Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: Identification of a dual cannabinoid receptor/TRPA1 channel agonist

Article abstract of DOI:10.1016/j.bmc.2014.07.006

In our ongoing program aimed at deeply investigating the endocannabinoid system (ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the importance of the carboxamide functionality. Binding studies on CB₁ and CB₂ receptors, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the newly developed compounds behaved as very potent cannabinoid receptor ligands (K_i in the nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH. Derivative 11 was a potent CB₁ and CB₂ ligand, with K_i values similar to WIN 55,212, exhibiting a CB ₁ and CB₂ agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain in mice, this compound showed a weak and delayed antinociceptive effect against the second phase of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower affinity but higher CB₂ selectivity than 11, proved to behave as a weak CB₂ competitive inverse agonist.

Full text of DOI:10.1016/j.bmc.2014.07.006

Accepted Manuscript
Structure-affinity relationships and pharmacological characterization of new al-
kyl-resorcinol cannabinoid receptor ligands: identification of a dual cannabinoid
receptor/TRPA1 channel agonist
Antonella Brizzi, Francesca Aiello, Pietro Marini, Maria Grazia Cascio,
Federico Corelli, Luciano De Petrocellis, Alessia Ligresti, Livio Luongo,
Stefania Lamponi, Sabatino Maione, Roger G. Pertwee, Vincenzo Di Marzo
PII:
S0968-0896(14)00509-4
DOI:
http://dx.doi.org/10.1016/j.bmc.2014.07.006
BMC 11700
Reference:
To appear in:
Bioorganic & Medicinal Chemistry
Received Date:
Revised Date:
Accepted Date:
7 March 2014
24 June 2014
2 July 2014
Please cite this article as: Brizzi, A., Aiello, F., Marini, P., Cascio, M.G., Corelli, F., De Petrocellis, L., Ligresti, A.,
Luongo, L., Lamponi, S., Maione, S., Pertwee, R.G., Di Marzo, V., Structure-affinity relationships and
pharmacological characterization of new alkyl-resorcinol cannabinoid receptor ligands: identification of a dual
cannabinoid receptor/TRPA1 channel agonist, Bioorganic & Medicinal Chemistry (2014), doi: http://dx.doi.org/
1
0.1016/j.bmc.2014.07.006
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Structure-affinity relationships and pharmacological characterization of new alkyl-resorcinol
cannabinoid receptor ligands: identification of a dual cannabinoid receptor/TRPA1 channel
agonist.
a,*
Antonella Brizzi, Francesca Aiello, Pietro Marini, Maria Grazia Cascio, Federico Corelli,
b
c
c,d
a,*
a
e
d
Vittorio Brizzi, Luciano De Petrocellis, Alessia Ligresti, Livio Luongo, Stefania Lamponi,
f
a
f
Sabatino Maione, Roger G. Pertwee and Vincenzo Di Marzo
c
d
a
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro
b
, 53100 Siena, Italy. Dipartimento di Farmacia e Scienze della Salute e della Nutrizione,
2
c
Università della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy. Institute of Medical
d
Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK. Endocannabinoid
Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via
e
Campi Flegrei 34, 80078 Pozzuoli, Napoli, Italy. Endocannabinoid Research Group, Istituto di
Cibernetica, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli, Napoli,
†
Italy. Dipartimento di Medicina Sperimentale, Sezione di Farmacologia “L. Donatelli”, Seconda
Università di Napoli, Via Costantinopoli 16, 80138 Napoli, Italy.
*
Correspondin authors. Full address: Via A. Moro, 2, 53100 Siena, Italy (A.B., F.C.); Phone +39
577 234327 (A.B.); +39 0577 234308 (F.C.); Fax: +39 0577 234333 (A.B., F.C.); e-mail:
0
antonella.brizzi@unisi.it (A.B.); federico.corelli@unisi.it (F.C.).
a
Abbreviations: ES, endocannabinoid system; CB, cannabinoid; MAGL, monoacylglycerol lipase;
9
FAAH, fatty acid amide hydrolase; TRPA1, transient potential ankirin type-1 receptor; THC, (-)-∆ -
tetrahydrocannabinol; eCBs, endocannabinoids; AEA, anandamide; 2-AG, 2-arachidonoyl-glycerol;
COX-2, cyclooxygenase type 2; 2-AGE, 2-arachidonyl-glycerol ether; NAM, N-
arachidonylmaleimide; EDC, N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide; HOBt, 1-
hydroxybenzotriazole; DMF, N,N-dimethylformamide; HBTU, N,N,N’,N’-tetramethyl-O-(1H-
benzotriazol-1yl)uranium hexafluorophosphate; DIPEA, N,N-diisopropylethylamine; THF,
tetrahydrofuran; DEAD, diethyl azodicarboxylate; CNS, central nervous system; TRPV1, transient
potential vanilloid type-1 receptor.

Abstract – In our ongoing program aimed at deeply investigating the endocannabinoid system
ES), a set of new alkyl-resorcinol derivatives was prepared focusing on the nature and the
importance of the carboxamide functionality. Binding studies on CB and CB receptors,
monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) showed that some of the
newly developed compounds behaved as very potent cannabinoid receptor ligands (K in the
nanomolar range) while, however, none of them was able to inhibit MAGL and/or FAAH.
Derivative 11 was a potent CB and CB ligand, with K values similar to WIN 55,212, exhibiting a
CB and CB agonist profile in vitro. In the formalin test of peripheral acute and inflammatory pain
(
1
2
i
1
2
i
1
2
in mice, this compound showed a weak and delayed antinociceptive effect against the second phase
of the nocifensive response, exhibiting, interestingly, a quite potent transient receptor potential
ankyrin type-1 (TRPA1) channel agonist activity. Moreover, derivative 14, characterized by lower
2 2
affinity but higher CB selectivity than 11, proved to behave as a weak CB competitive inverse
agonist.
Keywords - cannabinoid ligands, transient receptor potential ankyrin type-1 channel, structure-
affinity relationships, alkyl-resorcinol derivatives, anandamide, endocannabinoids, lipid modulators

1. Introduction
The exciting and intensive research on the cannabinoid field started with the identification and
9
chemical synthesis of (-)-∆ -tetrahydrocannabinol (THC) and continued with the discovery of an
innate signaling system, the endocannabinoid system (ES), characterized by at least two
cannabinoid (CB) receptors [1], their endogenous ligands, i.e. endocannabinoids (eCBs), namely
anandamide (AEA) [2] and 2-arachidonoyl-glycerol (2-AG) [3], and the enzymes involved in the
1
synthesis and degradation of eCBs [4]. Constitutive cannabinoid-type 1 (CB ) receptors [5] are
found in most tissues and are mainly abundant in the brain where their presynaptic activation
reduces the release of both excitatory, i.e. glutamate, and inhibitory, i.e. γ-aminobutirric acid,
2
neurotransmitters [6]. Cannabinoid-type 2 (CB ) receptors [7,8] are present only in few areas of
brain but are most abundant in immune cells and appear to be up-regulated under several
pathological conditions [9]. AEA and 2-AG are produced from membrane phosphoglycerides via
calcium-sensitive biosynthetic pathways and their pharmacological actions are terminated by re-
uptake and metabolism by various enzymes, including fatty acid amide hydrolase (FAAH) [10],
monoacylglycerol lipase (MAGL) [11] and cyclooxygenase type 2 (COX-2) [12].
Currently, thanks to the extraordinary achievements in understanding this endogenous signalling
system, it is established that the ES is a regulatory and very complex apparatus exerting a
homeostatic function, potentially involved in many (patho)physiological conditions [9], such as
control of food intake, emesis, obesity and metabolic disorders, neuronal plasticity, mnemonic
processes, neuropsychiatric disorders, pain and inflammation. In fact, because of the lipophilic
nature of its mediators, it normally acts in a local- and time-depending way and, in the brain, as a
“
retrograde” neuromodulatory system. Moreover, whereas the biosynthetic precursors of eCBs
seem to be ubiquitous in cellular membranes, it is the mutual set of endocannabinoid
biosynthesizing enzymes and cannabinoid receptors expressed in “normal” or “dysregulated”
conditions that determines levels, specificity and duration of eCB effects [13,14]. As our
knowledge of the molecular architecture and biology of this complex system grows, new strategies

for the design and chemical synthesis of compounds with different and/or multiple pharmacological
targets are developed, hopefully with the aim to furnishing potential therapeutic agents.
Our initial efforts at designing metabolically stable and potent hybrids, which included the
pharmacophoric requirements of both THC and AEA [15-17], culminated in the synthesis of a new
class of cannabinoid receptor ligands, chemically characterized by an alkyl-resorcinol nucleus
(
Chart 1) carrying an amidic head [18]. In previous papers [19,20], the most important chemical
features of this novel pharmacophoric model were described, with structure-affinity relationship
studies focusing on the lipophilic alkyl resorcinol tail and the length of the alkyloxy chain, linking
the aromatic portion to the amide.
Chart 1. Chemical structure of reference compounds: alkyl-resorcinol derivatives I-VI
As an extension of our work, a number of new alkyl-resorcinol derivatives were synthesized and
evaluated in order to deeply investigate how the structural requirements of the amide fragment can
affect the ability of these compounds to bind cannabinoid receptors, by (a) introducing amines with
different electronic properties and size, (b) reversing the positions of the carbonyl and NH groups,
thereby producing cyclopropanecarboxamides, and, (c) removing the carbonyl function to obtain

amine analogues (Chart 2), while maintaining a free phenolic hydroxyl group and a linear alkyloxy
chain with a range of methylene groups optimal for the cannabinoid receptor interaction [18-20].
Indeed, numerous reports have described several head-analogues of AEA [21-23] highlighting how
in the endogenous ligand the structural features of the head group are rather stringent. On the other
hand, because of the high degree of stereochemical selectivity observed in AEA-analogues [24], we
have considered here the introduction of a (R)-methyl or hydroxymethyl group in the 1’-position of
the ethanolamine moiety as examples of aliphatic amides with a moderate sterical hindrance in
proximity of the amide bond. Besides, the replacement of the classical cyclopropyl portion by allyl,
trifluoroethyl, dimethylamino, phenyl, benzyl and piperidinyl groups has been also carried out in
order to obtain derivatives with a lipophilic aliphatic or aromatic amide head, ranging from small to
relatively large size and having different electron density properties. Additionally, to explore the
steric tolerance of the space around the amide function, a very bulky amine, i.e. adamantyl amine,
has been introduced. In light of the higher metabolic stability and similar binding affinity displayed
by retro-AEA [25] compared to AEA, the synthesis of new alkyl-resorcinol
cyclopropanecarboxamides has been pursued without altering the distance between the NH group
and the aromatic nucleus because in our previous studies alkyl-resorcinol cyclopropylamides with
an alkyloxy chain of 11 carbon atoms proved to be potent cannabinoid receptor ligands [18-20].
Despite the fact that the carbonyl function seems to play a critical role in eCB activity [26], noladin,
also known as 2-arachidonyl-glycerol ether (2-AGE) [27], has been proposed as “putative” eCB,
1 2
acting as full agonist at the CB , and much less so, CB receptors [28-30]. Accordingly, the
cannabinoid recognition properties of derivatives lacking the carbonyl group have been also
investigated.
The manipulation of the ethanolamine moiety of AEA seemed to be a logical and very efficient
approach to discover and identify FAAH and/or MAGL inhibitors [31]. Among a wide range of
chemical structures characterizing these indirect cannabinoid receptor agonists, the first designed
MAGL inhibitor was an AEA derivative, i.e. N-arachidonylmaleimide (NAM) [32], which showed

a 20-fold selectivity over FAAH. More recently, the screening of different cysteine traps has led to
the identification of isothiazolinone-based compounds as potent MAGL inhibitors [33], suggesting
the formation of a reversible disulfide adduct as a probable inhibition mechanism.
Moreover, many classes of these inhibitors are also characterized, like the set of compounds here
described, by the presence of an aliphatic chain bearing a terminal aryl ring rather tolerant to the
chemical decoration. Thus, we have planned to modulate the cannabinergic properties of these
1 2
alkyl-resorcinol derivatives, shifting their capability of interaction from CB and CB receptors to
catabolic enzymes, by transforming the amide moiety in the phthalimido functionality (Chart 2).
To date, the functional and chemical relationship between ES and TRP channels is well documented
[
34,35]. Specifically, within the superfamily of the TRP channels, TRPA1 and TRPV1, which are
co-expressed in primary sensory neurons [36], appear to play a key role as a biological sensors in
several physiological and pathophysiological conditions, such as neurogenic inflammation and pain,
overlapping only in part with those in which the cannabinoid receptors participate. Starting from the
endocannabinoid AEA, that is presently thought to be also an endovanilloid, the recognition of
some similar chemical features, i.e. a lipophilic moiety, a polar head and a connecting functionality,
within both classes of TRP and endocannabinoid system modulators led to the discovery and/or
identification of endogenous, natural and synthetic TRP and CB ligands [37]. Considering that these
alkyl-resorcinol derivatives share the above pharmacophore requirements, herein, the functional
1 2
activity at CB and CB receptors, the antinociceptive effect in mice, the interaction with both
transient potential vanilloid type-1 (TRPV1) and ankyrin type-1 (TRPA1) receptors, and the in vitro
cytotoxicity profile of the most interesting compound is also reported.

Chart 2. General chemical structures of new synthesized alkyl-resorcinol compounds
2. Results and Discussion
2.1. Chemistry
As depicted in Scheme 1, acids 37-41, obtained from hydrolysis of methyl esters 32-36 with
methanolic/aqueous sodium hydroxide solution, were coupled in dichloromethane as solvent with
the appropriate commercial amines in the presence of N-ethyl-N’-(3-
dimethylaminopropyl)carbodiimide (EDC) hydrochloride and 1-hydroxybenzotriazole (HOBt) to
give amides 1-20 in excellent yields. Using this method, final hydrazides 21 and 22 were obtained
only in small amounts; thus, acid 37 was reacted in dry N,N-dimethylformamide (DMF) with 1,1-
dimethylhydrazine and 1-aminopiperidine, respectively, in the presence of HOBt, N,N,N’,N’-
tetramethyl-O-(1H-benzotriazol-1yl)uronium hexafluorophosphate (HBTU) and N,N-
diisopropylethylamine (DIPEA), to provide the expected compounds in acceptable yields (Scheme
1
). Esters 32-36 were prepared following the synthetic pathway previously reported [18-20].

Scheme 1. Synthesis of amides 1-22. Reagents and reaction conditions. a: MeOH/NaOH aqueous,
reflux, 3h, 85-90%; b: R NH , HOBt, EDC, DCM, room temp., overnight, 75-90% (1-20); c: 1,1-
dimethylhydrazine or 1-aminopiperidine, HOBt, HBTU, DIPEA, dry DMF, room temp, overnight,
5-60% (21, 22).
1
2
5
For the synthesis of retro-amides we planned a synthetic approach which involved as key
intermediates the phthalimido derivatives designed as enzymatic inhibitors (Scheme 2). Olivetol, 5-
(
(
2-methyloctan-2-yl)resorcinol and 4-hexylresorcinol, respectively, dissolved in dry tetrahydrofuran
THF), were subjected to Mitsunobu reaction with the appropriate bromoalcohols in the presence of
triphenylphosphine and diethyl azodicarboxylate (DEAD), furnishing bromoethers 42-47 in
satisfactory yields. Then, compounds 48-53 were achieved by displacement of bromine atom with
potassium phthalimide, at 70-80 °C, in dry DMF.
Hydrazinolysis of N-isoindoline-1,3-diones 49 and 51-53 in refluxing ethanol [38] afforded
corresponding amines 54-57 that were coupled with the cyclopropanecarboxylic acid without
further purification, following the procedure previously described to give final amides 23-26.
Scheme 2. Synthesis of phthalimido derivatives 48-53 and cyclopropanecarboxamides 23-26.
Reagents and reaction conditions. a: bromoalcohol, triphenylphosphine, DEAD, dry THF, room

temp., overnight, 35-60%; b: potassium phthalimide, dry DMF, 70-80 °C, overnight, 70-80%; c:
hydrazine, absolute ethanol, 60-80 °C, 5h, 90-95% yield; d: cyclopropanecarboxylic acid, HOBt,
EDC, DCM, room temp., overnight, 55-65%.
By heating the bromoethers 42 and 43 with (R)-(-)-2-amino-1-propanol, allylamine and
benzylamine, the final amine derivatives 27-29 were obtained in good yields (Scheme 3, method
A). Conversely, being cyclopropylamine a low boiling liquid reagent, the synthesis of the
cyclopropylamine analogues 30-31 was carried out by reduction of the corresponding amides with
litium aluminium hydride in dry THF (Scheme 3, method B).
Amides 58 and 59 were prepared following the synthetic pathway previously reported [18,19].
Scheme 3. Synthesis of amine derivatives 27-31. Reagents and reaction conditions. Method A: (R)-
(-)-2-amino-1-propanol, allylamine, benzylamine, heating, 4-5h, 75-85%; Method B: LiAlH
THF, 50-60 °C, 3h, 70-75%.
4
, dry
2
.2. In vitro CB
Alkyl-resorcinol derivatives 1-31 were evaluated as ligands for the human recombinant CB
receptors hCB and hCB and were compared to reference compounds AEA, WIN 55,212-2 and
HU-210 and previous lead compounds I-VI [18-20] (Table 1).
1 2
and CB receptor binding assay
1
2
The binding affinities (K
i
values) for the receptor were evaluated using membranes from HEK cells
3
receptor and [ H]-CP-55,940 as high affinity ligand with
transfected with either the hCB
1
or hCB
2

K
d
values of 0.18 nM for CB
1
receptor and 0.31 nM for CB
2
receptor [39]. Displacement curves
and 0.31 nM for
3
were derived after incubation of the drugs with [ H]-CP-55,940 at 0.14 nM for CB
1
2 i
the CB binding assay. The K values were calculated from the IC50 values according to the Cheng-
Prusoff equation [40]. Analysis of the binding assay results of the compounds described here
confirmed the validity of the alkyl-resorcinol scaffold as a pharmacophore and allows to assess with
more accuracy the structure-affinity relationships regarding the amide functionality. In agreement
with literature data for the AEA analogues [41], in the series of amides 1-22, introduction of a
methyl group at C-1’ position to afford chiral compounds 1-4 resulted in an increase of affinity
compared to the analogous ethanol-amides I-IV. Compounds 1 and 3 behaved as CB
ligands (K of 12.8 and 17.2 nM, respectively) with higher affinity than AEA (K = 72.0 nM) and the
same affinity as WIN 55,121-2 (K = 21.0 nM), although not very selective over CB receptors (K
of 119.3 and 50.2 nM, respectively), while compound 4 was the most potent CB receptor ligand
with highest affinity (K = 21.2 nM) in this subfamily of derivatives. A further increase of the
bulkiness and hydrophilic properties of the substituent at C-1’ position with the introduction of a
1
receptor
i
i
i
2
i
2
i
hydrogen-bonding hydroxymethyl group, i.e. compounds 5-9, caused a considerable loss of affinity
for both cannabinoid receptors. This drop in cannabinoid receptor binding properties may indicate a
stringent steric and hydrophobic requirement in this position. Previous studies [27] actually
suggested the existence of a hydrophobic subsite for the anandamide head group in both CB
1
and
CB receptors, capable of accommodating relatively bulky substituents. In agreement with data
2
from literature, the gradual enhancement of the head group size within these new derivatives
resulted in a parallel loss of cannabinoid receptor affinity.

Table 1. Structure, CB
1
and CB
2
Receptor Affinity (K
i
Values), and Selectivity of Alkyl-Resorcinol
a
Derivatives 1-31 and Reference Compounds I-VI, AEA, WIN 55,212-2 and HU-210.
b
b
c
d
Compd
R
n
X-Y
R
1
K
i
(nM)
hCB
K
i
(nM)
hCB
SI
vs CB
SI
vs CB
2
1
2
CB
2
1
CB
1
1
2
3
4
5
6
7
8
9
5-n. C
5
H
11
7
CONH (R)-CH(CH
3
)CH
)CH
)CH
)CH
OH)CH
OH)CH
2
OH
OH
OH
OH
OH
OH
OH
OH
OH
12.8
264.4
17.2
119.3
97.2
0.11
9.32
5-n.C
5
H
11
10 CONH (R)-CH(CH
CONH (R)-CH(CH
13 10 CONH (R)-CH(CH
10 CONH CH(CH
CONH CH(CH
13 10 CONH CH(CH
3
2
2.72
0.34
6.24
0.37
2.92
0.16
5-C(CH
3
3
)
2
C
6
6
H
13
7
3
2
50.2
5-C(CH
)
2
C
H
3
2
132.2
21.2
5-n. C
5
H
11
2
2
>10000
177.8
540.0
814.8
230.0
2370
>18.52
0.22
8.22
>4.22
-
<0.05
4.60
0.12
<0.24
-
5-C(CH
3
3
)
2
C
6
6
H
13
7
2
2
5-C(CH
)
2
C
H
2
OH)CH
2
1890
2-n.C
4-n.C
5-n.C
6
H
13
13
11
10 CONH CH(CH OH)CH
2
2
>10000
>10000
136.3
6
H
10 CONH CH(CH
2
OH)CH
CH=CH
CH=CH
2
>10000
16.4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
5
H
10 CONH
CONH
10 CONH
CONH
CH
CH
CH
CH
2
2
8.31
0.98
4.55
14.23
>78.25
>49.50
-
0.12
1.02
0.22
0.07
<0.01
<0.02
-
5-C(CH
5-n.C
5-C(CH
3
)
2
C
6
H
13
7
2
2
7.22
7.36
5
H
11
2
CF
3
3
438.0
96.30
27.9
3
)
2
C
6
11
11
11
H
13
7
2
CF
397.0
5-n.C
5-n.C
5-n.C
5
H
10 CONH
10 CONH
10 CONH
6
C H
5
>10000
>10000
>10000
>10000
>10000
>10000
>10000
845.5
127.8
202.3
>10000
>10000
>10000
>10000
>10000
182.6
677.8
460.0
5
H
2 6 5
CH C H
5
H
1-adamantyl
1-adamantyl
1-adamantyl
1-adamantyl
1-adamantyl
5-C(CH
3
3
)
2
C
6
6
H
13
7
CONH
-
-
5-C(CH
)
2
C
H
13 10 CONH
10 CONH
10 CONH
10 CONH
10 CONH
11 NHCO
-
-
2-n.C
4-n.C
5-n.C
5-n.C
5-n.C
6
H
13
13
11
11
11
-
-
6
H
-
-
5
H
N(CH
c-N(CH
c-C
3
)
2
4.63
2.63
6.02
0.22
0.38
0.17
5
H
2
)
5
1782
5
H
3
H
5
2770

2
2
2
2
2
2
3
3
4
5
6
7
8
9
0
5-C(CH
3
)
2
C
6
H
13 11 NHCO
c-C
c-C
c-C
3
3
3
H
5
2070
900.0
>10000
1060
1140
1240
2080
830.0
130.0
800.0
56.0
650.0
250.0
>10000
1520
1850
830.0
1890
>10000
390.0
160.0
160.0
30.0
3.18
3.60
-
0.31
0.28
-
2-n.C
4-n.C
5-n.C
5-n.C
5-n.C
5-n.C
5-n.C
5-n.C
5-n.C
6
H
13
13
11
11
11
11
11
11
11
11 NHCO
H
5
6
H
11 NHCO
H
5
5
H
8
CH
10 CH
10 CH
10 CH
11 CH
2
NH (R)-CH(CH
3
)CH
CH=CH
CH
2
OH
0.70
0.62
1.49
1.10
<0.08
1.43
1.62
0.67
0.91
>12.05
5
H
2
NH
NH
NH
NH
CH
2
2
5
H
2
2
C
6
H
5
5
H
2
c-C
c-C
3
3
H
5
1
5
H
2
H
5
e
I
5
H
7
CONH
10 CONH
CONH
2
CH CH
2
2
2
2
OH
OH
OH
OH
f
II
5
H
2
CH CH
g
III
5-C(CH
3
3
)
2
C
6
6
H
13
7
2
CH CH
g
IV
5-C(CH
)
2
C
H13 10 CONH
2
CH CH
310.0
5.20
f
V
5-n.C
5-C(CH
5
H
11
10 CONH
c-C
c-C
3
3
H
5
13.0
g
VI
3
)
2
C
6
H13 10 CONH
H
5
21.0
7.9
AEA
72.0
-
WIN 55,212-2
21.0
2.1
HU-210
-
0.15
a
Data are mean values for at least three separate experiments. Reference compounds were tested under the same
conditions in this study and anandamide was tested in the presence of PMSF (100nM). Binding affinity constants of the
most potent compounds (K < 50 nM) are in bold as well as the most selective compounds for CB and CB . Standard
errors of means (SEM) are not shown for the sake of clarity and were never higher than 5% of the mean.
i
1
2
b
K
i
values (nM) for CB
SI: CB selectivity index was calculated as K
SI: CB selectivity index was calculated as K
1 2
and CB binding assays are defined in experimental section.
c
d
e
f
2
i
(CB
(CB
1
)/K
)/K
i
(CB
(CB
2
) ratio.
1
i
2
i
1
) ratio.
Lit. [19]; in the paper I is denoted as compound 10.
Lit. [18]; in the paper II and V are denoted as compound 24 and 25, respectively.
Lit. [20]; in the paper III, IV and VI are denoted as compound 25, 26 and 33, respectively.
g
While a relatively hindered substituent, as the phenyl, benzyl and 1-piperidinyl group (compounds
4, 15 and 22, respectively), was still tolerated, the spherical and bulky 1-adamantyl nucleus
afforded derivatives completely devoid of ability to bind both cannabinoid receptors (compounds
6-20). Intriguingly, the CB selectivity-enhancing effect of the aromatic group (SI, calculated as
(CB )/K (CB ) > 78 and > 49 for compounds 14 and 15, respectively), although providing
compounds with lower affinity, might suggest a higher steric tolerance of the CB binding site and a
1
1
2
K
i
1
i
2
2

possible π-π interaction. We also explored how the electron density of the head group fragment
could affect the affinity of these derivatives. The introduction of a double bond, i.e. allyl-amides 10
and 11, gave analogues with 2-fold higher affinity than similar ethanol-amides, their K
reaching the low nanomolar range. Particularly, compound 11, which contains the 5-(1,1’-
dimethylheptyl)resorcinol nucleus, proved to be the most potent CB (K = 7.22 nM) and CB
.36 nM) ligand among the alkyl-resorcinol derivatives reported herein. Conversely, replacement of
the ethanolamine in the amide head with the 2’,2’,2’-trifluoroethylamine, in compounds 12 and 13,
or the N,N-dimethylhydrazine, in compound 21, did not influence significantly the K values. In
i
values
1
i
2 i
(K =
7
i
agreement with our previous studies, current data showed that the 1,1-dimethylheptyl series gave
the most potent compounds (i.e. compounds 3, 11 and 13 with the linker of 8 carbon atoms and
compound 4 with the linker of 11 carbon atoms). On the other hand, the binding properties of
derivatives having the olivetol nucleus, where an alkyloxy chain of 10 methylene groups was found
optimal for cannabinoid receptor affinity [18], appeared to be more affected by the nature of the
amide moiety.
The reversal of the carbonyl and NH groups in the amide functionality (cyclopropanecarboxamides
2
3-26) as well as the replacement of carbonyl moiety with a methylene group (amine-analogues 27-
1) afforded very weak ligands (affinity values in the micromolar range) for both receptor subtypes,
3
independently of their aromatic structure and the length of the connecting alkyloxy chain. In fact, in
the “inverse amides” the presence of both the cyclopropane moiety and of an alkyloxy chain of 11
carbon atoms, characteristics which conferred the best cannabinoid receptor interaction in the alkyl-
resorcinol family [18-20], is not enough to provide the optimal ligand recognition properties.
Similarly, all the amino derivatives 27-31 did not show good binding affinities, in face of the 5-
pentylresorcinol nucleus (olivetol backbone), a variable but appropriate chain length, and head
residues usually providing a high cannabinoid receptor affinity (i.e. cyclopropyl and allyl groups) or
subtype selectivity (i.e. 1-hydroxypropn-2-yl and benzyl groups). Specifically, compounds 23 and

30 are the retro-amide and amine analogues, respectively, of the reference amide V, which showed
affinity values in the nanomolar range (see table 1).
Taken together, these results suggest that the carbonyl functionality is essential for interaction with
the cannabinoid receptor and even relatively small variations in its position might result in a
considerable impairment of such interaction. Moreover, according with our previous results, the
resorcinol scaffold afforded very potent compounds when the saturated alkyl tail was placed at the 5
position in the aromatic nucleus, symmetrically to both hydroxy groups.
2.3. In vitro MAGL and FAAH interaction
Despite their different catalytic triad, FAAH and MAGL are known to be inhibited by various non-
selective hydrolase inhibitors which possess a hydrophobic fragment, covalently binding groups,
and a heterocyclic subunit. The series of N-isoindoline-1,3-diones 48-53 and the two hydrazide
derivatives 21 and 22 were tested for their ability to inhibit MAGL and/or FAAH activity but
unexpectedly, no inhibitor of MAGL and/or FAAH activity could be found (see the supplementary
data). Although derivatives 48-53 and 21, 22 shared chemical features reportedly relevant for
interaction with both enzymes, still they proved to be devoid of any inhibitory activity. Perhaps, the
length of the alkyl spacer between the imido or the hydrazido functionality and the phenyl moiety
could be a key parameter in the interaction with these enzymes, whereas, in the phthalimido series,
the steric hindrance of the heterocyclic head could be detrimental to the inhibitory activity.
1 2
2.4. Functional Activity of compounds 11 and 14 at CB and CB receptors
3
When tested in the [ H]CP-55,940 displacement binding assay, compound 11 exhibited the highest
affinity for both CB
1
(K
i
= 7.22nM) and CB
(K = 127.8nM, SI, calculated as K
). With the aim to investigate whether these two compounds are able to activate or block
2
(K
i
= 7.36nM) receptors, while compound 14 showed
the best selectivity for CB
2
i
i
(CB )/K (CB ), > 78) receptor (Table
1
i
2
1
3
5
cannabinoid CB
1
and/or CB
-CHO and hCB
S]GTPꢀS binding was first investigated using hCB
2
receptors, we performed [ S]GTPꢀS binding assays using membranes
-CHO cells. The ability of compound 11 to stimulate
-CHO cell membranes (for the 95%
obtained from hCB
1
2
3
5
[
1

confidence intervals of the mean values see the supplementary data). We found that the compound
3
5
was able to induce a strong stimulation of [ S]GTPꢀS binding to hCB
Figure 1a) although its potency (EC50 = 138.40 nM) was significantly lower than that of the well-
known CB /CB receptor full agonist CP-55,940 (EC50 = 1.43 nM). In particular, compound 11
behaved as a full agonist since its Emax value expressed as percentage of stimulation of [ S]GTPꢀS
binding above basal (Emax = 60.58%) was not significantly different from that of CP-55,940 (Emax
2.10%).
1
-CHO cell membranes
(
1
2
35
=
7
3
5
Figure 1. a) The effect of CP-55,940 and 11 on [ S]GTPꢀS binding to hCB
1
-CHO cell membranes
-CHO cell membranes
n=6). Each symbol represents the mean percentage change in binding ± SEM.
3
5
(
n=6). b) The effect of CP-55,940 and 11 on [ S]GTPꢀS binding to hCB
2
(
When tested in hCB
2
-CHO cell membranes, compound 11 produced only slight stimulation in the
S]GTPꢀS binding assay (Figure 1b), albeit with a potency (EC50 = 44.70 nM) that was not
statistically different than that of CP-55,940 (EC50 = 2.37 nM). Compound 11 behaved as a partial
agonist in hCB -CHO cells, since its Emax value (13.44%) was significantly lower than that of CP-
5,940 (Emax = 66.52%).
Because of the K values obtained for compound 14 (Table 1), this ligand was tested only on hCB
CHO cell membranes. We found that at the lowest concentrations tested (1-100 nM), compound 14
3
5
[
2
5
i
2
-
3
5
had no detectable effect in the [ S]GTPꢀS binding assay. Conversely, at higher concentrations it
3
5
2
produced a slight but significant inhibition of [ S]GTPꢀS binding to hCB -CHO cell membranes

(
Figure 2a) with a mean EC50 value of 701.20 nM and a mean Emax value of -14.41%. Under the
same experimental conditions, the well-established CB /CB agonist CP-55,940 was able to induce
1
2
35
a full stimulation of [ S]GTPꢀS binding, with a mean EC50 value of 6.58 nM. Since compound 14
behaved as a low-efficacy inverse agonist in this assay, its ability to antagonize CP-55,940 was
tested, using the highest concentration (1 µM) at which it did not show any significant stimulatory
3
5
effect in the [ S]GTPꢀS binding assay.
3
5
Figure 2. a) The effect of CP-55,940 and 14 on [ S]GTPꢀS binding to hCB
n=6). b) The mean log concentration-response curve of CP-55,940 was constructed in the presence
of vehicle (DMSO) or 1µM 14 (n=6). Each symbol represents the mean percentage change in
2
-CHO cell membranes
(
35
binding of [ S]GTPꢀS to hCB
2
-CHO cell membranes ± SEM. The right-ward shift produced by
1
µM 14 (Hill slope: 0.71, 95% confidence interval from 0.24 to 1.18) in the log concentration
response curve of CP-55,940 (Hill slope: 0.82, 95% confidence interval from 0.2 to 1.31) did not
deviate significantly from parallelism since the 95% confidence intervals of the two Hill slopes
overlapped. DMSO, dimethyl sulphoxide. Asterisks denote values that are significantly different
**
from zero ( P<0.01; one sample test).
At this concentration compound 14 was able to antagonize CP-55,940-induced stimulation of
3
5
[
S]GTPꢀS binding to hCB
in the dose/response curve of the agonist. The mean apparent K
4 for its antagonism of CP-55,940 did not differ significantly from its mean K
2
-CHO cell membranes (Figure 2b), as indicated by the right-ward shift
value (184.00 nM) of compound
value (127.84 nM)
B
1
i
3
determined in the [ H]CP-55,940 displacement binding assay described above (Table 1). The
rightward shift induced by compound 14 in the dose/response curve of CP-55,940 (Figure 2b) did
not deviate significantly from parallelism, since the 95% confidence interval of the Hill slopes

overlap (Figure 2b). Taken together, these findings support the hypothesis that compound 14 can
behave as a weak CB competitive inverse agonist.
.5. Antinociceptive activity of compound 11 in mice
Based on the results obtained in in vitro assay, we decided to investigate whether compound 11, like
other dual CB /CB agonists, displayed any analgesic activity in vivo. To this end, the formalin test
2
2
1
2
of peripheral acute and inflammatory pain in mice was employed. This test is a well-established
model of persistent pain in which mice exhibit a transient, biphasic pattern of pain behaviour. The
early, short lasting first phase of the nociceptive response is characterized by the activation of C and
Aδ fibres and is followed first by a quiescent period and then by a second, prolonged phase of tonic
pain, involving an inflammatory reaction in peripheral tissue, an activation of primary afferent
nerve fibres [42] and the development of central nervous system (CNS) sensitization [43]. We
found that i.p. administration of compound 11 caused a moderate reduction of the second phase of
nociceptive behaviour induced by formalin only at the highest doses used (3 and 4 mg/kg, i.p.)
(
Figure 3) and, unexpectedly, the antinociceptive effect became statistically significant only in the
latter part of the second phase (4 mg/kg, i.p., after 40 min) (Figure 3).
Figure 3. Antinociceptive effect of subcutaneous formalin (1.25%, 30 mL) injections into the hind
paws of mice on the time course of nociceptive behaviour. Formalin was injected 10 min after the
systemic administration of vehicle (0.9% NaCl, i.p.) or test compound 11, here denoted as CB148.
Recording of nociceptive behaviour began immediately after the injection of formalin (time 0) and
was continued for 60 min. Each point represents the total time of the nociceptive responses (mean ±
SEM) of 8-10 animals per group, measured every 5 min. Data were analysed using the one-way
ANOVA followed by the Bonferroni’s test, and statistical significance was taken as P < 0.05.

At doses higher than 4 mg/kg, the compound caused abdominal writhing, which prevented us from
determining a fully analgesic dose and to investigate this effect in the presence of CB /CB
1
2
antagonists. In any attempt to explain the possible cause of abdominal writhing, which is a typical
capsaicin-mediated behaviour, the interaction of compound 11 with both transient potential
vanilloid type-1 (TRPV1) and ankyrin type-1 (TRPA1) receptors was studied in HEK293 cells
overexpressing either the human recombinant TRPV1 or the rat recombinant TRPA1. The increase
in intracellular calcium was used as a measure of these two effects, and values for both EC50 (for
activation) and IC50 (for desensitization of the cell response to either capsaicin, for TRPV1, or allyl
isothiocyanate, for TRPA1, after 5 min pre-incubation of compound 11 prior to these typical
agonists) were calculated (Table 2). Compound 11 was found to activate both TRP channels, and in
particular behaved as a potent TRPA1 agonist endowed with efficacy and potency similar to those
of allyl isothiocyanate [44], which produces abdominal pain via activation of this channel [45].
2.6. Cytotoxicity assay
Cytotoxicity assay was performed to establish effects of most potent cannabinoid receptor ligands,
i.e. compounds 3 and 11, on cell viability in vitro. IC50 values for the effect on the NIH3T3 cell line
for the two compounds were 69 µM and 188 µM, respectively (each value is the mean of six
determinations and SEM is ꢁ 5%). These data confirmed a low cytotoxic potential for both tested
compounds towards NIH3T3 cells.

Table 2. Results of TRPV1 and TRPA1 assays of compound 11.
b
c
d
e
TRPV1
efficacy)
TRPV1
TRPV1
TRPA1
(efficacy)
TRPA1
TRPA1
(
EC (µM)
0
IC50 (µM)
EC50 (µM)
IC50 (µM)
5
1
8.6 ± 0.4
6.9 ± 0.7
23.9 ± 2.3
51.3 ± 2.5
2.7 ± 0.8
7.4 ± 1.6
a
b
c
d
e
Data are means ± SEM of N = 3 determinations.
As percent of the effect of ionomycin (4 µM).
Determined against the effect of capsaicin (0.1 µM) after a 5 min pre-incubation with compound 11.
As percent of the effect of allyl isothiocyanate (100 µM).
Determined against the effect of allyl isothiocyanate (100 µM) after a 5 min pre-incubation with compound 11.
3. Conclusions
In this study, we have designed and synthesized new cannabinoid receptor ligands based on the
alkyl-resorcinol template and carrying an amide functionality as terminal head of its flexible chain.
Analysis of the binding assay results was not always easy and often multifaceted; nevertheless,
these data showed that affinity was strongly affected by (i) the nature of the amines forming the
amide head, (ii) the steric hindrance near the amide bond, and above all (iii) the presence and/or
position of the carbonyl functionality. In fact, compounds presenting lipophilic and relatively
hindered amide heads furnished the most potent cannabinoid receptor ligands while
cyclopropanecarboxamides and amine derivatives, these latter lacking the carbonyl group, exhibited
very limited capability of interacting with both cannabinoid receptors. On the other hand, analysis
2
of selectivity trends was more complex and the CB selectivity-enhancing effect of the aromatic
group seemed the only parameter able to markedly influence the relative interactions of this series
of compounds with either cannabinoid receptor subtype. Unfortunately, our attempt to modulate the
cannabinergic properties of this class of compounds by transforming the amide moiety in the
phthalimido functionality led to derivatives completely devoid of any enzyme inhibitory activity,
underlying the importance of further studies on the elucidation of the chemical determinants for the
receptor versus enzyme interaction.

In particular, N-allyl-8-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]octanamide 11 exhibited the
lowest K values and behaved as a potent CB and CB ligand, with affinities similar to WIN55,212-
and better than AEA. Moreover, compound 11 behaved as a full agonist and a partial agonist at
i
1
2
2
1 2
CB and CB receptors, respectively, endowed with moderate antinociceptive activity on the second
phase of the biphasic pattern of formalin-induced pain behaviour. Interestingly, this compound
turned out to activate also TRPA1 and TRPV1 channels, which may have decreased its analgesic
activity in the formalin test, representing one of the few examples of dual cannabinoid receptor and
TRPA1 channel ligand. On the other hand, N-phenyl-11-(3-hydroxy-5-
2
pentylphenoxy)undecanamide 14, although less potent, resulted in a CB selective ligand with a
functional profile of competitive inverse agonist.
Overall, the results presented herein confirm that the alkyl-resorcinol nucleus is a valuable scaffold
for the design of potent cannabinoid receptor modulators and prompts us to further investigate
whether it can represent a suitable lead for the design of new TRP channel ankyrin type-1 ligands.
4. Experimental protocols
4.1. Chemistry
All starting materials, reagents and solvents were purchased from common commercial suppliers
and were used as received unless otherwise indicated. 5-(1,1-Dimethylheptyl)resorcinol was
obtained with 85% yield by cleavage of two methoxy groups from commercial 1,3-dimethoxy-5-(2-
methyloctan-2-yl)benzene using boron tribromide in dry dichloromethane, as already described in
our previous study [31]. Organic solutions were dried over anhydrous sodium sulphate and
concentrated with a Büchi rotary evaporator R-110 equipped with KNF N 820 FT 18 vacuum pump.
Melting points were determined on a Kofler hot stage apparatus (K) or using a Mettler FPI
1
13
apparatus (2 °C/min, M) and are uncorrected. H NMR and C NMR spectra were recorded in the
indicated solvent at 25 °C on a Bruker AC200F or on a Bruker Advance DPX400 employing TMS
as internal standard and chemical shifts were expressed as δ (ppm). The chromatography-mass
spectrometry (LC-MS) system consisted of an Agilent 1100 series liquid cromatograph system

including a 1100 MSD model VL benchtop mass spectrometer with API-ES interface, a binary
high-pressure gradient pump (0.4 mL/min low flow rate, employing a binary solvent system of 95/5
methanol/water), and a solvent degassing unit. Nitrogen (purity 99.995%) was used as nebulizer and
drying gas. UV detection was monitored at 254 nm. Mass spectra were acquired in positive or
negative mode scanning over the mass range m/z of 150-1500. The structures of final compounds
1
13
were unambiguously assessed by H NMR, C NMR and MS. Optical rotations were measured
with a Perkin-Elmer 343 automatic polarimeter in a 0.1 dm tube (c = g/mL), using as wavelength
the sodium-D line. All compounds were checked for purity by TLC on Merck 60 F254 silica plates.
For column chromatography, Merck 60 silica gel, 230-400 mesh, was used. Final products were
purified by a Biotage flash chromatography system with columns 12.25 mm, packed with KP-Sil,
60A, 32-63 µM. Compound purity was assessed by elemental analysis on a Perkin-Elmer elemental
apparatus model 240 for C, H, N, and the data are within ±0.4% of the theoretical values. All the
tested compounds possessed a purity >95.0%.
4.1.1. General procedure for the synthesis of final amides 1-20 and retro-amides 23-26
To a stirred solution of the appropriate acid (1.0 mmol, acids 37-41 or cyclopropanecarboxylic acid)
and amine (1.2 mmol, (R)-(-)-2-aminopropanol, allylamine, trifluoroethylamine, aniline,
benzylamine, adamantylamine or amines 54-57) in dichloromethane, kept at 0 °C in an ice bath,
solid HOBt (1.0 mmol) and then a solution in the same solvent of EDC (1.5 mmol) were added. The
reaction was allowed to warm to room temperature and stirring was continued for 24 h. The organic
3
solution was washed with 5% aqueous NaHCO , then with 1M HCl, and dried over anhydrous
sodium sulfate. After evaporation of solvent to dryness, the crude product was purified by silica gel
column chromatography.
4.1.1.1. (R)-8-(3-Hydroxy-5-pentylphenoxy)-N-(1-hydroxypropan-2-yl)octanamide 1
1
Eluent: CHCl
3
/MeOH = 47/3. Yield 70% as transparent oil. H-NMR (CDCl
3
): δ 6.25-6.24 (m,
O), 4.07-3.98 (m, 1H), 3.87 (t, 2H,
J = 6.5 Hz), 3.64 (dd, 1H, J = 3.6 Hz, J = 11.0 Hz), 3.49 (dd, 1H, J = 5.8 Hz, J = 11.0 Hz), 2.46 (t,
3
H), 5.92 (br d, 1H, J = 7.2 Hz, disappears on treatment with D
2

2
H, J = 7.6 Hz), 2.16 (t, 2H, J = 7.4 Hz), 1.70-1.58 (mm, 6H), 1.50-1.31 (mm, 10H), 1.14 (d, 3H, J
1
3
=
3
6.7 Hz), 0.86 (t, 3H, J = 6.2 Hz). C-NMR (CDCl ): δ 174.43, 160.11, 157.16, 145.59, 108.04,
107.00, 99.29, 67.80, 66.88, 47.73, 36.62, 36.06, 31.53, 30.85, 28.82 (x2), 28.68, 25.59, 25.47,
+
2.54, 17.00, 14.02. MS m/z: 402 [M+Na] (100). [α]
20
D
2
= + 9.13° (c = 0.01204; dichloromethane).
Anal. calcd. for C22H37NO
4
: C, 69.62%; H, 9.83%; N, 3.69%. Found: C, 69.57%; H, 9.86%; N,
3.68%.
5.1.1.2. (R)-11-(3-Hydroxy-5-pentylphenoxy)-N-(1-hydroxypropan-2-yl)undecanamide 2
1
Eluent: CHCl
3
/MeOH = 48/2. Yield 65% as transparent oil. H-NMR (CDCl
3
): δ 6.25-6.24 (m,
O), 4.08-3.99 (m, 1H), 3.88 (t, 2H,
J = 6.4 Hz), 3.64 (dd, 1H, J = 3.8 Hz, J = 11.0 Hz), 3.50 (dd, 1H, J = 5.6 Hz, J = 11.1 Hz), 2.46 (t,
3
H), 5.98 (br d, 1H, J = 7.1 Hz, disappears on treatment with D
2
2
1
1
2
8
3
5
H, J = 7.6 Hz), 2.16 (t, 2H, J = 7.6 Hz), 1.74-1.68 (m, 2H), 1.63-1.56 (m, 4H), 1.48-1.26 (mm,
1
6H), 1.14 (d, 3H, J = 6.8 Hz), 0.86 (t, 3H, J = 6.4 Hz). C-NMR (CDCl
3
3
): δ 174.50, 160.22,
57.15, 145.51, 107.99, 106.76, 99.45, 67.80, 66.93, 47.73, 36.78, 36.08, 31.53, 30.86, 29.12 (x2),
+
9.04 (x2), 28.87 (x2), 25.74 (x2), 22.54, 17.01, 14.03. MS m/z: 444 [M+Na] (100). [α]
20
D
= +
.30° (c = 0.01265; dichloromethane). Anal. calcd. for C25H43NO : C, 71.22%; H, 10.28%; N,
4
.32%. Found: C, 71.12%; H, 10.30%; N, 3.31%.
.1.1.3. (R)-8-[3-Hydroxy-5-(2-methyloctan-2-yl)phenoxy]-N-(1-hydroxypropan-2-yl)octanamide 3
1
/MeOH = 50/2. Yield 68% as transparent oil. H-NMR (CDCl
Eluent: CHCl
3
3
): δ 6.40-6.39 (m,
O), 4.09-4.03 (m,
2
1
1
1
6
4
H), 6.24 (s, 1H), 5.80 (br d, 1H, J = 7.5 Hz, disappears on treatment with D
2
H), 3.89 (t, 2H, J = 8.0 Hz), 3.65 (dd, 1H, J = 4.0 Hz, J = 12.0 Hz), 3.52 (dd, 1H, J = 6.2 Hz, J =
2.0 Hz), 2.18 (t, 2H, J = 7.8 Hz), 1.74-1.71 (m, 2H), 1.64-1.61 (m, 2H), 1.52-1.41 (m, 4H), 1.35-
.34 (m, 4H), 1.24-1.18 (mm, 12H), 1.15 (d, 3H, J = 8.2 Hz), 1.04-1.03 (m, 2H), 0.82 (t, 3H, J =
1
3
3
.4Hz). C-NMR (CDCl ): δ 174.34, 159.87, 156.81, 152.88, 105.77, 105.42, 98.57, 67.82, 67.07,
7.81, 44.51, 37.80, 36.59, 31.79, 30.03, 28.90 (x2), 28.79 (x2), 28.67, 25.53, 25.43, 24.65, 22.67,

+
7.02, 14.07. MS m/z: 458 [M+Na] (100). [α]
20
D
1
= + 7.78° (c = 0.02700; dichloromethane). Anal.
calcd. for C26
H45NO
4
: C, 71.68%; H, 10.41%; N, 3.22%. Found: C, 71.59%; H, 10.44%; N, 3.21%.
4
.1.1.4. (R)-11-[3-Hydroxy-5-(2-methyloctan-2-yl)phenoxy]-N-(1-hydroxypropan-2-
yl)undecanamide 4
Eluent: CHCl
1
3
/MeOH = 50/2. Yield 73% as transparent oil. H-NMR (CDCl
3
): δ 6.41-6.38 (m,
O), 4.11-4.02
m, 1H), 3.90 (t, 2H, J = 6.0 Hz), 3.65 (dd, 1H, J = 4.0 Hz, J = 10.0 Hz), 3.52 (dd, 1H, J = 6.0 Hz,
J = 10.0 Hz), 2.17 (t, 2H, J = 7.2 Hz), 1.77-1.70 (m, 2H), 1.63-1.60 (m, 2H), 1.53-1.39 (m, 4H),
.35-1.27 (mm, 6H), 1.24-1.19 (mm, 16H), 1.16 (d, 3H, J = 7.8 Hz), 1.04-1.03 (m, 2H), 0.82 (t, 3H,
2
H), 6.24-6.23 (m, 1H), 5.72 (br d, 1H, J = 7.8 Hz, disappears on treatment with D
2
(
1
1
J = 6.5Hz). C-NMR (CDCl
3
3
): δ 174.30, 160.00, 156.71, 152.66, 105.73, 105.16, 98.80, 67.82,
6
2
6
2
4
7.23, 47.81, 44.53, 38.01, 36.79, 31.79, 30.03, 28.88 (x2), 28.77 (x2), 28.68 (x2), 25.69 (x2),
+
+
5.44 (x2), 24.65, 22.67, 17.04, 14.07. MS m/z: 500 [M+Na] (100), 478 [M+H] (25). [α]
20
D
= +
4
.52° (c = 0.03836; dichloromethane). Anal. calcd. for C29H51NO : C, 72.91%; H, 10.76%; N,
.93%. Found: C, 72.80%; H, 10.79%; N, 2.92%.
.1.1.5. N-(1,3-Dihydroxypropan-2-yl)-11-(3-hydroxy-5-pentylphenoxy)undecanamide 5
1
/MeOH = 46/4. Yield 70% as white solid, mp = 60-63 °C (K). H-NMR (CDCl
Eluent: CHCl
3
3
):
δ 6.28−6.24 (m, 3H), 3.93-3.82 (m, 5H), 3.75 (dd, 2H, J = 4.5 Hz, J = 11.0 Hz), 2.48 (t, 2H, J = 7.6
Hz), 2.22 (t, 2H, J = 7.5 Hz), 1.76-1.52 (mm, 6H), 1.49-1.23 (mm, 16H), 0.86 (t, 3H, J = 6.6 Hz).
1
3
3
C-NMR (CDCl ): δ 174.64, 160.43, 156.92, 145.65, 107.96, 106.78, 99.51, 67.80, 63.11 (x2),
52.33, 36.72, 36.08, 31.52, 30.87 (x2), 29.32, 29.19, 29.04 (x2), 28.90, 28.63, 25.60, 22.54, 14.03.
+
MS m/z: 460 [M+Na] (100). Anal. calcd. for C25
H43NO
5
: C, 68.64%; H, 9.90%; N, 3.20%. Found:
C, 68.51%; H, 9.93%; N, 3.19%.
4.1.1.6. N-(1,3-Dihydroxypropan-2-yl)-8-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]octanamide 6
1
Eluent: CHCl
3 3
/MeOH = 45/5. Yield 70% as white solid, mp 50-52 °C (K). H-NMR (CDCl ): δ
6.42-6.38 (m, 2H), 6.24-6.23 (m, 1H), 3.97-3.94 (m, 1H), 3.91 (t, 2H, J = 6.7 Hz), 3.85 (dd, 2H, J =

4.2 Hz, J = 11.1 Hz), 3.76 (dd, 2H, J = 4.2 Hz, J = 11.1 Hz), 2.23 (t, 2H, J = 7.4 Hz), 1.77-1.58 (m,
1
3
4
H), 1.53-1.40 (mm, 4H), 1.37-1.35 (m, 4H), 1.24-1.03 (mm, 14H), 0.82 (t, 3H, J = 6.9 Hz). C-
): δ 174.15, 160.04, 158.76, 152.96, 105.34, 104.89, 98.42, 67.87, 63.02 (x2), 52.13,
4.50, 37.83, 35.94, 31.78, 30.02, 29.15, 29.04 (x2), 28.96, 28.84 (x2), 25.73, 24.72, 22.66, 14.06.
NMR (CDCl
3
4
+
MS m/z: 474 [M+Na] (100). Anal. calcd. for C26
H45NO
5
: C, 69.14%; 10.04H, %; N, 3.10%.
Found: C, 69.08%; H, 10.02%; N, 3.09%.
4
.1.1.7. N-(1,3-Dihydroxypropan-2-yl)-11-[3-hydroxy-5-(2-methyloctan-2-
yl)phenoxy]undecanamide 7
Eluent:CHCl
1
3
/MeOH = 47/3. Yield 65% as white solid, mp = 56-58 °C (K). H-NMR (CDCl
3
): δ
6
1
2
1
.41 (s, 1H), 6.38 (s, 1H), 6.31 (br d, 1H, J = 7.1 Hz, disappears on treatment with D
2
O), 6.23 (s,
H), 3.97-3.93 (m, 1H), 3.90 (t, 2H, J = 6.4 Hz), 3.84 (dd, 2H, J = 4.1 Hz, J = 11.1 Hz), 3.74 (dd,
H, J = 4.1 Hz, J = 11.1 Hz), 2.20 (t, 2H, J = 7.5 Hz), 1.76-1.70 (m, 2H), 1.63-1.60 (m, 4H), 1.52-
.48 (m, 2H), 1.44-1.39 (m, 2H), 1.36-1.27 (mm, 6H), 1.23-1.03 (mm, 16H), 0.82 (t, 3H, J = 6.8
1
3
Hz). C-NMR (CDCl
3
): δ 174.43, 160.35, 157.96, 152.53, 105.34, 105.13, 97.17, 68.04, 63.15
(
x2), 52.48, 44.52, 37.97, 36.15, 31.78, 30.02 (x2), 29.34 (x2), 29.17 (x2), 29.02 (x2), 28.89, 26.09,
+
5.94, 24.65, 22.86, 14.07. MS m/z: 516 [M+Na] (100), 494 [M+H] (20). Anal. calcd. for
+
2
29 5
C H51NO
: C, 70.55%; H, 10.41%; N, 2.84%. Found: C, 70.37%; H, 10.45%; 2.83%.
4.1.1.8. N-(1,3-Dihydroxypropan-2-yl)-11-(2-hexyl-5-hydroxyphenoxy)undecanamide 8
1
/MeOH = 46/4. Yield 60% as white solid, mp 88-90 °C (K). H-NMR (CDCl
Eluent: CHCl
3
3
): δ
6.92 (d, 1H, J = 7.9 Hz), 6.37 (d, 1H, J = 2.6 Hz), 6.30 (dd, 1H, J = 2.6 Hz, J = 7.9 Hz), 3.92-3.83
(
m, 5H), 3.77 (dd, 2H, J = 4.1 Hz, J = 10.8 Hz), 2.49 (t, 2H, J = 7.6 Hz), 2.21 (t, 2H, J = 7.5 Hz),
1
3
1
.80-1.73 (m, 2H), 1.69-1.58 (m, 4H), 1.28-1.23 (mm, 18H), 0.86 (t, 3H, J = 6.1 Hz). C-NMR
): δ 173.59, 157.80, 156.83, 130.12, 123.75, 104.36, 99.14, 67.94, 63.27 (x2), 52.36, 36.11,
1.82, 30.14, 29.63, 29.35 (x2), 29.18 (x2), 29.07, 28.85, 28.18, 26.12, 25.43, 22.57, 14.10. MS
(
CDCl
3
3

+
+
5
m/z: 474 [M+Na] (100), 452 [M+H] (30). Anal. calcd. for C26H45NO : C, 69.14%; H, 10.04%; N,
3.10%. Found: C, 69.03%; H, 10.06%; N, 3.11%.
4.1.1.9. N-(1,3-Dihydroxypropan-2-yl)-11-(4-hexyl-3-hydroxyphenoxy)undecanamide 9
1
/MeOH = 47/3. Yield 65% as cream solid, mp = 91-93 °C (K). H-NMR (CDCl
Eluent: CHCl
3
3
): δ
6.92 (d, 1H, J = 8.1 Hz), 6.40 (d, 1H, J = 2.1 Hz), 6.31 (dd, 1H, J = 2.1 Hz, J = 8.3 Hz), 3.95-3.91
(
m, 1H), 3.86 (t, 2H, J = 6.4 Hz), 3.61-3.56 (m, 4H), 2.50 (t, 2H, J = 7.5 Hz), 2.18 (t, 2H, J = 7.4
1
3
Hz), 1.73-1.63 (m, 2H), 1.56-1.49 (m, 4H), 1.45-1.28 (mm, 18H), 0.85 (t, 3H, J = 6.5 Hz). C-
NMR (CDCl ): δ 174.27, 158.44, 157.03, 129.96, 120.81, 105.14, 100.24, 68.03, 63.32 (x2), 52.23,
4.14, 36.02, 31.74, 30.05, 29.26 (x2), 29.18, 29.12 (x2), 29.03 (x2), 25.98, 24.83, 22.62, 14.07.
3
3
+
+
5
MS m/z: 474 [M+Na] (100), 452 [M+H] (15). Anal. calcd. for C26H45NO : C, 69.14%; H,
10.04%; N, 3.10%. Found: C, 68.97%; H, 10.07%; N, 3.9%.
4.1.1.10. N-Allyl-11-(3-hydroxy-5-pentylphenoxy)undecanamide 10
1
. Yield 90% as pale yellow oil. H-NMR (CDCl
Eluent: CHCl
3
3
): δ 6.26 (s, 3H), 5.91-5.74 (m, 1H),
5
2
=
.70 (br s, 1H, disappears on treatment with D
2
O), 5.20-5.09 (m, 2H), 3.90-3.85 (m, 4H), 2.47 (t,
H, J = 7.6 Hz), 2.19 (t, 2H, J = 7.6 Hz), 1.75-1.56 (mm, 10H), 1.51-1.26 (mm, 12H), 0.86 (t, 3H, J
1
3
3
6.4 Hz). C-NMR (CDCl ): δ 173.62, 160.24, 157.18, 145.46, 134.05, 116.59, 107.97, 106.80,
9
2
3
4
9.42, 67.80, 42.05, 36.75, 36.07, 31.52, 30.85, 29.18 (x2), 29.08 (x2), 28.94 (x2), 25.74 (x2),
+
2.54, 14.02. MS m/z: 426 [M+Na] (100). Anal. calcd. for C25
H41NO
3
: C, 74.40%; H, 10.24%; N,
.47%. Found: C, 74.29; H, 10.26%; N, 3.46%.
.1.1.11. N-Allyl-8-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]octanamide 11
1
/MeOH = 50/2. Yield 85% as pasty yellow oil. H-NMR (CDCl
Eluent: CHCl
3
3
): δ 6.41 (s, 1H),
6
6
1
1
.39 (s, 1H), 6.25 (s, 1H), 5.85-5.78 (m, 1H), 5.19-5.11 (m, 2H), 3.91-3.88 (m, 4H), 2.23 (t, 2H, J =
.5 Hz), 1.76-1.65 (m, 4H), 1.52-1.48 (m, 2H), 1.43-1.35 (mm, 6H), 1.24-1.16 (mm, 12H), 1.06-
1
3
.03 (m, 2H), 0.82 (t, 3H, J = 6.8 Hz). C-NMR (CDCl
3
): δ 173.53, 159.89, 156.73, 152.84,
33.94, 116.72, 105.70, 105.59, 98.51, 67.84, 44.52, 42.14, 37.80, 36.51, 31.79, 30.03 (x2), 29.10

+
x2), 28.90 (x2), 25.59 (x2), 24.65, 22.67, 14.07. MS m/z: 440 [M+Na] (100), 418 [M+H] (40).
+
(
Anal. calcd. for C26 : C, 74.77%; H, 10.38%; N, 3.35%. Found: C, 74.54%; H, 10.41%; N,
H43NO
3
3.34%.
4.1.1.12. N-(2,2,2-Trifluoroethyl)-11-(3-hydroxy-5-pentylphenoxy)undecanamide 12
1
Eluent: CHCl
m, 3H), 5.88 (br s, 1H, disappears on treatment with D
Hz), 2.24 (t, 2H, J = 7.4 Hz), 1.75-1.48 (mm, 8H), 1.39-1.26 (mm, 14H), 0.86 (t, 3H, J = 6.6 Hz).
3
. Yield 85% as pale yellow solid, mp = 44-46 °C (K). H-NMR (CDCl
3
): δ 6.52-6.22
(
2
O), 4.10-3.82 (m, 4H), 2.47 (t, 2H, J = 7.6
1
3
C-NMR (CDCl
9.31, 67.86, 40.60 (q, CH
9.05 (x2), 25.84, 25.41, 22.53, 14.01. MS m/z: 468 [M+Na] (100), 446 [M+H] (20). Anal. calcd.
NO : C, 64.70%; H, 8.60%; N, 3.14%. Found: C, 64.59%; H, 8.61%; N, 3.13%.
.1.1.13. N-(2,2,2-Trifluoroethyl)- 8-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]octanamide 13
3
): δ 173.68, 160.30, 156.78, 145.62, 127.05 (q, CF
3
, J = 282 Hz), 107.83, 107.13,
9
2
2
CF , J = 35 Hz), 36.43, 36.04, 31.51, 30.83, 29.24 (x2), 29.11 (x2),
3
+
+
for C24
H
38
F
3
3
4
1
Eluent: CHCl
3
. Yield 75% as yellow oil. H-NMR (CDCl
br s, 1H, disappears on treatment with D O), 3.98-3.82 (m, 4H), 2.25 (t, 2H, J = 7.4 Hz), 1.76-1.62
m, 4H), 1.54-1.50 (m, 2H), 1.48-1.36 (mm, 6H), 1.21-1.17 (mm, 12H), 1.06-1.02 (m, 2H), 0.82 (t,
3
): δ 6.41-6.39 (m, 2H), 6.21 (s, 1H), 5.94
(
2
(
1
3
H, J = 6.3 Hz). C-NMR (CDCl
3
1
2
3 3
): δ 173.62, 159.96, 156.54, 152.93, 123.51 (q, CF , J = 278 Hz),
05.65, 105.59, 98.52, 67.82, 44.50, 40.60 (q, CH
2
CF
3
, J = 34 Hz), 37.81, 36.31, 31.78, 30.02 (x2),
+
9.04 (x2), 28.88 (x2), 25.74, 25.28, 24.64, 22.66, 14.06. MS m/z: 482 [M+Na] (100). Anal. calcd.
for C25
H
40
F
3
NO
.1.1.14. N-Phenyl-11-(3-hydroxy-5-pentylphenoxy)undecanamide 14
Eluent: CHCl /MeOH = 50/1. Yield 75% as yellow solid, mp = 49-51 °C (K). H-NMR (CDCl
δ 7.49 (d, 2H, J = 7.8 Hz), 7.29 (t, 2H, J = 7.8 Hz), 7.20 (br s, 1H, disappears on treatment with
O), 7.08 (t, 1H, J = 7.3 Hz), 6.29 (s, 1H), 6.24-6.23 (m, 2H), 3.88 (t, 2H, J = 6.5 Hz), 2.47 (t, 2H,
J = 7.7 Hz), 2.34 (t, 2H, J = 7.5 Hz), 1.75-1.67 (m, 4H), 1.60-1.52 (m, 2H), 1.49-1.29 (mm, 16H),
3
: C, 65.33%; H, 8.77%; N, 3.05%. Found: C, 65.20%; H, 8.80%; N, 3.04%.
4
1
3
3
):
D
2
1
3
0
3
.87 (t, 3H, J = 6.8 Hz). C-NMR (CDCl ): δ 174.05, 160.31, 156.79, 145.82, 129.03 (x2), 124.34,

1
2
7
4
19.90 (x2), 107.83, 107.15, 99.34, 67.84, 37.87, 36.04, 31.51, 30.83 (x2), 29.32 (x2), 29.12 (x2),
+
9.01 (x2), 25.82, 25.61, 22.53, 14.01. MS m/z: 462 [M+Na] (100). Anal. calcd. for C28
H41NO
3
: C,
6.50%; H, 9.40%; N, 3.19%. Found: C, 76.37%; H, 9.42%; N, 3.18%.
.1.1.15. N-Benzyl-11-(3-hydroxy-5-pentylphenoxy)undecanamide 15
1
Eluent: CHCl
3
. Yield 72% as transparent oil. H-NMR (CDCl
3
): δ 7.33-7.29 (m, 2H), 7.27-7.25 (m,
O), 4.42 (d, 2H, J = 5.7 Hz), 3.88
t, 2H, J = 6.4 Hz), 2.47 (t, 2H, J = 7.7 Hz), 2.20 (t, 2H, J = 7.6 Hz), 1.76-1.72 (m, 2H), 1.70-1.64
3
H), 6.26 (s, 3H), 5.85 (br s, 1H, disappears on treatment with D
2
(
(
1
3
m, 2H), 1.58-1.54 (m, 2H), 1.44-1.40 (m, 2H), 1.32-1.26 (mm, 14H), 0.86 (t, 3H, J = 6.8 Hz). C-
): δ 173.56, 160.26, 157.18, 145.49, 128.75 (x2), 127.88 (x2), 127.59, 107.98, 106.84,
9.42, 67.81, 43.74, 36.80, 36.07, 31.53, 30.85 (x2), 29.19 (x2), 29.09 (x2), 28.97 (x2), 25.79,
NMR (CDCl
3
9
2
9
4
+
3
5.73, 22.54, 14.02. MS m/z: 476 [M+Na] (100). Anal. calcd. for C29H43NO : C, 76.78%; H,
.55%; N, 3.09%. Found: 76.70%; H, 9.58%; N, 3.08%.
.1.1.16. N-(Adamantan-1-yl)-11-(3-hydroxy-5-pentylphenoxy)undecanamide 16
1
Eluent: CHCl
.23 (br s, 1H, disappears on treatment with D
Hz), 2.12-1.99 (mm, 10H), 1.74-1.56 (mm, 13H), 1.39-1.25 (mm, 16H), 0.86 (t, 3H, J = 6.36 Hz).
3
/MeOH = 50/0.3. Yield 93% as yellow oil. H-NMR (CDCl
3
): δ 6.28-6.26 (m, 3H),
5
2
O), 3.88 (t, 2H, J = 6.35 Hz), 2.47 (t, 2H, J = 7.64
1
3
3
C-NMR (CDCl ): δ 172.88, 160.24, 157.28, 145.41, 108.00, 106.76, 99.46, 67.76, 51.97, 41.69
(
x3), 37.92, 36.35 (x3), 36.08, 31.53, 30.85, 29.45 (x4), 29.10 (x3), 28.88 (x2), 25.83, 25.75, 22.54,
+
+
1
1
4
3
4.02. MS m/z: 498 [M+H] , 520 [M+23] (100). Anal. calcd. for C32H51NO : C, 77.22%; H,
0.33%; N, 2.81%. Found: C, 77.09%; H, 10.35%; N, 2.80%.
.1.1.17. N-(Adamantan-1-yl)-8-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]octanamide 17
1
Eluent: CHCl
3
/MeOH = 50/0.3. Yield 72% as transparent oil. H-NMR (CDCl
3
): δ 6.41-6.39 (m,
O), 3.89 (t, 2H, J = 6.72
Hz), 2.12- 1.98 (mm, 10H), 1.76-1.65 (mm, 10H), 1.59-1.34 (mm, 9H), 1.21-1.03 (mm, 14H), 0.82
2
H), 6.25-6.23 (m, 1H), 5.13 (br s, 1H, disappears on treatment with D
2
1
3
(
3
t, 3H, J = 6.39 Hz). C-NMR (CDCl ): δ 172.83, 159.88, 157.15, 152.63, 105.79, 105.28, 98.59,

67.84, 51.99, 44.54, 41.67 (x3), 37.80 (x2), 36.33 (x3), 31.79, 30.04 (x2), 29.44 (x3), 29.07 (x3),
+
8.90 (x2), 25.74, 24.65, 22.67, 14.07. MS m/z: 512 [M+H] , 534 [M+23] (100). Anal. calcd. for
+
2
33 3
C H53NO
: C, 77.45%; H, 10.44%; N, 2.74%. Found: C, 77.35%; H, 10.47%; N, 2.73%.
4.1.1.18. N-(Adamantan-1-yl)-11-[3-hydroxy-5-(2-methyloctan-2-yl)phenoxy]undecanamide 18
1
Eluent: CHCl
3
/MeOH = 50/0.3. Yield 71% as pale yellow oil. H-NMR (CDCl
3
): δ 6.40 (s, 2H),
O), 3.89 (t, 2H, J = 6.46 Hz),
.12-1.99 (mm, 10H), 1.76-1.65 (mm, 10H), 1.57-1.37 (mm, 9H), 1.26-1.03 (mm, 20H), 0.82 (t,
6
2
3
5
.28-6.27 (m, 1H), 5.19 (br s, 1H, disappears on treatment with D
2
1
H, J = 6.43 Hz). C-NMR (CDCl
3
3
): δ 172.83, 159.97, 156.95, 105.77, 105.10, 98.79, 67.78,
1.95, 44.54, 41.69 (x3), 37.92, 37.79, 36.35 (x3), 31.78, 30.04 (x2), 29.44 (x4), 29.10 (x4), 28.92
+
x2), 25.78 (x2), 24.65, 22.67, 14.07. MS m/z: 554 [M+H] , 573 [M+23] (100). Anal. calcd. for
+
(
36 3
C H59NO
: C, 78.07%; H, 10.74%; N, 2.53%. Found: C, 77.89%; H, 10.76%; N, 2.54%.
4.1.1.19. N-(Adamantan-1-yl)-11-(2-hexyl-5-hydroxyphenoxy)undecanamide 19
1
/MeOH = 50/0.5. Yield 76% as transparent oil. H-NMR (CDCl
Eluent: CHCl
3
3
): δ 6.88 (d, 1H, J =
O),
8
3
1
1
3
5
7
4
.00 Hz), 6.36 (s, 1H), 6.31 (d, 1H, J = 8.15 Hz), 5.15 (br s, 1H, disappears on treatment with D
2
.85 (t, 2H, J = 6.26 Hz), 2.46 (t, 2H, J = 7.48 Hz), 2.08-1.96 (mm, 11H), 1.75-1.62 (mm, 8H),
13
3
.54-1.41 (mm, 6H), 1.36-1.24 (mm, 16H), 0.83 (t, 3H, J = 6.00 Hz). C-NMR (CDCl ): δ 172.71,
57.81, 155.13, 129.97, 123.35, 106.39, 99.73, 67.70, 51.89, 41.71 (x3), 37.91, 36.36 (x3), 31.79,
+
0.19, 29.66 (x4), 29.45 (x3), 29.20, 29.09 (x3), 25.93, 25.86, 22.65, 14.13. MS m/z: 512 [M+H] ,
+
34 [M+23] (100). Anal. calcd. for C33
3
H53NO : C, 77.45%; H, 10.44%; N, 2.74%. Found: C,
7.38%; H, 10.45%; N, 2.73%.
.1.1.20. N-(Adamantan-1-yl)-11-(4-hexyl-3-hydroxyphenoxy)undecanamide 20
1
/MeOH = 50/0.3. Yield 77% as white solid, mp 78.0 °C (K). H-NMR (CDCl
Eluent: CHCl
3
3
): δ
6
.95 (d, 1H, J = 8.05 Hz), 6.43 (d, 1H, J = 2.16 Hz), 6.36 (dd, 1H, J = 2.08 Hz, J = 8.15 Hz), 5.16
br s, 1H, disappears on treatment with D O), 3.88 (t, 2H, J = 6.70 Hz), 2.51 (t, 2H, J = 7.51 Hz),
.11-1.99 (mm, 11H), 1.75-1.65 (mm, 8H), 1.58-1.45 (mm, 6H), 1.41-1.27 (mm, 16H), 0.86 (t, 3H,
(
2
2
1
3
3
J = 6.42 Hz). C-NMR (CDCl ): δ 172.73, 158.32, 154.90, 130.16, 121.07, 105.79, 102.45, 67.83,

51.93, 41.69 (x3), 37.90, 36.35 (x3), 31.80, 30.05, 29.46 (x4), 29.22, 29.07 (x3), 28.94 (x2), 28.75,
+
+
2
3
5.79, 25.68, 22.65, 14.10. MS m/z: 512 [M+H] , 534 [M+23] (100). Anal. calcd. for C33H53NO :
C, 77.45%; H, 10.44%; N, 2.74%. Found: C, 77.32%; H, 10.47%; N, 2.73%.
.1.1.21. N-[11-(3-Hydroxy-5-pentylphenoxy)undecyl]cyclopropanecarboxamide 23
4
This compound was prepared from amine 54 and cyclopropanecarboxylic acid. Eluent:
1
/MeOH = 50/0.2. Yield 60% as pasty yellow solid, mp < 30 °C (K). H-NMR (CDCl
CHCl
3
3
): δ
2
6.26-6.24 (m, 3H), 5.98 (br t, 1H, disappears on treatment with D O), 3.87 (t, 2H, J = 6.41 Hz),
3.27-3.18 (m, 2H), 2.46 (t, 2H, J = 7.58 Hz), 1.75-1.63 (m, 3H), 1.59-1.38 (mm, 8H), 1.31-1.25
1
3
(
mm, 14H), 0.99-0.92 (m, 2H), 0.86 (t, 3H, J = 6.48 Hz), 0.74-0.69 (m, 2H). C-NMR (CDCl
3
): δ
74.08, 160.21, 157.39, 145.36, 107.97, 106.77, 99.27, 67.80, 39.99, 36.06, 31.53, 30.84, 29.66,
9.31 (x2), 29.26 (x2), 29.18 (x2), 26.85, 25.91, 22.55, 14.82, 14.02, 7.12 (x2). MS m/z: 417
1
2
+
+
[
M+H] (20), 440 [M+23] (100). Anal. calcd. for C26
Found: C, 74.56%; H, 10.41%; N, 3.34%.
.1.1.22. N-[11-[3-Hydroxy-5-(2-methyloctan-2-yl)phenoxy]undecyl]cyclopropanecarboxamide 24
3
H43NO : C, 74.77%; H, 10.38%; N, 3.35%.
4
This compound was prepared from amine 55 and cyclopropanecarboxylic acid. Eluent:
1
CHCl
3
/MeOH = 50/0.2. Yield 65% as transparent oil. H-NMR (CDCl
3
): δ 6.41 (d, 1H, J = 1.70
O), 3.87
t, 2H, J = 6.43 Hz), 3.28-3.19 (m, 2H), 2.03-1.66 (m, 3H), 1.54-1.41 (m, 6H), 1.38-1.32 (mm, 8H),
Hz), 6.38 (s, 1H), 6.24 (d, 1H, J = 1.70 Hz), 5.97 (br t, 1H, disappears on treatment with D
2
(
1
3
1
.25-1.04 (mm, 18H), 0.98-0.93 (m, 2H), 0.82 (t, 3H, J = 6.32 Hz), 0.75-0.69 (m, 2H). C-NMR
): δ 174.17, 159.92, 157.20, 152.56, 105.76, 105.01, 98.59, 67.80, 44.53, 40.02, 37.76,
1.79, 30.05 (x2), 29.64 (x2), 29.32 (x2), 29.21 (x2), 28.92 (x2), 26.87, 25.96, 24.65, 22.68, 14.80,
(
CDCl
3
3
1
7
4
+
+
4.08, 7.14 (x2). MS m/z: 474 [M+H] (20), 496 [M+23] (100). Anal. calcd. for C30
6.06%; H, 10.85%; N, 2.96%. Found: C, 75.92%; H, 10.88%; N, 2.95%.
.1.1.23. N-[11-(2-Hexyl-5-hydroxyphenoxy)undecyl]cyclopropanecarboxamide 25
H
51NO
3
: C,
This compound was prepared from amine 56 and cyclopropanecarboxylic acid. Eluent:
1
/MeOH = 50/0.2. Yield 55 % as pasty yellow solid, mp < 30 °C (K). H-NMR (CDCl
CHCl
3
3
): δ