Pyridoxonium salts of chiral and cyclic dithiophosphoric and bisdithiophosphonic acids and their antimicrobial activities

Article abstract of DOI:10.1080/10426507.2020.1854255

Pyridoxonium salts of chiral linear and cyclic dithiophosphoric acids were obtained by the reactions of pyridoxine with bis{2-О-[2-methyl-(2S)-3-O-propionyl]}, bis{2-О-[1,4-О,О-dimethyl-(2S)-succinyl]}, and O,O-di-2-butyl dithiophosphoric acids, and cyclic dithiophosphoric acids of 1,3,2-dioxaphosphorinane, 1,3,2-dioxaphospholane, and 1,3,2-dioxaphosphepin structure. Syntheses of acetonide pyridoxonium О,О-dimenthyl dithiophosphates were carried out by the reaction of seven-membered pyridoxine acetonide with О,О-dimenthyl dithiophosphoric acids obtained from (–)-(1 R,2S,5R)-menthol and (+)-(1S,2R,5S)-menthol. Diacetonide pyridoxonium bisdithiophosphonate was also prepared. The antibacterial and antifungal activities of pyridoxonium chiral linear and cyclic dithiophosphates were evaluated.

Full text of DOI:10.1080/10426507.2020.1854255

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/gpss20
Pyridoxonium salts of chiral and cyclic
dithiophosphoric and bisdithiophosphonic acids
and their antimicrobial activities
Ilyas S. Nizamov, Timur G. Belov, Ilnar D. Nizamov, Yevgeniy N. Nikitin,
Gulnaz R. Akhmedova, Olga V. Shilnikova, Ildus D. Timushev, Ramazan Z.
Salikhov, Marina P. Shulaeva, Oscar K. Pozdeev, Elvira S. Batyeva & Rafael A.
Cherkasov
To cite this article: Ilyas S. Nizamov, Timur G. Belov, Ilnar D. Nizamov, Yevgeniy N. Nikitin,
Gulnaz R. Akhmedova, Olga V. Shilnikova, Ildus D. Timushev, Ramazan Z. Salikhov, Marina
P. Shulaeva, Oscar K. Pozdeev, Elvira S. Batyeva & Rafael A. Cherkasov (2021) Pyridoxonium
salts of chiral and cyclic dithiophosphoric and bisdithiophosphonic acids and their antimicrobial
activities, Phosphorus, Sulfur, and Silicon and the Related Elements, 196:4, 431-438, DOI:
10.1080/10426507.2020.1854255
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PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
021, VOL. 196, NO. 4, 431–438
2
https://doi.org/10.1080/10426507.2020.1854255
Pyridoxonium salts of chiral and cyclic dithiophosphoric
and bisdithiophosphonic acids and their antimicrobial activities
a,b
c
a
c
a
Ilyas S. Nizamov
, Timur G. Belov
, Ilnar D. Nizamov
, Yevgeniy N. Nikitin
, Gulnaz R. Akhmedova ,
a
a
a
d
d
Olga V. Shilnikova , Ildus D. Timushev , Ramazan Z. Salikhov , Marina P. Shulaeva , Oscar K. Pozdeev , Elvira S.
b
a
Batyeva , and Rafael A. Cherkasov
a
b
A.M. Butlerov Chemical Institute, Kazan Federal University, Kazan, Russia; A.E. Arbuzov Institute of Organic and Physical Chemistry, Federal
c
Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, Russia; Federal State Budgetary Institution of Science Federal
Research Center, Kazan Scientific Center of Russian Academy of Sciences, Kazan, Russia; Department of Microbiology, Kazan State Medical
d
Academy, Kazan, Russia
ABSTRACT
ARTICLE HISTORY
Pyridoxonium salts of chiral linear and cyclic dithiophosphoric acids were obtained by the reac-
tions of pyridoxine with bisf2-ꢀ-[2-methyl-(2S)-3-O-propionyl]g, bisf2-ꢀ-[1,4-ꢀ,ꢀ-dimethyl-(2S)-
succinyl]g, and O,O-di-2-butyl dithiophosphoric acids, and cyclic dithiophosphoric acids of 1,3,2-
dioxaphosphorinane, 1,3,2-dioxaphospholane, and 1,3,2-dioxaphosphepin structure. Syntheses of
acetonide pyridoxonium ꢀ,ꢀ-dimenthyl dithiophosphates were carried out by the reaction of
seven-membered pyridoxine acetonide with ꢀ,ꢀ-dimenthyl dithiophosphoric acids obtained from
Received 31 August 2020
Accepted 13 November 2020
KEYWORDS
Pyridoxine; phosphorus
dithioacids; antimicro-
bial activity
(–)-(1R,2S,5R)-menthol and (þ)-(1S,2R,5S)-menthol. Diacetonide pyridoxonium bisdithiophospho-
nate was also prepared. The antibacterial and antifungal activities of pyridoxonium chiral linear
and cyclic dithiophosphates were evaluated.
GRAPHICAL ABSTRACT
[
12]
Introduction
blooded animals.
The present work involves the synthesis
of pyridoxonium salts of chiral and cyclic dithiophosphoric
1–5] acids bearing pharmacophoric lactic, malic, cyclic, and mono-
There is a considerable interest in vitamin B (alkaloid pyri-
doxine and its derivatives) due to their biological activity.
6
[
terpenyl functionalities as well as bisdithiophosphonic acids
and evaluation of their bioactivity.
Alkaloid vitamin B is of significant interest for the treatment
6
of common and life-threatening viral and microbial infections
[
1,6]
that are resistant to existing drugs.
Among phosphorus
[
7]
containing pyridoxine derivatives, phosphonium salts of
pyridoxine ketals have been reported to exhibit structural
Results and discussion
[
8,9]
Synthesis of chiral dithiophosphoric acids containing
dependence with respect to Gram-positive bacteria.
,6-bis[triphenylphosphonio(methyl)]
1,3]-dioxino[4,5-c]pyridine dichloride has an inhibitory substituents
effect against staphylococcal infection (minimal inhibitory
Thus,
5
[
2,2,8-trimethyl-4H- methyl (S)-(–)-a-lactic and dimethyl (S)-(–)-a-malic
ꢀ
1
We believe that a simple, one-step reaction should be used
to develop a technologically advanced and economical
concentration (MIC) was 5 lg mL ). A crucial role of the
ketal protection group in phosphonium salts for their antibac-
[
8]
method
reported,
for
producing
antimicrobial
drugs.
As
terial properties was demonstrated.
Bis(triphenylmethyl)
[
13–15]
methods for the synthesis of biologically
phosphonium dichloride salts of pyridoxine are effective
active ionic structures of dithiophosphoric acids bearing pyr-
idinium cations by use of nicotinic, isonicotinic, and pico-
against biofilm-embedded Staphylococcus aureus and
[
10]
Staphylococcus epidermidis
and cause impaired cell div-
[
11]
ision.
In contrast to phosphonium salts of pyridoxine, linic acids and (S)-(–)-nicotine have been developed. Among
most dithiophosphates are known to be less toxic to warm- pyridine alkaloids, pyridoxine reacts with O,O-diterpenyl
CONTACT Ilyas S. Nizamov
isnizamov@mail.ru
A.M. Butlerov Chemical Institute, Kazan Federal University, Kremlievskaya Str., 18, Kazan, 420008, Russia.
Supplemental data for this article is available online at https://doi.org/10.1080/10426507.2020.1854255.
ß 2020 Taylor & Francis Group, LLC

4
32
I. S. NIZAMOV ET AL.
31
1
Table 1. Yields, analytical and ꢁf Hg NMR data of compounds obtained.
Found/Calc., %
N
3
1
1
Comp.
Yield, %
Molecular formula
C
H
P
S
ꢁf Hg d, ppm (solvent)
3
3
5
5
5
5
5
5
5
5
5
5
a
b
a
b
c
d
e
f
74
85
85
85
88
87
86
86
67
86
85
81
ꢂ
8
H
H
15
O
O
6
PS
10PS
2
34.74 31.78
34.74 34.45
40.98 40.76
40.53 40.88
46.33 46.70
42.14 42.50
40.44 40.78
41.12 40.78
53.76 53.44
60.55 60.46
60.67 60.46
57.25 56.92
4.93 5.00
4.93 4.58
5.21 5.56
5.52 5.15
7.02 7.35
6.40 6.04
5.32 5.70
5.34 5.70
4.13 4.48
8.64 8.84
8.55 8.84
5.33 5.70
–
–
7.57 7.40
7.57 7.40
6.21 6.57
4.93 5.27
7.87 7.53
8.12 8.43
8.99 8.76
8.44 8.76
6.53 6.89
5.01 5.03
5.34 5.03
5.32 5.65
15.05 15.33
15.05 15.33
13.97 13.60
11.24 10.92
15.90 15.58
17.82 17.45
18.43 18.15
18.52 18.15
14.65 14.27
10.80 10.41
10.56 10.41
12.01 11.69
87.4 (C
84.6 (C
6
H
H
6
)
)
ꢂ
12
16
20
16
19
2
6
6
C
H26NO
9
PS
2
2.64 2.97
2.02 2.38
3.12 3.40
3.48 3.81
3.64 3.96
3.58 3.96
2.74 3.12
2.29 2.27
2.02 2.27
2.23 5.32
114.2 (EtOH-C
117.2 (EtOH-C
6
H
H
6
)
)
C
H
30NO13PS
2
6
6
C
C
C
C
C
C
C
H30NO
H22NO
H20NO
H20NO
H20NO
H54NO
H54NO
5
5
5
5
5
5
5
PS
PS
PS
PS
PS
PS
PS
2
6 6
109.2, 110.8 (1:0.4) (EtOH-C H )
13
12
12
20
31
31
2
2
2
2
2
2
111.1 (EtOH-C
111.3 (EtOH-C
125.6 (EtOH-C
131.1 (EtOH-C
6
6
6
6
H
H
H
H
6
)
6
)
6
)
6
)
a
g
h
i
109.6 (EtOH)
104.5 (EtOH)
105.9 (EtOH)
j
52 62 2 12 2 4
C H N O P S
4
ꢀ
1
group ꢂ ꢃ O. In the FTIR spectra of 3a, similarly a band at
Table 2. Selected FTIR spectral data (cm ) of compounds obtained (film).
3
ꢀ
1
[18]
þ
1745 cm for the O ¼ C stretching vibrations exists.
Comp. ꢀ(ꢀꢃ) ꢀ(NH ) ꢀ(SH) ꢀ(C ¼ O) ꢀ[(P)ꢀ–C] ꢀ(P ¼ S)
ꢀ(P–S)
Taking into account the ready formation of 3a by use of
methyl (S)-(–)-a-lactate, we decided to prepare the corre-
sponding dithiophosphoric acid using dimethyl (S)-
3
3
5
5
5
5
5
5
5
5
5
5
a
a
b
a
b
c
d
e
f
–
–
–
–
2413
2413
–
–
–
–
–
–
–
1745
1741
1746
1741
–
–
–
–
–
–
–
–
1042
1047
1042
1046
1028
1023
1027
1019
1040
1043
1025
1031
675
654
695
702
645
691
691
681
691
668
672
542
518
571
520
583
546
530
569
565
572
522
3264
3358
3332
3314
3319
3267
3375
3357
3343
3320
2730
2734
2736
2708
2729
2722
2729
2730
2730
2736
(
–)-a-maleate. In fact, bisf2-ꢀ-[1,4-ꢀ,ꢀ-dimethyl-(2S)-
succinyl]g dithiophosphoric acid 3 b was obtained by the
reaction of tetraphosphorus decasulfide 1 with dimethyl (S)-
ꢁ
(–)-a-malate 2 b in benzene at 20 C for 2 h (Scheme 1).
a
g
h
i
31
1
–
–
–
A singlet at d ¼ 84.6 ppm was situated in the ꢁf Hg
31 1
NMR spectrum of 3 b in benzene. Thus, the ꢁf Hg NMR
spectral signal of 3 b shows no significant change in com-
j
694, 675 562, 559
In KBr pellet.
1
parison with 3a. In contrast to 3a, the H NMR spectrum of
3
b in CDCl reveals two singlets at d ¼ 3.65 and 3.74 ppm,
3
5
dithiophosphoric acids to form chiral pyridoxonium salts being attributable to the methyl protons of two ꢂ ꢃ O and
bearing pharmacophoric functionalities possessed high anti- ꢂ ꢃ O substituents. The data of FTIR spectra of 3a and 3 b
3
6
3
bacterial activity with MIC values against Gram-positive are very similar (see Table 2). Thus, chiral dithiophosphoric
ꢀ
1 [15]
bacteria as low as 10 mM (6 mg mL ).
emphasized that pyridoxonium O,O-di-(–)-menthyl dithio- using pyridoxine.
It should be acids 3a and 3 b can be transformed into pyridoxonium salt
Pyridoxine 4a readily reacts with the enantiomerically
pure acids 3a and 3 b and racemic O,O-di-2-butyl dithio-
phosphate is active against clinical strains of antibiotic-
resistant bacteria from burn wounds including methicillin
resistant Staphylococcus aureus.
The specific systems of study in the present work are
chiral dithiophosphoric acids, which can be obtained from
natural chiral carboxylic acids. Among carboxylic acids, we
have chosen methyl (S)-(–)-a-lactate and dimethyl (S)-
[
15]
phosphoric acid 3c in the mixture of benzene and ethanol
ꢁ
(
(
1:1) at 20 C for 1-2 h to give pyridoxonium salts 5a-c
Scheme 2).
A specific rotation value [a]
2
0
ꢀ1
2
ꢀ4.5 grad g
cm ,
D
c ¼ 0.93 (ethanol) has been measured for 5a. Compound 5 b is
20
ꢀ1
2
also optically active ([a]
ꢀ2.1 grad g cm , c ¼ 1.01, etha-
D
(–)-a-maleate to obtain chiral dithiophosphoric acids.
31
1
nol). The ꢁf Hg NMR spectra of 5a-c in the mixture of ben-
Methyl (S)-(–)-a-lactate reacted with 2,4-diaryl-1,3,2,4-
dithiadiphosphetane 2,4-disulfide to give optically active 2-
methyl-(2S)-3-O-propionyl aryldithiophosphonic acid as pre-
zene and ethanol (1:1) reveal signals in the region of d ¼ 109-
1
17 ppm, which are typical for the salts of dithiophosphoric
[
17]
1
acids.
In the H NMR spectrum of 5a, the proton signals of
[
16]
viously reported.
We have established that methyl (S)-
the bisf2-ꢀ-[2-methyl-(2S)-3-O-propionyl]g substituent are
(
–)-a-lactate 2a reacts with phosphorus pentasulfide 1 in
shifted to high field in comparison with that of acid 3a. Thus,
ꢁ
benzene at 20 C for 2 h to form bisf2-ꢀ-[2-methyl-(2S)-3-
4
the signal of the protons of the ꢂ ꢃ O substituent of 5a is sit-
3
O-propionyl]g dithiophosphoric acid 3a (Scheme 1).
13
uated at higher field (d ¼ 3.68 ppm). In the ꢂ spectrum of
20
ꢀ1
2
The acid 3a is optically active ([a]
ꢀ28.5 grad g cm ,
D
5
a in the mixture of CD OD and CCl , the carbon atom of
3 4
31 1
c ¼ 0.82, ethanol). The yields, analytical, and ꢁf Hg NMR
4
the same fragment C ꢃ O exhibits a singlet at d ¼ 51.1 ppm.
3
data of the compounds obtained are summarized in Table 1.
In the FTIR spectrum of 5a, the band of the C ¼ O stretching
1
13
13
1
ꢀ
1
Selected FTIR spectral data, H NMR, and ꢂ and ꢂf Hg
NMR data of the compounds are summarized in Tables 2–.4
The ꢁf Hg NMR spectrum of 3a in benzene reveals a singlet
vibrations appears in practically the same region (1745 cm
)
ꢀ
1
as that for acid 3a (1745 cm ) (Table 2). In contrast to 5a,
the H NMR spectrum of 5 b in CDCl reveals two singlets at
3
1
1
1
3
at d ¼ 87.4 ppm. This resonance is situated in practically the d ¼ 3.71 and 3.77 ppm, attributable to the methyl protons of
[
17]
5
6
same region as observed for other dithiophosphoric acids.
two ꢂ ꢃ O and ꢂ ꢃ O substituents. The data of FTIR spec-
3 3
1
In the H NMR spectrum of 3a in CDCl , a singlet at tra of 5a and 5 b are very similar (see Table 2). On the basis of
3
d ¼ 3.78 ppm is attributed to the protons of the methoxy the NMR spectra, it was established that 5c was formed as the

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
433
1
Table 3. H NMR data of compounds obtained.
Comp. (Solvent)
d, ppm
1
3
4
2
3
3
3
3
a (CDCl
b (CDCl
3
)
1.58 d (6ꢃ, ꢂ ꢃ ꢂꢃ, J ¼ 7.0 Hz), 3.78 s (6H, ꢂ ꢃ O), 5.12 d q (2H, POC HCH , J ¼ 7.0 Hz, J ¼ 14.6 Hz), 6.27 m (1ꢃ, PSH).
3
HH
3
3
HH
PH
2
3
2
3
5
6
2
3
3
)
2.77 d (4ꢃ, ꢂ ꢃ ꢂꢃ, J 6.0), 2.80 d (4ꢃ, ꢂ ꢃ ꢂꢃ, J 6.0), 3.65 s (6H, ꢂ ꢃ O), 3.74 s (6H, ꢂ ꢃ O), 5.22 d t (2H, POC HCH , J
2
HH
2
HH
3
3
2
HH
3
6
.0, JPH 13.6).
1
3
9’
2
4
7’
8’
5
a (CD
3
OD)
1.47 d [6ꢃ, ꢂ ꢃ
3
ꢂH
2
, JHH ¼ 7.0 Hz], 2.63 s (3H, C H
3
), 3.62 m (2H, ꢁꢀꢂ H), 3.68 s (6H, C ꢃ
3
O), 4.74 s (2H, C H
2
O), 5.09 s (2H, C H
2
O),
O),
),
2
’
8
.17 s (1ꢃ, C H).
2.55 s (3H, C H
9’
3
3
3
3
5
6
5
b (CD
3
OD)
3
7
), 2.74 d (4ꢃ, ꢂ ꢃ
O), 5.04 s (2H, C H
2
ꢂꢃ, JHH ¼ 6.0 Hz), 2.80 d (4ꢃ, ꢂ ꢃ
2
ꢂꢃ, JHH ¼ 4.9 Hz), 3.71 s (6H, ꢂ ꢃ
3
2’
O), 3.77 s (6H, ꢂ ꢃ
3
’
8’
2
3
3
4
.66 s (2H, C H
2
2
O), 5.28 d t (2H, POC HCH
2
, JHH ¼ 5.4 Hz, JPH ¼ 15.4 Hz), 8.04 s (1ꢃ, C H).
4
3
4
3
1
3
3
5
5
5
5
c (CD
3
OD)
0.937 t [6ꢃ, ꢂ ꢃ
3
ꢂH
2
, JHH ¼ 7.4 Hz], 0.942 t [6ꢃ, ꢂ ꢃ
3
ꢂH
2
O), 5.01 s (2H, C H O), 8.05 s (1ꢃ, C H).
9’
2
, JHH ¼ 7.5 Hz], 1.29 d [6ꢃ, ꢂ ꢃ
3
ꢂH, JHH ¼ 6.2 Hz], 1.71 m (4H, ꢂ H
2
9’
2
7’
8’
2’
2
.61 s (3H, C H
3
), 4.57 m (2H, ꢂ HOP), 4.67 s (2H, C H
2
7,8
4
6
9’
7’
8’
d (CD
3
OD)
OD)
OD)
0.92 s [6ꢃ, (ꢂ
ꢃ
3
)
2
ꢂ], 1.92 m (2H, ꢂ H
2
OP, 2H, ꢂ H
2
OP), 2.19 s (3H, C H
3
), 2.23 s (3H, C H
3
), 3.00 s (2H, C H
2
O), 3.37 s (2H, C H
2
O),
2’
6
.44 s (1ꢃ, C H).
7 3
7
3
5
5
6
e (CD
3
1.261 d (3H, C H
3
, JHH ¼ 6.2 Hz), 1.264 d (3H, C H
3
, JHH ¼ 6.2 Hz), 1.61 m (2H, C H
2
), 1.65 m (2H, C H
2
), 1.81 m (2H, ꢂ ꢃ
2
), 2.65 s (3H,
9’
4
7’
8’
2’
3 2 2
C H ), 4.56 m (1H, ꢂ ꢃ), 4.72 s (2H, C H O), 5.20 s (2H, C H O), 8.18 s (1ꢃ, C H).
6
4
7
5
3
9’
4
5
7’
8’
f (CD
3
1.29 d (3H, C H C H, 3H, C H C H, J ¼ 6.2 Hz), 2.66 s (3H, C H ), 4.57 m (2H, POC HC HOP), 4.70 s (2H, C H O), 5.11 s (2H, C H O),
3
2
3
HH
3
2
2
’
8
.18 s (1ꢃ, C H).
9’
7’
8’
9
14
10
13
8
5
5
g (CD
3
OD)
2.53 s (3H, C H
3
), 4.59 s (2H, C H
2
O), 4.93 s (2H, C H
2
O), 6.94 m (1ꢃ, C H, 1ꢃ, C H), 7.21 m (1ꢃ, C H, 1ꢃ, C H), 7.26 m (1ꢃ, C H, 1ꢃ,
15
11
12
2’
C H), 7.36 m (1ꢃ, C H, 1ꢃ, C H), 7.91 s (1ꢃ, C H).
8
3
8
3
9,10
3
h (CDCl
3
)
0.83 d (6ꢃ, ꢂ ꢃ
3
ꢂꢃ, Jꢃꢃ ¼ 8.8 Hz), 0.86 d (6ꢃ, ꢂ ꢃ
3
ꢂꢃ, Jꢃꢃ ¼ 8.8 Hz), 0.94 d (12ꢃ, (ꢂ
ꢃ
3
)
2
ꢂꢃ, Jꢃꢃ ¼ 6.6 Hz), 0.95 d (12ꢃ,
0
9
,10
3
7
5
11’,12
9’
(
(
ꢁ
(
ꢂ
ꢃ
3
)
2
ꢂꢃ, Jꢃꢃ ¼ 6.6 Hz), 1.15 m [2H, (CH
3
)
2
C H)], 1.43 m (2ꢃ, ꢂꢃ
3
ꢂ ꢃ), 1.49 s (12ꢃ, (ꢂ
3 2 3
ꢃ ) ꢂ), 2.69 s (3ꢃ, ꢂ ꢃ ), 1.69 m
4
6
3
3
6
3
4ꢃ, ꢂ ꢃ
2
), 1.99 d (2ꢃ, ꢂ ꢃ
2
, Jꢃꢃ ¼ 11.7 Hz), 2.09-2.21 m (4ꢃ, ꢂ ꢃ
2
), 2.38 d (2ꢃ, ꢂ ꢃ
2
, Jꢃꢃ ¼ 11.7 Hz), 3.44 d d t (2ꢃ,
2
3
1
3
3
7’
8’
ꢀꢂꢃꢂ H, Jꢃꢃ ¼ 6.6 Hz), 4.46 d d t (2ꢃ, ꢁꢀꢂ H, Jꢃꢃ ¼ 6.6 Hz, JꢁH ¼ 11.0 Hz), 4.80 s (2H, Oꢂ ꢃ
2
), 5.10 s (2H, Oꢂ ꢃ
2
), 8.01 s
2
’
1H, C H).
1
3
13
1
Table 4. ꢂ and ꢂf Hg NMR data of compounds obtained.
Comp. (Solvent)
d, ppm
, JCH ¼ 130.6 Hz), 52.1 q (s) (ꢂ ꢃ
3
1
3
1
6
1
5
1
3
b (CDCl
3
)
38.34 t (s) (ꢂ ꢃ
1
2
, JCH ¼ 131.3 Hz), 38.38 t (s) (ꢂ ꢃ
2
3
O, JCH ¼ 147.5 Hz), 52.8 q (s) (ꢂ ꢃ
3
O, JCH
¼
2
1
2
2
1
2
48.5 Hz), 71.93 d d (d) (POC H, JCH ¼ 149.7 Hz, JCP ¼ 19.8 Hz), 71.97 d d (d) (POC H, JCH ¼ 150.4 Hz, JCP ¼ 19.4 Hz), 72.11 d d (d)
2 1 2 2 1 2 4
(
(
POC H, JCH ¼ 149.7 Hz, JCP ¼ 15.8 Hz), 72.15 d d (d) (POC H, JCH ¼ 150.4 Hz, JCP ¼ 16.5 Hz), 171.1 m (s) (O-C ¼O), 173.6 s (s)
1
O-C ¼O).
a
9’
1
1
4
8’
7’
2
3
2’
5
a (CD
3
OD, CCl
4
)
13.3 s (C ꢃ
1
15.7 q (C ꢃ
(
3
), 18.65 s (C ꢃ
3
), 18.69 s (C ꢃ
3
), 51.1 s (C ꢃ
3
O), 58.3 s (C H
2
O), 58.5 s (C H
2
O), 70.4 d (ꢁꢀꢂ H, JPH ¼ 7.0 Hz), 130.3 s (C H),
3
3
’
4’
6’
5’
3
36.2 s (C ), 138.5 s (C ), 142.4 s (C ), 153.2 s (ꢂ OH), 173.29 s (O-C ¼O), 173.34 s (O-C ¼O).
b
9’
1
3
1
6
1
5
1
5
b (CD
3
OD, CCl
4
)
3
, JCH ¼ 129.9 Hz), 37.7 t (ꢂ ꢃ
2
, JCH ¼ 130.6 Hz), 51.4 q (ꢂ ꢃ
3
O, JCH ¼ 146.7 Hz), 51.8 q (ꢂ ꢃ
1
3
O, JCH ¼ 147.5 Hz), 58.5 t
8’
1
8’
1
1
2
1
2’
1
C H
2
O, JCH ¼ 146.0 Hz), 61.7 t (C H
2
O, JCH ¼ 141.6 Hz), 67.1 d d (POC H, JPH ¼ 8.8 Hz, JCH ¼ 146.0 Hz), 133.0 d (C H, JCH
¼
3’
4’
6’
5’
4
1
85.6), 134.7 c (C ), 135.7 c (C ), 143.8 c (C ), 152.9 c (ꢂ OH), 170.9 c (O-C ¼O), 173.4 c (O-C ¼O).
4 1 9’ 1 1 1
3 3 3
c
3
1
5
5
5
c (CD
3
OD, CCl
4
)
8.88 q (s) (ꢂ ꢃ
, JCH ¼ 125.1 Hz), 13.3 q (s) (C ꢃ
, JCH ¼ 131.0 Hz), 20.1 q (s) (C ꢃ
, JCH ¼ 126.2 Hz), 30.18 t (s) (C ꢃ
2
, JCH
¼
3
1
8’
1
7’
1
1
(
(
26.2 Hz), 30.23 t (s) (C ꢃ
2
, JCH ¼ 126.2 Hz), 57.7 t (s) (C H
2
O, JCH ¼ 143.4 Hz), 58.5 t (s) (C H
2
O, JCH ¼ 146.4 Hz), 74.7 d (d)
2
3
1
2’
1
3’
4’
6’
ꢁꢀꢂ H, JPH ¼ 7.0 Hz, JCH ¼ 140.9 Hz), 126.3 d (s) (C H, JCH ¼ 189.3 Hz), 135.3 s (s) (C ), 140.3 s (s) (C ), 140.9 s (s) (C ), 153.4 s
5’
s) (ꢂ OH).
c
9’
1
7
1
7
1
7
1
e (CD
3
OD, CCl
4
)
14.5 q (s) (C ꢃ
3
, JCH ¼ 130.8 Hz), 21.89 q (s) (C H
3
, JCH ¼ 126.3 Hz), 21.95 q (s) (C H
3
, JCH ¼ 126.6 Hz), 34.36 t (s) (C H
2
, JCH
¼
7
1
8’
1
7’
1
1
27.4 Hz), 34.38 t (s) (C H
2
, JCH ¼ 127.4 Hz), 57.1 t (s) (C H
2
O, JCH ¼ 141.3 Hz), 58.4 t (s) (C H
2
O, JCH ¼ 143.7 Hz), 64.5 d t (d)
6
1
4
1
4
1
2’
1
(C H
2
OP, JCH ¼ 145.1 Hz), 72.30 d (s) (C H, JCH ¼ 146.2 Hz), 72.35 d (s) (C H, JCH ¼ 146.2 Hz), 130.4 d (s) (C H, JCH ¼ 188.5 Hz),
3’
4’
6’
9’
5’
1
36.6 s (s) (C ), 138.5 s (s) (C ), 142.1 s (s) (C ), 153.5 s (s) (C OH).
c
8
1
1
9,10
1
9,10
h (CDCl
3
)
16.5 q (s) (ꢂ ꢃ
3
, JCH ¼ 130.6 Hz), 21.4 q (s) (C ꢃ
3
, JCH ¼ 125.1 Hz), 22.2 q (s) [(ꢂ
ꢃ
3
)
2
ꢂ, JCH ¼ 126.2 Hz), 22.2 q (s) [(ꢂ
3 2
ꢃ ) ꢂ,
0
1
11’,12
1
3
1
7
1
J
CH ¼ 126.2 Hz), 23.6 q (s) [(ꢂ
ꢃ
3
)
2
ꢂ, JCH ¼ 126.2 Hz), 25.2 t (s) (C H
2
, JCH ¼ 128.4 Hz), 25.8 d (s) (ꢂ ꢃ, JCH ¼ 125.4 Hz), 31.6
5
1
4
1
4
1
6
1
d (s) (ꢂ ꢃ, JCH ¼ 123.3 Hz), 34.4 t (s) (C H
2
, JCH ¼ 124.7 Hz), 34.5 t (s) (C H
2
, JCH ¼ 124.7 Hz), 43.2 t (s) (C H
2
, JCH ¼ 129.8 Hz),
6
1
2
1
2
1
8’
1
4
5.0 t (s) (C H
2
, JCH ¼ 128.4 Hz), 48.9 d (s) (ꢂ ꢃ, JCH ¼ 118.1 Hz), 49.0 d (s) (ꢂ ꢃ, JCH ¼ 118.1 Hz), 60.6 t (s) (C H
2
O, JCH
¼
7’
1
1
1
2
10’
1
(
17.4 Hz), 60.8 t (s) (C H
2
O, JCH ¼ 146.0 Hz), 78.3 d (d) (ꢁꢀꢂ H, JCH ¼ 116.6 Hz, JCP ¼ 9.2 Hz), 103.1 s (s) (C ), 128.6 d (s)
2
’
1
3’
4’
6’
5’
N ¼ C H, JCH ¼ 187.1 Hz), 136.4 s (s) (C ), 141.4 s (s) (C ), 144.8 s (s) (C ), 152.4 s (s) (C OH).
0
a
9’
11’,12
8’
7’
2
5
3
4
1
6
5
j (acetone-d
6
)
19.1 s (C ꢃ
3
), 24.4 s [(ꢂ
ꢃ
3
)
2
ꢂ], 59.5 s (C H
2
O), 61.1 s (C H
2
O), 67.0 s (C H
2
O, C H
2
O), 70.2 s (OC H
2
C H
2
O), 72.6 s (POC H
2
, POC H ),
2
1
0’
8”
12”
3” 5”
10”
1”
9” 11”
3’
4’
1
1
01.6 s [(ꢂꢃ
3
2
)
2
ꢂ
], 115.7 s (C HC H), 119.7 s (C HC H), 122.6 s (C H), 126.3 s (C P), 131.0 s (C HC H), 132.0 s (C ), 132.1 s (C ),
”
6”
2
4’
2’
5’
6’
7”
4”
32.3 d (PCC HC HCP, JCP ¼ 13.2 Hz), 133.1 s (C ), 138.8 s (C H), 146.8 s (C OH), 158.7 s (C CH
3
), 162.6 s (C O), 168.5 s (C O).
a13
b13
c
1
ꢂf Hg NMR;
ꢂ NMR;
13
1
In parentheses is a view of signal in ꢂf HgNMR.
mixture of stereoisomers as the racemic acid 3c was used. The
3
1
1
ꢁ
f Hg NMR spectrum of 5c in the mixture of benzene and
ethanol (1:1) shows two signals at d ¼ 109.2 and 110.8 ppm in
13
integral ratio 1:0.4. In the ꢂ spectrum of 5c in the mixture
of CD OD and CCl , the carbon atom of the fragment of
3
4
3
1
C ꢃ gives two triplets at d ¼ 30.18 ppm ( J ¼ 126.2 Hz)
2
CH
1
and 30.23 ppm ( J ¼ 126.2 Hz).
CH
We have chosen cyclic dithiophosphoric acids because
they and their derivatives have recently attracted attention
.
[19,20]
due to the antimicrobial activity
Pyridoxine 4a reacts
with 1,3,2-dioxaphosphorinanes 3d,e, 1,3,2-dioxaphospho-
lane 3f, and 1,3,2-dioxaphosphepin 3 g in the mixture of
Scheme 1. Synthesis of dithiophosphoric acids 3a and 3 b.

4
34
I. S. NIZAMOV ET AL.
Scheme 2. Synthesis of pyridoxonium dithiophosphates 5a-c.
Scheme 4. Synthesis of acetonide pyridoxonium ꢀ,ꢀ-dimenthyl dithiophos-
phates 5 h,i.
31
1
phosphorus atom. Unlike 5d,e, the ꢁf Hg NMR spectra of
five- and seven-membered cyclic salts 5f and 5e in the mix-
ture of benzene and ethanol (1:1) show signals at d ¼ 125.6
and 131.1 ppm, respectively. These resonances are shifted
toward downfield in comparison with the data of 5d,e. It
should be emphasized that 1,3,2-dioxaphosphorinane salt 5e
and 1,3,2-dioxaphospholane salt 5f contain the same struc-
4
tural fragment ꢂ ꢃOP the protons of which give multiplets
1
at d ¼ 4.56 and 4.57 ppm, respectively, in the H NMR spec-
tra in CD OD. The singlet due to the protons of the methyl
3
9’
substituent C H of the pyridoxonium cation of 1,3,2-dioxa-
3
phosphorinane salt 5d is shifted to high field (d ¼ 2.19 ppm)
compared to that of other pyridoxonium cyclic dithiophos-
phates 5e-g (d ¼ 2.65–2.53 ppm) as well as to linear salts 5a-
c (d ¼ 2.63–2.55 ppm). The carbon atom of the same sub-
9
’
stituent C H of pyridoxonium cation of 5a-c appears as a
3
1
quartet at d ¼ 13.3–15.7 ppm ( J
¼ 125–130 Hz) in the
CH
13
13 1
ꢂ spectra in CD OD and as a singlet in the ꢂf Hg
3
1
NMR spectra. In the H NMR spectrum in CD OD, 1,3,2-
3
dioxaphosphepin 5d exhibits a singlet at d ¼ 6.44 ppm due
2’
to the presence of the fragment C H of pyridoxonium cat-
ion. This resonance is shifted to high field compared to that
of other salts 5a-f (d ¼ 7.91–8.18 ppm).
Scheme 3. Synthesis of pyridoxonium cyclic dithiophosphates 5d-g.
ꢁ
This approach was extended to pyridoxine acetonide,
bearing an isopropylidene ether linker and possessing anti-
benzene and ethanol in the ratio 1:1 at 20 C for 1–2 h to
give pyridoxonium cyclic dithiophosphates 5d-g (Scheme 3).
.
[8,9]
However, to carry out the reaction with 1,3,2-dioxaphos- bacterial activity
Among chiral dithiophosphoric acids,
ꢁ
phorinanes 3d, heating at 50 C for 2 h was required.
we used ꢀ,ꢀ-dimenthyl dithiophosphoric acids 3 h,i pre-
Salts 5d,e containing the six-membered cycle in the pared from (–)-(1 R,2S,5R)-menthol and (þ)-(1S,2R,5S)-
.
[21]
dithiophosphate anions give signals at d ¼ 111.3 and menthol
Seven-membered pyridoxine acetonide 4 b
31
1
ꢁ
1
11.3 ppm, respectively, in the ꢁf Hg NMR spectra in the reacts with 3 h in dried ethanol at 50 C for 1.5 h to form
mixture of benzene and ethanol (1:1), similarly to the pyri- acetonide pyridoxonium ꢀ,ꢀ-di-(–)-menthyl dithiophos-
doxonium salts 5a-c bearing linear substituents at the phate 5 h. Isomeric acetonide pyridoxonium ꢀ,ꢀ-di-

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
435
Scheme 5. Synthesis of diacetonide pyridoxonium bisdithiophosphonate 5j.
(
þ)-menthyl dithiophosphate 5i was obtained similarly 1,3,2,4-dithiadiphosphetane 2,4-disulfide with tri(ethylene-
[22]
(Scheme 4).
glycol)
reacts with pyridoxine acetonide 4 b in dry etha-
ꢁ
The resonances at d ¼ 109.6 and 104.5 ppm observed in nol at 50 C for 2 h to give acetonide pyridoxonium
3
1
1
the ꢁf Hg NMR spectra in ethanol of 5 h and 5i are situ- bisdithiophosphonate 5j (Scheme 5).
ated in practically the same region as observed for in other
In spite of the presence of two phosphorus atoms and
1
31
1
linear salts 5a-c. In the H NMR spectrum in CDCl of 5 h, two pyridoxonium cations in salt 5j, its ꢁf Hg NMR spec-
3
a singlet at d ¼ 1.49 ppm was assigned to protons of three trum in ethanol exhibits a singlet at d ¼ 105.9 ppm. This
0
11’,12
methyl groups of the isopropylidene fragment (ꢂ
ꢃ ) ꢂ. indicates the equivalence and the similar environment of
3 2
1
3
1
13
1
In the ꢂf Hg NMR spectrum of 5 h, the carbon atoms both phosphorus atoms in 5j. In the ꢂf Hg NMR spec-
0
0
1
1’
12
11’,12
10’
ꢂ
and ꢂ of the same fragment (ꢂ
ꢃ ) ꢂ reveal a trum in acetone-d , two carbon atoms of the fragments
3 2
6
1
1
6
2 2
quartet at d ¼ 23.6 ppm ( J ¼ 126.2 Hz). The carbon atom POC H
CH
and POC H of triethyleneoxy linker appear as a
0
1
0’
11’,12
10’
C
of this fragment (ꢂ
ꢃ ) ꢂ
gives a singlet at singlet at d ¼ 72.6 ppm. A singlet at d ¼ 126.3 ppm has been
1”
3
2
d ¼ 103.1 ppm. The FTIR and NMR data of the isomeric assigned to two carbon atoms of both fragments C P,
acetonide pyridoxonium ꢀ,ꢀ-di-(þ)-menthyl dithiophos- whereas, in the FTIR spectrum of 5j, the stretching vibra-
phate 5i are identical to those of 5 h. In the ESI mass spec- tions of the P ¼ S bond appear as two bands at 694 and
ꢀ
1
ꢀ1
trum of 5 h, a peak at m/e 655.5 is assigned to the ion 675 cm . Two bands at 562 and 559 cm are due to the
[
M þ K]þ (calculated M 615.9).
stretching vibrations of the P–S bond. Thus, dithiophos-
It was interesting to establish whether phosphorus phoric and bisdithiophosphonic acids readily form pyridoxo-
dithioacids containing several dithiophosphoryl groups are nium salts with pyridoxine as well as its acetonide.
capable to form pyridoxonium salts. Among them, bisaryldi-
thiophosphonic acids containing a tri(ethyleneglycol) linker
between two phosphorus atoms are considered to yield dia-
Biological evaluation
mmonium salts by passing anhydrous gaseous ammonia Pyridoxonium dithiophosphates 5a-g (concentration in
.
[22]
through the benzene solutions of these acids
Triethyleneoxy-bis-(4-phenoxyphenyldithiophosphonic) acid coli, Bacillus cereus (ATCC 19637), Pseudomonas aeruginosa
j prepared by the reaction of 2,4-bis-(4-phenoxyphenyl)- (ATCC 27853), Staphylococcus aureus (ATCC 29213), and
1,8- DMSO was 1%) were studied for in vitro against Escherichia
3

4
36
I. S. NIZAMOV ET AL.
a
Table 5. Antimicrobial activity of 5a–5 g .
Comp.
2-sulfide 3d, 2-mercapto-4-methyl-1,3,2-dioxaphosphorinane
B. cereus Ps. aeruginosa S. aureus C. albicans 2-sulfide 3e and 2-mercapto-4,5-dimethyl-1,3,2-dioxaphos-
5
5
5
5
5
a
b
e
f
8
11
12
12
12
–
8
–
8
8
10
38
15
12
–
16
18
13
pholane 2-sulfide 3f were obtained by the reaction of tetra-
phosphorus decasulfide with 2,2-dimethylpropane-1,3-diol,
10
12
10
12
25
butane-1,3-diol and butane-2,3-diol respectively in 1:2 molar
g
.[14]
ratio in dry benzene
2-Mercaptodibenzo[d.f][1–3]-dioxa-
Cefazolin (1% in DMSO)
–
phosphepin 6-sulfide 3 g was synthesized by the reaction of
a
Inhibition zone in mm.
0
.[24]
P S (1) with 2,2 -biphenol by refluxing in xylene
4
10
ꢀ
,ꢀ-Di[(–)-(1R,2S,5R)-2-isopropyl-5-methylcyclohex-1-yl]
Candida albicans (ATCC 885-653) (Table 5). The antibiotic
cefazolin was applied as control sample (1% in DMSO)
Inspection of Table 5 proves that all prepared compounds
exhibit remarkable antifungal activity toward the tested C.
albicans (growth inhibition zones of 12–18 mm) as com-
pared to cefazolin (13 mm). Salt 5 g containing an aryl cyclic
dithiophosphate anion shows higher activity against all
tested microorganisms (10–18 mm). The salts 5a-g exhibit
.
[23] dithiophosphoric acid 3 h and its isomer 3i were prepared by
the reactions of
þ)-(1S,2R,5S)-menthol respectively
pyridoxine acetonide 4 b was obtained by the reaction of pyri-
1 with (–)-(1 R,2S,5R)-menthol and
.
[21]
(
Seven-membered
.
[25]
doxine with acetone
phenyldithiophosphonic) acid 3j was similarly synthesized by
the reaction of 2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiadiphos-
1,8-Triethyleneoxy-bis(4-phenoxy-
[
22]
the same activity against B. cereus (8–12 mm) and P. aerugi- phetane 2,4-disulfide with tri(ethyleneglycol).
nosa (11–12 mm) as compared to Slayt (12 mm). The eval-
uated salts reveal moderate activity against E. coli Electrothermal IA9000 apparatus (Bibby Scientific Ltd.,
8–10 mm) and S. aureus (8–10 mm). In general, the pyri- Staffordshire, Great Britain). FTIR spectra (KBr tablets or
Melting points (uncorrected) were detected by use of an
(
doxonium salts 5f and 5 g containing cyclic dithiophosphate films) were recorded with a Bruker Tensor 27 spectrometer
anions are more active antimicrobials than the linear salts (Bruker BioSpin AG, F €a llanden, Switzerland) in the range
ꢀ
1
5
a and 5 b. Thus, the results for 5 g seem promising for car- 400–4000 cm . Bands are designated as ꢀ ¼ the stretching
1 13 13 1
rying out the next steps in the antimicrobial activity study.
vibration. The H (400 MHz), ꢂ, and ꢂf Hg (100.6 MHz)
spectra were run on a Bruker Avance III 400 spectrometer
(
Bruker BioSpin AG, F €a llanden, Switzerland) in CDCl or
3
Conclusions
ꢂD OD. Multiplicity of signal is denoted in the NMR spectra
3
Chiral linear and cyclic dithiophosphoric and bisdithiophos- as m ¼ multiplet, s ¼ singlet, d ¼ doublet, t ¼ triplet,
3
1
1
phonic acids readily react with pyridoxine and pyridoxine
acetonide to give pyridoxonium dithiophosphates and bisdi-
thiophosphonates. The reactions proceed via an increase of
the coordination number at nitrogen. Dithiophosphoric
acids bearing (S)-(–)-a-lactic and (S)-(–)-a-malic scaffolds as
well as cyclic fragments have not been previously introduced
into the reactions with pyridoxine. We have prepared the
first representative of a diacetonide pyridoxonium salt of
bisdithiophosphonic acids. The synthesis of new pyridoxo-
nium salts of dithiophosphoric and bisdithiophosphonic
acids is important for obtaining new antimicrobial drugs.
q ¼ quartet. The ꢁf Hg NMR spectra were obtained on a
Bruker Avance-400 spectrometer (161.9 MHz) (Bruker
BioSpin AG, F €a llanden, Switzerland) in benzene with 85%
H PO as an external reference. High-resolution mass spectra
3
4
were recorded with a Bruker Compass DataAnalysis 4.0 instru-
ments (Bruker Daltonik GmbH, Bremen, Germany) in acetone
performing in the ESI mode. Optical rotations were deter-
mined on a Perkin–Elmer 341 polarimeter at 20 C (Norwalk,
CT, USA) (D-line of sodium, 589 nm, a path length 5.52 cm,
ꢁ
20
c ¼ 1%) and presented as specific rotations [a] D.
Compositions of carbon, hydrogen, nitrogen, and sulfur atoms
were obtained on
a EuroEA3000 CHNS-O Analyzer
Experimental
(EuroVector S.p.A., Milano, Italy). Compositions of phos-
phorus were determined by method of pyrolysis on a nonserial
General
1
instrument. The Supplemental Materials contain sample H,
13
31
ff flow of dry argon was used for all reactions. Benzene and
ethanol were dried by distillation over sodium.
Tetraphosphorus decasulfide (purity 99%), methyl (S)-
C, and P NMR spectra of the products (Figures S1–S18).
(
–)-a-lactate 2a (purity 98%), dimethyl (S)-(–)-a-malate 2 b
Synthesis
(purity 98%), pyridoxine 4a (purity 98%), 2,3-butanediol (pur-
0
Bisf2-ꢀ-[2-methyl-(2S)-3-O-propionyl]g dithiophosphoric
ity 98%), 2,2 -biphenol (purity 99%), and (–)-(1 R,2S,5R)-men-
thol (purity 99%) were purchased from Sigma-Aldrich Co. (St.
Louis, MO, USA). 2,2-Dimethylpropane-1,3-diol (purity 98%)
was purchased from Fluka kemika. Butane-1,3-diol (purity
acid (3a)
P4S10 1 (1.0 g, 2.3 mmol) was added to the solution of
methyl (S)-(–)-a-lactate 2a (1.88 g, 18.1 mmol) in 15 mL of
anhydrous benzene under dry argon flow with stirring at
9
9%) was purchased from Merck (Kenilworth, NJ, USA).
ꢁ
ꢁ
(
þ)-(1S,2R,5S)-Menthol (purity 99%) was purchased from Alfa 20 C. The suspension obtained was stirred at 20 C for 2 h,
Aesar (Heysham, UK). Racemic O,O-di-2-butyl dithiophos- filtered, and concentrated under reduced pressure (0.5 mm
ꢁ
ꢁ
phoric acid 3c was obtained by the reaction of 2-butanol with Hg) at 40 C for 1 h and then at 0.02 mm Hg at 40 C for
P S
.[13]
2-Mercapto-5,5-dimethyl-1,3,2-dioxaphosphorinane 1 h and gave 3a (2.0 g, 74%) as oily liquid (Tables 1–4)
4
10

PHOSPHORUS, SULFUR, AND SILICON AND THE RELATED ELEMENTS
437
Bisf2-ꢀ-[1,4-ꢀ,ꢀ-dimethyl-(2S)-succinyl]g dithiophosphoric 1,5-Dihydro-3,3,8-trimethyl-9-hydroxy-[1, 3]dioxepino-
acid (3 b)
[5,6-c]pyridinium ꢀ,ꢀ-di[(þ)-(1S,2R,5S)-2-isopropyl-5-
Acid 3 b was obtained similarly as oily liquid from 1 (0.34 g, methylcyclohex-1-yl] dithiophosphate (5i)
0
.77 mmol) and dimethyl (S)-(–)-a-malate 2a (1.0 g, Semisolid (Tables 1 and 2). The mass spectrum of ESI (acet-
0
.77 mmol) (Tables 1–4)
one) m/e: 655.5 [M þ K]þ (calculated M 615.9). The FTIR
1
and H NMR data of 5 h are similar to those of isomeric 5i.
Pyridoxonium bisf2-ꢀ-[2-methyl-(2S)-3-O-propionyl]g
dithiophosphate (5a). general procedure
The mixture of pyridoxine 4a (0.17 g, 1.0 mmol) and acid 3a
Bis(1,5-dihydro-3,3,8-trimethyl-9-hydroxy-[1, 3]dioxe-
pino-[5,6-c]pyridinium) 1,8-triethyleneoxy bis(4-phenoxy-
phenyldithiophosphonate) (5j)
(
0.3 g, 0.99 mmol) in 5 mL of ethanol and 5 mL of benzene
ꢁ
was stirred at 20 C for 2 h. The clear solution obtained was
The mixture of 1,8-triethyleneoxy-bis(4-phenoxyphenyldi-
thiophosphonic) acid 3j (0.16 g, 0.24 mmol) and pyridoxine
acetonide 4 b (0.1 g, 0.48 mmol) in 10 mL of dry ethanol was
ꢁ
concentrated under reduced pressure (0.5 mm Hg) at 40 C
ꢁ
for 1 h and then at 0.02 mm Hg at 40 C for 1 h and gave 5a
(0.4 g, 85%) of as yellow semisolid (Tables 1–4)
ꢁ
heated at 50 C for 2 h. The mixture was filtered. The filtrate
ꢁ
was evaporated at reduced pressure (0.5 mm Hg) at 40 C
for 1 h and then in vacuum (0.02 mm Hg) for 1 h to give 5j
Pyridoxonium bisf2-ꢀ-[1,4-ꢀ,ꢀ-dimethyl-(2S)-succinyl]g
dithiophosphate (5 b)
(0.21 g, 81%) as semisolid (Tables 1–4)
Yellow semisolid (Tables 1–4)
Antimicrobial assay
Pyridoxonium O,O-di-2-butyl dithiophosphate (5c)
Yellow semisolid (Tables 1–4)
Pyridoxonium dithiophosphates 5a,b and 5c-g (1% DMSO
solutions) were studied by use of bacterial and fungal cul-
tures of Escherichia coli, Bacillus cereus (ATCC 19637),
Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aur-
eus (ATCC 29213), and Candida albicans (ATCC 885-653)
by gel diffusion test on Mueller–Hinton agar. Daily cultures
of bacteria and fungi were washed with physiological solu-
tion from beef nutrient agar and standardized according to
the turbidity standard up to 0.5 by McFarland (1.5 ꢂ 108
Pyridoxonium 2-mercapto-5,5-dimethyl-1,3,2-dioxaphos-
phorinane 2-sulfide (5d)
Yellow semisolid (Tables 1–4)
Pyridoxonium 2-mercapto-4-methyl-1,3,2-dioxaphosphori-
nane 2-sulfide (5e)
Yellow semisolid (Tables 1–4)
ꢀ1
CFU mL ). Bacterial and fungal cultures (0.4 mL) were
ꢁ
added to melted and cooled (at 45 C) Mueller–Hinton agar
(10 mL). The mixture was stirred and poured on sterile Petri
dishes (90 mm) and allowed to solidify. The agar plate was
punched with a sterile borer with 6 mm diameter size, and
holes were filled with the test compounds. Antimicrobial
Pyridoxonium 2-mercapto-4,5-dimethyl-1,3,2-dioxaphos-
pholane 2-sulfide (5f)
Yellow semisolid (Tables 1–3)
activity of cefazolin was measured as 1% solution in DMSO
ꢁ
(
Table 5). Petri dishes were incubated at 35 C for 24–48 h
in incubator. After the incubation period, the diameter of
the growth inhibition zones was measured with an accuracy
of 0.1 mm.
Pyridoxonium 2-mercaptodibenzo[d.f][1–3]-dioxaphos-
phepin 6-sulfide (5 g)
ꢁ
White solid, m.p.: 144-146 C (Tables 1–3)
Acknowledgment
1
,5-Dihydro-3,3,8-trimethyl-9-hydroxy-[1, 3]dioxepino-
The authors are grateful to the staff of Distributed Spectral-Analytical
Center of Shared Facilities for Study of Structure, Composition, and
Properties of Substances and Materials of Federal Research Center of
Kazan Scientific Center of Russian Academy of Sciences for their
research and assistance in discussing the results.
[5,6-c]pyridinium ꢀ,ꢀ-di[(–)-(1R,2S,5R)-2-isopropyl-5-
methylcyclohex-1-yl] dithiophosphate (5 h). gen-
eral procedure
The mixture of 1,5-dihydro-3,3,8-trimethyl[1, 3]dioxepino-
[
5,6-c]pyridin-9-ol 4 b (0.07 g, 0.3 mmol) and acid 3 h
(
5
0.14 g, 0.3 mmol) in 10 mL of dried ethanol was heated at
ORCID
ꢁ
0 C for 1.5 h. The clear solution obtained was concentrated
ꢁ
Ilyas S. Nizamov
Timur G. Belov
Ilnar D. Nizamov
Yevgeniy N. Nikitin
http://orcid.org/0000-0002-8243-3533
http://orcid.org/0000-0002-1657-2850
http://orcid.org/0000-0002-2058-773X
http://orcid.org/0000-0001-6964-3715
under reduced pressure (0.5 mm Hg) at 40 C for 1 h and
then at 0.02 mm Hg at 40 C for 1 h and gave salt 5 h
ꢁ
(0.18 g, 86%) as semisolid (Tables 1–3)

4
38
I. S. NIZAMOV ET AL.
Their Isomers, 3-Hydroxypyridine, and 3-Pyridinemethanol.
Phosphorus Sulfur Silicon Relat. Elem. 2020, 193, 226–230. DOI:
10.1080/10426507.2019.1673749.
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