Ortho Substituent effects on the anticonvulsant properties of 4-hydroxy-trifluoroethyl phenols

Article abstract of DOI:10.1016/j.bmcl.2012.07.001

2,6-Dialkylphenols with isopropyl and sec-butyl substituent are well known anesthetic compounds. The 4-substitution with 1-hydroxy-2,2,2-trifluoroethyl (4-HTFE) group in these compounds led to the discovery of compounds with anticonvulsant activity in the

Full text of DOI:10.1016/j.bmcl.2012.07.001

Bioorganic & Medicinal Chemistry Letters 22 (2012) 5608–5611
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
ortho Substituent effects on the anticonvulsant properties of
4-hydroxy-trifluoroethyl phenols
⇑
Rajesh K. Mishra , Max T. Baker
Department of Anesthesia, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
2,6-Dialkylphenols with isopropyl and sec-butyl substituent are well known anesthetic compounds. The
4-substitution with 1-hydroxy-2,2,2-trifluoroethyl (4-HTFE) group in these compounds led to the discov-
ery of compounds with anticonvulsant activity in the 6 Hz (32 mA) model of partial epilepsy. In the
present study a series of 2-alkyl-4-HTFE phenols with the 6-position being replaced with either hydrogen
and bromine were designed, synthesized and tested to evaluate the effect of ortho-substitution on the
anticonvulsant property. The studies show that 2-substituted branched alkyl chain (iso-propyl and
sec-butyl) is necessary for the anti-seizure effect. Phenols with 2-substituted linear alkyl groups (methyl,
ethyl and n-propyl) having no substitution at 6-position were found to be devoid of antiseizure effects.
The 6-substitution with bromine moderately reduces the anticonvulsant effect in the compounds with
branched alkyl chains, but led to enhanced anticonvulsant effect in the compound with a linear alkyl
chain. This study shows that 4-HTFE phenols having isopropyl or sec-butyl ortho groups produce good
antiseizure protection in the 6 Hz therapy-resistant mouse model.
Received 2 May 2012
Revised 28 June 2012
Accepted 2 July 2012
Available online 10 July 2012
Keywords:
Alkyl phenol
Anticonvulsant
Antiseizure
Sedation
Ó 2012 Elsevier Ltd. All rights reserved.
2,6-Dialkylphenols having isopropyl and sec-butyl substituents
are potent anesthetic/sedative compounds.1,2 Accompanying these
CNS depressant effects are anticonvulsant properties that can
occur at sub-anesthetic doses. The only currently marketed anes-
thetic in this class of compounds, propofol (2,6-diisopropylphenol),
is sufficiently effective as an anticonvulsant that it is recom-
mended for the acute treatment of status epilepticus in humans.3,4
The anticonvulsant effects of propofol and of the related com-
pound, 2,6-di-sec-butylphenol, have been confirmed in animal
seizure models.5–7 2,6-Di-sec-butylphenol (R,R) is currently under-
going development as an anesthetic due to its anesthetic potency
and low cardiovascular side effects.8
It was previously demonstrated that the addition of a 4-(1-hy-
droxy-2,2,2-trifluoroethyl) group (4-HTFE) to propofol (MB003)
and 2,6-di-sec-butylphenol (MB050) (Fig. 1) results in compounds
that are also anticonvulsant.7 Anticonvulsant screening revealed
that these two 4-HTFE phenols are protective in the mouse 6 Hz
(32 mA) model of partial epilepsy, whereas they have little to no
protective effects in the mouse maximal electroshock (MES) and
subcutaneous Metrazol (scMET) models. The 6 Hz model is consid-
ered an important animal model for therapy-resistant epilepsy.9,10
Therapy-resistant epilepsy is defined as cases of epilepsy that are
not satisfactorily treated with available agents. This anticonvulsant
profile, effectiveness in the 6 Hz model, but not in MES and scMET
models, is similar to the profile of the successful anticonvulsant
levetiracetam.11
Another feature of 4-HTFE-substituted phenols is that this ring
addition reduces the sedative effects of these compounds. That is,
anticonvulsant effects occur at doses where animals can maintain
a gait on the rotorod. This is reflected in wider protective indices
(TD50/ED50). Propofol and 2,6-di-sec-butylphenol’s potent sedative
effects, properties considered toxic for anticonvulsant com-
pounds,12 limit their usefulness in the more widespread treatment
of seizures. However, the lower toxicity of the 4-HTFE-substituted
phenols suggests that such compounds may be useful as anticon-
vulsants outside the clinical setting where sedation is less well
tolerated. Furthermore, it suggests that the anticonvulsant effects
of alkyl phenols are not inherently linked to sedative effects of
these compounds.
Even though the anesthetic 2,6-dialkylphenols, when
substituted, yielded compounds having anticonvulsant properties,
4-HTFE substitution of a non-anesthetic 2,6-dialkyl phenol, 2,6-
dimethylphenol,2 yielded a compound that likewise did not have
anticonvulsant activity in the MES, scMET or 6 Hz models. These
results suggest that the 2,6-di-isopropyl and 2,6-di-sec-butyl
groups play important roles in protection in the 6 Hz seizure
model.
In an effort to clarify the role of the ortho alkyl groups in seizure
protection by 4-HTFE-substituted phenols, this study evaluated the
effects of modifications to the active 2,6-diisopropyl and 2,6-di-
sec-butyl 4-HTFE pharmacophores. These modifications include
⇑
Corresponding author. Tel.: +1 319 335 6585.
E-mail addresses: Mishra@Tansna.com (R.K. Mishra), Max-Baker@uiowa.edu
(M.T. Baker).
Present address: Tansna Therapeutics, Inc., Coralville, IA, United States.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.07.001

R. K. Mishra, M. T. Baker / Bioorg. Med. Chem. Lett. 22 (2012) 5608–5611
5609
animals.9 Seizures consist of a minimal clonic phase followed by
stereotyped automatistic behaviors. Animals not showing such
behaviors were considered protected. Toxicity was determined
by the rotorod test. For this test the animal are placed on a rotorod
at 6 rpm following dosing. The animal is considered toxic if it falls
off the rotorod three times in a 1 min period. The ED50, TD50 and
confidence intervals were determined by probit analysis.
The compounds ( Fig. 1) were synthesized as described in
Scheme 1. The 2-substituted alkyl phenols 1, were regiospecifically
brominated17 at 6-position using N-bromosuccinimide in carbon
disulfide to obtain 2-alkyl-6-bromo phenols 2. The 2-alklyl-6-bro-
mo phenols 2, were treated with trifluoroacetaldehyde ethyl hemi-
acetal and catalytic amount of potassium carbonate at 60–70 °C18
to get 3, the 2-alkyl-6-bromo-4-HTFE substituted phenols. The bro-
mine was removed by catalytic hydrogenation using Pd/C and a
hydrogen balloon to get 4, the 2-alkyl-4-HTFE substituted
phenols.19
OH
R1
R2
1
6
2
3
5
4
F3C
OH
Compound
R1
R2
MB003
MB050
DMPF
3d
- CH(CH3)2
- CH(CH3)2
- CH(CH3)CH2CH3
- CH3
- CH(CH3)CH2CH3
- CH3
Br
Br
Br
H
- CH(CH3)2
3e
- CH(CH3)CH2CH3
- CH2CH2CH3
- CH(CH3)2
- CH(CH3)CH2CH3
- CH3
3c
4d
4e
H
4a
H
4b
- CH2CH3
H
4c
- CH2CH2CH3
H
Figure 1. Structures of alkyl 4-HTFE phenol compounds.
All compounds were administered in a PEG solvent (30%) in or-
der to allow the best comparison between molecules. The protec-
tive effects of each compound in the MES test are shown in Table
1. All compounds showed poor to no protective effects in this mod-
el. Compounds 4a, 4c, 4d, 4e, and 3e provided some protection, but
only at the 300 mg/kg dose. Compounds 4a, 4c, and 4d exhibited
protection at both 0.5 and 4 h, whereas 4e and 3e protected only
at 0.5 h following this dosing. Compounds 4b, 3c, and 3d showed
no MES protection at any dose. The protective effects of each com-
pound in the scMET test are shown in Table 2. No protective effects
in the scMET model were seen with any compound except 4d and
4c. Compound 4d exhibited protection at the highest 300 mg/kg
dose at 0.5 and 4 h following dosing, and 4c at 0.5 h only.
The protective effects of each compound in the 6 Hz test are
shown in Tables 3 and 4. Compound 4b showed no protective ef-
fects at 100 mg/kg at any time point from 0.25 to 4 h following
dosing. 4a inhibited seizures in no more than 2 of 4 animals at
100 mg/kg at any time point from 0.25 to 4 h. 3c showed complete
protection (4/4) at 0.25 and 0.5 h and partial protection at 1 h.
Neither 4a nor 4b showed any evidence of toxicity at doses up to
300 mg/kg. Compound 3c showed only low toxicity.
Compounds 4d, 4e, 3d, and 3e, provided complete protection (4
of 4 animals) at 100 mg/kg at one or more time points from 0.25 or
1 h. Because of their protective activities in the 6 Hz model, their
toxic (TD50) as well as protective effects (ED50) were quantitated
(Table 4). These compounds exhibited a time-to-peak effect of
0.5 h except for 4d for which it was 0.25 h. Dose-response determi-
nations showed that 4e exhibited the greatest potency
(ED50 = 53.8 mg/kg), whereas 3d showed the weakest protection
(ED50 = 112 mg/kg) of these compounds. 4e was the most toxic,
having a TD50 of 86 mg/kg, whereas 3d was the least toxic with a
TD50 of 403 mg/kg. The protective indices (TD50/ED50) ranged from
a low of 1.6 for 4e to a high of 3.6 for 3d. No deaths occurred fol-
lowing the administration of any of these compounds.
substitution of an alkyl group with bromine (an isostere of isopro-
pyl),13 removal of an ortho group and varying the structure of the
alkyl group.13 Each compound was tested by the NINDS anticon-
vulsant screening program (ASP) for toxicity and seizure protection
in the MES, scMET and 6 Hz mouse models.
All compounds (Fig. 1) were screened in three whole mouse
models: the maximal electroshock model (MES), the scMET test
(pentylenetetrazole, Metrazol),14 and the 6 Hz psychomotor sei-
zure model of partial epilepsy (32 mA).9 Adult male CF No 1 albino
mice (26–30 g) were used for the 6 Hz test and 18–25 g mice were
used in the MES and scMet tests. The animals are housed, fed, and
handled in a manner consistent with the recommendations in the
National Council Publication, ‘Guide for the Care and Use of
Laboratory animals’. The animal studies were performed by the
NINDS Anticonvulsant Screening Program under IACUC number
09-12014. All compounds were administered ip in polyethylene
glycol, 30%.
The MES model, which generates generalized tonic-clonic sei-
zures, involved pre-treating mice with experimental compound,
and administering 60 Hz of alternating current (50 mA) for 0.2 s
via corneal electrodes. Prior to current administration, the animal’s
corneas were treated topically with 1% tetracaine. Animals are
considered protected if the hindlimb tonic extensor component is
absent.15 The scMET test was done by pretreating mice with exper-
imental compound and administering 85 mg/kg Metrazol into the
loose folds of the skin in the midline of the neck. Eighty-five milli-
gram per kilogram Metrazol is the dose that causes seizures in 97%
(CD97) of control animals. The animals were observed for 30 min
for progression or absence of seizure which consists of clonic
spasms of 3–5 s of the forelimbs, hindlimbs, jaws or vibrasse.16
The 6 Hz test (also known as the minimal clonic seizure, or psy-
chomotor test) involved delivering a corneal stimulus of 32 mA for
3 s. This current elicits psychomotor seizures in 97% of untreated
OH
OH
OH
OH
R
R
Br
R
R
Br
a
b
c
78 %a
82 %b
80 %c
84 %d
82 %e
65 %a
72 %b
68 %c
70 %d
74 %e
72 %a
70 %b
75 %c
78 %d
70 %e
1
2
F3C
OH
F3C
OH
3
4
a: R = Me; b: R = Et; c: R = n-Pr; d: R = i-Pr; e: R = sec-Bu
a. NBS, CS2, rt, 6 h; b. K2CO3, CF3CH(OH)OEt, 60-70 oC, 12 h; c.H2, Pd/C, MeOH, rt, 12 h.
Scheme 1. Synthesis of 4-HTFE phenols.

5610
R. K. Mishra, M. T. Baker / Bioorg. Med. Chem. Lett. 22 (2012) 5608–5611
Table 1
Table 3
Substituted phenol effects in the maximal electroshock (MES) modela
Toxicity and protective effects of RM170, RM166, RM1204 and RM1208 in the 6 Hz
(32 mA) modela
Compound
Dose, mg/kg, ip
Time (h)
Compound
Dose, ip
Time (h)
Toxicity
0.25
0/3
0.5
1
2
4
6
4a
4b
4c
4d
4e
3d
3e
3c
30
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
0/1
0.25
0/3
0.5
1
2
4
6
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
0/3
0/3
0/3
1/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/3
4a
4b
4c
3c
30
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
3/4
0/4
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/4
100
300
30
100
300
30
100
300
100
0/3
0/3
0/3
0/2
0/3
0/3
1/3
0/3
1/3
0/3
0/1
0/2
1/4
0/3
1/4
0/3
0/4
0/3
Protective effects
4a
4b
3c
100
100
100
0/4
0/4
4/4
0/4
0/4
4/4
2/4
0/4
2/4
1/4
0/4
0/4
1/4
1/4
0/4
a
Data represent the number of animals protected/number of animals tested.
0/3
0/3
Table 4
Protective effects of substituted phenols in the 6 Hz (32 mA) model
Compound Time to
peak
ED50, mg/kg
(95% CI)
TD50, mg/kg
(95% CI)
PI
a
Data represent number of animals protected/number of animals tested.
effect (h)
4d
4e
3d
3e
0.25
0.5
0.5
84.12 (52.93–147.82) 161.12 (128.83–191.36) 1.9
53.85 (30.02–66.14) 1.6
86.04 (72.37–97.2)a
112.45 (72.99–177.16) 403.12 (286.08–531.42) 3.6
87.6 (50.35–166.64) 144.4 (109.47–192.79) 1.7
Table 2
Protective effects of substituted phenols in the scMET modela
0.5
a
Compound Dose, mg/kg, ip Time (h) Compound Dose mg/kg, ip Time (h)
0.5 0.5
Anesthesia occurred in 4 of 4 animals at 300 mg/kg dose.
4
4
4a
4b
4c
4d
30
0/1 0/1 4e
0/1 0/1
0/1 0/1
0/1 0/1 3d
0/1 0/1
0/1 0/1
0/1 0/1 3e
0/1 0/1
1/1 0/1
0/1 0/1 3c
0/1 0/1
1/1 1/1
30
0/1 0/1
0/1 0/1
1/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
0/1 0/1
It has previously been shown that 4-HTFE phenols having 2,6-
100
300
30
100
300
30
100
300
30
100
300
100
300
30
100
300
30
100
300
30
100
300
di-isopropyl or sec-butyl groups (MB003, MB050) possess good
anticonvulsant activity in the 6 Hz model.7 This investigation of
4-HTFE phenols that are further modified about the ortho positions
reveals some of the molecular features that are important to anti-
seizure activity. Firstly, replacement of an alkyl group (6-position)
of MB003 and MB050 with bromine (3d and 3e, respectively),
creates compounds that also have antiseizure activity. The compar-
ative effect of bromine is to cause a moderate lessening of seizure
protection (84.12 [mg/kg] vs 112.45; 53.85 vs 87.6), but not elim-
ination of seizure protection. Taken alone it could be reasoned that
this halogen is serving in part as an isostere of the isopropyl group
where it maintains important molecular target interactions.
However, the relatively good antiseizure activity of the analogous
compounds having no 6-substituent (4d and 4e) indicates that bro-
mine is not serving a vital function in these compounds. Indeed the
data indicate that a second ortho substituent is not required for
anticonvulsant activity in the 2-isopropyl and 2-sec-butyl com-
pounds, and 6-substituents may be redundant.
The effect of varying the single ortho alkyl group on 4-HTFE
phenols having no 6-substituent shows that the nature of the alkyl
group is important to activity. Compounds having the 2-methyl, 2-
ethyl or 2-n-propyl group were poorly protective in contrast to
those possessing isopropyl and sec-butyl groups. The inactivity of
the 2-methyl compound is similar to the lack of activity of DMPF,
the 2,6-dimethyl analog.7 It is noteworthy that the apparent
requirement for isopropyl and sec-butyl groups for optimal activity
in these compounds is similar to the groups needed for good anes-
thetic activity among the alkyl phenols.2 A difference is that potent
anesthetics require placement of the isopropyl or sec-butyl groups
in both the 2- and 6- positions with the 4- position being free.1
Whereas, in the anticonvulsant 4-HTFE phenols, only a single ortho
substituent is required. It appears that alkyl groups having
a
Data represent number of animals protected/number of animals tested.
This study demonstrates that a number of alkyl-substituted
phenols can act as anticonvulsants in acute whole animal seizure
models. Of the three initial screening models used by ASP, these
small molecular weight phenols were predominately active against
seizures in the 6 Hz model (a model of partial or psychomotor epi-
lepsy), but not in the MES and scMET models.7 This profile suggests
that such compounds may have novel mechanisms of action. In
brief, compounds effective in the MES model, such as phenytoin,
are thought to be sodium channel blockers and block seizure
spread. Those effective in the scMET model are often GABAA ago-
nists and are thought to raise seizure threshold. The 6 Hz model
is an animal model of therapy-resistant epilepsy. To date, com-
pound effectiveness in this model is not reflective of any specific
anticonvulsant mechanism of action.9 For example, one compound
protective in the 6 Hz model is levetiracetam. This compound is
believed to act by stabilizing SV2A vesicles.20 Another 6 Hz active
compound is ganaxolone. It is thought to act as an allosteric GABAA
agonist.21 It is recognized, however, that most anticonvulsant act
by multiple mechanisms.22

R. K. Mishra, M. T. Baker / Bioorg. Med. Chem. Lett. 22 (2012) 5608–5611
5611
3. Prasad, A.; Worrall, B. B.; Bertram, E. H.; Bleck, T. P. Epilepsia 2001, 42, 380.
4. Marik, P. E.; Varon, J. Chest 2004, 126, 582.
5. Deriu, P. L.; Petruzzi, V.; Testa, C.; Mulas, M.; Melis, F.; Caria, M. A.; Mameli Br. J.
Anaesth. 1992, 69, 177.
6. Holtkamp, M.; Tong, X.; Walker, M. C. Ann. Neurol. 2001, 49, 260.
7. Baker, M. T. Anesth. Analg. 2011, 112, 340.
8. Rigby-Jones, A. E.; Sneyd, J. R. Br. J. Anaesth. 2010, 105, 246.
9. Barton, M. E.; Klein, B. D.; Wolf, H. H.; White, H. S. Epilepsy Res. 2001, 47, 217.
10. Loscher, W. Seizure Eur. J. Epilepsy 2011, 20, 359.
11. Wuttke, T. V.; Lerche, H. Expert Opin. Investig. Drugs 2006, 15, 1167.
12. Stables, J. P.; Kupferberg, H. J., Ed. The NIH anticonvulsant drug development
(ADD) program: Preclinical anticonvulsant screening project. In: Avanzini, G.,
Tanganelli P., Avoli, M. Eds.; Molecular and cellular targets for antiepileptic
drugs; London: John Libbey, 1997; pp 191–8.
13. Medicinal Chemistry: An Introduction; Gareth, T., Ed.; John Wiley & Sons, Ltd:
West Sussex, England, 2007.
14. White, H. S.; Johnson, M.; Wolf, H. H.; Kupferberg, H. J. Ital. J. Neurol. Sci. 1995,
16, 73.
15. Swinyard, E. A.; Woodhead, J. H.; White, H. S.; Franklin, M. R. General
principles:experimental selection, quantification, and evaluation of
anticonvulsants. In Antiepileptic Drugs; Levy, R. H., Mattson, R. H., Melrum, B.,
Penry, J. K., Dreifuss, F. E., Eds., Third Edition; Raven Press: New York, 1989; pp
85–102.
16. Swinyard, E. A.; Wolf, H. H.; Clark, L. D.; Miyahara, J. T. J. Pharmacol. Exp. Ther.
1961, 132, 97.
17. Basil, L. F.; Nakano, H.; Frutos, R.; Kopach, M.; Meyers, A. I. Synth. Stuttgart
2002, 2064.
18. Gong, Y.; Kato, K.; Kimoto, H. J. Heterocycl. Chem. 2001, 38, 25.
19. Spectral data for selected compounds: 2-Bromo-6-isopropyl-4-(2,2,2-trifluoro-1-
hydroxy-ethyl)-phenol (3d): 1H NMR (CDCl3, 300 MHz): d 7.47 (d, J = 2 Hz, 1H),
7.24 (d, J = 2 Hz, 1H), 5.73 (s, 1H), 4.98–4.92 (m, 1H), 3.33 (sep, J = 7.2 Hz, 1H),
2.6 (d, J = 4.4 Hz, 1H), and 1.26 (dd, J = 7.2 Hz, 0.8 Hz, 6H); 13C NMR (DMSO-d6,
100 MHz): d 151.67, 137.99, 129.66, 129.40, 125.69 (q, J2CF = 282 Hz), 125.49,
111.75, 70.32 (q, J2CF = 30 Hz), 27.75, 23.28, and 23.23. 19F NMR-1H Decoupled
increased spatial properties via branching, provide both optimal
anesthetic (2,6-dialkyl phenols)1 and antiseizure (2-alkyl-4-HTFE
phenols) activity. The anticonvulsant effects of compounds having
branched or linear groups greater than 4 carbons have not been
determined.
An exception to the need for a branched alkyl group is com-
pound 3c. It contains the 2-n-propyl group which as the lone ortho
substituent (4c) was not an active compound. However, the
addition of bromine as the second ortho substituent (3c) created
a compound exerting complete protection at two time periods
after dosing of 100 mg/kg, 0.25 and 0.5 h. The ED50 of this com-
pound was not determined. The reason for this improved activity
is not known. This bromine being in an equivalent ortho position
to the n-propyl, may act in this molecule as an isostere of isopropyl
by providing important target interactions not provided by n-pro-
pyl. As a whole, the data suggest that the 6-substitution may be
viewed not as redundant, but as modulatory. This is reflected by
the differing effects of alkyl group removal. MB003 has an ED50
of 38.6 mg/kg,7 whereas 4d (removal of an isopropyl) is less effec-
tive with an ED50 of 84. MB050 has an ED50 of 73 mg/kg, but 4e (re-
moval of a sec-butyl group) is more effective with an ED50 of 53.85.
Compound effectiveness determined by the ED50s in this study
should be interpreted with some caution. Compounds were admin-
istered ip. Although all were given in 30% polyethylene glycol,
there could be differences in absorption into the systemic circula-
tion. Plasma or CNS levels of compound causing anticonvulsant
activity were not determined. It is not likely that the alterations
of the alkyl groups alone, for example isopropyl versus n-propyl,
had major effects on plasma or CNS concentrations of these
compounds.
The protective indices of the present compounds ranged from
1.6 to 3.6. Prior studies of propofol and 2,6-di-sec-butylphenol
showed that these two compounds had protective indices of only
1.1 and 1.3, respectively. Therefore, similar to the effect of 4-HTFE
substitution on 2,6-dialkyphenols, protective indices were also
broad with the 4-HTFE phenols reported here. It is not apparent
why 6-bromination of 2-isopropy-4-HTFE phenol (4d) but not
2-sec-butyl-4-HTFE phenol (4e) caused a multi-fold widening of
the PI.
The specific role of 4-HTFE in anticonvulsant activity remains to
be determined. It is hypothesized that 4-HTFE substitution dimin-
ishes the binding of alkyl phenols to sites that cause anesthesia and
sedation while not substantially disrupting binding to targets that
prevent seizures in the 6 Hz mouse model. Ample evidence indi-
cates that the anesthetic/sedative effects of 2,6-dialkyphenols re-
sult from stimulation of the inhibitory GABAA receptors.23
Consequently, the anticonvulsant effects of 4-HTFE phenols may
not be primarily mediated by GABAA receptors.
(DMSO-d6, 282 MHz)
d
À77.36. 2-Bromo-6-sec-Butyl-4-(2,2,2-trifluoro-1-
hydroxy-ethyl)-phenol (3e): 1H NMR (CDCl3, 300 MHz): d 7.45 (t, J = 2.4 Hz,
1H), 7.17 (t, J = 2.4 Hz, 1H), 5.67 (s, 1H), 4.96–4.90 (m, 1H), 3.14–3.05 (m, 1H),
2.56 (d, J = 4.4 Hz, 1H) 1.71–1.54 (m, 1H), 1.21 (dd, J = 7.2 Hz, 1.2 Hz, 3H), and
0.85 (dt, J = 7.6 Hz, 1.2 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): d 152.01,
136.70, 129.55, 129.33, 126.16, 125.65 (q, J1CF = 280 Hz), 111.77, 71.23 (q,
J2CF = 280 Hz), 34.42, 29.86, 21.18 and 12.49. 19F NMR-1H Decoupled ((DMSO-
d6, 282 MHz) d À77.45. 2-Bromo-6-n-propyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-
phenol (3c): 1H NMR (CDCl3, 300 MHz): d 7.46 (s, 1H), 7.17 (s, 1H), 5.67 (s, 1H),
4.96–4.90 (m, 1H), 2.66 (t, J = 7.2 Hz, 2H), 2.55 (d, J = 4.0 Hz, 1H), 1.7–1.61 (m,
2H), and 0.97 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): d 152.40,
131.71, 130.04, 129.30, 128.98, 128.60 (q, J1CF = 280 Hz) 111.42, 70.15 (q,
J2CF = 30 Hz), 33.10, 23.2, and 14.4. 19F NMR-1H Decoupled ((DMSO-d6,
282 MHz) d À77.36. 2-Methyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenol (4a):
1H NMR (CDCl3, 300 MHz): d 7.25 (s, 1H), 7.20 (d, J = 8.0 Hz, 1H), 6.80 (d,
J = 8.0 Hz, 1H), 4.97–4.91 (m, 1H), 4.95 (s, 1H), 2.54 (d, J = 4.4 Hz, 1H), and (s,
3H); 13C NMR (DMSO-d6, 100 MHz): d 156.53, 130.54, 126.82, 126.59, 125.90
(q, J1CF = 280 Hz), 124.21, 114.81, 71.5 (q, J2CF = 30 Hz), and 16.69. 19F NMR-1H
Decoupled (CDCl3, 282 MHz)
d
À77.20. 2-Ethyl-4-(2,2,2-trifluoro-1-hydroxy-
ethyl)-phenol (4b): 1H NMR (CDCl3, 300 MHz): d 7.24 (d, J = 2.0 Hz, 1H), 7.18
(dd, J = 6.4 Hz, 2.0 Hz, 1H), 6.78 (d, J = 7.2 Hz, 1H), 4.96–4.91 (m, 1H), 4.92 (s,
1H), 2.65 (q, J = 7.2 Hz, 2H), 2.52 (d, J = 4.4 Hz, 1H), and 1.24 (t, J = 7.6 Hz, 3H);
13C NMR (DMSO-d6, 100 MHz): d 156.12, 130.22, 129.00, 126.77,125.94 (q,
J1CF = 284 Hz), 115.05, 71.11 (q, J2CF = 30 Hz), 23.47 and 14.82. 19F NMR-1H
Decoupled (CDCl3, 282 MHz) d À77.21. 2-n-Propyl-4-(2,2,2-trifluoro-1-hydroxy-
ethyl)-phenol (4c): 1H NMR (CDCl3, 300 MHz): d 7.21 (d, J = 3.0 Hz, 1H), 7.17
(dd, J = 6.4 Hz, 3.0 Hz, 1H), 6.77 (d, J = 9 Hz), 4.96–4.87 (m, 1H), 4.80 (s, 1H),
2.57 (t, J = 9 Hz, 2H), 2.42 (d, J = 6.0 Hz, 1H), 1.69–1.57 (m, 1H), and 0.95 (t,
J = 9.0 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz):
d 156.23, 129.90, 128.56,
126.79, 126.55, 125.96 (q, J1CF = 282 Hz), 151.10, 71.06 (q, J2CF = 30 Hz), 32.42,
23.15, and 14.55. 19F NMR-1H Decoupled ((DMSO-d6, 282 MHz) d À77.32. 2-
sec-Butyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenol (4e): 1H NMR (CDCl3,
300 MHz): d 7.25 (t, J = 2.8 Hz, 1H), 7.19 (td, J = 6.4 Hz, 2.8 Hz, 1H), 6.79 (d,
J = 8.4 Hz, 1H), 4.99–4.92 (m, 1H), 4.90 (s, 1H), 3.02–2.94 (m, 1H), 2.50 (d,
J = 4.4 Hz, 1H), 1.72–1.24 (m, 1H), 1.25 (dd, J = 6.8 Hz, 2.0 Hz, 3H), and 0.88 (dt,
J = 7.2 Hz, 1.2 Hz, 3H); 13C NMR (DMSO-d6, 100 MHz): d 155.82, 133.23, 126.83,
126.75, 126.33, 125.92 (q, J1CF = 284 Hz), 115.21, 71.5 (q, J2CF = 30 Hz), 33.78,
In summary, 4-HTFE phenols having isopropyl or sec-butyl ortho
groups produce good antiseizure protection in the 6 Hz therapy-
resistant mouse model. Such compounds may be useful for the
treatment of seizures.
Acknowledgments
29.71, 20.99, and 12.67. 19F NMR-1H Decoupled ((DMSO-d6, 282 MHz)
d
À77.38. 2-iso-Propyl-4-(2,2,2-trifluoro-1-hydroxy-ethyl)-phenol (4d): 1H NMR
(CDCl3, 400 MHz): d 7.28 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H),
4.97–4.92 (m, 1H), 3.26–3.15 (m, 1H), and 1.26 (dd, J = 7.2 Hz, 0.8 Hz, 3H). 13C
NMR (DMSO-d6, 100 MHz): d 155.52, 134.49, 126.81, 126.47, 126.10, 125.94 (q,
J1CF = 282 Hz), 115.16, 71.24 (q, J2CF = 30 Hz), 27.02, 23.14, and 23.11. 19F
NMR-1H Decoupled ((DMSO-d6, 282 MHz) d À77.36.
This work was supported by a University of Iowa GIVF Grant.
The authors thank the NINDS Anticonvulsant Screening Program
and Sr. Toxicologist (NINDS ASP) Tracy Chen, Ph.D., D.A.B.T, for
screening the compounds.
20. Rogawski, M. A. Epilepsy Res. 2006, 69, 273.
21. Mares, P.; Stehlikova, M. Neurosci. Lett. 2010, 469, 396.
22. Malawska, B. Curr. Top. Med. Chem. 2005, 5, 69.
References and notes
23. Krasowski, M. D.; Hopfinger, A. J. Expert Opin. Drug Discov. 2011, 6, 1187.
1. James, R.; Glen, J. B. J. Med. Chem. 1980, 23, 1350.
2. Krasowski, M. D.; Jenkins, A.; Flood, P.; Kung, A. Y.; Hopfinger, A. J.; Harrison, N.
L. J. Pharmacol. Exp. Ther. 2001, 297, 338.