Organotin(IV) derivatives of amide-based carboxylates: Synthesis, spectroscopic characterization, single crystal studies and antimicrobial, antioxidant, cytotoxic, anti-leishmanial, hemolytic, noncancerous, anticancer activities

Article abstract of DOI:10.1016/j.ica.2020.119433

Four new triorganotin(IV) amide based carboxylates of general formula R₃SnL¹ and R₃SnL², where R = Me(1,3) and n-butyl (2,4), and L¹= (Z)-4-(p-methoxyphenylamino)-4-oxo-2-butenoic acid (HL¹

Full text of DOI:10.1016/j.ica.2020.119433

Journal Pre-proofs
Organotin(IV) derivatives of amide-based carboxylates: Synthesis, spectro-
scopic characterization, single crystal studies and antimicrobial, antioxidant,
cytotoxic, anti-leishmanial, hemolytic, noncancerous, anticancer activities
Iftikhar Ahmad, Zia-ur-Rehman, Amir Waseem, Muhammad Tariq, Cora
Macbeth, John Bacsa, Deepak Venkataraman, Augustine Rajakumar, Nazif
Ullah, Saira Tabassum
PII:
S0020-1693(19)31397-0
https://doi.org/10.1016/j.ica.2020.119433
ICA 119433
DOI:
Reference:
Inorganica Chimica Acta
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 October 2019
8 January 2020
10 January 2020
Please cite this article as: I. Ahmad, Zia-ur-Rehman, A. Waseem, M. Tariq, C. Macbeth, J. Bacsa, D. Venkataraman,
A. Rajakumar, N. Ullah, S. Tabassum, Organotin(IV) derivatives of amide-based carboxylates: Synthesis,
spectroscopic characterization, single crystal studies and antimicrobial, antioxidant, cytotoxic, anti-leishmanial,
hemolytic, noncancerous, anticancer activities, Inorganica Chimica Acta (2020), doi: https://doi.org/10.1016/j.ica.
2020.119433
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Final_revised
Organotin(IV) derivatives of amide-based carboxylates:
Synthesis, spectroscopic characterization, single crystal studies
and antimicrobial, antioxidant, cytotoxic, anti-leishmanial,
hemolytic, noncancerous, anticancer activities
Iftikhar Ahmada, Zia-ur-Rehmana*, Amir Waseema, Muhammad Tariqb, Cora Macbethc, John
Bacsac, Deepak Venkataramand, Augustine Rajakumard, Nazif Ullahe, Saira Tabassumf
aDepartment of Chemistry, Quaid-i-Azam University Islamabad-45320, Pakistan
bInstitute of Chemical Sciences, Bahauddin Zakariya University Multan, 60000, Pakistan
cDepartment of Chemistry, Emory University Atlanta, Georgia, USA.
dDepartment of Gynecology and Obstetrics, Emory University Atlanta, Georgia, USA.
eDepartment of Biotechnology, Faculty of Chemical and Life Sciences, Abdul Wali Khan
University Mardan-23200 Pakistan.
fSchool of Applied Sciences and Humanities, National University of Technology Islamabad
Pakistan.
*Corresponding author
Email: zrehman@qau.edu.pk / hafizqau@yahoo.com
Tel: 92-(051)90642245
Fax: 92-(051)90642241
1

Final_revised
Abstract
Four new triorganotin(IV) amide based carboxylates of general formula R3SnL1and R3SnL2,
where R= Me(1,3) and n-butyl (2,4), and L1= (Z)-4-(p-methoxyphenylamino)-4-oxo-2-
butenoic acid (HL1) L2 = (Z)-4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxo-2-butenoic acid
(HL2) have been synthesized by refluxing methanolic solution of organtin(IV) chloride and
ligand (1:1 molar ratio). The synthesized compounds were characterized by FT-IR, elemental
13
analysis, NMR (1H, C, 119Sn &19F) and single crystal X-ray crystallography. The ligands
coordinate to tin atom through oxygens (carboxylate and amide) showing distorted trigonal
bipyramidal geometry with polymeric bridging behavior in solid state. However, the
geometry is switched over from trigonal bipyramidal to tetrahedral upon dissolution as
confirmed by multinuclear (1H, 13C, 19F and 119Sn NMR). The prepared ligands and
compounds 1-4 were screened for antimicrobial, antioxidant, cytotoxicity, hemolysis,
antileishmanial and anticancer and noncancerous activities. The results showed significant
antimicrobial activities, antioxidant, good cytotoxic LD50 values, percent hemolytic values,
antileishmanial and anti-cancer activities. Compound 2 and 4 were found the most active
antileishmanial and anticancer agent, respectively.
Keywords: Polymeric; Organotin(IV) carboxylates; Intramolecular hydrogen bond;
Antileishmanial activity; Anticancer activity
2

Final_revised
1. Introduction
Cancer, recognized by uncontrolled cell growth, is a reason for million deaths worldwide [1].
It is the leading cause of mortality after the heart disease. In USA every 5th mortality is due to
cancer [2]. In year 2005, cancer surpassed the heart diseases in USA. Chemotherapy is one of
the strategies used to cure cancer. In this context, the use of metallodrugs as anticancer agents
is track back to the fortunate discovery of cisplatin, which has shown the ability of halting
cell division and since then metallo-anticancer drugs remain the focus of intensive
investigations. Cisplatin has been approved as anticancer drug for testicular and ovarian
malignancies in 1971 [3]. Several other analogues including oxaliplatin, carboplatin,
lobaplatin and nedaplatin have got clinical status. Being similar in structure to cisplatin, the
mechanism of action of the aforesaid variants is almost the same – they form adduct with
DNA [4-6]. However, resistance and damaging side effects, due to their interaction with
sulfur containing off-target biomolecules [7], diverted the attention of bioinorganic chemists
to find alternate metal-based drugs. Among the known anticancer metallodrugs,
organotin(IV) based drugs have received more attention due to their better anticancer activity
[8,9]. In this context, organotin(IV) carboxylates have been evaluated and some of them were
found more active anticancer agents than other compounds. Furthermore, organotin(IV)
carboxylates unveiled a non-cross resistance and might have better activities as compared to
platinum complexes [10]. The anticancer activity depends on the alkyl/aryl group and ligands
attached to Sn atom. The better biological activities of triorganotin(IV) than the di- and
mono-organotin(IV) analogues are because of their higher lipophilic characteristics [11,12].
Due to this reason the research on triorganotin(IV) carboxylates got considerable attention.
Furthermore, structural modification of ligand and type of ligand’s substituents have marked
influence on the antiproliferative activity of organotin(IV) carboxylates [13].
3

Final_revised
Organotin(IV) carboxylates have also shown antileishmanial and antifungal properties [14].
According to WHO, Leishmaniasis is affecting twelve million people inhabitant of hot
climatic areas. Appropriate treatment is vital during the growth of this sandy-fly mediated
parasite disease otherwise patients may not be able to survive [15]. Scientists have developed
several antileishmanial agents (e.g., Miltefosine, Amphotericin B, Glucantine and
Pentamidine), that were not effective due to fluctuating degree of effectiveness and toxicity
[16,17]. The use of antimony salt has displayed the worst condition [18]. In view of this,
there is a dire need to develop new chemotherapeutic agent to treat leishmaniasis. Amide
based organotin(IV) carboxylates may be one of the better alternate drug against
leishmaniasis. Antibiotic resistance is another leading problem because of various types of
bacterial strains. In this context, metal based drugs like organotin(IV) may play an important
role in eliminating drug resistance issues. In view of the above, we have synthesized amide
based organotin(IV) carboxylates, and characterized their physical and biological activities
including anticancer, antileshmanial and antimicrobial activities. These complexes have also
been screened for their antibacterial, antifungal, cytotoxic, hemolytic and antioxidant
activities. In the current manuscript, we present some notable and novel biological data
regarding amide based organotin(IV) carboxylates.
2. Experimental
2.1. Chemicals and procedures
Precursors CH3SnCl, n-(C4H9)3SnCl, N-ethyl-3,5-bis(trifluoromethyl)aniline, p-anisidine,
maleic anhydride and sodium hydroxide were acquired from Sigma Aldrich. Solvents used in
the study were procured from Sigma Aldrich and were dried according to published
procedures [19]. M.P. was determined using a Melt-Temp (US) electro-thermal apparatus.
The FT-IR spectra (in mid-infrared regions) and elemental analysis were recorded on
4

Final_revised
ThermoNicolett Impact series 10 FT-IR and CE-440 Elemental Analyzer, respectively.
19
1H,13C, F and 119Sn NMR were determined on Bruker (600MHz) Avance III HD,INOVA
400MHz, INOVA 500MHz using DMSO as a solvent. Single crystal X-ray analysis was
performed on the Bruker Apex II Cu source CCD diffractometer. All non-hydrogen atoms
were refined anisotropically and riding model was used for hydrogen atoms bonded to
carbon. Hydrogen atoms bonded to nitrogen and oxygen were calculated from different maps
and their coordinates refined. ShelXT was used to solve the structure and ShelXL2014 to
polish the structures [20]
2.2 Synthetic procedures
2.2.1. Ligand synthesis: (Z)-4-(p-methoxyphenylamino)-4-oxo-2-butenoic acid (HL1)
(Z)-4-(p-methoxyphenylamino)-4-oxo-2-butenoic acid (HL1) was prepared by the reported
method [21-24]. p-Anisidine or 4-methoxybenzenamine (1.0 g, 8.1mmol) dissolved in glacial
acetic acid (40 mL) was added to round bottom flask (250 mL) containing maleic anhydride
(0.8g, 8.1mmol) solution (40 mL) in the same solvent. Yellow precipitates were formed
immediately. After 12 hours stirring, the precipitates obtained were filtered off, washed with
cold distilled water and air dried. Yellow prism like crystals was obtained by slow
evaporation of the acetonic solution at room temperature (Scheme 1). Numbering scheme for
ligands and Sn attached organic group is given in Scheme 2.
o
C11H11NO4: Yield: 89% (1.6 g): M.P. 199-200 C: Mol.Wt: 221.07. FT-IR (cm-1): 3284
ν(OH); 3124 ν(N-H); 1695 ν(NC=O); 1537 ν(COOasym); 1278 ν(COOsym); ∆ν (COOasym
-
1
3
1
COOsym) = 259: H NMR {DMSO-d6, δ (ppm)}: 6.27-6.33 (d, H2,1H, J(1H, H) =12.16 Hz;
3
1
3
1
6.44-6.49 (d, H3,1H, J(1H,
= 12.14 Hz; 7.51-7.53 (d,H6,6/,2H, J (1H, H) =9.4 Hz; 6.66-
H)
/
3
6.73(d,H7,7 ,2H, J (1 ,1 )= 9.14; 3.75 (s, H9,3H); 10.30 (s,1H, NH,);12.9 (s,1H,COOH).13 C
H
H
NMR (DMSO-d6) δ(ppm): 167.0 (C1);131.8 (C2);.132.09 (C3); 163.2 (C4); 131.72 (C5); 121.6
(C6); 114.4 (C7); 156.3 (C8); 55.6 (C9).
5

Final_revised
2.2.2. Synthesis of ligand 2: (Z)-4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxobut-2-
enoic acid(HL2)
(Z)-4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxobut-2-enoic acid(HL2) was synthesized by
the following reported procedure [25] using 3,5-bis(trifluoromethyl)benzenamine (1.0g,
5.5mmol) and maleic anhydride ((0.54g, 5.5mmol) dissolved in dichloromethane (100 mL).
After 8 hours reflux with constant stirring, the solution was left overnight to get white
precipitates. After filtration, the precipitates were washed with distilled water and 10 % dilute
HCl. White needle like crystals of HL2 were obtained by the slow evaporation of the
methanolic solution at room temperature (Scheme 1).
o
C12H7F6NO3: Yield: 1.31g, 85% M.P.153 C: Mol. Wt: 327.18, FT-IR (cm-1), 3286 ν(OH);
3102 ν(N-H); 1711 ν( NC=O); 1569 ν(COOasym); 1278 ν (COOsym); ∆ν (COOasym - COOsym)=
1
291 ∆ ν.1H NMR (DMSO-d6) δ(ppm): 6.40-6.36 ( d,H2,1H, 3J (1 , H)=11.91 Hz) ; 6.52-6.48
H
3
1
/
(d,H3, 1H, J (1 , H)=11.88 Hz); 8.39 (s,H6,6 ,2H); 7.78 (s,H8,1H); 10.70 (s,1H,NH); 12.88
H
(s,1H,COOH).13C NMR (DMSO-d6) δ(ppm): 170.6 (C1);130.5 (C2);140.5 (C3);166.7
(C4);132.5 (C5); 119.7 (C6);131.9 (C7); 118.7 (C8); 124.5 (C9).19F NMR: (DMSO-d6), 375
MHz) δ (ppm)= -57.
2.2.3. Synthesis of ligand salts
The ligand salts were synthesized by the dropwise addition of an aqueous solution of NaOH
(0.16 g, 4 mmol) to the ligand (HL1 and HL2) suspension in distilled water (1:1 molar ratio).
The resulting solution was stirred at room temperature until a clear solution was obtained,
which was then rotary evaporated to get sodium salt of the corresponding ligand (Scheme 1).
2.2.4. Preparation of oraganotin(IV) complexes
These organotin(IV) compounds were synthesized by refluxing stoichiometric amounts of
R3SnCl {trimethyltin(IV) chloride (0.4g, 2.0 mmol) and Tributyltin(IV) chloride (0.65g, 2.0
6

Final_revised
mmol) with sodium salt of the ligand {NaL1 (0.5g, 2.0mmol) and NaL2 (0.6 g, 2.0mmol) in
methanol for 10 hours. The reaction mixture was then left uninterrupted overnight to let the
NaCl precipitated. After filtration the solvent was rotary evaporated and the obtained solid
product was then recrystallized in chloroform and n-hexane mixture (4:1) (Scheme 1).
Glacial Acetic Acid
O
O
O
Stirring RT 1 h
HN
R1
OH
O
R1 NH2
CH2Cl2
heating
8 h
O
Reaction 1
NaOH
Reaction 2
R1 NH
O
O
O O
Methanol
R
NaCl
R3SnCl
HN
R1
ONa
O Sn R
R
12 h Reflux
Reaction 3
F3C
R1=
O
CF3
H2
C
R=
H3C
H3C
CH2
C
H2
Scheme 1: Synthesis of ligands, ligand salts and complexes.
H
N
H
N
6
6
5
5
F3C
9
O
2
O
2
7
7
O
1
O
1
4
4
3
6/
6/
9
8
3
OH
O
OH
7/
8
7/
CF3
H3C

R=
H3C CH2 CH2 CH2




Scheme 2: Numbering scheme for ligands and Sn attached organic group.
7

Final_revised
2.2.5. (Z)-trimethylstannyl 4-(4-methoxyphenylamino)-4-oxobut-2-enoate (1)
Yield: 0.62 g, 78%: M.P. 158oC: Mol.Wt: 385.03: Anal cal. for C14H19NO4Sn: C,
43.70(43.79); H, 5.10 (4.99); N, 3.72 (3.65): FT-IR (4000-400 cm-1): 3468 ν(N-H); 1711 ν(
NC=O); 1547 ν(COOasym); 1308 ν(COOsym); ∆ν (COOasym - COOsym) = 239; 530 ν(Sn-C); 460
3
1
ν(Sn-O).1H NMR (DMSO-d6) δ(ppm): 6.19-6.26 ( d,H2,1H, J (1 , H)=13.44 Hz);6.26-6.33
H
3
1
/
3
(d, H3,1H, J (1 , H)=13.45 Hz);7.51-7.53 (d,H6,6 ,2H, J (1 ,1 ) =12.59 Hz);6.98-6.83 (d,H7,
H
H H
3
2
7/,2H, J (1 ,1 )=13.44 Hz); 3.80 (s,H9,3H); 11.6 (s,1H,NH); 0.67(s,Hα,9H) J[119Sn-
H
H
1Hα]=57Hz); 13C NMR (DMSO-d6) δ(ppm): 170.1 (C1); 130.89 (C2); 138.7 (C3); 162.1 (C4);
128.92 (C5); 122.12 (C6); 113.7 (C7); 156.4 (C8); 55.5 (C9); -2.07 (Cα) [119Sn-13Cα] =446 Hz;
119Sn NMR: (DMSO-d6), 225 MHz) δ (ppm)= -16.
2.2.6. (Z)-tributylstannyl 4-(4-methoxyphenylamino)-4-oxobut-2-enoate (2):
Yield:0.82 g, 78%: M.P. 90oC: Mol.Wt: 511.17: Anal cal.for C23H37NO4Sn: C, 54.20 (54.14);
H, 7.26 (7.31); N, 2.78 (2.75):FT-IR (cm-1): 3327 ν(N-H); 1693 ν( NC=O); 1570 ν(COOasym);
1289 ν(COOsym); ∆ν (COOasym - COOsym) = 281∆ν; 523 ν(Sn-C); 470 ν(Sn-O).1H NMR
3
1
3
1
(DMSO-d6) δ(ppm): 6.33 ( d,H2,1H, J (1 , H)=13.44 Hz); 6.89 (d, H3,1H, J (1 , H)=13.45
H
H
/
3
3
Hz); 7.52 (d,H6,6 ,2H, J (1H,1H) = 12.59 Hz); 7.25-7.33 (d,H7, 7/,2H, J (1 ,1 ) =13.44); 3.73
H
H
(s,H9,3H); 11.5 (s,1H,NH); 1.30 (t,Hα,6H);3J(1 ,1 )=7.53Hz; 1.36 (m,Hβ,6H); 1.62 (t,Hγ,6H,);
H
H
3
0.89 (t,Hδ,9H), J(1H,1H)=7.33Hz. 13C NMR (DMSO-d6) δ(ppm): 172.1 (C1); 131.6 (C2);
138.0 (C3); 162.0 (C4); 127.9 (C5); 121.3 (C6); 114.0 (C7); 156.0 (C8); 55.4 (C9); 17 (Cα)
13
2
3
13
1J[119
-
Cα] =365 Hz; 25 (Cβ) J[119 -13 ] = 75 Hz; 27.7 (Cγ) J[119
- C]= 24 Hz; 13.5
Sn
Sn
C
Sn
(Cδ).119Sn NMR: (DMSO-d6) , 225 MHz) δ(ppm)= 136.
2.2.7. Trimethylstannyl 4-(3,5-bis(trifluoromethyl)phenylamino-4-oxobut-2-enoate (3)
Yield: 0.72 g, 80%: M.P. 123oC: Mol.Wt: 491: Anal cal. for C15H15F6NO3Sn: C, 36.89
(36.77); H, 3.2 (3.09); N, 2.74(2.86). FT-IR (cm-1): 3117ν(N-H); 1675ν(NC=O); 1575
8

Final_revised
1
ν(COOasym); 1275ν(COOsym); ∆ν (COOasym - COOsym)=300∆ν; 546ν(Sn-C); 452ν(Sn-O). H
NMR (DMSO-d6) δ(ppm): 6.30-6.35 ( d,H2,1H, 3J (1 , 1 )=13.47 Hz) ; 7.25 (d,H3, 1H, 3J (1 ,
H
H
H
1
/
2
H)=13.47 Hz); 8.11 (s,H6,6 ,2H); 7.57 (s,H8,1H); 9.5 (s,1H,NH); 0.68(s,Hα,9H) J[119
-
Sn
1
Hα]=58Hz);. 13C NMR (DMSO-d6) δ(ppm): 171.3 (C1); 130.4 (C2); 139.5 (C3);162.9
13
(C4);136.7 (C5); 119.8 (C6); 131.9 (C7); 117.2 (C8); 128.4 (C9); -1.7 (Cα)[119
-
Cα] = 392 Hz;.
Sn
19
119Sn NMR: (DMSO-d6) 225 MHz) δ (ppm) = 151. F NMR: (DMSO-d6) , 375 MHz) δ
,
(ppm)= -63.
2.2.8.Tributylstannyl 4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxobut-2-enoate (4)
Yield:0.81 g,71%: M.P. 104oC: Mol.Wt: 617.1: Anal cal. for C24H33F6NO3Sn: C,
46.92(46.78); H, 5.32 (5.4); N, 2.38 (2.27):FT-IR (cm-1): 3120 ν(N-H); 1683 ν( NC=O); 1576
ν (COOasym); 1274ν(COOsym); ∆ν (COOasym - COOsym)=302∆ν; 525ν(Sn-C); 452 ν(Sn-O).1H
NMR (DMSO-d6) δ(ppm): 6.34-6.39 ( d,H2,1H, 3J (1 , 1 )=13.47 Hz) ; 7.25 (d,H3, 1H, 3J (1 ,
H
H
H
1
/
H)=13.47Hz); 8.08 (s,H6,6 ,2H); 7.58 (s,H8,1H); 9.7 (s,1H,NH);1.30 (t,Hα,6H)
3J(1 ,1 )=7.4Hz, 2J[119Sn-1 ]=56 Hz); 1.34 (m,Hβ,6H);1.64 (t,Hγ,6H,); 0.91 (t,Hδ,3H)
H
H
H
3J(1 ,1 )=7.33 Hz .13C NMR (DMSO-d6) δ(ppm): 171.5 (C1);129.8 (C2);138.9 (C3);162.5
H
H
13
(C4);136.1 (C5); 119.7 (C6); 132.0 (C7); 117.2 (C8); 124.4 (C9);17.3 (Cα) [119
-
Cα] =416 Hz;
Sn
13
13
26.9 (Cβ) [119
-
Cβ]= 68 Hz; 27.6 (Cγ) [119
-
Cγ]= 24 Hz; 13.3 (Cδ).119Sn NMR: (DMSO-
Sn
Sn
d6) , 225 MHz) δ(ppm)= 137. 19F NMR: (DMSO-d6 , 375 MHz) δ(ppm) = -63
3. Results and Discussion:
3.1 FT-IR Studies
The infrared spectra of the synthesized ligands and their organotin(IV) complexes were
recorded in the mid-infrared region. The appearance of a broad peak (around 3100-2500 cm-
1) for OH and relatively sharp peak for NH (3057cm-1= HL1 and 3102 cm-1 = HL2) indicate
9

Final_revised
synthesis of the ligands. For organotin(IV) carboxylates, the absorption frequencies of prime
significance are ν(COO-), ν(Sn-O) and ν(Sn-C). The absence of a broad peak pertinent to OH
and a new peak for Sn-O (430-480 cm-1) has been appeared, indicating coordination of
carboxylate ligand to organotin moiety. The difference in COO- asymmetric and symmetric
stretch {(∆ν= ν(COOasym) - (COOsym) gives valuable information about the approach of
coordination of the carboxylate ligands to tin epicenter [26-28]. ∆ν value falls in the range
302-239 cm-1, signifying monodentate bonding of carboxylate to Sn atom. The presence of
Sn-C peak (580-520 cm-1) signifies that the alkyl groups remain intact with Sn during
synthesis [29,30].
3.2. 1H, 13C, 119Sn and 19F NMR studies
19
1H,13C,119Sn and F NMR spectra for the synthesized complexes was carried out in DMSO-
d6 solvent and the data is given in the experimental section.
3.2.1.1H NMR
In complexes 1-4, an absence of the acidic OH peak (10-13 ppm) has confirmed the
coordination of carboxylate anion to organotin(IV) moieties. The methyl proton in
2
1
trimethytin derivatives (1 and 3) gave a sharp singlet with J[119 H] with coupling values of
Sn,
57 Hz (1) and 58 Hz (2), thus confirming tetrahedral geometry around Sn. In tributyltin(IV)
complexes (2 and 4), β and γ protons of the tributyl were observed as a multiplet, Sn attached
CH2 as a triplet {1.62 ppm ( 2) 2J1 , 1 = 8.0 Hz and 1.64 ppm (4) 2J1 , 1 = 8.0 Hz} and
H
H
H
H
terminal CH3 as an upfield triplet {(0.96 ppm, 2J1 , 1H = 7.3 Hz (2) and 0.91 ppm (4), 2J1 , 1
H
H
H
= 7.3 Hz } [23]. The presence of NH signal confirms no deprotonation of amide upon ligand
coordination to tin. The calculate θ for complexes 1 and 2 using Lockhart equation has
confirmed the tetrahedral geometry in solution [31].
10

Final_revised
3.2.2. 13C NMR
In 13C NMR spectra of the organotin(IV) derivatives, the carboxylic carbon has been
observed downfield than the free ligand because of diminution of the electron density at
carboxylic carbon upon complexation (Fig.S1-S4). This downfield shift is a confirmation for
the coordination of carboxylate oxygen to Sn [32]. The signals for aryl, –C-N- and alkyl
1
groups connected to tin appeared in their expected regions [27-28]. By adding value of J
13
[119Sn, C] in the Lockhart's equation, C-Sn-C bond angle was calculated for methyltin(IV)
and butyltin(IV) derivatives (Table 1). The complexes 1-4 exhibit 1J[119Sn, 13C], 446 Hz
(114.8o), 365 Hz (108.7o), 392 Hz (111.14o) and 416 Hz (113.2o), respectively, which
represent tetra-coordinated tin(IV) in solution [33-35].
3.2.3. 119Sn NMR studies
The presence of 119Sn NMR peak at -46 (1), 136 (2), 151 (3) and 137 (4) ppm authenticated
tetra coordination of tin. The electron withdrawing and donating groups of ligand and the
substituent and it’s electronegativity effect at the tin atom seem responsible for variation
in119Sn NMR value [36-40].
3.2.4.19F NMR
The fluoro bonded 13C gave a specific pattern of 13C chemical shift values. In HL2 the
fluorine signal of CF3 appeared at -57 ppm, which was shifted upfield (-63 ppm) in
complexes 3 and 4. This upfield shift might be because of the back donation from metal to
ligand which in turn increasing electronic density on fluorine atom [41].
3.3. Single crystal X-ray studies
The crystal structures of compounds 1, 3 and 4 with intramolecular interactions are given in
Figures 1-7 and particular geometric parameters, bond lengths and bond angles are given in
11

Final_revised
Tables 2 and 3. While a related series of compounds (to be published elsewhere) refined
well, the anisotropic refinement of the atoms of 3 and 4 here resulted in elongated
temperature factors and disordered butyl groups (for compound 4) in sharp contrast to the
other compounds. The inability of these compounds (3 and 4) to form well-ordered crystals is
probably a consequence of the very weak intermolecular interactions between the CF3 and
CH2 groups (with very weak H…H and H…F interactions). Compound 4 goes through a phase
change on cooling (with the disintegration of the single crystal) and the data were collected at
173 K instead of 100 K. All the compounds having bridging polymeric structure in the solid
state and distorted trigonal bipyramidal with one elongated apical Sn-O bond. The three
organic groups (methyl and butyl groups) are mutually equatorial and form the base of the
bipyramid and the two oxygen atoms, one from carboxylate moiety and other from amide
carbonyl, occupy axial positions. It is the amide carbonyl that forms the weak bond to the Sn
atom. The Sn atom has a 5s25p24d10 configuration. The trigonal bipyramidal coordination
geometries are best rationalized in terms of electron configuration and the relative large
radius of a Sn atom. The four valence electrons are donated primarily to the three Sn-C bonds
and the short Sn-O bond. The second Sn—O bond is considered to be a weak hypervalent
interaction. Although higher coordination numbers are very rare in carbon and to a greater
extent for silicon; higher coordination numbers are accessible to Sn due to its relatively large
size. As in Inorganic Chemistry; the relative sizes of the cations and the anions play an
important role in the coordination numbers in tin compounds. In an analysis of the
coordination geometry in compounds 1 and 3, the three methyl groups that are connected to
tin form the basal plane with C2-Sn1-C1(118.7(2)o), C3-Sn1-C1(116.9(2)o), C3-Sn1-C2
(123.2(2)o), C13-Sn1-C15 (123.7(2)o), C13-Sn1-C14(115.9(2)o), C14-Sn1-C15(117.3(2)o).
The two oxygen atoms form the 3-fold axis in an idealized D3h trigonal bipyramid
arrangement one from carboxylate moiety and other from amide carbonyl occupy axial
12

Final_revised
positions with O1-Sn1-O3 (176.48(11)o) and 179.19(11)o) in compounds 1 and 3,
respectively. The pivot atom that best describes the Berry pseudorotation is C(1) in
compound 1 and C(14) in compound 3 with a 9% transformation to square pyramidal
geometry. In compound 4, the large values for the anisotropic temperature factors for the
butyl groups means that there is a large uncertainty in the ligand-Sn angles and this reflects
the considerable flexibility of the L-Sn-L angles. The trigonal carbon atoms have bond
angles ranging from 116.5(3)° to 120.0(3)° while two apical oxygen atoms, one from
carboxylate moiety and other from the amide group form angles of 176.48(11)o) and
179.19(11)o with the tin atom. The five-coordination of Sn atom can also be calculated by
using Tau value (τ =(β-α) / 60, where β is higher C-Sn-C basal angle and α is the second
higher basal angle [42]. The unitary value for τ indicates an exact trigonal bipyramid (β=180o
and α=120o) while zero indicates and exact square pyramid (α=β=180o) [19]. For compound
1 the τ value 0.89 (β= O1-Sn1-O31=176.48o and α= C3-Sn1-C2=123.23o), for the compound
3 the τ = 0.92 (β= O1-Sn1-O31=179.19o and α= C13-Sn1-C15=123.66o). There are two
independent molecules in compound 4. For molecule 1 the τ = 0.97 (β= O1-Sn1-
O31=178.06o and α = C12(2)-Sn1-C12(8)=116.5). For Sn(2) the τ=0.93 (β= O1-Sn1-
O31=175.76o and α= C12(2)-Sn1-C12(8)=119.86) which designates a relatively undistorted
trigonal bipyramidal geometry [43]. The trend of shifting from trigonal bipyramidal to square
planar geometry is associated with secondary intermolecular Sn…O interactions [44,45]. One
ligand carboxylate oxygen is attached with Sn atom in mono-dentate fashion with tin-oxygen
covalent bond [(Sn(1)–O(1) = 2.118 Å and [(Sn(1)–O(1) = 2.169 Å respectively, which is
almost near to the covalent radii (2.13Å) and other amide linked oxygen of another
carboxylate ligand coordinated with tin-oxygen bond by coordinate covalent bond. The
bond distance Sn(1)–O(31) = 2.399 Å) and Sn(1)–O(31) = 2.527 Å), are lesser than the
totality of the Van der Waals radii of tin and oxygen (3.68 Å) and greater than the totality of
13

Final_revised
the covalent radii of tin and oxygen (2.13Å) which is feeble type of interaction between these
atoms [46]. The two ligands are interrelated with one another by oxygen atoms involving Sn
moiety, thus making a 1D polymeric network. Among the two Sn-O bonds, one of the Sn-O
bond is longer than its counterpart. As being weak in nature, this Sn-O bond is probably
prone to dissociate in solution altering the geometry from trigonal bipyramidal to tetrahedral
one (Table 3). The solid state structure of 1 which is depicted in Figures 1 and 2 and
interatomic parameters are exhibited in Tables 1 and 2. The crystal structure of this
compound is mediated by intramolecular O...H interactions. This interaction makes a seven
membered ring in the compound which are rarely seen in organotin(IV) complexes in the
polymer chain in solid state. The polymeric chain is alleviated by C-H…π interactions and
intramolecular hydrogen bond in a zigzag manner, which is associated into a 3-D network via
C-H…π interactions [47,48].
4. Biological activities
4.1. Antibacterial activities
The ligands (HL1 and HL2) and their complexes (1-4) were screened against three Gram
negative bacterial strains (B. bronchiseptica ATCC#4617, S. typhimurium ATCC#14028 and
E. aerogenes ATCC#13048) according to the formerly described procedure [49] and the
statistics are represented in Figure 8a. A criterion for the activity was based on zone of
inhibition. All the compounds, except compound 3, showed activity against all strains. A
mixed behavior of activity was observed among ligands and their complexes-sequence varies
from strain to strain. The data revealed that triorganotin(IV) compounds are more active than
their corresponding ligands, an observation in consonance with the earlier reports [50].
Furthermore, ligand HL1 and its organotin compounds were found more active than the
ligand HL2 and its organotin compounds. Compound 1 was found active against all the three
14

Final_revised
strains, however, 2 showed better activity than 1 against B.Bronchiseptaca. Higher activity of
4 than 3 can be attributed to more lipophilic nature of the tributyltin than trimethyltin [51].
4.2. Antifungal activities
Antifungal activity of extracts was evaluated following previously described standard
protocol [52]. The antifungal activity (Figure 8b) of the synthesized ligands (HL1&HL2) and
complexes (1-4) were tested against three fungal strains (A. fumigatus FCBP#66, F. solani
FCBP#0291, N.niger FCBP#0300). Antifungal activity of the complexes was found greater
than the ligands with few exceptions. Tributyltin(IV) derivatives were found more active than
the trimethyltin(IV) derivatives, a behavior reasonably consistent with the earlier report [56].
4.3. Antioxidant Activities
Total antioxidant activity of extracts was evaluated by method [53]. The antioxidant activities
of the prepared compounds were evaluated by the method described in earlier reports. The
antioxidant activities of the prepared compounds were evaluated by the method described in
earlier reports. A significant antioxidant capacity 25.0, 22.0, 21.0 and 11.5 μg Ascorbic acid
Equivalent (AAE)/mg extract was found in compound 2, 4, 1 and 3, respectively as depicted
in Figures 9a. In total reducing power (TRP) assay, the highest reducing power potential was
observed for HL2, followed by 2, HL1, 4, 3 and 1 (Figure 9b). DPPH free radical scavenging
potential was found by the ability of antioxidants to decolorize 2,2-diphenyl-2-picryl-
hydrazyl. Among all compounds analyzed the %inhibition ranged from 55 to 33.1. The
activity varies the following sequence 2 > 1 > HL2 > HL1 > 3 > 4 (Figure 9c). The results are
comparable to the earlier reports [54].
15

Final_revised
4.4. Cytotoxicity
Lethality test was performed in a 96 well plate against brine shrimp (Artemia salina) larvae
as previously described [53] with slight modification. A. salina eggs (Ocean star, USA) were
incubated for 24-48 h under light at 30-32°C in simulated sea water (38 g/L supplemented
with 6 mg/L dried yeast) in a specially designed two-compartment plastic tray. Ten mature
phototropic nauplii were harvested with the help of Pasteur pipette and transferred to each
well of plate. Corresponding volume of each extract containing ≤ 1% DMSO in sea water at
final concentrations of 500 and 200 µg/mL was transferred to the wells containing sea water
and shrimp larvae. The final volume in each well was kept 300 µL. Positive and negative
control wells included serial concentrations of doxorubicin and 1% DMSO, respectively.
After 24 h incubation, live shrimps were counted and percentage of deaths was determined.
Median lethal concentration (LC50) was calculated using table curve 2D v5.01 software.
The synthesized ligands (HL1 & HL2) and complexes1-4 were also screened for cytotoxicity
using Brine shrimp (Artemia asalina) bioassay lethality method [55] and results are shown in
the Figure 9b. The data illustrate that all compounds are cytotoxic and the LD50 values
decreased in following sequence: 1>3>2>4.
4.5. Hemolysis Assay
Hemolysis assay was performed in order to check the cytotoxicity of the compounds on
human blood erythrocytes. For this 8mL of the blood was taken from an anonymous human
donor with prior consent and as per ethical guidelines provided by ethical committee of the
Department of Biotechnology Abdul Wali Khan University Mardan and pour directly into
K2-EDTA tubes to prevent coagulation. The blood was diluted 1:3 with autoclaved Phosphate
Buffer Saline (PBS) pH 7.04 by. Erythrocytes were collected by centrifugation at 1500rpm
for 10 minutes. The supernatant was discarded and pellet was washed with PBS three times
16

Final_revised
and centrifuged after each wash with above-mentioned condition. The pellet was transferred
into a 50mL conical flask and PBS was added three times to the actual volume of the blood.
The screening compounds HL1, HL2, 1, 2, 3 and 4 were added into Eppendorf tubes already
containing 1 mL of blood erythrocytes to make three different concentrations i.e. 25ppm,
50ppm and 100ppm. Triton X-100 (0.5%) was used as positive control as it has 100%
hemolysis ration while DMSO was taken as negative control. The Eppendorf tube containing
the target compound and blood erythrocytes were incubated for one hour at 37ºC. After
incubation, the erythrocyte suspensions were centrifuged at 1000 ×g for 10 min and the cell
lysis (haemoglobin release) was determined spectrophotometrically at 576 nm on
spectrophotometer (Agilent-DAD, 8453, Agilent Tech., Germany) 1,2. The results were
determined by evaluating the percentage of hemolysis compared to the negative and positive
controls using the following formula;
Hemolysis (%) = [(O.D. 576 nm in the sample solution – O.D. 576 nm in DMSO)/ (O.D. 576
nm in 0.5% Triton X-100 – O.D. 576 nm in DMSO)] x 100
Hemolysis assay was done in order to evaluate the cytotoxicity of the compounds on human
blood erythrocytes. The synthesized compounds were checked for it’s cytotoxic activity and
was likened with Triton X-100 (0.5%). The results (Table 4) showed that HL2 was found to
be the least toxic in term of percent hemolysis, followed by 1, 3 and HL1, while 4 and 2 were
observed to be highly toxic as compared to Triton X-100 with high percent hemolysis ratio.
In nutshell, compound with low percent hemolysis and high IC50 (HL1, HL2 and 3) value is
considered the best.
4.6. Antileishmanial assay
17

Final_revised
The promastigote forms of L. tropica (1 x 104 cells/well) were seeded in 96-well microtiter
plates in RPMI-1640 (Gibco®) supplemented with 10% FBS (Gibco®) and 1% antibiotics and
allowed to grow either in the presence of various concentrations (1000, 500 and 250 µg/mL)
of test compounds (I-C-30, I-C-11, L-7, L-9, I-C-19 and I-C-20) or in the absence (negative
control) of the test compound for 72 hours at 25ºC. After the incubation period was
completed, viability of the promastigote form was assessed by MTT (3-(4,5- dimethylthiazol-
2yl)-2,5-diphenyltetrazolium bromide) colorimetric method (Mosmann, 1983). For this a
100µl of the MTT dye were added to each well and the plates were incubated for 3 hours at
37ºC. In last, 40µl of the DMSO as solubilization solution was added into each well and the
readings were recorded using an ELISA plate reader (Biotek Elx800) at 570 nm.
Amphotericin-B was taken as positive control. The experiment was performed in triplicates
while counting of leishmania promastigote was done using neubauer chamber.
For the anti-leishmanial assay, the synthesized ligands (HL1 & HL2) and complexes 1-4 were
solubilized in DMSO. The percent inhibition and IC50 values are given in the Table 5 and
represented in Figure 10a. All compounds showed good result except HL1 in terms of
percentage inhibition. Interestingly, HL2 showed high percentage inhibition at higher
concentration but its potency lowers at low concentrations. It is worth mentioning that
compound 4 also showed high anti-leishmanial activity which decreases with the decrease
in concentration. Amphotericin-B used as positive control showed 100% inhibition at all
the concentration tested. The observed anti-leishmanial activity order is 2 > 3 > 4 > 1.
4.7. Anticancer and non-cancerous cells activity
Breast cancer cell line (MCF-7) and human endometrial stromal cells (hESCs) were used for
cytotoxic analysis. MCF-7 was grown in EMEM with 1% penicillin/streptomycin, 10% FBS
and 0.01 mg/ml insulin. hESCs were grown in DMEM/Ham’s F12 with 10 % FBS and 1%
18

Final_revised
penicillin/streptomycin. Both the cells were maintained in a humidified incubator with 5%
CO2.For cytotoxic analysis, 4 X 104 cells were seeded per well in a 96 well plate and allowed
to reach 80% confluence. The salts were dissolved in DMSO, added to the cells (final
concentrations of 1000, 500, 250, 125, 62.5, 31.25 & 15.63 µM) and incubated for 48 h. The
cell survival was determined by MTT assay according to the manufacturer’s instruction
(VybrantTM MTT Cell Proliferation Assay Kit, Thermofisher).
In order to determine the cytotoxic effect of compounds on cancer and normal cell line, the
cells were treated with ligands (HL1, HL2) and complexes 1-4 at various concentrations and
determined the cytotoxicity by MTT assay. The IC50 values of the compounds are given in
Table 6 and represented in Figure 10b. The compounds 2 and 3 have shown strong growth
inhibition properties with IC50 < 15.6. However, 4 can be a good anticancer compound for
further evaluation as it is twenty times more active against anticancer cells as compared to
normal cells.
5. Structure-activity relationship
The biological action of organotin(IV) carboxylates depends on their geometry and types
ligands coordinated to tin atom. It is well documented fact that triorganotin(IV) compounds
are being more active than their di-analogues owing to more lipophilic character enabling
them to cross lipid layer of the cell membrane of microbes with more ease [48]. For
complexes 2 and 4, the better antimicrobial, anti-oxidant, anti-leishmanial, hemolytic and
anticancer activity, despite of few exceptions, are due to more lipophilic organic groups and
presence of electronegative substituent i.e. fluoro. The latter enable the complexes to bind
strongly with cell vital components altering their structural and functional chemistry-
ultimately death of the microbe [49].
19

Final_revised
6. Conclusion
Four new triorganotin(IV) amide based carboxylates {R3SnL1and R3SnL2, Where R= Me(1,3)
and n-butyl(2,4), and L1=(Z)-4-(4-methoxyphenylamino)-4-oxobut-2-enoic acid (HL1) L2=
(Z)-4-(3,5-bis(trifluoromethyl)phenylamino)-4-oxobut-2-enoic acid (HL2)} of biological
significance have been synthesized and characterized by FT-IR, elemental analysis, and
NMR (1H, 13C, 119Sn, & 19F). In solid state, these complexes are polymeric in nature in which
each Sn atom is five-coordinated (IR and X-ray single crystal), however, in solution, one of
the two Sn-O bonds is no more intact rendering monomeric form having Sn atom in four-
coordination environment (NMR). The compounds 1-4 were screened for antimicrobial,
antioxidant, cytotoxicity, hemolysis, antileishmanial, and anticancer activities. The results
showed significant antimicrobial activities, good cytotoxic LD50 values, percent hemolytic
values and good IC50 values for anti-cancer activities with few exceptions. Remarkably
compound 4 is twenty times more anticancerous as compared to normal cells.
Supplementary material
Single-crystal X-ray diffraction data for the structural analyses have been deposited with the
Cambridge Crystallographic Data Center, CCDC Nos. 1941613 (1), 1941614 (2) and
1941615 (4) A copy of this information may be obtained free of charge from the Director,
CCDC, 12 Union Road, Cambridge, CBZ 1EZ, UK (Fax: +44 1223 336033; Email:
deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk). Further experimental details
regarding the materials used and the methods employed, together with anticancer and
antioxidant assay data are also given here.
Acknowledgements
We acknowledge the financial support from Higher Education Commission of Pakistan.
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Final_revised
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Figure 1. A perspective of one of the linear polymeric chains of compound 1. The
displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as
small circles of arbitrary radii.
Figure 2. A perspective of the monomeric structural unit of compound 1.
26

Final_revised
Figure 3. A perspective of one of the linear polymeric chains of compound 3. The
displacement ellipsoids are drawn at the 50% probability level and H atoms are shown as
small circles of arbitrary radii.
Figure 4. A perspective of the monomeric structural unit of compound 3.
27

Final_revised
Figure 5. A perspective of one of the two crystallographically distinct one-dimensional
polymeric chains of the crystal structure of compound 4.
28

Final_revised
Figure 6. A perspective of one of the two crystallographically distinct the monomeric
structural unit of compound 4.
Figure 7. Perspective view of 1D monomeric structure of compound 4
29