Synthesis, characterization, crystal structures, QSAR study and antibacterial activities of organotin bisphosphoramidates

Article abstract of DOI:10.1016/j.jorganchem.2015.09.030

Organotin complexes of bisphosphoramidates were prepared by the reaction of SnR¹R²R³Cl (where R = alkyl/aryl/Cl) and Ph₂P(O)XP(O)Ph₂ligands (where X = diamine). All the compounds were characterized by

Full text of DOI:10.1016/j.jorganchem.2015.09.030

Accepted Manuscript
Synthesis, characterization, crystal structures, QSAR study and antibacterial activities
of organotin bisphosphoramidates
Khodayar Gholivand, Ali Asghar EbrahimiValmoozi, Akram Gholami, Michal Dusek,
Vaclav Eigner, Sara Abolghasemi
PII:
S0022-328X(15)30159-5
10.1016/j.jorganchem.2015.09.030
JOM 19245
DOI:
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 9 May 2015
Revised Date: 22 September 2015
Accepted Date: 23 September 2015
Please cite this article as: K. Gholivand, A.A. EbrahimiValmoozi, A. Gholami, M. Dusek, V. Eigner, S.
Abolghasemi, Synthesis, characterization, crystal structures, QSAR study and antibacterial activities
of organotin bisphosphoramidates, Journal of Organometallic Chemistry (2015), doi: 10.1016/
j.jorganchem.2015.09.030.
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Graphical Abstract
Log (1/MIC) = -14.093QSn + 0.032LP-O + 14.109PLSn-O – 33.098ω + 0. 001Mν -11.849
n = 10; R2 = 0.832; Sreg = 0.257; r = 0.103; Fstatistic = 3.971

ACCEPTED MANUSCRIPT
Synthesis, characterization, crystal structures, QSAR study and
antibacterial activities of organotin bisphosphoramidates
Khodayar Gholivanda,*, Ali Asghar EbrahimiValmoozia, Akram Gholamia, Michal
Dusekb, Vaclav Eignerb, Sara Abolghasemia
aDepartment of Chemistry, Faculty of Sciences, TarbiatModares University, Tehran, Iran
bInstitute of Physics of the ASCR, v.v.i., Na Slovance 2, 182 21 Praha 8, Czech Republic
* Corresponding author’s E-mail address: gholi_kh@modares.ac.ir
Tel.: +98 21 82883443; Fax: +98 218006544.
1

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Abstract
Organotin complexes of bisphosphoramidates were prepared by the reaction of
SnR1R2R3Cl (where R=alkyl/aryl/Cl) and Ph2P(O)XP(O)Ph2 ligands (where X=diamine).
All the compounds were characterized by NMR and IR spectroscopy. X-Ray
crystallography confirms that the bridging ligand produces binuclear complexes with
SnPh3Cl acceptors in Ca3 and Ca4 and offers a polymeric structure toward SnMe2Cl2 in
Cc5. The synthesized compounds were screened for the antibacterial activity against B.
cereus and E. coli. Based on the MIC test, the ligands are devoid of antibacterial activity.
Notably, among the complexes, triphenyltin adducts exhibited a marked activity only
against Gram-positive bacterium B. Cereus (IC50 = 0.78 µg/mL for Ca3 and Ca5). DFT–
QSAR models revealed that the descriptor of the electrophilicity (ω) parameter is
correlated with the inhibition activity on B. cereus. The correlation matrix of QSAR
models and docking analysis confirmed that the electrophilicity parameter controls the
influence of the net charge (QSn) and polarizability of Sn atom of complexes on the
inhibition of B. cereus
.
2

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Keywords: Bisphosphoramidate, Organotin compounds, Crystal structure, Antibacterial
activity,
QSAR
3

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1. Introduction
Research on medicinal applications of metal complexes is an area of current interest and
one of the most studied in biomedical and inorganic biochemistry. In this context, the
potent therapeutic properties of tin complexes are well known [1-3]. The chemistry of
organotins has received considerable attention during the last few decades owing to their
industrial (catalysts in PVC and foam production), agricultural (fungicides and acaricides,
wood preservatives) and medicinal applications (antibacterial and anticancer agents) [4-
7]. Biological activity of organotin complexes is apparently correlated with the kind of
the organic group and the donor ligand bound to tin [8], no method has been published so
far to clarify the mechanism of the antibacterial potency of OTPA derivatives in the
electronic and structural levels. To extend and evaluate this issue, new method is
introduced by other authors in order to elucidate this mechanism. Quantitative structure–
activity relationship (QSAR) equations enabled to create the correlation between the
electronic and structural parameters of OTPA derivatives and the antibacterial activity [9-
13]. From the above consideration, in connection with our current work on tin complexes
of phosphoramidates [14-18] and to investigate the biological aspects of them, herein, we
report synthesis and spectroscopic characterization (1H, 13C, 31P, 119Sn NMR and IR) of a
series of organotin bisphosphoramidates prepared by the reaction of SnR1R2R3Cl (R =
alkyl/aryl/Cl) and Ph2P(O)XP(O)Ph2 ligands where X = diamine (Scheme 1). The
structure of ligand L4 and three complexes Ca3, Ca4 and Cc5 were determined using X–ray
crystallography. All the compounds were screened for the antibacterial activity against B.
4

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cereus and E. coli. In order to understand the influence of electronic and structural
properties for the titled compounds, an integrated molecular docking and QSAR models
approaches were used to evaluate the binding interactions between the OTPA analogous
and the B. cereus.
2. Experimental
2.1. Material and calculations
31
1H, P and 119Sn NMR spectra were recorded on a Bruker Avance 300 spectrometer at
1
300.13, 121.50 and 111.86 MHz, respectively. H chemical shifts were determined
31
relative to internal TMS. P and 119Sn chemical shifts were measured relative to 85%
H3PO4 and SnMe4 as external standard respectively. Infrared (IR) spectra were recorded
on a Shimadzu model IR-60 spectrometer using KBr pellets. Density functional
calculations (DFT) at B3LYP level have been carried out using Gaussian 09 package
[19]. The correlation analysis was performed by the Statistical Package for Social
Scientists (SPSS), version 16.0 for Windows [20].
2.2. General procedure for the preparation of ligands
All the ligands were synthesized by the procedure reported in the literature [17]. A
solution of diamine (1 mmol) and triethylamine (2 mmol, as HCl scavenger) in THF was
added at 0 °C to a solution of diphenylposphinic chloride (2 mmol) in THF. After 4 h
stirring, the solvent was removed in vacuum and the resulting was washed with distilled
5

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water. Compound L4 was recrystallized from a mixture of THF and H2O at room
temperature to obtain crystals suitable for X-ray analysis. Physical and spectroscopic data
of new ligands (L1-L4 and L6) are presented below. Characterization of L5 and L7 were
reported in our previous work [17].
Ph2P(O)NH–(CH2)2–HNP(O)Ph2 (L1)
Mp: 228–230 °C. 1H NMR (d6–DMSO, ppm); δ= 2.88 (m, 4H, CH2), 5.51 (m, 2H, NH),
13
7.43–7.47 (m, 8H, Ph), 7.49–7.52 (m, 4H, Ph), 7.73–7.77 (m, 8H, Ph). C NMR (d6–
DMSO, ppm); δ= 42.0 (d, 2JPC = 6.1 Hz, CH2), 128.3 (d, 3JPC = 12.1 Hz, m–Ph), 131.4 (s,
p–Ph), 131.6 (d, 2JPC = 9.4 Hz, o–Ph), 133.6 (d, 1JPC = 126.5 Hz, ipso–Ph). 31P{1H} NMR
~
(d6–DMSO, ppm); δ= 21.9 (m). IR (KBr, cm-1):
= 3199 (N–H), 2928 (s), 1438 (s),
υ
1186 (s, P=O), 1111 (s), 722 (m).
Ph2P(O)NH–(CH2)3–HNP(O)Ph2 (L2)
1
Mp: 222–225 °C. H NMR (d6–DMSO, ppm); δ= 1.60 (q, 2H, β-CH2), 2.84 (td, 4H, α-
CH2), 5.37 (m, 2H, NH), 7.44–7.47 (m, 8H, Ph), 7.49–7.52 (m, 4H, Ph), 7.72–7.76 (m,
8H, Ph). 13C NMR (d6–DMSO, ppm); δ= 33.1 (m, β-CH2), 37.3 (s, α-CH2), 128.4 (d, 3JPC
= 12.0 Hz, m–Ph), 131.4 (s, p–Ph), 131.6 (d, 2JPC = 9.2 Hz, o–Ph), 133.9 (d, 1JPC = 126.1
~
31
1
υ
Hz,, ipso–Ph). P{ H} NMR (d6–DMSO, ppm); δ= 21.8 (m) ppm. IR (KBr):
= 3178
(N–H), 2921 (s), 1437 (s), 1180 (s, P=O), 1120 (s), 725 (m).
Ph2P(O)NH–(CH2)4–HNP(O)Ph2 (L3)
1
Mp: 186–188 °C. H NMR (d6–DMSO, ppm); δ= 1.61 (m, 4H, β-CH2), 2.93 (m, 4H, α-
CH2), 5.18 (m, 2H, NH), 7.39–7.44 (m, 8H, Ph), 7.45–7.48 (m, 4H, Ph), 7.82–7.89 (m,
6

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13
8H, Ph). C NMR (d6–DMSO, ppm); δ= 29.1 (m, β-CH2), 38.0 (m, α-CH2), 128.9 (d,
2
1
3JPC = 12.0 Hz, m–Ph), 131.9 (s, p–Ph), 132.1 (d, JPC = 9.2 Hz, o–Ph), 134.5 (d, JPC
=
=
~
31
1
-1
υ
126.0 Hz, ipso–Ph). P{ H} NMR (d6–DMSO, ppm); δ= 23.8 (m). IR (KBr, cm ):
3247 (m, N–H), 2939 (s), 1431 (s), 1188(s, P=O), 1115 (s), 722 (m).
Ph2P(O)NMe–(CH2)2-NMeP(O)Ph2 (L4)
1
3
Mp: 199–201 °C. H NMR (d6–DMSO, ppm); δ= 2.38 (d, JP–H = 10.8 Hz, 6H, CH3),
3.07–3.09 (m, 4H, CH2), 7.39–7.44 (m, 8H, Ph), 7.46–7.49 (m, 4H, Ph), 7.76–7.80 (m,
13
2
8H, Ph). C NMR (d6–DMSO, ppm); δ= 34.3 (d, JPC = 2.6 Hz, CH3), 47.4 (m, CH2),
3
2
128.6 (d, JPC = 12.5 Hz, m–Ph), 131.9 (s, p–Ph), 132.2 (d, JPC = 9.1 Hz, o–Ph), 131.4
1
31
(d, JPC = 128.5 Hz,, ipso–Ph). P{1H} NMR (d6–DMSO, ppm); δ= 31.6 (m). IR (KBr,
~
-1
υ
cm ): = 2930 (s), 1441 (s), 1161 (s, P=O), 1112 (s), 984 (s), 731 (m).
1,4-[Ph2P(O)O-C6H4-OP(O)Ph2] (L6)
1
Mp: 206-208 °C. H NMR (DMSO-d6, ppm): δ = 7.16 (s, 4H, Ph), 7.51-7.60 (m, 12H,
31
4Ph), 7.71-7.84 (m, 8H, 4Ph). P NMR (DMSO-d6, ppm): δ = 29. 8. [1H NMR (CDCl3,
31
ppm): δ = 7.06 (s, 4H, Ph), 7.40-7.56 (m, 12H, 4Ph), 7.79-7.86 (m, 8H, 4Ph). P NMR
~
-1
υ
(CDCl3, ppm): δ = 28.4.] Selected IR data (KBr, cm ):
= 1235 (s), 1180 (s, P=O), 914
(s).
2.3. General procedure for the preparation of complexes
7

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The complexes were prepared by using the similar procedure: Methanol-chloroform
solutions of 2 eq. organotin chloride (SnMe2Cl2, SnPh3Cl, SnPh2Cl2 or SnPhCl3) with 1
eq. the bisphosphoramide ligand were mixed. Suitable crystals of Ca3, Ca4 and Cc5 for X–
ray diffraction were obtained from slow evaporation of the solution at room temperature.
Physical and spectroscopic data of the complexes are given below: Characterization of L5
and L7 were reported in our previous work [17].
µ-[Ph2P(O)NH–(CH2)2–HNP(O)Ph2][SnPh3Cl]2 (Ca1)
1
M.p. 138-140 °C. H NMR (CD3OD, ppm): δ= 2.99–3.03 (m, 4H, CH2), 7.43–7.55 (m,
30H, Ph-P + m, p-Ph-Sn), 7.76-7.84 (m, 20H, 3J(119/117Sn,1H) = 58.6Hz, Ph-P + o-Ph-Sn).
13C NMR (CD3OD, ppm): δ= 37.1 (d, 3JPC = 19.2 Hz, CH2), 128.4 (s, 3J(119/117Sn, 13C) =
73.0 Hz, m-Ph-Sn), 128.6 (s, m–Ph-P), 129.2 (s, p–Ph-Sn), 131.6 (s, o–Ph-P), 131.8 (s, p–
2
Ph-P), 132.0 (s, ipso–Ph-P), 136.0 (s, J(117/119Sn, 13C) = 47.0 Hz, o-Ph-Sn). 31PNMR
(CD3OD, ppm): δ = 24.6 (m). 119Sn NMR (CD3OD, ppm): δ = -181.0 ppm. IR (KBr,
~
−1
υ
cm ):
= 3175 (m, N–H), 2928 (m), 1434 (w), 1306 (w), 1177 (s, P=O), 1111 (s), 868
(w), 727 (w), 694.9 (w), 554 (w), 447 (w).
[Ph2P(O)NH–(CH2)2–HNP(O)Ph2.SnPh2Cl2]n (Cb1)
1
M.p. 176-178 °C. H NMR (CD3OD, ppm): δ= 3.18 (m, 4H, CH2), 7.46–7.75 (m, 18H,
Ph-P + Ph-Sn), 7.90-8.03 (m, 12H, Ph-P + Ph-Sn). 13C NMR (CD3OD, ppm): δ= 41.0 (m,
3
13
CH2), 128.4 (s, J(119/117Sn, C) = 100 Hz, m-Ph-Sn), 128.6 (s, m-Ph-P), 128.8 (s, p-Ph-
31
Sn), 131.2-131.6 (m, Ph-P), 135.9 (s, o-Ph-Sn). P NMR (CD3OD, ppm): δ = 24.9 (m).
8

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~
119Sn NMR (CD3OD, ppm): δ = low solubility. IR (KBr, cm−1):
= 3391 (m, N–H),
υ
3056 (m), 1432 (w), 1131 (s, P=O), 866 (w), 735 (w), 693.8 (w), 558 (w), 457 (w).
[Ph2P(O)NH–(CH2)2–HNP(O)Ph2.SnMe2Cl2]n (Cc1)
M.p. 174-176 °C. Anal. Calc. for C28H32Cl2N2O2P2Sn: C, 49.45; H, 4.74; N, 4.12; found:
C, 44.72; H, 4.79; N, 3.69%. 1H NMR (CD3OD, ppm): δ = 1.08 (s, 6H, 2J(119/117Sn, 1H) =
91.5 Hz, Me-Sn), 3.02–3.22 (m, 4H, CH2), 7.47–7.56 (m, 12H, Ph), 7.76–7.86 (m, 8H,
Ph). 13C NMR (CD3OD, ppm): δ = 38.2 (s, Sn–Me), 42.2 (m, CH2), 128.4-128.8 (m, Ph),
131.2-132.6 (m, Ph). 31P NMR (CD3OD, ppm): δ = 24.6 (m). 119Sn NMR (CD3OD, ppm):
~
−1
υ
δ= -245.5 ppm. IR (KBr, cm ): = 3247 (m, N–H), 2925 (m), 1434 (w), 1146 (s, P=O),
945 (w), 750 (w), 693 (w), 559 (w), 448 (w).
µ-[Ph2P(O)NH–(CH2)3–HNP(O)Ph2][SnPh3Cl]2 (Ca2)
M.p. 105-107 °C.1H NMR (CD3OD, ppm): δ= 1.74 (t, 2JHH = 6.7 Hz, 2H, β-CH2), 2.95–
2.98 (m, 4H, α-CH2), 7.43–7.59 (m, 30H, Ph-P + Ph-Sn), 7.75–7.98 (m, 20H, Ph-P + Ph-
Sn). 13C NMR (CD3OD, ppm): δ= 29.3 (m, β-CH2), 37.2 (m, α-CH2), 128.3-129.1 (m, m-
Ph-P + m, p-Ph-Sn), 131.2-132.6 (m, Ph-P), 136.0 (s, o-Ph-Sn). 31P NMR (CD3OD,
~
119
−1
υ
ppm): δ = 24.4 (m). Sn NMR (CD3OD, ppm): δ = -181.2 ppm. IR (KBr, cm ):
=
3181 (m, N–H), 3055.1 (s), 2929 (m), 1431 (w), 1304 (w), 1156 (s, P=O), 1117 (s), 863
(w), 731 (w), 694 (w), 554 (w), 449 (w).
[Ph2P(O)NH–(CH2)3–HNP(O)Ph2.SnPh2Cl2]n (Cb2)
9

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M.p. 161-163 °C. Anal. Calc. for C39H38Cl2N2O2P2Sn: C, 57.24; H, 4.68; N, 3.42; found:
1
C, 58.74; H, 5.18; N, 3.81%. H NMR (CD3OD, ppm): δ= 1.78 (t, 2JHH = 7.5 Hz, 2H, β-
CH2), 2.94–3.08 (m, 4H, α-CH2), 7.52–7.56 (m, 18H, Ph-P + Ph-Sn), 7.79–7.85 (m, 12H,
13
Ph-P + Ph-Sn). C NMR (CD3OD, ppm): δ= 33.3 (m, β-CH2), 37.6 (m, α-CH2), 128.36
(s, 3J(119/117Sn, 13C) = 85.9 Hz, m-Ph-Sn), 128.6 (s, m-Ph-P), 129.3 (s, p-Ph-Sn), 131.6 (s,
13
p-Ph-P), 131.8 (s, o-Ph-P), 132.0 (s, ipso-Ph-P), 136.0 (s, 2J(119/117Sn, C) = 48.0 Hz, o-
31
Ph-Sn). P NMR (CD3OD, ppm): δ = 25.6 (m). 119Sn NMR (CD3OD, ppm): δ = -452.5
~
−1
υ
ppm. IR (KBr, cm ):
= 3386 (m, N–H), 3056 (m), 1434 (w), 1126 (s, P=O), 993 (w),
730 (w), 694 (w), 556 (w), 451 (w).
[Ph2P(O)NH–(CH2)3–HNP(O)Ph2.SnMe2Cl2]n (Cc2)
1
2
1
M.p. 107 °C. H NMR (CD3OD, ppm): δ = 1.08 (s, 6H, J(119/117Sn, H) = 95.0 Hz, Me-
2
Sn), 1.76 (t, JHH = 6.7 Hz, 2H, β-CH2), 2.95–3.08 (m, 4H, α-CH2), 7.48–7.59 (m, 12H,
Ph), 7.76–7.87 (m, 8H, Ph). 13C NMR (CD3OD, ppm): low solubility. 31P NMR (CD3OD,
~
119
−1
υ
ppm): δ = 24.5 (m). Sn NMR (CD3OD, ppm): δ = -120.4 ppm. IR (KBr, cm ):
=
3278 (N–H), 2924 (m), 1443 (w), 1157 (s, P=O), 802 (w), 735 (w), 687 (w), 555 (w), 449
(w).
µ-[Ph2P(O)NH–(CH2)4–HNP(O)Ph2][SnPh3Cl]2 (Ca3)
M.p. 117-120 °C. Anal. Calc. for C64H60Cl2N2O2P2Sn2: C, 61.03; H, 4.80; N, 2.22; found:
C, 61.07; H, 4.98; N, 2.38%. 1H NMR (CD3OD, ppm): δ= 1.56 (m, 4H, β-CH2), 2.83 (m,
3
4H, α-CH2), 7.44–7.58 (m, 30H, Ph-P + m, p-Ph-Sn), 7.72–7.98 (m, 20H, J(119/117Sn,1H)
13
3
= 59.0 Hz, Ph-P + o–Ph-Sn). C NMR (CD3OD, ppm): δ= 28.8 (d, JPC = 6.4 Hz, β-
10

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3
13
CH2), 40.0 (m, α-CH2), 128.3 (s, J(119/117Sn, C) = 71.0 Hz, m-Ph-Sn), 128.5 (s, m–Ph-
P), 129.2 (s, p–Ph-Sn), 131.7 (s, o–Ph-P), 131.8 (s, p–Ph-p), 132.0 (s, ipso–Ph-P), 136.0
3
31
(s, J(117/119Sn–13C) = 47.5 Hz, o-Ph-Sn). P NMR (CD3OD, ppm): δ = 24.3 (m). 119Sn
~
−1
υ
NMR (CD3OD, ppm): δ = -180.5 ppm. IR (KBr, cm ):
= 3362 (m, N–H), 3055 (s),
2941 (m), 1428 (w), 1307 (w), 1157 (s, P=O), 1110 (s), 837.3 (w), 731 (w), 695 (w), 561
(w), 449 (w).
[Ph2P(O)NH–(CH2)4–HNP(O)Ph2.SnPh2Cl2]n (Cb3)
1H NMR (CD3OD, ppm): δ= 1.55–1.70 (m, 4H, β-CH2), 2.99–3.10 (m, 4H, α-CH2), 7.58–
13
7.66 (m, 18H, Ph-P + Ph-Sn), 7.88–7.97 (m, 12H, Ph-P + Ph-Sn). C NMR (CD3OD,
4
13
ppm): δ= 28.6 (d, JPC = 4.7 Hz, β-CH2), 42.8 (m, α-CH2), 127.2 (s, 3J(117/119Sn, C) =
123.2 Hz, m-Ph-Sn), 127.7 (s, p-Ph-Sn), 128.4 (d, 3JPC = 11.9 Hz, 8C, m–Ph-P), 131.4 (s,
2
3
p–Ph-P), 131.7 (d, JPC = 9.2 Hz, o–Ph-P), 133.1 (s, ipso–Ph-P), 134.7 (s, J(117/119Sn,
31
13C) = 71.9 Hz, o-Ph-Sn), 155.5 (s, ipso-Ph-Sn). P NMR (CD3OD, ppm): δ 24.5 (m).
~
119
−1
υ
Sn NMR (CD3OD, ppm): δ = -471.5 ppm. IR (KBr, cm ):
= 3343 (m, N–H), 3053
(m), 2942 (s), 1433 (w), 1148 (s, P=O), 936 (w), 732 (w), 695 (w), 553 (w), 455 (w).
[Ph2P(O)NH–(CH2)4–HNP(O)Ph2.SnMe2Cl2]n (Cc3)
1H NMR (d6–DMSO, ppm): δ = 1.03 (6H, 2J(119/117Sn, 1H) = 111.8 Hz, Me-Sn), 1.47 (m,
4H, β-CH2), 2.66–2.69 (m, 4H, α-CH2), 5.24–5.27 (m, 2H, NH), 7.42–7.52 (m, 12H, Ph),
7.72–7.78 (m, 8H, Ph). 13C NMR (CD3OD, ppm): δ = 38.2 (s, Sn–Me), 40.9 (m, β-CH2),
31
42.2 (m, α-CH2), 128.4-128.8 (m, Ph), 131.2-132.6 (m, Ph). P NMR (CD3OD, ppm): δ
11

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~
−1
= 26.9 (m). 119Sn NMR (d6–DMSO, ppm): δ = low solubility. IR (KBr, cm ):
= 2930
υ
(m), 1434 (w), 1144 (s, P=O), 796 (w), 731 (s), 694 (w), 559 (w), 448 (w).
µ-[Ph2P(O)NMe–(CH2)2–NMeP(O)Ph2][SnPh3Cl]2 (Ca4)
M.p. 217-2219 °C.1H NMR (CD3OD, ppm): δ= 2.53–2.57 (m, 6H, Me), 3.21–3.25 (m,
4H, CH2), 7.54–7.75 (m, 30H, Ph-P + Ph-Sn), 7.89–7.96 (m, 20H, Ph-P + Ph-Sn). 13C
NMR (CD3OD, ppm): δ= 33.7 (s, Me), 46.5 (s, CH2), 128.3 (s, Ph-Sn), 128.9 (s, Ph-Sn),
3
2
128.7 (d, JPC = 12.1 Hz, m–Ph-P), 131.1 (s, p–Ph-P), 131.9 (d, JPC = 9.3 Hz, o–Ph-P),
3
13
132.9 (s, ipso–Ph-P), 136.0 (s, J(117/119Sn, C) = 67.8 Hz, m-Ph-Sn) 162.0 (s, ipso-Ph-
Sn). 31PNMR (CD3OD, ppm): δ = 31.5 (m). 119Sn NMR (CD3OD, ppm): δ = -153.3 ppm.
~
−1
υ
IR (KBr, cm ):
= 2931 (m), 1435 (w), 1309 (w), 1138 (s, P=O), 991 (s), 731 (w), 696
(w), 557 (w), 454 (w).
[Ph2P(O)NMe–(CH2)2–NMeP(O)Ph2.SnPh2Cl2]n (Cb4)
Anal. Calc. for C40H40Cl2N2O2P2Sn: C, 57.72; H, 4.84; N, 3.37; found: C, 56.88; H, 5.05;
N, 3.52%. 1H NMR (CD3OD, ppm): δ= 2.53–2.57 (m, 6H, Me), 2.91–3.23 (m, 4H, CH2),
7.59–7.75 (m, 20H, Ph-P + Ph-Sn), 7.88–7.99 (m, 10H, Ph-P + Ph-Sn). 13C NMR
(CD3OD, ppm): δ= 128.6-137.2 (m, Ph-P + Ph-Sn).31PNMR (CD3OD, ppm): δ = 31.2
~
119
−1
υ
(m). Sn NMR (CD3OD, ppm): δ = -156.0 ppm. IR (KBr, cm ):
= 3055 (m), 1438
(w), 1144 (s, P=O), 994 (w), 734 (w), 696 (w), 561 (w), 463 (w).
µ-[Ph2P(O)N(C4H8)NP(O)Ph2][SnPh3Cl]2 (Ca5) [17]
12

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1H NMR (CD3OD, ppm): δ = 3.10 (m, 8 H, C4H8), 7.50–7.57 (m, 12H, Ph-P), 7.80–7.91
(m, 8H, Ph-P), 7.44–7.51 (m, 18H, m, p–Ph-Sn), 7.67–7.70 (m, 12H, o-Ph-Sn). 13C NMR
3
13
(CD3OD, ppm): δ= 44.52–44.62 (m, C4H8), 128.4 (s, J(119/117Sn, C) = 59.5 Hz, m-Ph-
Sn), 128.7 (s, p-Ph-Sn), 128.9 (d, 3JPC = 8.4 Hz, m-Ph-P), 130.6 (s, p-Ph-P), 132.0 (d, 3JPC
13
= 7.8 Hz, o-Ph-P), 132.2 (s, ipso-Ph-P), 136.0 (s, 2J(119/117Sn, C) = 39.8 Hz, o-Ph-Sn).
31P NMR (CD3OD, ppm): δ = 31.8. 119Sn NMR (CD3OD, ppm): δ = -180.7 ppm. IR
~
−1
υ
(KBr, cm ):
= 2906 (m), 1431 (w), 1150 (s, P=O), 1120 (s), 958 (w), 727 (w), 696
(w), 544 (w), 450 (w).
[Ph2P(O)N(C4H8)NP(O)Ph2.SnPh2Cl2]n (Cb5)
1H NMR (CD3OD, ppm): δ = 2.93 (m, 8H, C4H8), 7.24–7.36 (m, 6H, Ph), 7.46-7.57 (m,
10H, Ph), 7.75–7.81 (m, 8H, Ph), 7.89–7.91 (m, 6H, Ph). 13C NMR (CD3OD, ppm): low
31
solubility. P NMR (CD3OD, ppm): δ = 32.1. 119Sn NMR (CD3OD, ppm): δ = -74.6. IR
~
−1
υ
(KBr, cm ):
= 3056 (m), 1437 (w), 1139 (s, P=O), 10718 (s), 971 (w), 724 (w), 697
(w), 552 (w), 457 (w).
[Ph2P(O)N(C4H8)NP(O)Ph2.SnMe2Cl2]n (Cc5)
2
1
1H NMR (CD3OD, ppm): δ = 1.03 (6H, J(119/117Sn, H) = 111.3 Hz, Me-Sn), 2.93–2.95
13
(m, 8H, C4H8), 7.46–7.56 (m, 12H, Ph), 7.74–7.81 (m, 8H, Ph). C NMR (CD3OD,
ppm): δ= 41.8 (s, Me-Sn), 44.9 (m, C4H8), 128.5-129.2 (m, Ph), 131.2-132.9 (m, Ph). 31P
NMR (CD3OD, ppm): δ = 31.5. 119Sn NMR (CD3OD, ppm): δ = low solubility. IR (KBr,
~
−1
υ
cm ):
= 3061, 2920, 1438 (w), 1154 (s, P=O), 1119 (m), 965 (w), 935, 784, 722 (w),
582 (w), 545 (w).
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µ-[1,4-Ph2P(O)O-C6H4-OP(O)Ph2][SnPh3Cl]2 (Ca6) [17]
Mp: 171-173 °C. 1H NMR (CDCl3, ppm): δ = 7.04 (s, 4H, C6H4), 7.41–7.57 (m, 30H, Ph-
3
P + Ph-Sn), 7.66–7.70 (m, 12H, J(119/117Sn,1H) = 60 Hz, o-Ph3Sn), 7.79–7.86 (m, 8H,
Ph-P). 31P NMR (CDCl3, ppm): δ = 28.5. 119Sn NMR (CDCl3, ppm): δ = -49.7. IR (KBr,
~
−1
υ
cm ): = 1210, 1173 (s, P=O), 918 (s).
µ-[1,4-Ph2P(O)O-C6H4-OP(O)Ph2][SnPh2Cl2]2 (Cb6)
Mp: 191-193 °C. 1H NMR (CDCl3, ppm): δ = 6.95 (s, 4H, C6H4), 7.40–7.57 (m, 24H, Ph-
P + Ph-Sn), 7.70–7.74 (m, 8H, 3J(119/117Sn,1H) = 60 Hz, o–Ph-Sn), 7.76–7.81 (m, 8H, Ph-
31
P). P NMR (CDCl3, ppm): δ = 28.6. 119Sn NMR (CDCl3, ppm): δ = -66.0. IR (KBr,
~
−1
υ
cm ): = 1163 (P=O), 936 (s).
µ-[1,4-Ph2P(O)O-C6H4-OP(O)Ph2][SnPhCl3]2 (Cd6)
Mp: 1196-198 °C 1H NMR (CDCl3, ppm): δ = 6.91 (s, 4H, C6H4), 7.38–7.50 (m, 14H,
31
Ph-P + Ph-Sn), 7.59–7.68 (m, 8H, Ph-Sn), 7.76–7.80 (m, 8H, Ph-P). P NMR (CDCl3,
~
−1
ppm): δ = 30.2. 119Sn NMR (CDCl3, ppm): δ = -54.0. IR (KBr, cm ):
= 1166 (P=O),
υ
933 (s).
µ-[1,3-(Ph2P(O)NHCH2)2C6H4][SnPh3Cl]2 (Ca7)
1
Mp: 171-173 °C. H NMR (CDCl3, ppm): δ = 3.11 (ps-q, 2H, 3JPH = 5.8 Hz, N–H), 3.96
(ps-t, 4H, 3JPH = 7.6 Hz, CH2), 7.19–7.27 (m, 4H, C6H4), 7.41–7.49 (m, 30H, Ph-P + Ph-
3
31
Sn), 7.75–7.87 (m, 20H, J(119/117Sn,1H) = 63 Hz, Ph-P + o–Ph-Sn). P NMR (CDCl3,
14

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~
−1
ppm): δ =24.5. 119Sn NMR (CDCl3, ppm): δ = -80.8. IR (KBr, cm ):
= 3341 (N–H),
υ
1132 (P=O), 996s (P–N).
[1,3- (Ph2P(O)NHCH2)2C6H4.SnPh2Cl2]n (Cb7)
1
Mp: 191-194 °C. H NMR (CDCl3, ppm): δ = 3.11 (m, 2H, N–H), 4.09 (m, 4H, CH2),
6.92–7.93 (m, 48H, Ph-P + Ph-Sn). 31P NMR (CDCl3, ppm): δ =31.5. 119Sn NMR
~
−1
υ
(CDCl3, ppm): δ = low solubility. IR (KBr, cm ): = 3436 (N–H), 1133 (P=O).
[1,3- (Ph2P(O)NHCH2)2C6H4.SnMe2Cl2]n (Cc7)
Mp: 196-198 °C. 1H NMR (CDCl3, ppm): δ =1.21 (s, 6H, 2J(119/117Sn, 1H) = 77.9 Hz, Me-
3
Sn), 3.68 (ps-q, 2H, 3JPH = 6.5 Hz, N–H), 4.11 (ps-t, 4H, JPH = 7.5 Hz, CH2), 7.20–7.27
(m, 8H, Ph), 7.48–7.52 (m, 12H, Ph), 7.80–7.86 (m, 8H, Ph), 7.94 (m, 8H, Ph). 31P NMR
(CDCl3, ppm): δ = 26.6. 119Sn NMR (CDCl3, ppm): δ = low solubility. IR (KBr, cm−1):
~
υ
= 3318 (m, N–H), 3059, 1146 (s, P=O), 996 (s).
2.4. Crystallography
Single crystal X-ray data of compounds L4, Ca3 and Cc5 was collected on Bruker
APEX-II diffractometer with CCD area detector [21] using graphite monochromated Mo-
Ka radiations (λ= 0.71073 Å) while for Ca4 we used Gemini of Agilent with Atlas CCD
detector, mirror-collimated Cu-Ka radiation (λ= 1.5418 Å) and software package
CrysAlis PRO [22]. The structures were refined by full-matrix least-squares methods
against F2 with Jana2006 (Ca4) [23] and SHELXL-97 (L4, Ca3 and Cc5) [24]. The
15

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crystallographic and refinement data are summarized in Table 1.
2.5. Statistical analysis for QSAR model
In order to identify the effect of physicochemical parameters on the antibacterial activity,
QSAR studies were undertaken using the approach described by Hansch and Fujita [25].
The stepwise multiple linear regression (MLR) procedure is a common method in QSAR
studies for selection descriptors. The MLR method performed by the software package
SPSS 16.0 was used for selection of the electronic and structural descriptors obtained by
the quantum chemical calculations. 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
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 toxicities of
phosphorhydrazide analogues are expressed in terms of log(1/MIC) as an antibacterial
activity. The descriptor values were related with activity using MLR analysis. MLR of
descriptors, selected for biological activity, gives rise to the problem of multicollinearity.
This problem can be solved by using the principal component analysis (PCA) by
MINITAB14 software. These linear combinations form a new set of variables, namely
principal components (PCs), which are mutually orthogonal. The first PC contains the
largest variance and the second new variable contains the second largest variance, and so
on. The variable selection in this PCA study was performed by using the Fisher’s
weights. The descriptors with higher correlation coefficient and lower correlation (|r| <
16

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0.5) to log(1/MIC) were selected to carry out stepwise MLR analysis and to optimize the
QSAR equation [26]. The stable geometry structures of compounds were further fully
optimized using the Density functional theory (DFT).
2.6. Antimicrobial assay
The antibacterial activity of all the compounds was screened in vitro against Gram-
negative: E. coli (ATCC 10553), and Gram-posetive: B. cereus (prepared from a teaching
microbiological laboratory) bacteria. We used paper broth microdilution method
according to the international guideline of the CLSI (Clinical and Laboratory Standard
Institute) [27]. Minimum inhibitory concentrations (MIC) for the tested compounds were
determined by broth microdilution method. A stock solution of compounds in methanol
was prepared and serially twofold diluted using Nutrient Broth to give final
concentrations of 0.25-512µg/mL in sterile 96-well microplates. 100 µL of each cell
suspension of approximately 105 CFU/mL was added into the wells (each containing 100
µL of different concentration of compounds). The maximum percentage of methanol
present in the wells was 5% v/v (a control treatment, with all tested bacteria, using 5%
methanol showed no antibacterial activity). The MIC, defined as the lowest concentration
of the compound which inhibited the visible growth of bacteria, was determined visually
after incubation for 24 h at 37 °C. Results were generated from at least three independent
experiments, triplicate each. Testes using SnPh3Cl, SnPh2Cl2, SnMe2Cl2, SnPhCl3 and
gentamicin as positives controls were carried out in parallel [28] (Table 3).
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3. Results and discussion
3.1. Synthesis and spectroscopic characterization
The ligands were prepared using the same method from the reaction of Ph2P(O)Cl with
the corresponding diamine (2:1 molar ratio) in presence of Et3N as HCl scavenger.
Among the ligands, suitable crystal of L4 for X-ray analysis was obtained from a
THF:H2O solution (2:1). Various solvents were assessed in the crystallization of
complexes. However, single crystals of only three complexes were obtained by
evaporation from solutions of HCCl3:CH3OH (1:1), at room temperature and attempts to
grow good quality crystals of the other compounds were unsuccessful. All the
compounds were characterized by IR and multinuclear NMR spectroscopy. A significant
decreasing of the P=O stretching frequencies is observed by ligation of the diphosphoryl
ligands. Other prominent bands at 3175-3390 cm-1are assigned to N-H vibrational
modesthat shift toward higher frequencies in the coordinated ligands. Whereas the N–H
bond participates in the hydrogen bonding, the positive shift of υ(N–H) may be attributed
to the weakening of the hydrogen bonds from NH…OP=O in NH…Cl of complexes.
NMR spectroscopic results indicated that chemical shift (δ
) of 31P for the complexes was
almost more up-fielded than those of the corresponding ligands. The integrated 1H NMR
spectra of SnPh3Cl complexes are suggestive of binuclear structures, which exhibit the
expected proton signals for a bridging ligands and two triphenyltin(IV). The single
resonance at -80.8 to -181.2 ppm in the 119Sn NMR spectra of these compounds provides
additional evidence for five-coordinated tin centers in this solution [29]. Since methanol
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is a coordinating solvent, binding to Sn and replacing with ligand is also probable.
Besides, the 119Sn signal for diorganotin complexes lies (-452.5, -471.5 and -245.5 ppm
for Cb2, Cb3 and Cc1, respectively) at higher frequencies which strongly supports the six
1
coordination around the tin centers [30]. The integrated H NMR spectra of them are
consistent with the formula of 1:1 adducts.
Conclusive information is obtained from the values of the coupling constants, nJ(119/117Sn,
n
1
1H) and J(119/117Sn, 13C) from the H and 13C NMR spectra. The coupling constants
3
2J(119/117Sn, 13C) and J(119/117Sn, 13C) for triphenyltin adducts (40-47 and 60-73 Hz,
respectively) lie within the range of five-coordinated species; but the higher values for
diphenyltins (48-72 and 86-123 Hz, respectively) indicates the higher coordination
1
number of tin in these complexes. Besides, 2J(119/117Sn, H) for dimethyltin(IV)
compounds (78-112 Hz) is higher than original SnMe2Cl2 (68.7 Hz) and falls in the range
for six-coordinated dimethyltin(IV) species [31]. In the case of Cc5, substitution of
1
2J(119/117Sn, H) Lockhart-Manders [32] equation gives a value of 178.5° for the Me-Sn-
Me angle, in accordance with the value in the solid-state structure (168.4°). The other
remarkable coupling constant values cannot be extracted from the spectra because of the
complexity and overlapping of peaks in the aromatic region (for di- and tri-phenyltin
complexes) or disappearing of Me satellites in 13C NMR spectra of low soluble
dimethyltin species.
1
Finally, it should be noted that the integrated H NMR spectra of all complexes with L6
(Ca1, Cb6 and Cd6) are consistent with the formula of binuclear adducts. However, this
result is not informative enough to be evidence of the adducts in solution. Although the
119Sn NMR resonance of them shift from the values observed for the parent
19

ACCEPTED MANUSCRIPT
organotins(IV), such chemical shifts are not still in the range typical for the five-
coordinated tin compounds. This might be a hint that they partially or almost completely
dissociated in the solution.
3.2. X-ray crystallography investigation
3.2.1. Crystal structure of Ph2P(O)NMe–(CH2)2–NMeP(O)Ph2 (L4)
The structure of L4 is shown in (Fig 1a) and the most relevant bond distances are listed in
Table 2. The P=O groups are on opposite sides of the molecules. Crystal lattice of L4
contains one-dimensional hydrogen-bonded chains along c-axis which is produced by the
O-Hw…OP=O interactions. Water molecules, as bifurcated H-donors to P=O groups, build
up (8) rings between two adjacent diphosphoryl units into the [001] chains (Fig 1b).
Weaker CH…O (C3…O1w: 3.357(1) Å, C3-H3: 0.95 Å, C3-H3…O1w: 140°) and
CH…π interactions are also the driving force in generating a 3D network in L4 (Fig. S1).
Similar crystal packing pattern were already observed for the analogous structure of L5
including water molecule [17].
3.2.2. Crystal structure of triphenyl tin(IV) complexes Ca3 and Ca4
Both of complexes Ca3 and Ca4 crystalize in the monoclinic space group P 21/n with two
symmetry-independent molecules in the unit cell. Fig. 2 and 3 shows an ORTEP
representation of the molecular structures for these complexes, and selected bond
distances and angles are listed in Table 2. The complexes have a binuclear structure, with
centrosymmetric bridging molecules of the diphosphoryl ligand and tin moieties.
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The central tin atoms are in trigonal–bipyramidal environments formed by three phenyl
groups in the equatorial plane, one chloride ion and the phosphoryl group in the apical
(trans) positions. The trans angles around tin are 179.07(9)° and 177.51(3)°, and the sum
of angles in the trigonal girdle around Sn are 357.40° and 358.94° (for Ca3 and Ca4,
respectively.
The Sn–C bond distances (Table 2) are in a good agreement with the published values
[15, 17]. These values also correspond well with the sum of the covalent radii (2.15 Å) of
tin and carbon [33]. The Sn–Cl bond lengths are 2.5075(9) and 2.5000(5) Å (in Ca3 and
Ca4, respectively), lying in the normal covalent radii 2.37–2.60 Å while the Sn–O bonds
(2.363(2) and 2.3258(12) Å in Ca3 and Ca4, respectively) are in accordance with the
coordinate bond. A comparison between the crystal structures of Ca4 and its ligand, L4,
reveals that by coordinating the ligand to Sn, the P=O bond gets longer (about 0.013 Å).
Lengthening of the P=O bond is simply described by polarization of the phosphoryl
group in the electrostatic field of the tin(IV) atom. In return, the P-N and P-C bonds are
shortened about 0.011 Å in the complex Ca4 (Table 2).
The crystal structure of Ca4 is governed by CH…Cl interactions which build up a 3D
network. Here, the chlorine atom acts as a trifurcated acceptor involved in hydrogen
bonding with ligand-bound Ph rings of other molecular units (Fig. S2). These non-classic
hydrogen bonds are established in this compound with different donor–acceptor distances
of 3.5677(18) (C21H21…Cl1), 3.708(2) (C28H28…Cl1) and 3.768(2)
(C22H22…Cl1).
Å
In contrast, the presence of N–H moieties in Ca3 leads to the formation of interesting
inter-molecular hydrogen bonding. Each molecule of the complex is associated with other
21

ACCEPTED MANUSCRIPT
four molecules through symmetry-equivalent NH…Cl linkages (N…Cl: 3.664(3) Å, N-
H: 0.86 Å, N-H…Cl: 148°) in a two-dimensional arrangement (Fig. S3). Besides, the
crystal packing of Ca3 is further stabilized by weaker intermolecular C-H…π interactions
between hydrogen-bonded neighboring complexes.
3.2.3. Crystal structure of dimethyl tin(IV) complex Ca5
In the crystalline state, the title complex adopts an infinite zigzag chain structure which is
produced by the bidentate bridging diphosphoryl ligand and the Sn(IV) center. As shown
in Fig. 4, each central tin atom is surrounded by two carbon, two chlorine and two
oxygen atoms in a trans-cis octahedral geometry. The trans bond angles around the
Sn(IV) centers are 168.37(5) ( C1–Sn1–C2), 169.53(2) ( O1–Sn1–Cl1) and 175.94(2)°
( O2–Sn1–Cl2), indicating a distortion of the geometry. The cis bond angles are in the
range of 87.23(4) ( C2–Sn1–O1) to 98.30(4)° ( C1–Sn1)–Cl1) and deviate from the
idealized value (90°), close to the reported values for other trans–cis dimethyltin(IV)
adducts [31].
As usually, the methyl groups are in trans positions with almost equal distances (Table
2). Non-symmetrical coordination of the bidentate O2-ligand to tin can be observed with
two different Sn–O distances (2.3486(10) and 2.2718(10) Å) and also two different P–O–
Sn angles (163.35(5) and 149.66(5)°, respectively). There are chlorine atoms in trans
position of the two oxygen atoms and distances are correlated: the shorter is Sn–O, the
longer is Sn–Cl (trans effect), in agreement with other organotin phosphoramidates [34].
The P=O bond distances of 2.5006(9) and 2.5030(9) A are in the range found for P–O-
22

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single bonds in other phosphoryl compounds, indicating a considerable lengthening of the
P=O bond by (P–O→Sn) coordination.
As mentioned earlier, Sn-O interactions have a substantial contribution to the
organization and stabilization of the crystal structure. 1D infinite coordination chains
extend in the crystallographic b-direction with Sn-Sn separation of 10.529 Å. The
neighboring chains are correlated by CH…Cl interactions (C14H14…Cl2: 3.606(2) Å
and C5H5…Cl1: 3.606(2) Å along c axis and C26H26…Cl1: 3.606(2) Å in a-direction),
generating a 3D network (Fig S4).
3.5. Bioassay
Broth microdilution susceptibility tests were conducted to evaluate the antibacterial
activity of tin complexes and the corresponding ligands. Two Gram-negative (E. coli) and
Gram-posetive (B. cereus) was examined. To substantiate the results, tests were carried
out for SnPh3Cl, SnPh2Cl2, SnPhCl3, SnMe2Cl2 and the commercial antibiotic gentamicin
as positive controls. The MIC values (µg/mL) are presented in Table 3. Based on the MIC
test, the ligands are devoid of antibacterial activity. Notably, among the compounds,
triphenyltin complexes exhibited a marked activity only against Gram-positive bacterium
B. Cereus (IC50 = 0.78 µg/mL for Ca3 and Ca5). In addition, the antibacterial activity of
Ca3 and Ca5 exceeded those of the primary compounds SnPh2Cl2, SnPhCl3 and SnMe2Cl2.
Besides, the antibacterial activity of gentamicin was higher than that of Ca3 and Ca5
(Table 3). Literature survey reveals that Sn complexes have a variety of remarkable
antimicrobial potencies, although mode of action and mechanism has not been clarified
23

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yet. Three possible mechanisms for biocidal ability of aqueous Sn ions can be
distinguished: (i) binding to bacterial enzymes and inhibiting them from their functions,
(ii) binding to bacterial DNA and leading to inhibition of cell replication, and (iii)
interaction with the cell membrane of the bacteria and ultimately causing cell death [35].
To gain a better understanding of the inhibitory potential of the synthesized complexes
and to study on their mechanism in more detail, it was necessary to examine the
interaction of the derivatives with the bacterial structures by QSAR method. QSAR
technique was used to find the effective electronic and structural parameters.
3.6. QSAR analysis
According to Hansch and his co-workers, there is a relationship between the physico-
chemical properties of a molecule, mainly electronic, steric and hydrophobic factors, and
its biological activity. In our previous works, the QSAR studies have been performed on
some bisphosphoramide compounds relating to their anticholineaterase activities, and
showed that the electronic properties are closely correlated with biological potency of the
studied compounds. Here, with Sn complexes attached to phosphorus atoms of
bisphosphoramide ligand, we used quantum chemical calculations in order to obtain
electronic and structural properties of the complexes, to see if such correlation is also
valid. QSAR studies were done in order to recognize the effect of descriptors on the
activity of bacterial. The stepwise MLR procedure was used for model selection, which is
a common method used in QSAR studies.
24

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To obtain the electronic and structural descriptors given in Table 4, we used the
optimization structures to calculate by the level of B3LYP/LANL2DZ and 6-311G* basis
set in the water solvent used for all molecules. Using the descriptors from Table 4, the
following equation was obtained:
log(1/MIC) = −15.543QP − 7.156QO + 4.262QN + 0.016PLP−O −10.092PLSn−O
+ 46.963EHOMO + 944.0331ELUMO + 545.572ω + 0.193µ + 0.002Mv − 61.187
(2)
n =12;R2 = 0.996;Sreg = 0.080;r = 0.146;F
= 28.049
statistic
Where, n is the number of compounds, r is the correlation coefficient (sig.), R2 is the
determination coefficient, is the standard deviation of regression and Fstatistic is the
Sreg
Fisher statistic [36]. The high values of Variance Inflation Factor (VIF >10) caused
impossibility to calculate MIC. The best way to deal with such a problem is to calculate
variance inflation factor (VIF). We calculated VIF, which is a measure of
multicollinearity, for each of the parameters involved in models. The VIF is defined as
2
, where R is the multiple correlation coefficient of the ith independent variable
1/(1− Ri )
i
on all of the other independent variables. A VIF 10 or more (no upper limit is defined) for
large data sets indicates a collinearity problem. For small data sets, even VIFs of five or
more (here also no upper limit is defined) can indicate collinearity. Therefore, the
variables with a high VIF are candidates for exclusion from the model [37]. To clarify
this problem the PCA method must be used. Fisher’s weight approach is a method for the
reduction and selection of the best descriptors, which have high correlation between the
variables and principal components. PC eqs. 3a and 3b were obtained with eight variables
from among seventeen descriptors:
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PC1 = +0.254QSn + 0.390QP + 0.463QO −0.014PLP=O
−0.143PLSn−O + 0.483ELUMO −0.476 + 0.057Mv
(3a)
(3b)
ω
PC2 = +0.512QSn −0.231QP + 0.108QO + 0.392PLP=O
+ 0.556PLSn−O −0.007ELUMO −0.029 −0.335Mv
ω
The main variables were found from the principle scores of the normalized eigenvalue of
the two principal components. The results showed that the first and second factor PC on
the total variance 37.2% and 23.6%, respectively. Then, the new MLR was performed
using these eight descriptors (QSn, QP, QO, PLP=O, PLSn-O, ELUMO, ω and Mv) which
resulted following equation:
log(1/MIC) = −38.509QSn −14.844QP + 0.767QO −0.051PLP−O −9.323PLSn−O
+ 725.846ELUMO + 406.202 + 0.001Mv + 55.304
ω
(4)
n = 12;R2 = 0.762;Sreg = 0.329;r = 0.289;F
=1.845
statistic
The low determination coefficient (R2 = 0.762 and F = 1.845) with high Variance
Inflation Factor (VIF) > 10 (Table 5) indicated the multicollinearity problem. The
improvement in the eq. 4 was carried out by omitting the compounds Cb3 and Cb4 from
tested compounds and replacing the
Q
with QP and QO as well as ω with ELUMO.
Sn
Multiple regressions performed using these six parameters yielded the following model
with increasing the R2 = 0.832 and decreasing the Sreg = 0.257.
log(1/MIC) = −14.093QSn + 0.032PLP−O +14.109PLSn−O
−33.098ω + 0.001Mv −11.849
(5)
n =10;R2 = 0.832;Sreg = 0.257;r = 0.103;F
= 3.971
statistic
The correlating parameters have VIF<10, thus there is no colinearity problem (Table 5).
In this equation, the inhibitory potency of B. Cereus is influenced mainly by the
26

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electronic parameters with preferential order as
ω
> QSn > PLSn-O > PLP=O versus
structural descriptor (Mv). Comparison of the correlation coefficient of
ω (-33.098) with
random error (-11.849) demonstrates that
of the complexes with B. Cereus. The positive sing of
compound with higher electropilicity ( )is indicative of higher activity against bacterial.
ω
can play a crucial function in the interaction
in disclose that the
ω
log(1/ MIC)
ω
The correlation matrix was used to determine the interrelationship between the
independent variables (Table 6). As shown in Table 6, the majority of regression
coefficients were closely correlated. Therefore, orthogonalization of the molecular
descriptors was conducted. Orthogonalization of molecular descriptors is undertaken to
avoid collinearity among variables and model overfitting. The high interrelationships
were observed between
ω and QSn (r = –0.514), and QSn and PLSn−O (r = +0.660),
respectively. A result was obtained from the above data; the electrophilicity parameter
controls the influence of the net charge and polarizability of Sn atom of complexes in
inhibition of B. Cereus.
4. Conclusions
In this work, SnPhnCl4-n (n=1-3) and SnMe2Cl2 adducts with a family of diphosphoryl
ligands, (Ph)2P(O)–X–P(O)(Ph)2, have been introduced. The prepared compounds have
been characterized by IR and multinuclear NMR spectroscopy. X-Ray crystallography
confirms the bridging ligands produce binuclear structures with SnPh3Cl acceptors and
offer 1D polymeric arrangement toward SnMe2Cl2. The analysis of the crystal packing
reveals non-covalent interactions, including Sn-O bonds (in Cc5), NH…Cl and CH…Cl
27

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interactions, to be the main factor governing the supramolecular assembly of the
crystalline complexes. The synthesized compounds were screened for the antibacterial
activity against B. cereus and E. coli. DFT–QSAR models revealed that the descriptor of
the electrophilicity (ω) is related with the inhibition of B. cereus. The correlation matrix
of QSAR models and docking analysis confirmed that the electrophilicity parameter
controls the influence of the net charge (QSn) and polarizability of Sn atom of complexes
in inhibition of B. cereus.
Acknowledgment
The financial support of Tarbiat Modares University’s Research Council and the project
14-03276S of the Czech Science Foundation are gratefully acknowledged.
Appendix A. Supplementary material
Crystallographic data for the structural analysis has been deposited with the Cambridge
Crystallographic Data Center, CCDC No. 1027074, 1027642, 1027641 and 1027071 for
L4
,
Ca3
,
Ca4 and Cc5, respectively. These data can be obtained free of charge via
or from the Cambridge
http://www.ccdc.cam.ac.uk/conts/retrieving.html,
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)
1223-336-033; or e-mail: deposit@ccdc.cam.ac.uk.
References
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