOCH3); 13C NMR (DMSO-d6), δ (ppm):
159.9 (Ar–O); 159.7 (C=N); 131.4; 130.2; 129.6; 127.3;
126.9; 126.7; 119.4; 117.5; 55.7 (OCH3). Anal. calcd. for
C14H13BN2O2: C, 66.71; H, 5.20; N, 11.11; found:
C, 66.98; H, 5.51; N, 10.88.
5-(4-methoxyphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadia-
zaborole (7c) yield 78 %; mp: 145–148 °C; IR (ATR), υ
(cm−1): 3358 (N–H), 1603 (C=N), 1414 (B–N), 1236 (B–O);
1H NMR (DMSO-d6), δ (ppm): 10.27 (s, 1H, NH);
7.96–7.85 (m, aromatic, 4H); 7.55–7.52 (t, J = 3.8 Hz,
aromatic, 3H); 7.06 (d, J = 8.4 Hz, aromatic, 2H); 3.79
(s, 3H, ArOCH3); 13C NMR (DMSO-d6), δ (ppm): 162.3
(Ar–O); 159.8 (C=N); 136.3; 131.3; 129.6; 127.5; 126.9;
114.6; 55.7 (OCH3). Anal. calcd. for C14H13BN2O2:
C, 66.71; H, 5.20; N, 11.11; found: C, 66.75; H, 5.59;
N, 11.33.
5-(4-bromophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7i) yield 56 %; mp: 228–229 °C; IR (ATR),
υ (cm−1): 3363 (N–H), 1587 (C=N), 1415 (B–N), 1203
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.50 (s, 1H, NH);
7.98–7.95 (m, aromatic, 2H); 7.89–7.85 (m, aromatic, 2H);
7.75–7.72 (m, aromatic, 2H); 7.59–7.56 (m, aromatic, 3H);
13C NMR (DMSO-d6), δ (ppm): 160.0 (C=N); 136.5;
132.0; 131.5; 129.7; 127.2; 126.9; 125.9. Anal. calcd.

Med Chem Res
for C13H10BBrN2O: C, 51.88; H, 3.35; N, 9.31; found:
C, 51.49; H, 3.28; N, 9.25.
5-(3-nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7o) yield 53 %; mp: 241–243 °C; IR (ATR),
υ (cm−1): 3400 (N–H), 1610 (C=N), 1448 (B–N), 1215
1
5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7j) yield 84 %; mp: 220–222 °C; IR (ATR),
υ (cm−1): 3364 (N–H), 1595 (C=N), 1418 (B–N), 1204
(B–O); H NMR (DMSO-d6), δ (ppm): 10.71 (s, 1H, NH);
8.77 (s, aromatic, 1H); 8.39–8.29 (m, aromatic, 2H);
7.99–7.95 (m, aromatic, 2H); 7.83–7.78 (t, J = 7.6 Hz,
aromatic, 1H); 7.60–7.58 (t, J = 3.5 Hz, aromatic, 3H); 13C
NMR (DMSO-d6), δ (ppm): 160.0 (C = N); 148.3; 140.6;
131.6; 130.6; 129.7; 128.8; 128.7; 127.0; 126.9; 126.3.
Anal. calcd. for C13H10BN3O3: C, 58.47; H, 3.77; N, 15.74;
found: C, 58.82; H, 3.77; N, 15.69.
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.50 (s, 1H, NH);
7.96–7.94 (t, J = 1.7 Hz, aromatic, 4H); 7.59–7.57 (t, J =
3.2 Hz, aromatic, 5H); 13C NMR (DMSO-d6), δ (ppm):
160.0 (C=N); 136.8; 136.3; 131.5; 129.6; 129.1; 127.2;
126.9. Anal. calcd. for C13H10BClN2O: C, 60.87; H, 3.93;
N, 10.92; found: C, 60.52; H, 3.89; N, 10.87.
5-(4-methanesulfonylphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-
oxadiazaborole (7p) yield 82%; mp: 220–222.5 °C; IR
(ATR), υ (cm−1): 3389 (N–H), 1601 (C = N), 1408 (B–N),
1206 (B–O); 1H NMR (DMSO-d6), δ (ppm): 10.69
(s, 1H, NH); 8.21 (d, J = 8.4 Hz, aromatic, 2H); 8.10
(d, J = 8.2 Hz, aromatic, 2H); 8.00–7.97 (m, aromatic,
2H); 7.60–7.58 (t, J = 3.5 Hz, aromatic, 3H); 3.29 (s, 3H,
CH3); 13C NMR (DMSO-d6), δ (ppm): 160.1 (C=N);
143.5; 135.4; 135.3; 131.6; 129.7; 128.7; 127.2; 127.1;
126.9; 44.0 (CH3). Anal. calcd. for C14H13BN2O3S:
C, 56.02; H, 4.37; N, 9.33; found: C, 55.96; H, 4.38;
N, 9.61.
5-(3-chlorophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7k) yield 82 %; mp: 155–157 °C; IR (ATR), υ
(cm−1): 3381 (N–H), 1592 (C=N), 1408 (B–N), 1207 (B–O);
1H NMR (DMSO-d6), δ (ppm): 10.54 (s, 1H, NH); 7.99–7.96
(m, aromatic, 3H); 7.89 (d, J = 7.3 Hz, aromatic, 1H);
7.60–7.52 (m, aromatic, 5H); 13C NMR (DMSO-d6), δ
(ppm): 160.0 (C=N); 134.0; 132.9; 131.6; 131.5; 131.0;
129.7; 127.2; 126.9. Anal. calcd. for C13H10BClN2O: C,
60.87; H, 3.93; N, 10.92; found: C, 60.78; H, 4.11; N, 10.80.
5-(3-bromophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7l) yield 77 %; mp: 158–160 °C; IR (ATR), υ
(cm−1): 3383 (N–H), 1605 (C=N), 1418 (B–N), 1209
5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7r) yield 51 %; mp: 257–259 °C; IR (ATR),
υ (cm−1): 3417, 3377 (N–H), 1602 (C=N), 1415 (B–N),
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.52 (s, 1H, NH);
8.24–7.37 (m, aromatic, 10H); 13C NMR (DMSO-d6), δ
(ppm): 160.0 (C=N); 139.9; 134.5; 133.2; 131.5; 131.4;
129.7; 127.2; 126.9; 122.8. Anal. calcd. for C13H10
BBrN2O: C, 51.88; H, 3.35; N, 9.31; found: C, 52.00; H,
2.89; N, 9.39.
1
1200 (B–O); H NMR (DMSO-d6), δ (ppm): 10.73 (s, 1H,
NH); 8.36 (d, J = 8.4 Hz, aromatic 2H); 8.20 (d, J = 8.4 Hz,
aromatic, 2H); 7.99–7.96 (m, aromatic, 2H); 7.59–7.58 (m,
aromatic, 3H); 13C NMR (DMSO-d6), δ (ppm): 160.1
(C=N); 149.8; 135.7; 131.6; 129.7; 127.0; 126.9; 123.6.
Anal. calcd. for C13H10BN3O3: C, 58.47; H, 3.77; N, 15.74;
found: C, 59.02; H, 3.83; N, 15.80.
5-(4-acetylphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7m) yield 74 %; mp: 205–207 °C; IR (ATR),
υ (cm−1): 3397 (N–H), 1549 (C=N), 1414 (B–N), 1202
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.57 (s, 1H, NH);
5-butyl-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole (7s)
yield 49 %; mp: 92–94 °C; IR (ATR), υ (cm−1): 3260
(N–H), 2926 (CH2), 1558 (C=N), 1427 (B–N), 1223 (B–O);
1H NMR (DMSO-d6), δ (ppm): 9.82 (s, 1H, NH); 7.88–7.85
(m, aromatic, 2H); 7.49–7.47 (m, aromatic, 3H); 1.53–1.11
(m, 6H, CH2–CH2–CH2); 0.89–0.84 (t, J = 7.0 Hz, 3H,
CH3); 13C NMR (DMSO-d6), δ (ppm): 159.2 (C=N); 131.1;
129.5; 127.5; 126.8; 27.3, 25.5 (CH2–CH2–CH2); 14.4
(CH3). Anal. calcd. for C11H15BN2O: C, 65.39; H, 7.48; N,
13.86; found: C, 65.59; H, 8.05; N, 14.25.
8.04 (s, aromatic, 4H); 7.96–7.93 (m, aromatic, 2H);
7.56–7.54 (m, aromatic, 3H); 2.60 (s, 3H, COCH3); 13C
NMR (DMSO-d6), δ (ppm): 198.7 (C=O), 160.1 (C=N);
139.2; 134.8; 131.5; 129.7; 128.7; 128.4; 127.2; 127.0; 27.5
(CH3). Anal. calcd. for C15H13BN2O2: C, 68.22; H, 4.96;
N, 10.61; found: C, 68.67; H, 5.07; N, 10.70.
5-(3-cyanophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiaza-
borole (7n) yield 70 %; mp: 236–239 °C; IR (ATR), υ
(cm−1): 3381 (N–H), 1599 (C=N), 1429 (B–N), 1221
1
(B–O); H NMR (DMSO-d6), δ (ppm): 10.54 (s, 1H, NH);
8.28 (s, aromatic, 1H); 8.19 (d, J = 7.3 Hz, aromatic, 1H);
7.99–7.90 (m, aromatic, 3H); 7.72–7.67 (t, J = 7.6 Hz,
aromatic, 1H); 7.56–7.54 (t, J = 3.2 Hz, aromatic, 3H); 13C
NMR (DMSO-d6), δ (ppm): 160.0 (C=N); 138.7; 138.0;
135.1; 131.6; 130.1; 129.7; 128.7; 127.1; 126.9; 119.3;
112.3 (C≡N). Anal. calcd. for C14H10BN3O: C, 68.06; H,
4.08; N, 17.01; found: C, 68.20; H, 4.55; N, 16.52.
Biological assays
The antibacterial activities of 35 oxadiazaboroles (4a–r and
7a–s) have been determined by the broth microdilution
susceptibility test, which is outlined by the Clinical and
Laboratory Standards Institute M7–A7 (CLSI, 2006). MICs
for each compound were determined against S. aureus

Med Chem Res
(ATCC 25983), E. faecalis (ATCC 29212), P. aeruginosa
(ATCC 27853), and E. coli (ATCC 25922).
Then, the solutions were diluted once more (1/10), and final
concentrations became 1 × 107 CFU/mL. Five microliters
from each dilution was placed into each well containing
100 µL of dilutions of the compounds so that each well
contained 5 × 105 CFU/mL of inoculum. All the inoculated
plates were incubated at 35 °C for 16–20 h. The lowest
concentration of the compounds that prevents visible
growth was considered to be the MIC. To control the
reliability of the results, ampicillin and ciprofloxacin were
used as reference antimicrobial reagents. The parameters of
these reagents were compared with the data obtained from
the method applied in this study.
The bacteria (S. mutans) were cultivated on a sheep agar
plate for 36–48 h at 37 °C in 5–10 % CO2, and incubation
was done in a candle extinction jar. After diluting the
compounds, standardized inoculum of each bacterium (0.5
Mc Farland standard unit, 1 × 108 CFU/mL; colony form-
ing unit/mL) was prepared in Brain-Heart Infusion broth.
Then the compounds were diluted once more (1/10), and the
final concentrations became 1 × 107 CFU/mL. Five
microliters from each dilution was placed into each well
containing 100 μL of dilutions of compounds so that each
well contained 5 × 105 CFU/mL of inoculum. All the
inoculated plates were incubated at 35 °C for 36−48 h with
5–10 % CO2. The lowest concentration of compounds that
prevents visible growth was considered to be the MIC.
Ampicillin was used as reference antimicrobial reagent to
compare its parameters with the data that result from the
method applied in this work and to control the reliability of
the latter.
MIC values for each compound were also determined
against S. mutans (ATCC 25175). The antibacterial activ-
ities of oxadiazaboroles also have been evaluated using
Mueller–Hinton broth with 2–5 % lyophilized horse blood
for the determination of the wells in the microdilution plate
containing the lowest concentration that has completely
inhibited visible bacterial growth as recommended by the
standards of the Committee Laboratory Standards Institute
(CLSI, 2005).
Sterile, disposable, multiwell microdilution plates (96 U-
shaped wells) have been used for broth microdilution pro-
cedures. The stock solutions were prepared in pure ethanol
(Sigma). In the concentrations studied, ethanol had no effect
on the microorganisms.
The antifungal activities of the compounds were also
determined by using broth microdilution susceptibility
test outlined by Clinical and Laboratory Standards Insti-
tute M27–A2 (CLSI, 2002). MIC values for each com-
pound were also determined against C. albicans (ATCC
90028). Also, sterile, disposable, multiwell microdilution
plates (96 U-shaped wells) have been used for broth
microdilution procedures. The stock solutions were pre-
pared in pure ethanol (Sigma) and again ethanol has no
effect on the microorganisms in the concentrations
studied.
Dilutions of the compounds
For antibacterial activities, all the dilutions of oxadiaza-
borole solutions were done in the wells of microdilution
plates by Mueller–Hinton Broth (Oxoid). For S. mutans
antimicrobial activity tests, Mueller–Hinton Broth (Oxoid)
with lyophilized horse blood was used. The concentrations
of the compounds were 1600, 800, 400, 200, 100, 50,
25, 12.5, 6.25, 3.12, 1.56, 0.78, 0.39, 0.19, 0.09, and
0.04 µg/mL. Ampicillin and ciprofloxacin were used
as reference compounds, which were obtained from the
manufacturers.
For antifungal activity, all dilutions of the compounds
were done with RPMI medium with L-glutamine buffered,
pH 7, with MOPS (Sigma) in the wells of microdilution
plates. The concentrations of the compounds are the same as
above. The fluconazole was used as a reference compound,
which was also obtained from the manufacturers.
For antifungal activity, Candida isolates were sub-
cultured in SDA plates, incubated at 35 °C for 24–48 h
prior to antifungal susceptibility testing, and passaged at
least twice to ensure purity and viability. An inoculum
suspension was prepared from individual five colonies
(diameter 1 mm). The suspension was adjusted to 0.5 Mc
Farland Standard (1–5 × 106 CFU/mL) and further
diluted to 1/20 (1–5 × 105 CFU/mL), then to 1/50
(0.5–2.5 × 105 CFU/mL) in RPMI medium. Hundred
microliters from each dilution was placed into each well
containing 100 µL of dilutions of compounds so that
each well contained 1 × 103 CFU/mL of inoculum. The
MIC plates were incubated at 37 °C for 48 h. The end
point was determined when the concentration produced
optically clear wells (MIC-0) compared with that of
drug-free growth control. To control the reliability of
the results, fluconazole was used as reference antifungal
reagent. The parameter of this reagent was compared
with the data obtained from the method applied in this
study. Every experiment for the antibacterial and anti-
fungal assays was replicated twice. MIC values for
antimicrobial activities are given in Tables 1 and 2,
respectively.
Inoculum preparation
After the dilutions of oxadiazaborole solutions, standar-
dized inoculum of each bacterium (S. aureus, E. faecalis,
P. aeruginosa, and E. coli) (0.5 Mc Farland standard unit,
1 × 108 CFU/mL; colony forming unit/mL) was prepared.

Med Chem Res
Compliance with ethical standards
Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Men-
nucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji
H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida
M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X,
Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jar-
amillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ,
Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K,
Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich
S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD,
Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG,
Clifford S, Cioslowski J, Stefanov BB, Liu G, Liashenko A,
Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham
MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW,
Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA (2004)
Gaussian 03. Gaussian, Inc, Wallingford, CT, Revision B. 05
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synthesis, and antioxidant activity of amphiphilic oximes and
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91:165–195
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Aromatic substituent constants for structure-activity correlations.
J Med Chem 16(11):1207–1216
HyperChem 7.2 for Windows (2002) Hypercube, Inc., Gainesville, FL
Jabbour A, Steinberg D, Dembitsky VM, Moussaieff A, Zaks B,
Srebnik M (2004) Synthesis and evaluation of oxazaborolidines
for antibacterial activity against Streptococcus mutans. J Med
Chem 47:2409–2410
Conflict of interest The authors declare that they have no conflicting
interests.
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