Selenium analogues of anti-thyroid drugs

Article abstract of DOI:10.1080/10426500801898259

The inhibition of lactoperoxidase (LPO)-catalyzed oxidation of ABTS by anti-thyroid drugs and related derivatives is described. The commonly used anti-thyroid agent methimazole (MMI) inhibits the LPO with an IC50 value of 7.0 1.1 M which is much lower than that of the other two anti-thyroid drugs, PTU and MTU. The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC50 value of 16.4 1.5 M, which is about 4-5 times lower than that of PTU and MTU. In contrast to thiones and selones, the S- and Se-protected compounds do not show any noticeable inhibition under identical experimental conditions. While the inhibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide concentration, the inhibition by MSeI can be completely reversed by increasing the peroxide concentration. Experimental and theoretical studies were performed on a number of selones, which suggest that these compounds exist as selenolates or zwitterions in which the selenium atom carries a large negative charge. The structures of selones were studied in solution by NMR spectroscopy and the 77Se NMR chemical shifts for the selones show large upfield shifts in the signals, confirming the zwitterionic structure of the selones in solution. The thermal isomerization of some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the thermodynamically more stable N-substituted derivatives is described.

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Selenium Analogues of Anti-
Thyroid Drugs
Gouriprasanna Roy a & Govindasamy Mugesh a
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Indian Institute of Science, Bangalore, India
Published online: 29 Oct 2008.
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Phosphorus, Sulfur, and Silicon, 183:908–923, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500801898259
Selenium Analogues of Anti-Thyroid Drugs
Gouriprasanna Roy and Govindasamy Mugesh
Department of Inorganic & Physical Chemistry, Indian Institute
of Science, Bangalore, India
The inhibition of lactoperoxidase (LPO)-catalyzed oxidation of ABTS by anti-
thyroid drugs and related derivatives is described. The commonly used anti-thyroid
agent methimazole (MMI) inhibits the LPO with an IC50 value of 7.0
1.1 µM
which is much lower than that of the other two anti-thyroid drugs, PTU and MTU.
The selenium analogue of methimazole (MSeI) also inhibits LPO with an IC value
50
of 16.4 1.5 µM, which is about 4–5 times lower than that of PTU and MTU. In
contrast to thiones and selones, the S- and Se-protected compounds do not show
any noticeable inhibition under identical experimental conditions. While the in-
hibition of LPO by MMI cannot be reversed by increasing the hydrogen peroxide
concentration, the inhibition by MSeI can be completely reversed by increasing the
peroxide concentration. Experimental and theoretical studies were performed on
a number of selones, which suggest that these compounds exist as selenolates or
zwitterions in which the selenium atom carries a large negative charge. The struc-
77
tures of selones were studied in solution by NMR spectroscopy and the Se NMR
chemical shifts for the selones show large upfield shifts in the signals, confirming
the zwitterionic structure of the selones in solution. The thermal isomerization of
some S- and Se-substituted methyl and benzyl imidazole derivatives to produce the
thermodynamically more stable N-substituted derivatives is described.
Keywords Anti-thyroid drugs; bioinorganic chemistry; iodine; methimazole; selenium
INTRODUCTION
Thyroid hormones, thyroxine (T4) and triiodothyronine (T3), have var-
ious physiological effects.1−6 They exert actions in all tissues and affect
essentially every metabolic pathway. Thyroid peroxidase (TPO), which
is responsible for the synthesis of thyroid hormones, is synthesized on
polysomes and inserted in the membrane of the endoplasmic reticulum.
TPO is then transported to the Golgi, where it is subjected to terminal
This study was supported by the Department of Science and Technology (DST), New
Delhi, India.
Address correspondence to Govindasamy Mugesh, Department of Inorganic &
Physical Chemistry, Indian Institute of Science, Bangalore 560 012, India. E-mail:
mugesh@ipc.iisc.ernet.in
908

Selenium Analogues of Anti-thyroid Drugs
909
FIGURE 1 Mechanism for the synthesis of thyroid hormones (T4 and T3) by
heme-containing Thyroid Peroxidase (TPO).
glycosylation and packaged into transport vesicles along with tyroglob-
ulin (Tg).7,8 The synthesis of thyroid hormones (T4 and T3) is catalyzed
by TPO, a heme-containing enzyme, in the presence of H2O2 on the
apical membrane of the thyroid follicular cells. It is known that thy-
roid peroxidase (TPO), myeloperoxidase (MPO), eosinophil peroxidase
(EPO), and lactoperoxidase (LPO) belong to the peroxidase superfamily
of “mammalian peroxidases.”9−11
TPO catalyzes two very different types of reactions in the thyroid
gland: iodination and coupling (Figure 1). The iodination of tyrosyl
residues in thyroglobulin may be considered as an electrophilic substi-
tution reaction. On the other hand, the coupling of two iodinated tyrosyl
residues to form T4 may be treated as a phenolic condensation reaction.
Several experiments with model iodinating systems reveal that the iod-
ination and coupling reactions occur concurrently, suggesting that TPO
catalyzes both the reactions simultaneously. The iodination is generally
believed to involve a two-electron oxidation of iodide, although a radi-
cal mechanism has also been proposed.12−16 The coupling reaction may
follow either a radical pathway or an ionic mechanism. However, the
iodination and coupling reactions are not completely TPO specific as
LPO and MPO also catalyze these processes.17−21
The inhibition of Peroxidase-catalyzed oxidation reactions by
thiourea compounds (1, 3, 4 and 6) has been routinely used not only
to determine the potency of clinically useful anti-thyroid drugs, but

910
G. Roy and G. Mugesh
FIGURE 2 Chemical structures of some anti-thyroid drugs and their selenium
analogues.
also to understand the mechanism by which the drugs exert their anti-
thyroidal activity.16,22−24 Although the inhibition of thyroid peroxidase
(TPO) and a related enzyme, lactoperoxidase (LPO) by anti-thyroid
agents has been studied extensively in recent years, the mechanism
of the inhibition of heme-peroxidases or the inhibition of peroxidase-
catalyzed oxidation and iodination reactions is still not clear. Magnus-
son et al. suggested that the inhibition of TPO or LPO by the thiourea
drugs may occur through competition with hydrogen peroxide for a com-
mon form of oxidized iodine.25 Davidson et al. proposed that anti-thyroid
drugs block the iodination in vivo by reducing the concentration of oxi-
dized iodide generated by the TPO/H2O2 system, thus diverting it from
the natural substrate tyrosyl residues. In contrast, Engler et al. sug-
gested that MMI (1) and PTU (4) exert their activity by reacting with
the oxidized TPO heme group and thus inactivating the enzyme.26 It is
also possible that the thiourea drugs can be oxidized by the TPO/H2O2
system and the drugs in their oxidized forms may bind to the heme
group of the enzyme. Taurog and Dorris, on the other hand, suggested
that the inhibition of iodination by compounds such as PTU involves
a competitive reaction between the drugs and tyrosine residues of thy-
roglobulin (Tg) for oxidized iodine.22,27
Although the selenium analogues of anti-thyroid drugs have at-
tracted considerable attention in recent years, the inhibition of thy-
roid activity by these compounds appears to be more complicated as
compared with their sulfur analogues (Figure 2).28−33 The literature
data derived from the inhibition of TPO by selenium compounds show
that these compounds may inhibit the TPO activity by a different
mechanism.28,29 Therefore, further studies are required to understand
the mechanism by which the selenium compounds exert their inhibitory
action. In view of the current interest in anti-thyroid drugs and their
mechanism,30−33 we extended our approach to the synthesis and biologi-
cal activities of a number of sulfur and selenium derivatives bearing the
methimazole pharmacophore. In this article, we summarize our recent

Selenium Analogues of Anti-thyroid Drugs
911
results on the inhibition of LPO-catalyzed oxidation and iodination by
several thiones and selones related to methimazole.
RESULTS AND DISCUSSION
Inhibition of LPO-catalyzed Oxidation of ABTS
by Anti-thyroid Drugs
The enzyme inhibition experiments were carried out with lactoper-
oxidase (LPO) since it is readily available in purified form. Further-
more, LPO has been shown to behave very similarly to TPO with re-
spect to iodination of thyroglobulin, the natural substrate, and other
iodide acceptors.34 Edelhock et al. have reported the inactivation of
LPO by thiourea-based drugs using LPO-N-acetyltyrosylamide assay.35
We have employed 2,2ꢀ-azino-bis-3-ethylbenthiazoline-6-sulphonic acid
(ABTS) and H2O2 as substrates to determine the half-maximal in-
hibitory concentration (IC50) of test compounds.36 The LPO activities
at different concentration of MMI (1) and MSeI (2) are summarized in
Figure 3 and the corresponding concentration-inhibition plots and IC50
values are given in Figure 4 and Table I, respectively.
We carried out the experiment with the reduced species (2), which
was obtained by reducing the diselenide (9) with NaBH4 in an aqueous
solution. The extraction of the aqueous solution with dichloromethane,
followed by drying over anhydrous Na2SO4 and evaporation of the
FIGURE 3 Inhibition of LPO-catalyzed oxidation of ABTS by MMI (A) and
MSeI (B) at pH 7 and 30◦C. The incubation mixture contained 0.5 µg/mL LPO,
1.4 mM ABTS, 0.067 M phosphate buffer (pH 7) and 28.67 µM H2O2. The
reaction was initiated by the addition of H2O2. The initial formation of ABTS
radical cation was monitored by an UV-Vis spectrophotometer at 411 nm.

912
G. Roy and G. Mugesh
FIGURE 4 Concentration-inhibition curves for the inhibition of LPO-
catalyzed oxidation of ABTS by MMI and MSeI at pH 7.0 and 30◦C. The in-
cubation mixture contained 0.5 µg/mL LPO, 1.4 mM ABTS, 0.067 M phosphate
buffer (pH 7) and 28.67 µM H2O2. The reaction was initiated by addition of
H2O2.
organic solvent afforded 2 as pale yellow solid. Similarly to the inhi-
bition of LPO by MMI, the LPO activity decreased with an increase
in the concentration of MSeI (Figure 3, B). As expected, MMI exhibited
high inhibitory activity towards LPO with an IC50 value of 7.0 1.1 µM,
which is much lower than that observed with PTU and MTU. The sele-
nium analogue (MSeI) also inhibited LPO, and the IC50 value was found
to be almost 4–5 times lower than that of PTU and MTU. The higher
TABLE I Inhibition of LPO Activity by
Compounds 1, 2, 4, 6, 12, and 13
No.
Compd.
IC50(µM)a
1
2
3
4
5
6
7
8
9
MMI (1)
MSeI (2)
PTU (4)
MTU (6)
12
7.0 1.1
16.4 1.5
45.0 2.1
47.8 0.1
24.4 1.9
22.6 2.8
Inactive
13
14
15
16
Inactive
Inactive
aConcentration of the compound causing 50%
inhibition. Each IC50 value was calculated from at
least three independent experiments.

Selenium Analogues of Anti-thyroid Drugs
913
FIGURE 5 A hypothetical model for the coordination of thiourea drugs to the
Fe-center of TPO.
activity of MMI as compared with PTU and MTU is in agreement with
the previous studies on the inhibition of TPO.22,26 Since the activation
of the iron center in TPO must proceed through an interaction of Fe(III)
with H2O2, the inhibition of TPO may occur through a competitive co-
ordination of the drug to iron, assisted by hydrogen bonding with a his-
tidine residue of the TPO enzyme (Fig. 5).37,38 Under these conditions,
MMI might compete more successfully than PTU with H2O2, because
the hydrogen-bond (hard) basicity pkHB value of MMI (2.11) is much
higher than that of PTU (∼1.32). Similar to PTU, the methyl derivative
6 (MTU) is also expected to be a weak inhibitor of TPO. On the other
hand, the nucleophilicity of the selenium moiety in compound 2 that ex-
ists predominantly in its zwitterionic form is expected to be much higher
than that of the sulfur analogue. However, the lower activity of MSeI as
compared with MMI indicates that the selenium analogue of MMI may
inhibit LPO by a different mechanism. Although compound 2 is exhibits
high inhibition activity towards LPO-catalyzed oxidation reaction, the
selenium protected compounds 10 and 11 do not show any significant
inhibition activity. However, these compounds exhibits good activity af-
ter thermal isomerization to form compounds 12 and 13 (Fig. 6).
During the summer, when the temperature was about 32◦C, the
Se-substituted compounds 10 and 11 underwent thermal isomerization
to produce the corresponding N-substituted derivatives 12 and 13,
respectively (Fig. 6). The migration of methyl and benzyl groups from
selenium to nitrogen atom was readily occurred when the samples
were heated to 40–50◦C. The isomerization was followed by 1H,
13C and 77Se NMR spectroscopy and the thermodynamically stable
final products were characterized by single crystal X-ray studies.

914
G. Roy and G. Mugesh
FIGURE 6 Heat-induced isomerization in monoselenides: Migration of methyl
and benzyl groups from selenium to nitrogen.
Compounds 12 and 13 were also synthesized by independent methods
and compared with the isomerized products. It is important to note
that the doublets observed for the imidazolyl ring hydrogens in 11
(Se-substituted) have smaller coupling constants (∼1 Hz) than those
of the C-N isomer (selone) (2.2 Hz). In addition, the resonance for
–CH2– hydrogens occurs further upfield in 11 (δ: 4.16 ppm) than in 13
(δ: 5.35 ppm). Thus, the coupling constants and chemical shifts of the
–CH2– resonance can be used to distinguish between a C–Se– versus
a C–N– bonded isomer in this family of compounds. However, the 77Se
satellites observed in the 1H NMR spectra and the 77Se NMR chemical
shifts are found to be quite informative. The singlet signal observed in
the 1H NMR spectra of compounds 10 and 11 for the methyl and –CH2–
groups showed 77Se satellites for the expected selenium coupling to the
protons. The 77Se NMR chemical shifts for the products (12: -6 ppm,
13: -3 ppm) are much upfield shifted as compared with the starting
materials 10 and 11, which exhibited signals at 117 ppm and 282 ppm,
respectively. The migration of alkyl or benzylic groups from selenium
to nitrogen appears to be faster than that involves sulfur. This type of
tautomerization is expected to be faster in the case of MSeI (2) and such
processes may account for the facile oxidation of 2 to the diselenide 9.
It should be mentioned that the selones 12 and 13 were also obtained
in trace amounts during our syntheses of Se-substituted methyl and
benzylic derivatives (10, 11). The formation of these unexpected prod-
ucts can be ascribed to the presence of the lithium selenolate in different
isomeric forms. The low-temperature metallation of 1-methylimidazole
with n-BuLi affords the lithiated species, which in turn reacts with
elemental selenium to produce the corresponding lithium selenolate.
The straightforward reactions of this species with methyl iodide and
benzyl chloride afforded the Se-substituted methyl (10) and benzyl (11)

Selenium Analogues of Anti-thyroid Drugs
915
FIGURE 7 Proposed pathway for the formation of compound 12 and 13.
derivatives, respectively. However, the migration of Li from selenium to
nitrogen would yield the corresponding selone having a little charge on
selenium and a large negative charge on the nitrogen (Figure 7), which
further reacts with methyl iodide and benzyl chloride to produce the
selones 12 and 13, respectively.
SCHEME 1 Chemical structures of compounds 14–16.
On the other hand, the N3-methylated derivative of MMI and TMTU
(compounds 14–16, Scheme 1) do not inhibit the LPO-catalyzed oxida-
tion reaction, because the N−C bonds in this compound are stable and
cannot be cleaved under acidic conditions. Surprisingly, the replace-
ment of sulfur in compound 14 with selenium (compound 12) led to
almost a complete inhibition of LPO activity with an IC50 value of 24.4
µM, which is slightly higher than that of MSeI (16.4 µM), but this com-
pound is much more active than the 2-thiouracil derivatives (4 and 6).
An almost identical activity was observed with compound 13 (22.6 µM),
which also does not have any free N−H moiety.
Although compounds 12 and 13 lack the essential N−H group, the
higher inhibitory activity of these compounds as compared with their
sulfur analogues can be ascribed to the existence of 12 and 13 in zwitte-
rionic structures where the selenium moiety acts as a selenolate rather
than a selone (Figure 8). Similarly to MSeI (2), the negatively charged
selenium moiety may scavenge the H2O2 substrate, which effectively
FIGURE 8 Proposed structures of compounds 12 and 13. Both compounds
exist predominantly in zwitterionic form, which may have only a partial C−Se
double bond character.

916
G. Roy and G. Mugesh
present in the model system (ABTS assay) or this compound may inter-
fere with the oxidized LPO species, leading to a reversible inactivation.
Interestingly, the Se-substituted derivatives 10 and 11, on the other
hand, do not show any noticeable inhibition of the LPO-catalyzed oxi-
dation, but they show high inhibition after the thermal isomerization.
To understand the effect of peroxide (H2O2) on the reaction rate and
the inhibition, the LPO activity was determined at various concentra-
tions of hydrogen peroxide. In addition, the effect of hydrogen peroxide
on the inhibition of LPO-catalyzed iodination by selenium analogue of
anti-thyroid drugs (2, 12, and 13) was evaluated by carrying out the
experiments at various concentrations of H2O2. The initial rates (v0)
derived from various concentrations of H2O2 were plotted against the
concentrations of H2O2. Although the LPO activity was inhibited by
selones (2, 12 and 13) at lower concentrations of H2O2, the enzyme’s
activity could be completely recovered by increasing H2O2 concentra-
tion (up to certain concentration of selones). These results suggest that
the concentration of H2O2 has a dramatic effect on the inhibition of
iodination reaction by selones. The inhibition curves at different con-
centrations of inhibitors (selones) were characterized by a lag phase
whose length is related to the amount of inhibitors (selones) present in
the reaction mixture. After the lag phase, the rate of formation of MIT
was increased to the control value with an increase in the concentration
of H2O2. The control experiments indicate that the lag phase is probably
due to the hydrogen peroxidase depletion and not an enzyme inactiva-
tion. These observations support our conclusions on the inhibition of
LPO-catalyzed oxidation reactions that the selenium analogue of anti-
thyroid drugs (2, 12, and 13) reversibly inhibits the enzyme’s activity.
Theoretical Studies on Selones
All calculations were performed using Gaussian98 suite of quan-
tum chemical programs.39 The hybrid Becke 3-Lee-Yang-Parr (B3LYP)
exchange correlation functional was applied for DFT calculations.40,41
Geometries were fully optimized at B3LYP level of theory using the
6-311++G(d,p) basis sets. All stationary points were characterized as
minima by corresponding Hessian indices. The NMR calculations were
done at B3LYP/6-311++G(2d,p) level on B3LYP/6-311++G(d,p) level
optimized geometries using the GIAO method.42−48 Orbital interac-
tions were analyzed using the Natural Bond Orbital (NBO) method
at the B3LYP/6-311++G(2d,p) level and charges were calculated from
Natural Population Analysis (NPA).49 In general, theoretical investi-
gations on selones are highly limited to the compounds having simple
substituents, mainly due to the requirement of large basis sets for the
calculations.50−52 The relatively larger size and more polarizability of

Selenium Analogues of Anti-thyroid Drugs
917
selenium as compared with those of sulfur have led to the assump-
tion that the compounds with selone moiety are less stable than their
sulfur analogues. In addition to structure optimizations, we performed
NBO analysis to understand further the nature of Se atoms in selones
and calculated bond order between C−Se of all selones. The reactiv-
ity and reaction patterns of selones, in general, vary considerably de-
pending upon the substituents adjacent to the selenocarbonyl group.
Therefore, the heteroatom-substituted selones are more polar than se-
lenoaldehydes and selenoketones.53 In view of this, we have undertaken
further studies to understand the effect of substituents on selenocar-
bonyl moiety.
SCHEME 2 Chemical structures of some selones.
The exocyclic C−Se bond length in compound 17a, which is not con-
˚
taining any heteroatom in the ring, is 1.774 A and considered as a true
selone in the present discussion. The C−Se bond order for this com-
pound is close to two (1.87). However introducing one nitrogen atom
into the ring (Compound 18, Scheme 2) increases the C−Se bond length
˚
˚
significantly from 1.775 A to 1.805 A as well as bond order decreases
dramatically from 1.87 to 1.58 (Table II), indicates delocalization of
π-electron from C−Se bond to C−N bond (resonance structure I is pos-
sible). Furthermore, incorporation of one more nitrogen atom at 3- posi-
tion of the heterocycle (Compound 20, Scheme 2) increases C−Se bond
˚
˚
length further from 1.805 A to 1.831 A. The bond order for compound
20 is 1.38 which is no longer contains C−Se double bond. In this case

918
G. Roy and G. Mugesh
TABLE II Summary of DFT Calculations on Selenium Compounds at
B3LYP/6-311+G(d,p) Level and GIAO 77Se NMR Chemical Shifts
Calculated at B3LYP/6-311+G(d,p)//B3LYP/6-311++G(2d,p) Level
using Gaussian03 suite of Quantum Chemical Calculations Along
with Experimental 77Se NMR Chemical Shifts.
C−Se bond C−Se bond C−Se
length
length
bond Charge on
order Se (NBO) (ppm) (Exp.) (ppm) (Calc.)a
77Se NMR
77Se NMR
˚
˚
Compd. (A) (Calc.)
(A) (Exp.)
17a
17b
18
19a
19b
20
2a
2b
2c
12
1.774
1.915
1.805
1.812
1.908
1.831
1.835
1.917
1.835
1.838
1.844
—
—
—
—
—
—
1.848
—
—
1.843
1.843
1.87
1.03
1.58
1.55
1.02
1.38
1.37
1.02
1.37
1.36
1.34
0.098
0.138
−0.101
−0.124
0.123
−0.252
−0.262
0.132
−0.261
−0.269
−0.272
—
—
—
—
—
2094
—
632
652
—
10
23
—
—
—
−5
—
—
−6
39
−2
13
−3
aThe chemical shifts (δ) are cited with respect to dimethyl selenide. The calculated
chemical shift for dimethyl selenide in B3LYP/6-311+G(d,p)//B3LYP/6-311++G(2d,p)
level is 1637.6348. b77Se NMR for all compounds were taken in CDCl3 except
compound 73, which is not soluble in CDCl3 taken in D2O.
π-electrons are more delocalized among the four atoms (two resonance
structures are possible II and III).
Replacement of H atom with methyl substituent has a little effect on
the 77Se NMR as well as charge on the selenium atom since the bigger
selenium atom has a p orbital which overlaps less effectively with the
ring π-orbital. Thus, the charge on the selenium atom in compounds
18 and 19a has a very little difference; and the same is true for com-
pounds 12 and 13. NBO calculation shows that the charge on selenium
moiety in compound 17a is positive (0.098), whereas that for compound
18 is negative (−0.101) and the corresponding charge for compound 20
is even more negative (−0.252). This clearly indicates that compound
20 does not contain a true C−Se double bond; in fact, it can best be rep-
resented as zwitterionic structure having negative charge on selenium
and positive charge on carbon atom (IV, Scheme 3).
The X-ray structure of 1,3-Dimethyl-2(3H)-imidazolethione (14) was
first reported by Ansel et al. and best on the C−N bond lengths and C C
˚
˚
bond length [C(thionyl)−N: 1.350 A; C(ethylenic)−N: 1.41 A and C C:
˚
1.31 A] in the imidazole ring they have proposed that the electronic
structure of compound 14 would best be represented by a resonance
hybrid of structures (V) and (VIII) (Scheme 3).54 However, Tomlin et al.

Selenium Analogues of Anti-thyroid Drugs
919
SCHEME 3 Chemical structures of some selones showing resonance struc-
tures of the compounds.
reported the crystal structure of the same compound (14) and based
˚
on the bond distances found in their study [C(thionyl)−N: 1.346 A;
˚
˚
C(ethylenic)−N: 1.39 A and C C: 1.329 A], they have proposed more
delocalized zwitterionic structure (IX).55 Crystal structure of 2 clearly
shows that there are no significant differences in the lengths of the two
unique C−N bonds (Table 3). This strongly suggests that the n elec-
trons are delocalized and aromatic character exists in the heterocyclic
ring. The structure of compound 2 can, therefore, be represented as
zwitterionic 2c.
Similarly, the crystal structures of all N,N-disubstituted thiones and
selones (12, 13, 14 and 15) indicate that these compounds do not have a
TABLE III C−C and C−N bond lengths in the imidazole ring of
some thione and selone compounds
˚
Compd.
C−N bond length (A)
1a
C1−S: 1.685; N1−C1: 1.353; N1−C2: 1.382; N2−C1: 1.342; N2−C3: 1.369;
C2−C3: 1.322
2
C1−Se: 1.848; N1−C1: 1.350; N1−C2: 1.375; N2−C1: 1.346; N2−C3: 1.376;
C2−C3: 1.336
14b
14c
12d
13
C1−S: 1.695; N1−C1: 1.350; N1−C2: 1.410; N2−C1: 1.350; N2−C3: 1.410;
C2−C3: 1.310
C1−S: 1.681; N1−C1: 1.346; N1−C2: 1.390; N2−C1: 1.346; N2−C3: 1.390;
C2−C3: 1.329
C1−Se: 1.843; N1−C1: 1.342; N1−C2: 1.371; N2−C1: 1.342; N2−C3: 1.371;
C2−C3: 1.346
C1−Se: 1.843; N1−C1: 1.349; N1−C2: 1.371; N2−C1: 1.351; N2−C3: 1.365;
C2−C3: 1.330
aRaper et al.;56 bAnsell et al.;54 cTomlin et al.55

920
G. Roy and G. Mugesh
FIGURE 9 Optimized structure of compounds 10, 11, 12 and 13 showing the
charges on selenium, carbon and nitrogen atoms. The structure optimization
and NBO analysis were performed at B3LYP/6-311+G(d,p)/6-311++G(2d,p)
level of theory.
true C S or C Se double bond. The C S bond length in the thiones are
˚
in the range of 1.678 to 1.695 A, which are shorter than the single bond
˚
˚
value of 1.81 A and greater than the C S double bond value of 1.61 A.
This clearly suggests that the C S bonds in these thiones have only
a partial double bond character. Similarly, the C Se bond distances in
all the selones lie in between single bond and double bond. Significant
shortening of the adjacent C N bond, or lengthening of the olefinic dou-
ble bond (C C bond) from the true double bond and as well as significant
shortening of the C (ethylenic)−N in the imidazole ring of all thione or
selone reported here suggest the formation of a more delocalized struc-
ture corresponding to IX (zwitterionic structure).57 Interestingly, the
NBO analysis on compounds 10 and 11 suggest that the selenium atom
in 10 carries a positive charge (+0.336), but the selenium atom in 12
carries a negative charge (−0.269) (Figure 9). This indicates that the
selenium center is changed from an electrophilic selenium to a nucle-
ophilic selenium upon isomerization.
CONCLUSIONS
The commonly used anti-thyroid agent methimazole (MMI) inhibits the
LPO activity with an IC50 value of 7.0 1.1 µM, which is much lower
than that of the other two anti-thyroid drugs, PTU and MTU. The se-
lenium analogue of methimazole (MSeI) also inhibits the LPO activity
with an IC50 value of 16.4 1.5 µM, which is about 4–5 times lower than
that of PTU and MTU. N,N-disubstituted thiones do not inhibit the LPO
activity, whereas the N,N-disubstituted selones completely inhibit LPO-
catalyzed oxidation reaction and the activities of these selones are com-
parable with that of MSeI. In contrast to thiones and selones, the S- and
Se-protected compounds do not show any noticeable inhibition under

Selenium Analogues of Anti-thyroid Drugs
921
identical experimental conditions. While the inhibition of LPO by MMI
cannot be reversed by increasing the hydrogen peroxide concentration,
the inhibition by MSeI can be completely reversed by increasing the
peroxide concentration.
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