Bisphosphoramidate derivatives: synthesis, crystal structure, anti-cholinesterase activity, insecticide potency and QSAR analysis

Article abstract of DOI:10.1007/s13738-016-0991-y

A series of temephos (Tem) derivatives with the general structure of P(O)NH–X–NHP(O) (1–22) were synthesized and characterized by ³¹P, ¹³C, ¹H NMR and FT-IR spectral techniques. The electron density (ρ) value at the bond critical point (bcp) of P(1′)–O(1′)···(1)H–N(1) (0.040?e??^?3) P(1)–O(1)···(1′)H–N(1′) (0.031?e??^?3) as well as the stabilization energy of electronic delocalization of results of NBO analysis showed the hydrogen bonding energy in P(1′)–O(1′)···(1)H–N(1) model (E²?=??72.15?kJ?mol^?1) and P(1)–O(1)···(1′)H–N(1′) (E²?=??45.67?kJ?mol^?1) of the crystal cluster 7. The activities of Tem derivatives were evaluated using the modified Ellman’s method on cholinesterase (ChE) enzymes. The insecticide activity of Tem analogous appraised for the elm leaf beetle in which the 18 had more effective than the other compounds in inhibition α-esterase of insect. Principal component analysis–quantitative structure activity relationship (PCA–QSAR) models indicated that it was deduced that the frontier molecular orbital energy parameters in PC₁ are predominated from those related to electronic in PC₂ and structural parameters in PC₃ equation. Multiple linear regressions–QSAR models clarified that the molecular descriptors like an integrated net charge of nitrogen atom (Q_N), polarizability (PL_N–H) and lowest unoccupied molecular orbital (E_LUMO) proved important in defining the activity of the candidates.

Full text of DOI:10.1007/s13738-016-0991-y

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0991-y
ORIGINAL PAPER
Bisphosphoramidate derivatives: synthesis, crystal structure,
anti‑cholinesterase activity, insecticide potency and QSAR
analysis
Khodayar Gholivand1 · Ali Asghar Ebrahimi Valmoozi1 · Mina Salahi1 ·
Fatemeh Taghipour1 · Elham Torabi1 · Saied Ghadimi2 · Mahboobeh Sharifi3 ·
Mohammad Ghadamyari3
Received: 10 July 2016 / Accepted: 3 October 2016
© Iranian Chemical Society 2016
Abstract A series of temephos (Tem) derivatives with
the general structure of P(O)NH–X–NHP(O) (1–22) were
unoccupied molecular orbital (ELUMO) proved important in
defining the activity of the candidates.
1
synthesized and characterized by 31P, 13C, H NMR and
FT-IR spectral techniques. The electron density (ρ) value
at the bond critical point (bcp) of P(1′)–O(1′)···(1)H–N(1)
Keywords Bisphosphoramidate · Temephos · Hydrogen
bond · Cholinesterase inhibitor · QSAR
(0.040 e Å−3) P(1)–O(1)···(1′)H–N(1′) (0.031 e Å−3
)
as well as the stabilization energy of electronic delo-
calization of results of NBO analysis showed the hydro-
gen bonding energy in P(1′)–O(1′)···(1)H–N(1) model
(E2 = −72.15 kJ mol−1) and P(1)–O(1)···(1′)H–N(1′)
(E2 = −45.67 kJ mol−1) of the crystal cluster 7. The activi-
ties of Tem derivatives were evaluated using the modified
Ellman’s method on cholinesterase (ChE) enzymes. The
insecticide activity of Tem analogous appraised for the
elm leaf beetle in which the 18 had more effective than the
other compounds in inhibition α-esterase of insect. Prin-
cipal component analysis–quantitative structure activity
relationship (PCA–QSAR) models indicated that it was
deduced that the frontier molecular orbital energy param-
eters in PC1 are predominated from those related to elec-
tronic in PC2 and structural parameters in PC3 equation.
Multiple linear regressions–QSAR models clarified that
the molecular descriptors like an integrated net charge of
nitrogen atom (QN), polarizability (PLN–H) and lowest
Introduction
Bisphosphoramidates (BPAs) are best known for their
highly toxic effect as agricultural chemicals. BPAs with
the general structure of P(O)NH–X–NHP(O) skeleton are
important class of compounds that exhibit the insecticide
properties to inhibit the cholinesterase acetylcholinest-
erase (AChE) enzymes [1, 2]. Little attention has been
given to the interaction mechanism of the ChE enzymes
and BPAs [3, 4]. The famously derivative in the BPAs cat-
egory is attributed to temephos (Tem) pesticide because it
is a useful insecticide to control the larvae of mosquitoes,
midges and moths [5, 6]. However, Tem has side effects
on human as anti-AChE and carcinogenic potential [7].
Therefore, designing and producing the selective com-
pounds of Tem category having high insecticide potential
with less anti-AChE and carcinogenic effects are required.
To extend and to evaluate this problem, QSAR method
has been introduced in order to overcome the inhibition
mechanism [8]. The elm leaf beetle Xanthogaleruca lute-
ola Müll is the most serious pest of the elm tree. Larvae
feed on the parenchyma of leaves, without consuming the
veins, and cause severe damage to trees. If the damage is
severe and occurs several years in a row, the trees develop
deformed canopies and suffer vigor loss, physiological
disorders and reduced photosynthesis, which predispose
them to the action of other pests, plant disease and stress
factors. They become particularly susceptible to scolytid
* Khodayar Gholivand
gholi_kh@modares.ac.ir
1
Department of Chemistry, Tarbiat Modares University, P.O.
Box: 14115-175, Tehran, Iran
2
Department of Chemistry, Imam Hossein University, Tehran,
Iran
3
Department of Plant Protection, Faculty of Agricultural
Science, University of Guilan, Rasht, Iran
1 3

J IRAN CHEM SOC
beetles carrying spores of the fungus Ceratocystis novo
ulmi Brasier, which causes the elm tree disease, a serious
threat to survival of these trees [9]. In this study, 22 novel
Tem analogous with the general formula of (R)2P(O)–X–
P(O)(R)2, (X = NH(C6H4)2NH, NH(C6H4)SO2(C6H4)NH,
NH(C6H4)O(C6H4)NH; R=(NC4H8O, NC5H10, NC6H12,
OC6H5, C6H5, N(C2H5)2, OCH3, OCH2CH3, NC4H9,
NC3H8) (1–22) were synthesized and characterized by 31P,
[12]. X-ray data of compounds 1 and 7 were collected on
a Bruker SMART 1000 CCD area detector with graphite
monochromated Mo-Kα radiation (λ = 0.71073 Å) and
refined by full-matrix least squares methods against F2 with
SHELXL97 [13].
General synthesis
1
13C, H NMR and IR spectroscopy. The solid-state struc-
Compounds 1–22 were prepared by the reaction of a solu-
tion of diamine (1 mmol), and triethylamine (2 mmol)
in CH3CN was added at 0 °C to a solution of Cl3P(O)
(2 mmol) in CH3CN. After 3- to 5-h stirring, it was filtered
and the some varied amine was added to solution. After 6 h
in −5 °C, it was filtered and powder washed with distilled
water and ethanol. The synthesis pathway of compounds is
represented in Scheme 1.
tures of (NC4H8O)2(O)PNH(C6H4)2NHP(O)(NC4H8O)2
(1) and (CH3O)2P(O)NH(C6H4)2NHP(O)(OCH3)2 (7) were
determined by X-ray crystallography and used as reference
for quantum mechanical (QM) calculations at B3LYP level.
The activity of Tem derivatives on AChE was determined
using a modified Ellman’s method [10]. QSAR analyses
were used to find the most efficient parameters to introduce
a better mechanism of interaction between the selected
molecules and the receptor site of human AChE. The
insects Xanthogaleruca luteola Müll were collected from
elm trees leaves and reared on leaves of Ulmus densa Litw.
Same-aged larvae (third instars) were randomly selected
for the bioassay.
(NC4H8O)2(O)P−NH(C6H4)2NH−P(O)(NC4H8O)2 (1)
Powder sample; m.p. 187 °C. 31P{1H} NMR (DMSO-d6,
1
298 K); δ = 10.35 (m) ppm. H NMR (DMSO-d6, 298 K);
δ = 3.02 (m, 16 H, CH2), 3.47 (m, 16 H, CH2), 7.17 (d,
2
3J(H–H)ben = 8.45, 4 H, Ar–H), 7.30 (d, J(PNH) = 9.55, 2
H, NHben), 7.43 (d, 3J(H–H)ben = 8.45, 4 H, Ar–H) ppm. 13
C
Materials and methods
NMR (DMSO-d6, 298 K); δ = 44.8 (s, CH2), 66.9 (d, 3J(P,C)
3
= 5.86 Hz, CH2), 118.6 (d, J(P,C)ben = 6.74 Hz, CH),
mor
Instrument and calculations
126.6 (s, CH), 132.4 (s, C), 141.5 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3139.26 (NH), 2953, 2851, 1612, 1500, 1264,
1195 (P=O), 1114, 968 (P–N), 827, 726, 683, 507.
The enzyme AChE (human erythrocyte; Sigma, Cat. No.
C0663), AChE (insect, EC 3.1.1.7), Triton X-100, bovine
serum albumin, alpha-naphthyl acetate, beta-naphthyl
acetate, fast blue RR, DMSO and sodium dodecyl sulfate
(SDS) were all from Sigma-Aldrich. Acetylthiocholine
iodide (ATCh, 99 %, FLUKA), 5, 5′-dithiobis (2-nitroben-
zoic acid) (DTNB, 98 %, Merck), Na2HPO4, NaH2PO4
(99 %) were used as supplied. 1H, 13C and 31P spectra were
recorded on a Bruker Avance DRX 250, 300 and 500 spec-
trometers. 1H and 13C chemical shifts were determined rel-
ative to internal TMS, and 31P chemical shifts were deter-
mined relative to 85 % H3PO4 as the external standard.
Infrared (IR) spectra were recorded on a Shimadzu model
IR-60 spectrometer using KBr pellets. Melting points
of the compounds were obtained with an electrothermal
instrument. UV spectrophotometer was operated using a
PerkinElmer Lambda 25. Differential scanning calorim-
etry (DSC) was performed on a Du Pont® 910 Calorim-
eter, controlled by a 1090 Thermal Analyzer System. The
insecticide and anti-AChE activities of these compounds
were predicted by the Prediction of Activity Spectrum for
Substances (PASS) software (version 1.193) [11]. The cor-
relation analysis was performed by the Statistical Pack-
age for Social Scientists (SPSS) version 16.0 for Windows
(NC5H10)2(O)P−NH(C6H4)2NH−P(O)(NC5H10)2 (2)
Powder sample; m.p. 190 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 11.48 (m) ppm. 1H NMR (DMSO-d6, 298 K);
δ = 1.38-1.63 (m, 24 H, CH2), 2.98 (m, 16 H, CH2),
2
3
7.02 (d, J(PNH) = 9.7 Hz, 2 H, NHben), 7.15 (d, J(H–H)
3
= 8.30 Hz, 4 H, Ar–H), 7.39 (d, J(H–H)ben = 8.35 Hz,
ben
4H, Ar–H) ppm. 13C NMR (DMSO-d6, 298 K); δ = 24.5
3
(s, CH2), 26.3 (d, J(P,C)py = 4.71 Hz, CH2), 45.4 (s, CH2),
118.3 (s, CH), 126.3 (s, CH), 131.9 (s, C), 142.0 (s, C).
IR (KBr, cm−1): υ˜ = 3425, 3185 (NH), 2929, 2848, 1613,
1498, 1376, 1210 (P=O)1113, 1069, 955 (P–N), 826, 722,
557.
(NC6H12)2(O)P−NH(C6H4)2NH−P(O)(NC6H12)2 (3)
Powder sample; m.p. 175 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 13.71 (m) ppm. 1H NMR (DMSO-d6, 298 K);
δ = 1.48-1.53 (m, 32 H, CH2), 3.06 (m, 16 H, CH2),
2
3
6.98 (d, J(PNH) = 9.13 Hz, 2 H, NHben), 7.21 (d, J(H–H)
ben = 8.40 Hz, 4 H, Ar–H), 7.39 (d, 3J(H–H)ben = 8.35 Hz, 4
H, Ar–H) ppm. 13C NMR (DMSO-d6, 298 K); δ = 26.1(s,
1 3

J IRAN CHEM SOC
O
P
NH (C H ) NH
2
Triethylamine
CH3CN
+
2
6
4 2
Cl
Cl
Cl
0 °C
O
P
O
P
R
N
H
N
H
R
R
R
O
NH (C H )SO (C H )NH
2
+
2
6
4
2
6
4
R = NC4H8O (1), NC5H10 (2), NC6H12 (3),
OC6H5 (4), N(C2H5)2 (5), OCH3 (6),
OCH2CH3 (7)
P
Triethylamine
CH3CN
Cl
0 °C
O
Diamine
Triethylamine
CH3CN
+
O
P
O
P
S
O
NH (C H )O(C H )NH
+
2
6
4
6
4
2
Triethylamine
CH3CN
R
0 °C
N
N
H
R
H
R
0 °C
R
O
P
O
P
R = NC4H8O (9), N(C2H5)2 (10), NC5H10 (11),
NC6H12 (12), OC6H5 (13), NC4H9 (14),
OCH3 (15), OCH2CH3 (16)
X
O
P
O
O
HN
X =
NH (5)
P
R
N
N
H
R
O
H
R
R
S
R = NC4H8O (19), NC5H10 (22),
NC6H12 (20), HNC3H7 (21)
O
HN
HN
NH (17)
NH (18)
O
Scheme 1 The pathway of Temephos derivatives
3
2
CH2), 29.8 (d, J(P,C)hexa = 3.77 Hz, CH2), 47.0 (d, J(P,C)
1490, 1398, 1321, 1264, 1231, 1184 (P=O), 1070, 1031,
3
= 3.72 Hz,CH2), 117.2 (d, J(P,C)ben = 6.66 Hz,CH),
1006, 982 (P–N), 948, 824, 752, 683, 567, 518, 484.
hexa
127.9 (s, CH), 132.1 (s, C), 148.2 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3410, 3208 (NH), 2924, 2854, 1613, 1497,
1380, 1190 (P=O), 1113, 1058, 931 (P–N), 825, 703, 526.
(C6H5)2(O)P−NH(C6H4)2NH−P(O)(C6H5)2 (5)
Powder sample; m.p. 280 °C. 31P{1H} NMR (DMSO-
2
1
(OC6H5)2(O)P−NH(C6H4)2NH−P(O)(OC6H5)2 (4)
d6, 298 K); δ = 16.36 (s, J(P,H) = 11.35 Hz) ppm. H
NMR (DMSO-d6, 298 K); δ = 7.07 (m, 16 H, CH), 7.28
(m, 8 H, CH, Ar–H), 7.17 (d, 4 H, Ar–H), 8.28 (s, 2 H,
2J(P,H) = 11.35 Hz, NHben) ppm. 13C NMR (DMSO-d6,
298 K); δ = 117.76 (s, Ar), 118.47 (m, CH), 120.48 (s,
CH), 126.17 (s, CH), 126.63 (s, Ar), 128.23 (s, C), 128.51
(s, CH). 128.71 (s, Ar), 130.86 (s, Ar), 133.83 (s, CH),
140.71 (s, C), 150.5 (m, Cipso), 151.26 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3378 (NH), 3170, 2850, 1612, 1498, 1441,
1386, 1269, 1185 (P=O), 1117, 928 (P–N), 819, 724, 695,
527.
Powder sample, m.p. 251 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = −6.69 (d) ppm. 1H NMR (DMSO-d6, 298 K);
δ = 7.07 (t, 4 H, CH, Ar–H), 7.28 (d, 8 H, CH, Ar–H), 7.17
2
(t, 8 H, Ar–H), 8.82 (d, 2 H, J(PNH) = 22.9 Hz, NHben
)
ppm. 13C NMR (DMSO-d6, 298 K); δ = 118.6 (d, J(P,C)
3
3
= 7.81 Hz, CH), 120.4 (d, J(P,C)oph = 4.59 Hz, CH),
ben
125.7 (s, CH), 127.5 (s, C), 130.4 (s, CH). 133.5 (s, CH),
2
139.2 (s, C), 150.5 (d, J(POC) = 6.31 Hz, Cipso) ppm. IR
(KBr, cm−1): υ˜ = 3142 (NH), 3054, 2947, 1611, 1589,
1 3

J IRAN CHEM SOC
(N(C2H5)2)2(O)P−NH(C6H4)2NH−P(O)(N(C2H5)2)2 (6)
(N(C2H5)2)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)
(N(C2H5)2)2 (10)
Powder sample; m.p. 196 °C. 31P{1H} NMR (DMSO-d6,
1
298 K); δ = 14.04 (m) ppm. H NMR (DMSO-d6, 298 K);
Powder sample; m.p. 193 °C. 31P{1H} NMR (DMSO-
1
δ = 1.00 (t, 24 H, CH3), 2.98 (m, 16 H, CH2), 6.88 (d, 2 H,
d6, 298 K); δ = 13.61 (m) and 15.33 (s) ppm. H NMR
3
2J(PNH) = 8.85 Hz, NH2-ben), 7.18 (d, 4 H, J(H–H)ben = 7.4,
(DMSO-d6, 298 K); δ = 0.95 (m, 24 H, CH3), 2.97 (m,
Ar–H), 7.37 (d, 4 H, 3J(H–H)ben = 7.40, Ar–H) ppm. 13C NMR
16 H,CH2), 7.29 (d, J(H–H)Sulf = 8.7 Hz, 4 H, Ar–H),
3
2
2
3
(DMSO-d6, 298 K); δ = 11.55 (s, CH3), 14.57 (d, J(PNC)
7.51 (d, J(PNH)Sulf = 9.0 Hz, 2 H, NHSulf), 7.61 (d, J(H–H)
diet = 1.53 Hz, CH2), 118.4 (d, 3J(P,C) = 6.57 Hz, CH), 126.2
(s, CH), 131.9 (s, C), 142.3 (s, C) ppm. IR (KBr, cm−1):
υ˜ = 3184 (NH), 2972, 2876, 1614, 1498, 1464, 1380, 1209,
1175 (P=O), 1026, 940 (P–N), 823, 793, 711, 663, 529.
= 8.7 Hz, 4 H, Ar–H). 13C NMR (DMSO-d6, 298 K);
Sulf
3
δ = 14.13 (m, CH3), 41.20 (s, CH2), 117.19 (d, J(P,C)
= 6.2 Hz, CH), 128.08 (s, CH), 132.14 (s, C), 148.21
Sulf
(s, C) ppm. IR (KBr, cm−1): υ˜ = 3323 (N–H), 3189, 2973,
2874, 1594, 1498, 1467, 1382, 1300 (SO2), 1214, 1178
(P=O), 1150 (SO2), 1104, 1028, 945 (P–N), 910, 838, 792,
665, 578.
(OCH3)2(O)P−NH(C6H4)2NH−P(O)(OCH3)2 (7)
Powder sample; m.p. 190 °C. 31P{1H} NMR (DMSO-
d6, 298 K); δ = 5.28 (m) ppm. 1H NMR (DMSO-d6,
(NC5H10)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(NC5H10)2
(11)
3
298 K); δ = 3.59 (d, 12 H, J(P,H) = 11.03 Hz, CH3), 7.03
3
3
(d, 4 H, J(H–H)ben = 8.35 Hz, Ar–H), 7.44 (d, 4 H, J(H–H)
2
= 8.4 Hz, Ar–H), 8.12 (d, 2 H, J(PNH) = 9.25 Hz,
Powder sample; m.p. 243 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 11.03 (s) ppm. 1H NMR (DMSO-d6,
298 K); δ = 1.42 (m, 24 H, CH2), 2.95 (m, 16 H, CH2),
ben
NH2-ben) ppm. 13C NMR (DMSO-d6, 298 K); δ = 53.29
3
(s, CH3), 118.0 (d, J(P,C) = 7.37 Hz, CH), 127.1 (s, CH),
133.0 (s, C), 140.0 (s, C) ppm. IR (KBr, cm−1): υ˜ = 3150
(NH), 2947, 2856, 1614, 1502, 1317, 1228 (P=O), 1043,
966 (P–N), 836, 753, 645, 597, 535.
7.26 (d, J(H–H)Sulf = 8.3 Hz, 4 H, Ar–H),7.63 (d, J(PNH)
3
2
3
= 9.1 Hz, 2 H, NHSulf), 7.65 (d, J(H–H)Sulf = 8.3 Hz, 4
Sulf
H, Ar–H).13C NMR (DMSO-d6, 298 K); δ = 24.5 (s, CH2),
3
26.3 (d, J(P,C)py = 4.7 Hz, CH2), 45.4 (s, CH2), 118.3 (s,
(OCH2CH3)2(O)P−NH(C6H4)2NH−P(O)(OCH2CH3)2 (8)
CH), 126.3 (s, CH), 131.9 (s, C), 142.0 (s, C) ppm. IR
(KBr, cm−1): υ˜ = 3182 (N–H), 2931, 2847, 1593, 1496,
1378, 1301 (SO2), 1209 (P=O), 1151 (SO2), 1107, 1068,
955 (P–N), 916, 840, 686, 583.
Powder sample; m.p. 168 °C. 31P{1H} NMR (DMSO-
d6, 298 K); δ = 2.41 (m) ppm. 1H NMR (DMSO-d6,
298 K); δ = 1.22 (t, 12 H, CH3), 4.02 (m, 8 H, CH2), 7.04
3
3
(d, 4 H, J(H–H)ben = 7.9 Hz, Ar–H), 7.44 (d, 4 H, J(H–H)
(NC6H12)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(NC6H12)2
(12)
2
= 7.9 Hz, Ar–H), 8.01 (d, 2 H, J(PNH) = 8.9 Hz,
ben
NH2-ben) ppm. 13C NMR (DMSO-d6, 298 K); δ = 16.49(d,
3J(P,C) = 6.52 Hz, CH3), 62.4 (d, J(P,C) = 4.98 Hz, CH2),
Powder sample; m.p. 250 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 13.45 (m) ppm. 1H NMR (DMSO-d6,
298 K); δ = 1.46 (m, 32 H, CH2), 3.02 (m, 16 H, CH2),
2
118.00 (d, 3J(P,C)ben = 7.52 Hz, CH), 126.98 (s, CH), 132.82
(s, C), 140.28 (s, C) ppm. IR (KBr, cm−1): υ˜ = 3191 (NH),
3043, 2981, 1614, 1501, 1396, 1220 (P=O), 1026, 972
(P–N), 823, 745, 646, 523.
3
2
7.32 (d, J(H–H)Sulf = 8.5 Hz, 4 H, Ar–H), 7.58 (d, J(PNH)
3
= 13.0 Hz, 2 H, NHSulf), 7.62 (d, J(H–H)Sulf = 8.5 Hz,
Sulf
4H, Ar–H) ppm. 13C NMR (DMSO-d6, 298 K); δ = 26.1
3
2
(NC4H8O)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)
(NC4H8O)2 (9)
(s, CH2), 29.8 (d, J(P,C)hexa = 3.7 Hz, CH2), 47.0 (d, J(P,C)
3
= 3.7 Hz,CH2), 117.2 (d, J(P,C)Sulf = 6.6 Hz, CH),
hexa
127.9 (s, CH), 132.1 (s, C), 148.2 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3147 (NH), 2926, 2855, 1593, 1496, 1463,
1381, 1301 (SO2), 1232, 1185 (P=O), 1151 (SO2), 1106,
1059, 1004, 909 (P–N), 840, 686, 582.
Powder sample; m.p. 263 °C. 31P{1H} NMR (DMSO-d6,
1
298 K); δ = 9.83 (s) ppm. H NMR (DMSO-d6, 298 K):
δ = 3.00 (m, 16 H, CH2), 3.45 (m, 16 H,CH2), 7.23 (d, 3J(H–H)
3
= 8.6 Hz, 4H, Ar–H), 7.70 (d, J(H–H)Sulf = 8.6, 4H,
Sulf
Ar–H), 7.83 (d, 2J(PNH)Sulf = 9.5, 2 H, NHSulf) ppm. 13C NMR
(OC6H5)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(OC6H5)2
(13)
3
(DMSO-d6, 298 K); δ = 44.23 (s, CH2), 66.38 (d, J
(P,C)
mor = 5.7 Hz, CH2), 117.46 (d, 3J(P,C)sulf = 6.7 Hz, CH), 128.35
(s, CH), 132.67 (s, C), 147.38 (s, C) ppm. IR (KBr, cm−1):
υ˜ = 3403 (N–H), 3141, 2851, 1594, 1496, 1303 (SO2), 1257,
1195 (P=O), 1111 (SO2), 968 (P–N), 923, 837, 698, 587.
Powder sample; m.p. 287 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = −7.74 (s) ppm. 1H NMR (DMSO-d6, 298 K);
3
δ = 1.90 (d, J(H–H)Sulf = 9.2 Hz, 4 H, Ar–H), 7.09 (d,
1 3

J IRAN CHEM SOC
3
12 H, CH, Ar–H), 7.36 (d, 8 H, Ar–H), 7.82 (d, J(H–H)
(SO2), 1230 (P=O), 1152 (SO2), 1106, 1026, 970 (P–N),
= 9.2 Hz, 4 H, Ar–H), 9.5 (m, 2 H, NHSulf) ppm. 13C
832, 693, 584.
Sulf
NMR (DMSO-d6, 298 K): δ = 118.6 (d, 3J(P,C)Sulf = 7.8 Hz,
3
CH), 120.4 (d, J(P,C)oph = 4.5 Hz, CH), 125.7 (s, CH),
(C6H5)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(C6H5)2 (17)
127.5 (s, C), 130.4 (s, CH), 133.5 (s, CH), 139.2 (s, C),
150.5 (d, J(POC) = 6.3 Hz, Cipso) ppm. IR (KBr, cm−1):
Powder sample; m.p. 272 °C. 31P{1H} NMR (MeOD-d4,
2
1
υ˜ = 3149 (N–H), 3058, 2944, 1593, 1490, 1392, 1301
(SO2), 1189 (P=O), 1152 (SO2), 1100, 951 (P–N), 833,
763, 687, 588, 512.
300 K); δ = 21.55 (s) ppm. H NMR (MeOD-d4, 300 K):
δ = 6.62 (d, 3J(H–H)Sulf = 8.7 Hz, 4 H, Ar–H), 7.10 (d, 3J(H–H)
Sulf = 8.7 Hz, 4 H, Ar–H), 7.49 (m, 4 H, Ar–H), 7.59 (m, 8
H, Ar–H), 7.79 (m, 8 H, Ar–H) ppm. 13C NMR (MeOD-d4,
2
(NC4H9)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(NC4H9)2
(14)
300 K); δ = 128.60 (s, C), 129.32 (d, J(P,C)ph = 7.3 Hz,
3
CH), 130.01 (s, CH), 130.19 (s, C), 130.37 (d, J(P,C)
Sulf = 7.8 Hz, CH), 132.93 (s, CH), 133.07 (s, CH), 133.90
(s, C) ppm. IR (KBr, cm−1): υ˜ = 3364 (N–H), 3106, 2925,
2854, 1710, 1593, 1496, 1438, 1392, 1298, 1248 (P=O),
1182, 1142 (SO2), 1105, 923 (P–N), 834, 693, 583, 526.
Powder sample; m.p. 243 °C. 31P{1H} NMR (DMSO-d6,
1
298 K): δ = 2.45 (m) ppm. H NMR (DMSO-d6, 298 K);
δ = 1.14 (s, 36 H, CH3), 3.92 (d, 4 H, 2J(PNH)amin = 9.3 Hz,
3
NHamin), 7.18 (d, J(H–H)Sulf = 8.7 Hz, 4 H, Ar–H),
3
7.53 (d, 2 H, NHSulf), 7.58 (d, J(H–H)Sulf = 8.7 Hz, 4 H,
(C6H5)2(O)P−NH(C6H4)O(C6H4)NH−P(O)(C6H5)2 (18)
Ar–H) ppm. 13C NMR (DMSO-d6, 298 K); δ = 13.16 (d,
3J(P,C)amin = 4.9 Hz, CH3), 50.35 (s, C), 117.19 (d, J(P,C)
Powder sample; m.p. 97 °C. 31P{1H} NMR (CDCl3,
3
1
= 6.2 Hz, CH), 128.08 (s, CH), 132.14 (s, C), 148.21
300 K); δ = 19.03 (s) ppm. H NMR (CDCl3, 300 K);
Sulf
(s, C) ppm. IR (KBr, cm−1): υ˜ = 3370 (m, N–H), 2968,
1596, 150, 1384, 1304 (SO2), 1224 (P=O), 1146 (SO2),
1105, 1017, 912 (P–N), 840, 698, 587.
δ = 6.72 (m, 4 H, Ar–H), 7.10 (m, 4 H, Ar–H), 7.47 (m,
4 H, Ar–H), 7.69 (m, 8 H, Ar–H), 7.89 (m, 8 H, Ar–H)
ppm. 13C NMR (DMSO-d4, 300 K); δ = 119.02 (m, CH),
119.73 (m, CH), 128.47 (m, CH), 128.74 (m, CH), 130.95
(d, 2J(P,C)ph = 2.79 Hz, CH), 131.69 (m, CH), 133.83 (s, C),
134.16 (s, C), 135.94 (s, C), 137.39 (s, C), 151.07 (s, C),
151.26 (s, C) ppm. IR (KBr, cm−1): υ˜ = 3385 (N–H), 3106,
3056, 2853, 1618, 1498, 1439, 1384, 1214, 1182 (P=O),
1120, 932 (P–N), 835, 696, 522.
(OCH3)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)(OCH3)2
(15)
Powder sample; m.p. 170 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 3.88 (m) and 4.50 (s) ppm. 1H NMR (DMSO-d6,
3
298 K): δ = 3.63 (d, 12 H, J(P,H) = 4.3 Hz, CH3), 7.13
3
3
(d, 4 H, J(H–H)Sulf = 8.2 Hz, Ar–H), 7.74 (d, 4 H, J(H–H)
(NC4H8O)2(O)P−NH(C6H4)O(C6H4)NH−P(O)(NC4H8O)2
(19)
2
= 8.2 Hz, Ar–H), 8.71 (d, 2 H, J(PNH) Sulf = 8.7 Hz,
Sulf
NHSulf). 13C NMR (DMSO-d6, 298 K): δ = 53.29 (s, CH3),
118.0 (d, 3J(P,C)Sulf = 7.3 Hz, CH), 127.1 (s, CH), 133.0 (s,
C), 140.0 (s, C) ppm. IR (KBr, cm−1): υ˜ = 3147 (N–H),
3052, 2951, 1596, 1499, 1395, 1305 (SO2), 1234 (P=O),
1150 (SO2), 1107, 1038, 951 (P–N), 839, 755, 694, 579.
Powder sample; m.p. 135 °C. 31P{1H} NMR (DMSO,
1
300 K); δ = 10.75 (s) ppm. H NMR (CDCl3, 300 K);
3
δ = 3.02 (d, 16 H, CH2), 3.46 (d, J(P,H) = 4.1 Hz, 16 H,
3
3
CH2), 6.52 (d, J(H–H) = 8.1 Hz, 4 H, CH), 6.62 (d, J(H–H)
= 8.1 Hz, 4 H, CH) ppm. 13C NMR (DMSO-d6, 300 K);
δ = 42.60 (s, CH2), 44.41 (s, CH2), 63.23 (s, CH2), 66.49
(OCH2CH3)2(O)P−NH(C6H4)SO2(C6H4)NH−P(O)
(OCH2CH3)2 (16)
3
(d, J(P,C)mor = 5.8 Hz, CH2), 115.11 (s, CH), 118.94 (s,
CH), 143.55 (s, C), 148.63 (s, C) ppm. IR (KBr, cm−1):
υ˜ = 3445 (N–H), 3224, 2961, 2854, 1621, 1500, 1217
(P=O), 1106, 967 (P–N), 840, 722, 601, 494.
Powder sample; m.p. 188 °C. 31P{1H} NMR (DMSO-d6,
298 K); δ = 0.99 (m) and 1.52 (s) ppm. 1H NMR
(DMSO-d6, 298 K); δ = 1.18 (t, 12 H, CH3), 3.98 (m,
3
8 H, CH2), 7.13 (d, 4 H, J(H–H)Sulf = 5.9 Hz, Ar–H),
(NC6H12)2(O)P−NH(C6H4)O(C6H4)NH−P(O)(NC6H12)2
(20)
3
7.72 (d, 4 H, J(H–H)Sulf = 5.7 Hz, Ar–H), 8.62 (d, 2 H,
2J(PNH)Sulf = 7.6 Hz, NHSulf) ppm. 13C NMR (DMSO-d6,
3
298 K); δ = 16.49 (d, J(P,C) = 6.5 Hz, CH3), 62.4 (d,
Powder sample; m.p. 178 °C. 31P{1H} NMR (CDCl3,
1
2J(P,C) = 4.9 Hz, CH2), 118.00 (d, 3J(P,C)Sulf = 7.5 Hz, CH),
126.98 (s, CH), 132.82 (s, C), 140.28 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3187 (N–H), 2982, 1596, 1501, 1395, 1305
300 K); δ = 14.65 (s) ppm. H NMR (CDCl3, 300 K);
δ = 1.60 (m, 32 H, CH2), 3.18 (m, 16 H, CH2), 4.49 (m,
2 H, NH), 6.80 (m, 4 H, Ar–H), 7.06 (m, 4 H, Ar–H) ppm.
1 3

J IRAN CHEM SOC
13C NMR (CDCl3, 300 K); δ = 24.83 (s, CH2), 26.41 (s,
absorbance change at 37 °C was monitored with the spec-
trophotometer at 412 nm for 3 min, and three replicates
were run in each experiment. In the absence of inhibitor,
the absorbance change was directly proportional to the
enzyme level. The reaction mixtures for determination
of IC50 values (the median inhibitory concentration) con-
sisted DTNB solution, 100 μl; inhibitor, x μl; acetylthi-
ocholine iodide (ATCh) solution, 40 μl; phosphate buffer,
(850 − x) μl; and AChE solution, 10 μl. The activity of
BChE was determined the same as the AChE activity by
measuring the concentration of thiocholine, which reacted
with DTNB after hydrolysis of BTCh. The lyophilized
BChE was diluted with 100 mM phosphate buffer (pH 7.4)
for using in the activity assay. The plot of VI/V0 (VI and V0
are the activity of the enzyme in the presence and absence
of inhibitors, respectively) against log[I] (where, [I] is
the inhibitor’s concentration) gave the IC50 values of 16
compounds 1, 3, 6–11, 13–16, 18–19 and 21–22 (as anti-
AChE) (Table 1; Fig. 1).
3
CH2), 29.97 (d, J(P,C)hexa = 4.3 Hz, CH2), 45.22 (s, CH2),
47.48 (s, CH2), 115.77 (s, CH), 118.76 (m, C), 119.07 (s,
C) ppm. IR (KBr, cm−1): υ˜ = 3203 (NH), 2925, 2854,
1622, 1499, 1381, 1218, 1189 (P=O), 1112, 1058, 1004,
937 (P–N), 702, 512.
(HNC3H7)2(O)P−NH(C6H4)O(C6H4)NH−P(O)(HNC3H7)2
(21)
Powder sample; 31P{1H} NMR (CDCl3, 300 K); δ = 7.50
1
(s) ppm. H NMR (CDCl3, 300 K): δ = 1.14 (m, 24 H,
CH3), 2.42 (m, 4 H, CH), 3.46 (d, 2J(PNH) = 13.0, 2 H, NH),
5.11 (d, 2J(PNH) = 13.0, 2 H, NH), 6.80 (d, 3J(H–H) = 8.5 Hz,
3
4 H, Ar–H), 7.06 (d, J(H–H) = 8.5 Hz, 4 H, Ar–H) ppm.
13C NMR (DMSO-d6, 300 K); δ = 25.13 (m, CH3), 42.32
(m, CH), 117.98 (s, Ar), 119.06 (s, Ar), 117.98-150.00 (Ar)
ppm. IR (KBr, cm−1): υ˜ = 3224 (NH), 2967, 2848, 1623,
1501, 1389, 1218, 1174 (P=O), 1033, 932 (P–N), 510.
(NC5H10)2(O)P−NH(C6H4)O(C6H4)NH−P(O)(NC5H10)2
(22)
Insect AChE assay
For sample preparation, adults were treated with differ-
ent concentrations collected and transferred to a freezer
(−20 °C). For measuring of enzyme activity, the sample
was homogenized in cold double-distilled water using a
hand-held glass homogenizer and centrifuged at 10,000 rpm
for 10 min at 4 °C. After homogenization, they were cen-
trifuged at 10,000 rpm for 15 min at 4 °C. AChE activity
was determined at room temperature in 50 mM phosphate
buffer (pH 7), 0.01 m DTNB and 0.01 m acetylthiocholine
iodide stock solutions. Appropriate amounts of the sub-
stances were dissolved in phosphate buffer, pH 7, and these
solutions were kept at 5 °C not longer than 2–3 days. The
suitable working concentrations of DTNB and acetylthi-
ocholine iodide were prepared immediately before use by
dilution with buffer solution. The supernatant (40 µl) was
added to a tube containing 140 µl of the buffer and 20 µl
of DTNB and 40 µl ATCH. The concentration of reduc-
ing sugars obtained from the catalyzed reaction was meas-
ured by the method according to Elman [10]. Absorbance
was measured at 412 nm. The sample was homogenized
in 200 µl phosphate buffer. The homogenates were centri-
fuged at 12,000 g for 10 min at 4 °C. The supernatants as
the enzyme source were pooled and stored at −20 °C for
later use. For enzyme assay, 12.5 µl of supernatant was
mixed with equal volume of substrates (6.4 mM alpha-
naphthyl acetate or 6.4 mM beta-naphthyl acetate) and
incubated at 30 °C for 3 min. Then, 50 µl of fast blue solu-
tion (0.07 % and SDS 5 %) was added and esterase activity
was determined in a spectrophotometer at 405 and 454 nm,
respectively (Table 1).
Powder sample; m.p. 135 °C. 31P{1H} NMR (CDCl3,
300 K): δ = 12.61 (s) ppm. 1H NMR (300.13 MHz, CDCl3,
300 K): δ = 1.54 (m, 24 H, CH2), 3.06 (m, 16 H, CH2),
6.64 (m, 4 H, Ar–H), 6.82 (m, 2 H, NH), 7.01(m, 4 H,
Ar–H). 13C NMR (DMSO-d6, 300 K); δ = 21.88 (s, CH2),
22.16 (s, CH2), 24.28 (s, CH2), 25.88 (d, 3J(P,C)py = 4.8 Hz,
CH2), 43.44 (s, CH2), 44.93 (s, CH2), 114.77 (s, CH),
118.76 (s, CH), 150.64 (s, C) 157.64 (s, C) ppm. IR (KBr,
cm−1): υ˜ = 3182 (N–H), 2931, 2847, 1593, 1496, 1378,
1301 (SO2), 1209 (P=O), 1151, 1107, 1068, 955 (P–N),
916, 840, 686, 583.
Evaluation of biological activity
Human AChE assay
Human cholinesterase activity measurements were taken
essentially according to the method of Ellman [10]. The
reaction was carried out at 37 °C in 70 mM phosphate
buffer (Na2HPO4/NaH2PO4, pH 7.4) containing the AChE
enzyme (10-µl volume, diluted 100 times in phosphate
buffer, pH 7.4), DTNB (5, 5′-dithiobis (2-nitrobenzoic
acid)) (10−4 M concentration) and ATCh (1.35 × 10−4
M
concentration). Each compound was dissolved in dimethyl
sulfoxide (DMSO), which was then added to the buffer
for in vitro cholinesterase assays. The highest concentra-
tion of DMSO used in the assays was 5 %. In the inde-
pendent experiments without the inhibitor, 5 % DMSO
had no effect on the inducing activity of the enzyme. The
1 3

J IRAN CHEM SOC
Table 1 Experimental, predication and external validation step of the biological activity of the BPAT compounds
Compound
Prediction (PASS)
Experimental
HAChEa IAChEb
Anti-AChE Insecticide
IC50
Mortality (%) (5000 ppm)a IC50
(NC4H8O)2(O)P–NH(C6H4)2NH–P(O)(NC4H8O)2 (1)
(NC5H10)2(O)P–NH(C6H4)2NH–P(O)(NC5H10)2 (2)
(NC6H12)2(O)P–NH(C6H4)2NH–P(O)(NC6H12)2 (3)
(OC6H5)2(O)P–NH(C6H4)2NH–P(O)(OC6H5)2 (4)
0.212
0.257
0.257
0.551
0.244
0.311
0.593
0.529
0.217
0.299
0.255
0.255
0.520
0.307
0.556
–
0.313
–
–
–
–
–
–
–
0.177
–
–
–
0.538
0.390
0.192
0.619
0.506
–
–
–
(C6H5)2(O)P–NH(C6H4)2NH–P(O)(C6H5)2 (5)
–
–
–
(N(C2H5)2)2(O)P–NH(C6H4)2NH–P(O)(N(C2H5)2)2 (6)
(OCH3)2(O)P–NH(C6H4)2NH–P(O)(OCH3)2 (7)
0.510
0.490
0.860
2.390
0.150
0.066
–
–
–
–
–
(OCH2CH3)2(O)P–NH(C6H4)2NH–P(O)(OCH2CH3)2 (8)
(NC4H8O)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(NC4H8O)2 (9)
(N(C2H5)2)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(N(C2H5)2)2 (10)
(NC5H10)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(NC5H10)2 (11)
(NC6H12)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(NC6H12)2 (12)
(OC6H5)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(OC6H5)2 (13)
(NC4H9)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(NC4H9)2 (14)
(OCH3)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(OCH3)2 (15)
–
–
–
–
–
–
–
–
–
–
–
–
–
0.475
–
0.720
0.240
0.165
0.019
–
–
–
–
–
0.561
0.446
0.285
0.455
0.188
0.234
0.348
0.234
–
–
(OCH2CH3)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(OCH2CH3)2 (16) 0.501
–
–
(C6H5)2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)(C6H5)2 (17)
(C6H5)2(O)P–NH(C6H4)O(C6H4)NH–P(O)(C6H5)2 (18)
(NC4H8O)2(O)P–NH(C6H4)O(C6H4)NH–P(O)(NC4H8O)2 (19)
(NC6H12)2(O)P–NH(C6H4)O(C6H4)NH–P(O)(NC6H12)2 (20)
(HNC3H7)2(O)P–NH(C6H4)O(C6H4)NH–P(O)(HNC3H7)2 (21)
(NC5H10)2(O)P–NH(C6H4)O(C6H4)NH–P(O)(NC5H10)2 (22)
0.244
0.223
0.201
0.241
0.496
0.241
–
–
0.436
1.027
–
20
5
405
1125
3807
487
702
0
1.505
0.146
20
10
a
Human AChE
b
Insecticide AChE
Insecticide assay
cannot determine accurately the position of hydrogen
atoms, optimization of hydrogen atoms positions was
performed to investigate the hydrogen bond characters in
solid-state structures. The H atoms of N–H groups were
objectively localized in the difference Fourier synthesis and
refined in isotropic approximation. To achieve this goal, the
solid-state structure of crystal was modeled as four clusters
(Fig. 6). Other atoms were kept frozen during the optimi-
zation. Such computational justifications have also been
used to describe well the geometry and electronic aspects
of X-ray structure [14]. Taking into consideration the large
number of atoms in the model cluster, all optimizations
were performed at B3LYP/6-311+G** level. The NBO
[15] analysis was performed to compare the electronic fea-
tures of gas-phase structures of compound 7 with those of
the model clusters at B3LYP/6-311+G** level [16]. As
part of this study deals with investigation of the hydrogen
bonds between O···H atoms, AIM analysis at the B3LYP/6-
311+G** has much importance. Two hydrogen bonds with
different lengths were observed in compound 7. The hydro-
gen bonding energies have been calculated, on the basis
Compounds 18–22 were dissolved in DMSO and diluted
with water (1:3) to obtain series concentrations of 5000,
2500, 1250, 850 and 650 ppm. The insects Xanthogaleruca
luteola Müll were collected from elm trees leaves in Gui-
lan provinces of Iran and reared on leaves of Ulmus densa
Litw. Same-aged larvae (third instars) were randomly
selected for the bioassay. Third instars larvae were dipped
on each solution for 30 s, then put them on fresh leave in
conditioned room (23
tality was assessed after 24 h, and data were corrected and
subjected to probit analysis (Table 1).
2 °C, 75 % RH) after that mor-
Crystal structure determination
A crystal suitable for X-ray crystallography was obtained
from a mixture of CH3CN at room temperature for com-
pounds 1 and 7 (Figs. 2, 3). The solid-state structure as
starting point was fully optimized by using DFT calcula-
tions in the gas phase. Whereas X-ray crystallography
1 3

J IRAN CHEM SOC
the descriptors. The electronic and structural descriptors
are obtained by either the quantum chemical calculations
or theoretical and experimental studies. The electronic
descriptors include the energy of frontier orbital (EHOMO
and ELUMO), electrophilicity (ω), polarizability (PL, the
charge difference between the atoms in functional groups)
and the net atomic charges (Q). Also hydrophobic coef-
ficient (log P), dipole moment (μ) and molecular volume
(Mv) are the structural descriptors. EHOMO, ELUMO, ω, P, Q,
μ and Mv values are obtained from the DFT results. The
logarithm of partition coefficient (log P) is measured by the
ChemDraw software. The toxicities of Tem analogous are
expressed in terms of log(1/IC50) as an anti-cholinesterase
activity. The descriptor values were related to toxicity using
MLR analysis. MLR of descriptors, selected for biologi-
cal activity, gives rise to the problem of multicollinearity.
The descriptors with lower residuals and standard error
(Sreg < 0.5) to log(1/IC50) were selected to carry out step-
wise MLR analysis and to optimize the QSAR equation.
The stable geometry structures of compounds were further
fully optimized using the density functional theory (DFT)
at the B3LYP/6-311+G** level of theory [20]. Statisti-
cal analysis of insecticide data was compared by one-way
analysis of variance (ANOVA) followed by Tukey’s test
when significant differences were found at P = 0.05 using
SAS program [21].
Results and discussion
Spectra study
The 31P NMR chemical shift at room temperature in
Fig. 1 Plot of VI/V0 against log[I] for inhibitors. VI and V0 are the
AChE enzyme (A and B), activities (OD min−1), and [I] is the inhibi-
tor concentration (μM)
CDCl3 and DMSO appears in the range −7.74 ppm (13)
1
to 21.55 ppm (17). The H NMR spectra of compounds
1, 2, 3, 9, 11–12, 19, 20 and 22 exhibited two signals for
the methylene protons of the six-membered piperazinyl
rings. Two protons of the NH group as two doublets are
exhibited as a multiple peak at the range 4.49 ppm (20) to
9.50 ppm (13) and 2JPNH = 7.6 Hz (16) to 2JPNH = 13.1 Hz
(12). The 13C NMR spectra of compounds 1, 2, 3, 9, 11–
12, 19, 20 and 22 indicated three separated peaks for the
six carbon atoms that are due to different orientations of
of energy difference between the hydrogen bonded dim-
mer and its monomers, as represented in equation ΔEHB
=
(Edimer − 2Emonomer)/2 and corrected for basis set superposi-
tion error (BSSE) using the counterpoise method [17]. All
quantum chemical calculations were carried out by using
the Gaussian 03 program package [18].
3
the aliphatic six-membered rings. The JPC have maxi-
Statistical analysis
mum value (3JPC = 7.3 Hz) in compound 17 arises from
spin coupling of CH group carbon atom with phospho-
3
In order to identify the effect of physicochemical param-
eters on the AChE inhibition activity, QSAR studies were
undertaken using the approach described by Hansch and
Fujita [19]. The stepwise multiple linear regression pro-
cedure is a common method in QSAR studies for selec-
tion descriptors. The MLR method performed by the
software package SPSS 16.0 was used for selection of
rus atom. The JPC values in titled compounds indicate
3
3
that JPC(aromatic) are greater than JPC(aliphatic). The analysis
of the IR spectra indicated that the fundamental ν(P=O)
stretching modes for compounds 1–22 appeared at the
range 1175–1234 cm−1. Moreover, the N–H stretching fre-
quencies for all compounds were observed at the range of
3139–3445 cm−1
.
1 3

J IRAN CHEM SOC
Fig. 2 ORTEP view of the first symmetrically independent molecule of 1
Crystal structures
difference in the bond lengths is correlated with the vari-
ous orientations of benzene rings and OCH3 groups. These
orientations lead to the creation of different hydrogen bond-
ing patterns between the P=O and N–H functional groups
(Fig. 6). The one-dimensional polymeric chains form in
the crystal lattice with cyclic R44(16) motifs in which the
monomers are connected to each other via four P=O···H–
N hydrogen bonds distance of 2.868(2) and 2.782(2) Å
(Fig. 6, Table 3). The RYX(Z) graph–set notation is descrip-
tive of a Z-membered ring produced by the X hydrogen
bonds between the Y donor–acceptor units [22]. The low
atomic radius and the large electronegativity of oxygen
atoms increased the strength of the hydrogen bonding
between P=O and NH. The electronic parameters of the
hydrogen bonded clusters of compound 7 were calculated
by AIM and NBO methods. The results of AIM and NBO
analyses for the mentioned clusters are presented in Table 3.
As shown, the bond lengths in this cluster are equal to those
obtained from the X-ray structures, except for the C–H and
N–H bonds, since the optimizations have been performed
only for the hydrogen atoms’ positions. Also the donor–
acceptor distances for the hydrogen bonds in the model
cluster are equal to the experimental values. The results of
AIM analysis show that the electron density (ρ) value at
Single crystal of both compounds 1 and 7 suitable for
X-ray diffraction analysis was grown from an acetonitrile
solution after slow evaporation at room temperature. The
crystal data and the details of X-ray analysis are given in
Table 2; also molecular structures are shown in Figs. 2 and
3 for compounds 1 and 7. Compound 1 crystallized in the
monoclinic C 2/c space group. The phosphorus atom has
a slightly distorted tetrahedral configuration in compound
1 that is the surrounding angles around the P atom are in
the range of 104.85(6)°–115.67(5)°. The P=O bond dis-
tance is in 1 (1.4904(10) Å). The P–N bond distances in 1
(1.6384(11) Å), (1.6445(11) Å), (1.6552(11) Å) bond are
shorter than the single bond P–N distance of 1.77 Å. The
structure is not a traditional pillared material where the
inorganic layer is linked by organic groups. Instead, the
H2O centers act as pillars that link organic layers together
(Fig. 4). The asymmetric unit consists of four compound 1
sited on of symmetry with fourteen water molecule in the
center and twenty-two of them in sides.
The thermogravimetric analysis is used to prove the
existence of water in the composition 1. The differential
scanning calorimetry (DSC) curve of the dehydration of
compound 1 (Fig. 5) shows that the dehydration occurs in
the one step. Water molecules per structure unite is released
in the temperature 278.83 °C. The crystal data and the
details of the X-ray analysis of the compound 7 are given
in Table 2. The phosphorus centers are in typical tetrahe-
dral environments. The P=O bond lengths with the anti-
configuration were observed for of 1.4708(10) Å for P(1)–
O(1) and 1.4686(11) Å for P(1′)–O(1′), in (CH3O)2P(O)
NH(C6H4)–(C6H4)NHP(O)(OCH3)2 (7). It seems that the
the bond critical point (bcp) of O(1′)···H(1) (0.040 e Å−3
)
bond path is larger in magnitude than the that calculated
for the O(1)···H(1′) (0.031 e Å−3) in the model cluster. The
smaller ρ value at the bcp of N–H bond confirms the pres-
ence of the stronger hydrogen bonds in P(1′)–O(1′)···(1)
H–N(1) with the linear N–H···O contact angle in compari-
son with the values obtained for P(1)–O(1)···(1′)H–N(1′).
The ρ value at the bcp of N–H bonds is 0.332 e Å−3 for the
fully optimized structure in the gas phase, which decreases
1 3

J IRAN CHEM SOC
Table 2 Crystallographic data
of compounds
Forms
1
7
Empirical formula
C28H62N6O16P2
800.78
C36H30N2O6P2
648.56
Formula weight
Temperature (K)
100(2)
100(2)
Wavelength (Å)
0.71073
0.71073
Crystal system, space group
Monoclinic, C 2/c
Monoclinic, P 21/c
Unit cell dimensions
a (Å)
19.4798(6)
26.3273(9)
8.4918(3)
90
8.2558(7)
33.787(3)
11.4912(10)
90
b (Å)
c (Å)
α (°)
β (°)
113.0160(10)
90
94.6057(19)
90
γ (°)
V (Å3)
4008.3(2)
4
3195.0(5)
4
Z, calculated density (Mg m−3
Density (calculated) (Mg/m3)
)
1.327
1.348
Absorption coefficient (mm−1
)
0.181
0.186
F(000)
1720
1.88°–29.00°
0.40 × 0.15 x 0.14 mm3
1352
Crystal size (mm)
0.35 × 0.25 × 0.25 mm3
2.27°–29.00°
−26 ≤h ≤26
−35 ≤k ≤35
−11 ≤l ≤11
θ range for data collection (°)
Limiting indices
−9 ≤h ≤11
−46 ≤k ≤43
−15 ≤l ≤15
Reflections collected/unique
24,387
25,961
5323 [R(int) = 0.0204]
8496 [R(int) = 0.0790]
Completeness to theta (%)
Absorption correction
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices
99.5
99.8
Semiempirical from equivalents
Full-matrix least squares on F2
5323/0/236
Semiempirical from equivalents
Full-matrix least squares on F2
5323/0/236
1.006
1.006
R1 = 0.0409, wR2 = 0.1259
R1 = 0.0457, wR2 = 0.1326
0.943 and −0.351
R1 = 0.0409, wR2 = 0.1259
R1 = 0.0457, wR2 = 0.1326
0.943 and −0.351
R indices (all data)
Largest diff. peak and hole (e Å−3
)
to 0.308 and 0.312 e Å−3, respectively, in N(1)–H(1) and
N(1′)–H(1′). The mean N–H distance increases from the
isolated molecules from 0.90 to 1.031 Å in their hydrogen
bonded of the modeled cluster. The electronic delocalization
of Lp(O)i → σ*(N–H)j occurs when the hydrogen bonds are
formed between the subunits i and j within a cluster. Such
an electronic effect leads to weakening of the N–H bond.
It has been previously explained that the stabilizing energy
E2 increases by a decrease in the donor–acceptor distance
of hydrogen bond [23]. The stabilizing energies E2 of
Lp(O)i → σ*(N–H)j electron density transfer in P=O···H–N
hydrogen bonds in the model cluster have been calculated as
32.63 and 27.89 kJ mol−1, respectively. This is in agreement
with the values of distance for these hydrogen bonds in two
P(1′)–O(1′)···(1)H–N(1) (2.782(2) Å) and P(1)–O(1)···(1′)
H–N(1′) (2.868(2) Å) models. The hydrogen bonding
is higher than the value calculated for P(1)–O(1)···(1′)
H–N(1′) (–45.67 kJ mol−1) (Table 3). It is noteworthy that
the term E2 refers to the stabilization energy of electronic
delocalization between the donor–acceptor orbital and dif-
fers from the hydrogen bonding energy.
Prediction of insecticide potential
PASS software predicts 900 types of biological activities
based on the structural formula. The default list of pre-
dictable biological activities (Pa) includes the main and
side pharmacological effects, molecular mechanisms and
specific toxicities. The PASS prediction results for a com-
pound are presented as a list of activity names and proba-
bility activity (Pa) values. The Pa values are interpreted as:
if Pa > 0.7, 0.5 < Pa < 0.7, and Pa < 0.5, then the chance
of finding this activity in the experiments is high, low and
energy in P(1′)–O(1′)···(1)H–N(1) model (–72.15 kJ mol−1
)
1 3

J IRAN CHEM SOC
Fig. 3 ORTEP view of the first symmetrically independent molecule of 7
lower, respectively [24]. Insecticide potential and anti-
AChE activities of 23 Tem analogous have been obtained
by using the PASS software, and the results are summa-
rized in Table 1. The insecticidal properties of all com-
pounds are predicted in the range of 0.188 (19) to 0.619
(7). As shown in Fig. 7a, a linear relationship gives the
plot of probable insecticide potential against anti-AChE
activity. To test the anti-AChE activity of the synthesized
compounds, we evaluated the inhibitory potential of titled
compounds against AChE enzyme by Ellman assay.
Bioassay
AChE assay
The inhibition constant (IC50) values of AChE against
compounds 1, 3, 6–11, 13–16, 18–19 and 21–22 were in
the range of 0.019 mM (16) to 2.390 (9) mM (Fig. 1a, b;
Table 1). The comparison of experimental data (log(1/
IC50) and the prediction of anti-AChE activities are shown
in Fig. 7b. In the terminal position of the compounds 1–8
with the NH(C6H4)(C6H4)NH skeleton, cyclic aliphatic
substitutions (NC5H10; IC50 = 0.313 mMol) inhibitory
activity are higher than the non-cyclic aliphatic substitu-
tions (NC4H10; IC50 = 0.510 mMol). The compound 16
with the NH(C6H4)SO2(C6H4)NH skeleton versus AChE
displayed the most potent inhibitory activity. The inhibitory
of compound 16 is higher than that of compound 13 with
the R2(O)P–NH(C6H4)SO2(C6H4)NH–P(O)R2 (R=OC2H5,
OC6H5)., because the presence of the electron acceptor
substituent in the around P=O group increases the inhibi-
tory potential of Tem derivatives. The mixed-type and
reversible mechanisms of Tem analogous were evaluated
by Lineweaver–Burk plots in previous work [25]. To gain a
better understanding of the inhibitory potential of the syn-
thesized compounds and to study on the reversible mecha-
nism in more detail, it was necessary to examine the inter-
action of the Tem derivatives with the AChE structures by
QSAR method.
Fig. 4 Asymmetric unit consists of four compound 1 sited on of
symmetry with fourteen water molecule in the center and twenty-two
of them in sides
Fig. 5 DSC curve of compound 1
1 3

J IRAN CHEM SOC
Fig. 6 Tetramer motifs R44(16)
formed by four hydrogen bonds
of P=O···H–N
Table 3 Hydrogen bonds data for the X-ray structure (the values in brackets), model cluster (at B3LYP/6-311+G**), charge densities (from
AIM analysis), delocalization energy (from NBO analysis) and bonding energy (at B3LYP/6-311+G**) for the model cluster
D–H···A
d(N–H)
d(H···O)
d(N···O)
∠NHO
ρ at the b.c.p.
E(2)a
EbHB
(e Å−3
)
N–H
H···O
N(1)–H(1)···O(1′)c
[1.031]0.90
[1.029]0.90
0.83
[1.728]1.90
[1.844]1.98
1.97
[2.782(2)]
[2.868(2)]
2.7985(13)
2.7472(15)
2.7938(18)
3.0366(15)
2.8599(14)
2.7683(17)
2.9117(17)
2.8139(15)
2.8847(17)
2.8531(16)
2.7924(15)
[171.1]168.0
[172.3]169.0
174
0.308
0.040
32.63
–72.15
N(1′)–H(1′)···O(1)d
0.312
0.031
27.89
–45.67
O(1W)–H(1WA)···O(1)e
O(1W)–H(1WB)···O(2)f
O(2W)–H(2WA)···O(5W)g
N(3)–H(3 N)···O(1W)h
O(2W)–H(2WB)···O(1)f
O(3W)–H(3WA)···O(6W)f
O(3W)–H(3WB)···O(1W)i
O(4W)–H(4WA)···O(3W)f
O(5W)–H(5WA)···O(2W)f
O(5W)–H(5WB)···O(4W)j
O(6W)–H(6WA)···O(2W)f
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
0.93
1.82
172
0.94
1.87
168
0.84
2.20
176
0.89
1.97
177
0.87
1.90
177
0.94
1.97
176
0.90
1.91
176
0.92
1.97
173
0.93
1.93
173
0.92
1.92
158
a
The stabilizing energy E2 refers to the effect of Lp(OP)i → σ*(N–H)j delocalization
b
c
d
e
f
The binding energy in kJ mol−1 for N–H···S hydrogen bonds
−x + 1, −y + 1, −z + 1
x + 1, y − 1, z
x, y, z + 1
x, y, z
g
h
i
x, −y, z − 1/2
−x + 1/2, −y + 1/2, −z + 3
−x, y, −z + 5/2
−x, −y, −z + 2
j
Insecticide potential
their external loops and in the tilt of the C-terminal helix,
differences that are unlikely to affect catalytic function
directly. The result of five monitoring showed that two
compounds had the mortality effect nearly 20 % when we
used the 5000-ppm concentration, in second section moni-
toring of compounds done, five of them selected for bioas-
say (Table 1). Also the amounts of IC50 for the enzyme of
Like the vertebrate AChEs, invertebrate AChEs belongs to
α/ß hydrolase fold family, with a core of eight ß-sheets con-
nected by α-helices [10]. The 3D structures of invertebrates
are folded similarly, and their active sites closely overlap.
The main structural differences between them are found in
1 3

J IRAN CHEM SOC
Fig. 8 PCA score plot for Tem derivatives
one of the important enzymes in insect. Most of them have
a toxification role when the insects encounter to toxin com-
pounds. As the alpha and beta esterase were measured from
the treated larvae. The result showed compound 18 could
inhibit α-esterase more than the other enzymes, because the
AChE in most of insects belongs to this grope of esterase
(Table 1). The comparison of experimental data and the
prediction of insecticide activities are shown in Fig. 7c.
QSAR study
PCA‑QSAR: PCA method was used to reduce the inde-
pendent variables. The principal components (PCs) as a
new set of variables (mutually orthogonal) were obtained
by this method. The first PC contains the largest variance,
and the second PC contains the second largest variance.
The variable selection in PCA was performed by using the
Fisher’s weights approach [26], and the results are summa-
rized as the following Eqs. (1a–1c):
PC1 = + 0.172QP + 0.344QN − 0.251PLP=O + 0.087PLN−H
− 0.456EHOMO − 0.432ELUMO + 0.431ω
+ 0.353µ − 0.225 log P + 0.146Mv
(1a)
Fig. 7 Plot of probable insecticide potential against probable anti-
AChE activity of selected compounds (a); the plot of experimental
values against prediction of anti-AChE activity (b); the plot of prob-
able insecticide potential against experimental insecticide potency (c)
PC2 = − 0.586QP + 0.232QN + 0.450PLP=O
− 0.339PLN−H + 0.099EHOMO − 0.113ELUMO (1b)
+ 0.113ω − 0.035µ − 0.255 log P + 0.430Mv
human and insect treated with any compounds. Four con-
centrations 2500, 1250, 850 and 650 selected to apply the
bioassay in third instars larvae of X. luteola. Our investiga-
tions demonstrate the compound of 18 had an insecticidal
effect better than the other compounds, as the IC50 of it that
was lesser. The high activity of compound 18 is depended
to the increasing of concentration of inhibitor. Esterase is
PC3 = + 0.200QP + 0.242QN − 0.375PLP=O − 0.575PLN−H
− 0.078EHOMO + 0.187ELUMO − 0.169ω
(1c)
− 0.026µ + 0.414 log P + 0.434Mv
The main variables were found from the principle
scores of the normalized eigenvalue of the three principal
1 3

J IRAN CHEM SOC
Table 4 Quantum chemical and
geometrical descriptors for the
titled compounds computed at
B3LYP/6-311+G** level
No. Electronic descriptors
Charge Polarizability
Structural descriptors
Lipophilicity Steric
Frontier molecular
orbital
QP (a.u) QN (a.u) PLP=O PLN–H EHOMO ELUMO
ω
μ (Debye) log P Mv (cm3/mol)
1
2.337
2.066
2.386
2.461
2.377
2.381
2.390
2.381
2.480
2.351
2.470
2.469
2.047
2.363
2.346
2.377
−0.964 −3.499 1.389 −0.209 −0.038 0.089 6.98
−2.42 389.618
3.42 490.038
1.49 256.537
0.56 266.537
1.93 435.756
−4.23 520.925
−0.12 472.238
0.01 452.332
−2.90 511.893
−2.49 492.878
−1.24 314.121
−0.13 389.618
−6.80 442.067
−1.76 485.257
−2.23 408.458
−0.63 549.027
3
−0.965 −3.204 1.377 −0.204 −0.036 0.092 3.943
−0.996 −3.512 1.387 −0.204 −0.035 0.084 9.91
−0.986 −3.303 1.405 −0.206 −0.028 0.077 6.71
−0.964 −3.499 1.389 −0.211 −0.039 0.091 6.13
−0.950 −3.506 1.401 −0.233 −0.056 0.118 9.42
−0.950 −3.520 1.380 −0.225 −0.036 0.090 12.19
−0.945 −3.504 1.370 −0.231 −0.057 0.119 13.809
−0.963 −3.557 1.397 −0.244 −0.062 0.127 14.673
−0.950 −3.488 1.378 −0.226 −0.052 0.106 14.03
−0.950 −3.578 1.432 −0.238 −0.058 0.121 11.65
−0.960 −3.577 1.380 −0.239 −0.059 0.123 16.03
−0.964 −3.168 1.389 −0.213 −0.056 0.115 13.01
−0.966 −3.440 1.376 −0.217 −0.035 0.087 5.70
−0.968 −3.476 1.386 −0.213 −0.033 0.084 14.514
−0.972 −3.509 1.395 −0.213 −0.033 0.084 9.70
6
7
8
9
10
11
13
14
15
16
18
19
21
22
a
Not tested due to insufficient quantities
components. The results showed the total variance of the
first, second and third factor PC as 44.2, 21.4 and 12.8 %,
respectively. Also, from the above equations, it was
deduced that the frontier molecular orbital energy param-
eters (EHOMO, ELUMO, ω) in PC1 are predominated from
log(1/IC50)
= + 0.130 log P + 0.033µ − 4.213QP − 8.915QN
− 0.317PLP=O + 4.539PLN−H − 64.050EHOMO
− 64.143ELUMO − 69.962ω − 0.002Mv − 62.072
n = 16; R2 = 0.334; Sreg = 0.715; Fstatistic = 0.251
those related to electronic (QP, QN, PLP=O and PLN–H
)
in PC2 and structural parameters (log P and Mv) in PC3
equation. Figure 8 shows the score and a loading plot of
PC1 × PC2. The score plot shows that separation of the
compounds with (NH(C6H4)2NH and NH(C6H4)O(C6H4)
NH moieties (left side), and NH(C6H4)SO2(C6H4)NH
moiety (right side) has been provided by PC1. PC1 equa-
tion was separated the compounds based on changing
value of molecular orbital energy descriptors. For example,
compounds 1–9 and 18–22 with the ELUMO = −0.028 to
−0.038 are in the right side of graph, whereas compounds
10–17 are in the left side (with the ELUMO = −0.052 to
−0.062). PCA-QSAR method cannot partially separated
descriptors; it is just a total separation. The MLR-QSAR
method can be used to solve this problem.
MLR-QSAR The stepwise MLR procedure which is a
common method used in QSAR studies was used for model
selection. The electronic and structural descriptors were
obtained by quantum chemical calculations (Table 4). An
optimal QSAR equation based on calculation data shown in
Table 4 was obtained for 16 compounds as following:
(2)
where n is the number of compounds, R2 is the determina-
tion coefficient, Sreg is the standard deviation of regression,
and Fstatistic is the Fisher statistic. The low determination
coefficient value (R2 = 0.334), the high values of standard
error (Sreg = 0.715) and variance inflation factor (VIF > 10)
lead to refuse the calculation of IC50. The best way to deal
with such a problem is to calculate variance inflation fac-
tor (VIF). We calculated VIF, which is a measure of multi-
collinearity, for each of the parameters involved in models.
The VIF is defined as 1/(1 − Ri2), where Ri is the multiple
correlation coefficient of the ith independent variable on all
of the other independent variables. A VIF 10 or more (no
upper limit is defined) for large data sets indicates a col-
linearity problem. For small data sets, even VIFs of five
or more (here also no upper limit is defined) can signify
collinearity. On the other hand, the VIF value greater than
10 (Table 5) is associated with multicollinearity problem.
Therefore, the variables with a high VIF are candidates for
1 3

J IRAN CHEM SOC
Table 5 VIFa values for the QSAR equations
log(1/IC50)
= + 0.144 log P + 0.034µ + 1.860QP + 36.554QN
Independent variable
Equation 1a
Equation 2
Equation 3
+ 3.284PLP=O − 29.078PLN−H
QP
14.058
3.767
24.417
7.451
5.487
3.709
6.055
3.898
− 35.394ELUMO − 0.006Mv + 83.965
QN
n = 13; R2 = 0.926; Sreg = 0.256; Fstatistic = 6.257
PLP=O
PLN–H
EHOMO
ELUMO
ω
5.115
6.587
2.021
4.829
(4)
46.756
161.187
231.713
3.416
82.306
185.315
307.941
4.923
The correlating parameters have VIF < 10; thus,
there is no collinearity problem (Table 5). In this equa-
tion, the inhibitory potency of AChE is influenced mainly
by the electronic parameters with preferential order as
QN > ELUMO > PLN–H > PLP=O > QP versus structural
descriptors (log P, μ and Mv). From the QSAR model
in Eq. 4, the molecular descriptors like an integrated net
charge of nitrogen atom (QN), PLN–H and ELUMO proved
important in defining the activity of the candidates. The cor-
relation matrix was used to determine the interrelationship
between the independent variables (Table 6). Table 6 shows
that the majority of regression coefficients among show-
ing that they were closely correlated. Therefore, orthogo-
nalization of the molecular descriptors was conducted.
Orthogonalization of molecular descriptors is undertaken
to avoid collinearity among variables and model overfit-
ting. The high interrelationships were observed between
ELUMO and QN (r = −0.566). A result was obtained from
the above data; the high electrophilicity of the compounds,
and thereby accepting electrons to its lowest unoccupied
molecular orbital, would help them to improve the biologi-
cal activity. Moreover, ELUMO parameter controls the influ-
ence of the net charge of nitrogen atom of Tem derivatives
in inhibition of AChE enzyme.
3.124
μ
3.762
2.801
5.734
log P
Mv
2.693
4.206
3.092
7.257
VIF = 1/(1 − R2i ); where Ri is the multiple correlation coefficient of
the ith independent variable on all of the other independent variables
a
exclusion from the model [27]. Regression was significant;
however, it gave high residuals for compounds 1, 11 and
22. As a result, a MLR was done excluding these three
compounds from the data set using all the ten descriptors
that gave Eq. 3.
log(1/IC50)
= + 0.128 log P − 0.002µ − 1.363QP + 23.768QN
+ 2.841PLP=O − 31.446PLN−H − 61.586EHOMO
− 33.712ELUMO − 24.775ω − 0.008Mv + 71.121
n = 13; R2 = 0.992; Sreg = 0.117; Fstatistic = 25.767
(3)
The equation was significant with low residuals and
low standard error of mean. The VIF value showed that ω
and EHOMO are highly inter correlated with ELUMO. There-
Conclusions
fore, a MLR was performed by removing ω and EHOMO
,
which was correlated with ELUMO and Eq. 4 was obtained
A series of temephos (Tem) derivatives (1–22) were syn-
as follows;
thesized and characterized. Also, the crystal structure of
Table 6 Correlation matrix for
the anti-AChE parameters and
the selected variables in Eq. (3)
Selected variables
QP
QN
PLP=O
1.000
PLN–H
ELUMO
μ
log P
Mv
QP
1.000
−0.001
−0.838 −0.269
QN
1.000
PLP=O
PLN–H
ELUMO
μ
+0.385 +0.086 −0.213
1.000
−0.106 −0.566 +0.302 −0.321
1.000
0.276 +0.306 −0.442 +0.045 −0.595
1.000
log P
Mv
0.131 −0.365 −0.065 −0.158 +0.568 −0.526
1.000
−0.310 +0.665 +0.045 −0.439 −0.313 +0.040 −0.340
1.000
1 3

J IRAN CHEM SOC
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Acknowledgments The financial support of Tarbiat Modares, Gui-
lan and Imam Hossein University’s Research Council is gratefully
acknowledged.
Supplementary data
CCDC 1027644 and 1027645 contain the supplementary
crystallographic data for compounds 1 and 7. These data
can be obtained free of charge via http://www.ccdc.cam.
ac.uk/conts/retrieving.html, or from the Cambridge Crys-
tallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (+44) 1223-336-033; or e-mail: deposit@
ccdc.cam.ac.uk.
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