Synthesis and Bioactivity of Benzothiazaphosphepines and Relevant Phosphonates as Antioxidant/Antidiabetic Agents

Article abstract of DOI:10.1080/00397911.2014.912329

An efficient approach to a new series of benzothiazaphosphepines and their derived phosphonates in good yields (64-75%) was reported. The strategy relied on the reactions of the easily available 2-arylmethylene-aminobenzenethiols with different types of Wadsworth-Horner-Emmons (WHE) reagents in dimethylformamide (DMF)/lithium hydride (LiH) solution. All new compounds were bioscreened and showed, in vitro, moderate to good antioxidant and antidiabetic activities.

Full text of DOI:10.1080/00397911.2014.912329

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Synthesis and Bioactivity of
Benzothiazaphosphepines and
Relevant Phosphonates as Antioxidant/
Antidiabetic Agents
Wafaa M. Abdou a , Neven A. Ganoub a & Reham F. Barghash a
a Chemical Industries Division , National Research Centre , Cairo ,
Egypt
Accepted author version posted online: 14 May 2014.Published
online: 02 Jul 2014.
To cite this article: Wafaa M. Abdou , Neven A. Ganoub & Reham F. Barghash (2014) Synthesis and
Bioactivity of Benzothiazaphosphepines and Relevant Phosphonates as Antioxidant/Antidiabetic
Agents, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:18, 2669-2678, DOI: 10.1080/00397911.2014.912329
To link to this article: http://dx.doi.org/10.1080/00397911.2014.912329
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Synthetic Communications1, 44: 2669–2678, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2014.912329
SYNTHESIS AND BIOACTIVITY OF
BENZOTHIAZAPHOSPHEPINES AND RELEVANT
PHOSPHONATES AS ANTIOXIDANT/ANTIDIABETIC
AGENTS
Wafaa M. Abdou, Neven A. Ganoub, and Reham F. Barghash
Chemical Industries Division, National Research Centre, Cairo, Egypt
GRAPHICAL ABSTRACT
Abstract An efficient approach to a new series of benzothiazaphosphepines and their
derived phosphonates in good yields (64–75%) was reported. The strategy relied on the
reactions of the easily available 2-arylmethylene-aminobenzenethiols with different types
of Wadsworth–Horner–Emmons (WHE) reagents in dimethylformamide (DMF)/lithium
hydride (LiH) solution. All new compounds were bioscreened and showed, in vitro,
moderate to good antioxidant and antidiabetic activities.
Keywords Antioxidants=antidiabetics; N,S,P-heterocycles; phosphonates; phosphonyl
carbanions; Schiff bases
INTRODUCTION
Phosphorus compounds play important roles in all living organisms,
and there are many reports on the preparation and biochemistry of such
compounds.[1,2] Phosphorus heterocyclic systems in particular continues to be
some of most active areas; the introduction of the phosphor moiety into N-
and=or S-heterocycles has attracted much attention in recent years because this
system of heterocycles usually enhances the biological and pharmacological
activities.[3–6]
In view of these observations, a series of N,S,P-heterocyclic systems, thiaza-
phosphepines, and relevant phosphonates were herein synthesized. The methodology
Received March 3, 2014.
Address correspondence to Wafaa M. Abdou, Chemical Industries Division, National Research
Centre, Elbohouth St., D-12311, Dokki, Cairo, Egypt. E-mail: wabdou@link.net
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2669

2670
W. M. ABDOU, N. A. GANOUB, AND R. F. BARGHASH
relied on addition–cyclization reactions of different types of Wadsworth–Horner–
Emmons (WHE) reagents to a,b-bifunctional systems: arylideneaminothio-
phenols. Bioscreening of antioxidant and the antidiabetic properties of the
products was also reported. This investigation is a continuation of our research
program[7–10] for the application of phosphorus reagents to different systems of
Schiff bases. Many of the synthesized materials showed significant analgesic=
anti-inflammatory properties; particularly remarkable is their anticancer
activity.[7–10]
RESULTS AND DISCUSSION
The substrates 2-[(2-mercaptophenyl)imino]methyl]phenol (1a) and 2-(4-
(dimethylamino)-benzylideneamino)benzenethiol (1b) were synthesized according
to the reported methods via the condensation of o-aminothiophenol with the proper
aldehyde in ethanol.[11,12] Schiff bases 1a or 1b were added to 1.3 molar equiv of
diethyl vinylphosphonate (2) in dimethylformamide (DMF) solution containing
3 molar equiv of LiH. Further heating of the reaction mixture under reflux for
the proper time afforded 4-aryl-3-ethoxy-2-methyl-3-oxido-2,3-dihydro-1,5,3-
benzothiaza-phosphepines 4a or 4b in ꢀ73% yield. Structure 4 was verified from
the analytical and the spectroscopic data. Thiazaphosphepines 4a and 4b showed
1
the lack of SH moiety in the infrared (IR) and H NMR spectra, confirming the
=
=
involvement of this moiety in the cycloaddition reaction. Bands for C N, P O,
and P-O-C groups appeared in the IR spectra at ꢀ1574, 1241, 1078 cmꢁ1, whereas
1H and 13C NMR spectra confirmed the presence of [–HC–Me and EtOP]
functionalities. The molecular weights (MS) and the relevant fragments were also
in accordance with the assigned structure (see experimental section). The 31P
NMR spectra showed one singlet signal for each at upfield dp ¼ 14.2 and 14.8 ppm
for 4a and 4b, which is within the range expected for thiazaphosphenine-2--
oxides.[13,14]
Scheme 1. Preparation of thiazaphosphepine-3-oxides 4a and 4b.

AZEPINE-PHOSPHOR ESTERS AS ANTIOXIDANT/ANTIDIABETIC AGENTS
2671
Compounds 4 may be formed via an initial [2 þ 2] addition of 2 to 1 to give
the intermediate 3, which underwent intramolecular cyclization to give the target
compounds 4, under partial collapse of the phosphonate moiety, and extrusion of
ethyl alcohol molecule as depicted in Scheme 1. The latter step was previously
reported in similar occasions.[13,15]
In a systematic study, diethyl 4-aryl-2,2-dimethyl-2,5-dihydro-benzo[b][1,4]-
thiazepin-3-yl-phosphonates 7a, 7b (ꢀ66%) were isolated from the reactions of the
imines 1a and 1b with diethyl 2-methallylphosphonate 5 (Scheme 2). We assumed
the initial formation of the vinyl phosphonate 5b via the rearrangement 5a to 5b.
Addition of 5b to 1a and 1b afforded intermediates 6a and 6b, followed by
intramolecular cyclization, giving rise to the phosphonates 7a and 7b, as described
in the previous reaction.
Chemical structure of 7 (dP ꢀ 27 ppm) was delineated from the elemental
1
analysis and spectral data (IR, H, 13C, 31P NMR, and MS). The distinguishing
1
features of 13C NMR of 7 were the presence of signals around d ꢀ 110 (d, Jp-c
ꢀ
2
2
82 Hz, C-P), ꢀ47 (d, Jp-c ꢀ 16 Hz, C-Me2), and ꢀ154 (d, Jp-c ꢀ 32 Hz, C-4) ppm.
The magnitudes of the phosphorus coupling with C-2, C-3, and C-4 were in accord
with the suggested structures. The mass spectrum of compound 7a recorded the
molecular ion peak at m=z ¼ 418 (17%) [Mþ– 1], and the base peak was displayed
at 234 (100).
Next, another series of seven-membered phosphorus heterocycles, benzothia-
zaphosphepine derivatives 10a–10h, were obtained in ꢀ70% yield, by applying
the saturated WHE reagents 8a–8d to the Schiff bases 1a/1b in dimethylformamide
(DMF)=LiH solution (Scheme 3). Obviously, compounds 10a–10h formed through
the intermediates 9a–9h initially formed via the nucleophilic attack of the
phosphonyl carbanions on the imino-C in 1. Further intramolecular cyclization
and auto-oxidation resulted in the formation of 10 in tandem loss of ethanol and
hydrogen molecules. The latter step was promoted by the thermal energy, the
alkaline medium, and the aromatization of the final products.[15] Furthermore,
the process of homo-oxidation was previously observed in similar occasions.[15,16]
New compounds were clearly verified by studying their elemental analyses and
1
spectral data (IR; H, 13C, and 31P NMR; and MS).
Scheme 2. Preparation of benzothiazapinephosphonates 7a and 7b.

2672
W. M. ABDOU, N. A. GANOUB, AND R. F. BARGHASH
Scheme 3. Preparation of thiazaphosphepine-2-oxides 10a–10h.
PHARMACOLOGY
Antioxidant Activity
Organophosphorus compounds[17,18] and P-heterocycles in particular[18] have
been recognized as antioxidant drugs. Furthermore, their mechanism of action
and the structure–activity relationships (SAR) were extensively studied.[18,19] There-
fore, the antioxidant activity of the new synthesized benzothiazaphosphepines 4a, 4b,
10a–10h and relevant phosphonates 7a and 7b were in vitro evaluated using lipid
peroxidation (LPO) by two methods: 2,20-azobis-(2-amidino-propane)dihydrochlo-
ride (AAPH), and 2,20-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS). The
activity expresses their ability to inhibit LPO in rat’s brain homogenate and the
rate of erythrocyte hemolysis. Pro-oxidant activities of the formed compounds were
also assayed for their effect on bleomycin-induced DNA damage. Vitamin C (Y) was
used as a positive standard for the antioxidant activity in all experiments. The results
of antioxidant assay by erythrocyte hemolysis (1 – A=B ꢂ 100), antioxidant assay by
ABST method [Abs (control) – Abs (test)=Abs (control) ꢂ 100], and the assay
for protection of bleomycin=DNA damage were presented in Tables 1–3 in the
Supplementary Material.
The data presented in Tables 1–3 showed that all new synthesized compounds
showed good to moderate antioxidative activity. Nevertheless, N,S,P- heterocycles
4a, 4b, and 10a–10h exhibited good radical scavenging ability (96. 65%) as compared
to standard ascorbic acid (95.16%), whereas compounds 7a and 7b displayed
moderate radical scavenging activity (ꢃ60%). However, the starting compound 1b
showed minimum activity (26.6%). Furthermore, it is obvious that compounds 4a,
4b, and 10a–10h have greater antioxidative activity in the lipid per-oxidation assay

AZEPINE-PHOSPHOR ESTERS AS ANTIOXIDANT/ANTIDIABETIC AGENTS
2673
and inhibitory effect in the hemolysis assay than thiazapinephosphonates 7a and 7b.
On the other hand, 7a, 7b, and 10d and 10h, indicated better protection for DNA
from the damage induced by bleomycin. Furthermore, other phosphepines 10a,
10b, 10c, and 10e–10g exhibited moderate protective activity.
Antidiabetic Evaluation
Diabetes mellitus II is a metabolic disorder characterized by chronic hypergly-
cemia with disturbances of carbohydrate, fat, and protein metabolism resulting from
defects in insulin secretion or insulin action, or both.[20,21] Heterocyclic phosphor
esters are known to serve as both hyperglycemic and hypoglycemic agents in differ-
ent concentrations.[22,23] In addition, earlier literature on the effect of organopho-
sphorus compounds (OPC) on carbohydrate metabolism showed an increase in
blood glucose and decrease in glycogen in various constituents of brain rats after
treatment with malathion.[22] Nevertheless, glycogen levels were decreased in rat liver
when treated with dichlorovos.[23] Several drugs such as biguanides, sulfonylureas
(glibenclamide), and others are presently available to reduce hyperglycemia in
diabetes mellitus. Despite their widespread use, none of the presently available
agents is ideal; each has its shortcomings,[24] and therefore search for a new class
of compounds is essential to overcome these problems. The antidiabetic activity of
cyclic P-heterocycles 4a, 4b, and 10a–10h, phosphonates 7a and 7b, glibenclamide
(Z, standard) and also the substrate 1b has been studied at the same dose (50 mg=
kg), and the results of blood glucose levels of diabetic rats treated with thiaphos-
phepines 4a, 4b, and 10a–10h, phosphonates 7a and 7b, substrate 1b, and Z (gliben-
clamide) are displayed in Table 4 in the Supplemental Material.
Other than the substrate 1b, all tested compounds 4a, 4b, 7a, 7b, and 10a–10h
showed hypoglycemia effect that can decrease the blood glucose levels in diabetic
rats. The screening showed that after 7 days, supplementation of EtOH solutions
of the tested compounds resulted in a significant diminution of fasting blood glucose
level in respect to diabetic rat, but no significant alteration of fasting blood glucose
level to the control, which further strengthens the antidiabetogenic action of these
compounds. Fasting blood glucose level of all animals before treatment was within
the normal range (Table 4). Fasting blood glucose level was significantly elevated
after 24 h of streptozotocin injection in respect to the control level. From the
observed data it has been noticed that the tested compounds reflect moderate or
no activity at all on decreasing the blood glucose levels in diabetic rats in relative
to the control data (520.26) and comparable to the positive reference (140.74).
However, few compounds (10g and 10h) showed good antidiabetic potency (ꢃ145)
compared to the positive control glibenclamide.
EXPERIMENTAL
Melting points were determined with an open capillary tube on an Electro-
thermal (variable heater) melting-point apparatus. Later, the thermometer was
calibrated by using standard compounds of known mps and the melting points of
the new compounds were corrected exclusively. IR spectra were recorded on a Jasco
FT-IR 6100 using KBr the bromide disc. NMR spectra were measured using Jeol

2674
W. M. ABDOU, N. A. GANOUB, AND R. F. BARGHASH
E.C.A. 500-MHz (1H: 500.7 MHz,13C: 125.4 MHz, 31P: 200.7 MHz) spectrometer.
The mass spectra were performed at 70 eV on an MS-50 Kratos (A.E.I.) spec-
trometer provided with a data system. Elemental analysis of the products was
carried out at the Microanalysis Laboratory, Cairo University, Cairo, Egypt, using
an elemental C, H, N analyzer (Vario EL II I, Germany). The purity of all new
samples was verified by microchemical analysis (C=H=N=P=S) and spectroscopy.
Thin-layer chromatography (TLC) used Merck 0.2-mm silica-gel 60 F254 analytic
aluminum plates.
Synthesis
The substrates 2-[(2-mercaptophenyl)imino]methyl]phenol (1a) and 2-(4-
(dimethylamino) benzylideneamino)benzenethiol (1b) were synthesized according
to the reported methods from the condensation of o-aminothiophenol with the
proper aldehyde in ethanol.[11,12]
Reaction of 1a and 1b with Wadsworth–Horner–Emmons (WHE)
reagents 2, 5, and 8a–8d: Synthesis of 4a, 4b, 7a, 7b, and 10a–10h. A solution
of dry DMF (20 mL) containing 3.9 mmol of LiH and 1.3 mmol of diethyl vinylpho-
sphonate (2), diethyl 2-methallyl-phosphonate (5), methyl diethyl phosphonoacetate
(8a), triethyl phosphonoacetate (8b), diethyl methylthiomethyl- (8c), or diethyl
2-amino-2-thioxoethyl-phosphonate (8d) was treated, under stirring, with 1 mmol
of 1a or 1b in DMF (15 mL) in one portion at rt. The suspension was further heated
under reflux for the proper time (18–25 h, TLC). The reaction mixture was poured
into distilled water (100 mL), acidified with HCl (1N), and extracted with AcOEt.
The organic phase was washed and dried over anhydrous sodium sulfate, followed
by removal of the solvents under reduced pressure. The resulting residue was col-
lected and crystallized from the proper solvent to give the benzothiazaphosphepines
4a, 4b, 10a–10h or the phosphonates 7a and 7b.
4-(3-Ethoxy-2-methyl-3-oxido-2,3-dihydro-1,5,3-benzothiazaphosphepin-
4-yl)phenol (4a). Compound 4a was obtained as yellow crystals (0.25 g, 72%); mp
138 ꢄC (EtOH); nmax=cmꢁ1 3417, 1574, 1241, 1078; dH (500.7 MHz, CDCl3) 1.17 (dt,
4
JH-H ¼ 6.6 Hz, JP-H ¼ 4.6 Hz, 3H, MeCO), 1.29 (dd, JHH ¼ 8.7 Hz, JP-H ¼ 8.9 Hz,
3
3H, Me), 4.19 (dq, JH-H ¼ 6.6 Hz, JP-H ¼ 5.7 Hz, 2H, H2C), 5.05 (dq, JH-H
¼
2
8.7 Hz, JP-H ¼ 14.7 Hz, 1H, HC), 7.02-7.96 (m, 8H, H-Ar) 12.5 (s, 1H, HO); dC
(125.4 MHz, CDCl3) 191.4 (d, JP-C ¼ 78.5 Hz, C-4), 160.9, 152.2, 134.8, 133.2,
129.7, 127.0, 126.3, 126.0, 125.2, 121.7, 117.9, 112.0 (C-Ar), 62.4 (d, 2JP-C ¼ 10.5 Hz,
1
3
CH2OP), 32.4 (d, JP-C ¼ 68.8 Hz, CHMe), 16.7 (d, JP-C ¼ 6.9 Hz, MeCOP), 15.7
2
(d, JP-C ¼ 11.8 Hz, C-2-Me); dP (200.7 MHz, CDCl3) dP 14.2; m=z (%) 346 (11)
[Mþ– 1], 238 (100). Anal. calcd. for C17H18NO3PS (347.3): C, 58.78; H, 5.22;
N, 4.03; P, 8.92; S, 9.23. Found: C, 58.86; H, 5.13; N, 3.98; P, 8.98; S, 9.38.
Methyl 2-ethoxy-4-(4-hydroxyphenyl)-2,5-dihydro-1,5,2-benzothiazapho-
sphepine-3-carboxylate 2-oxide (10a). Compound 10a was obtained as yellow
crystals (0.27 g, 69%); mp 150 ꢄC (CH2Cl2); nmax=cmꢁ1 3434, 1697, 1256, 1087; dH
3
(500.7 MHz, CDCl3) 1.24 (dt, JH-H ¼ 6.7 Hz,4JP-H ¼ 4.3 Hz, 3H, MeCOP), 3.61
3
(s, 3H, H3C, ester), 4.39 (dq, JH-H ¼ 6.7 Hz, JP-H ¼ 6.7 Hz, 2H, H2COP),

AZEPINE-PHOSPHOR ESTERS AS ANTIOXIDANT/ANTIDIABETIC AGENTS
2675
6.91–8.01 (m, 8H, H-Ar), 9.56 (s, 1H, HN), 12.56 (br, 1H, HO); dC (125.4 MHz,
2
CDCl3) 166.6 (d, JP-C ¼ 11.4 Hz, C-4), 160.4 (d, JP-C ¼ 7.6 Hz, C¼O), 156.6,
141.3, 130.8, 130.3, 129.1, 126.9, 126.3, 123.9, 119.7, 118.9, 118.7 (C-Ar), 91.3
1
2
(d, JP-C ¼ 123.1 Hz, C-P), 61.5 (d, JP-C ¼ 10.4 Hz, CH2), 52.2 (Me), 15.8 (d, JPC
¼
7.5 Hz, MeCOP); dP (200.7 MHz, CDCl3) 13.2; m=z (%) 390 (9) [Mþ ꢁ 1], 282 (100).
Anal. calcd. for C18H18NO5PS (391.3): C, 55.24; H, 4.64; N, 3.58; P, 7.91; S, 8.19.
Found: C, 55.33; H, 4.52; N, 3.46; P, 7.82; S, 8.06.
Bioscreening Assays
All international principles and local regulations concerning the care and use of
laboratory animals were considered during the pharmacological screening.
Antioxidant evaluation.
Assay for erythrocyte hemolysis. Erythrocyte hemolysis was proceeded
using the proxyl radicals as mediator in this assay system.[25] A 10% suspension
of erythrocyte in pH 7.4 phosphate-buffered saline (PBS) was added to the same
volume of 200 mM 2,20-azobis-(2-amidino-propane)dihydrochloride (AAPH) con-
taining samples to be tested: 1b, 4a, 4b, 7a, 7b, 10a–10h, or vitamin C (Y) (2 mM).
The absorbance A of the supernatant was read at 540 nm. Similarly, the absorbance
B of the supernatant was measured after complete hemolysis and measured at
540 nm. Data were expressed as mean standard deviation and the percentage of
hemolysis was calculated using the equation [(1 – A=B) ꢂ 100]. The results are dis-
played in Table 1.
Antioxidant activity screening assay-, ABTS method. For each of
the tested compounds 1b, 4a, 4b, 7a, 7b, and 10a–10h, 2 mL of 2,20-azino-bis(3-
ethylbenzthiazoline-6-sulfonic acid) (ABTS, pH 7.0) solution containing MnO2
solution was processed in the usual manner. The absorbance (Acontrol) of the result-
ing green-blue solution was adjusted at ca. 0.5 at k 734 nm. Then 50 mL of (2 mM)
solution of each of the tested compound in EtOH=PBS was added. The absorbance
(Atest) was measured and the reduction in color intensity was expressed as percent
of inhibition. The percent of inhibition for each compound is calculated from
the following equation:[26]
%Inhibition ¼ f½Acontrol ꢁ Atestꢅ=Acontrolg ꢂ 100
The results are displayed in Table 2.
Bleomycin-dependent DNA damage. The assay for protection of bleomycin=
DNA damage by the selected samples to be tested Y, 4b, 7a, 7b, 10a, 10b, 10g, and
10h (2 mM) was done according to the reported method.[27] The extent of DNA
damage was measured by the increase in absorbance at 532 nm. The resulting data
are displayed in Table 3.
Antidiabetic evaluation. Diabetes was induced in rats (five groups, eight
rats in each group) by the intraperitoneally (i.p.) injection of streptozocin (STZ)
dissolved in freshly prepared phosphate buffer saline (PBS). The antidiabetic activity

2676
W. M. ABDOU, N. A. GANOUB, AND R. F. BARGHASH
of new compounds 4a, 4b, 7a, 7b, 10a–10h, glibenclamide (Z, standard), and the
substrate 1b has been studied at the same dose (50 mg=kg).[28] The results of blood
glucose levels of diabetic rats treated with the tested samples 4a, 4b, 10a-10h,
7a, 7b, and Z are displayed in Table 4.
CONCLUSION
In this investigation, an efficient and simple method for the synthesis of a series
of new benzothiazaphosphepines and their relevant phosphonates is accomplished.
Antioxidant evaluation revealed the ability of benzothiazaphosphepines and relevant
phosphonates to inhibit LPO in rat’s brain homogenate and the rate of erythrocyte
hemolysis. In parallel, the data of our study indicated that ethanolic solutions of ben-
zothiazaphosphepines have beneficial effects on diabetes mellitus II, suggesting new
generation of antidiabetogenic drugs. Comprehensive chemical and pharmacological
research is, however, required to find out the exact mechanism of these OPC for the
antidiabetogenic effect and to identify the active constituents responsible for the
effect.
ACKNOWLEDGMENT
The authors thank the Central Laboratory, Faculty of Pharmacy, Alexandria
University, Egypt, for carrying out the pharmacological screening.
FUNDING
The authors gratefully acknowledge the financial support by the National
Research Centre, Dokki, Cairo Egypt, Project No. 10010101.
SUPPORTING INFORMATION
Full experimental details, complete characterization of the synthesized
1
compounds, and copies of H, 13C, and 31P NMR spectral data as well as the
methods and results of the biological testing for this article can be accessed on
the publisher’s website.
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