Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: Dual inhibitors of cyclooxygenases and lipoxygenases

1668

J. Med. Chem. 2006, 49, 1668-1683

Synthesis and Structure-Activity Relationship Studies of 1,3-Diarylprop-2-yn-1-ones: Dual

Inhibitors of Cyclooxygenases and Lipoxygenases

P. N. Praveen Rao, Qiao-Hong Chen, and Edward E. Knaus*

Faculty of Pharmacy and Pharmaceutical Sciences, UniVersity of Alberta, Edmonton, Alberta, T6G 2N8, Canada

ReceiVed October 18, 2005

A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO₂Me COX-2

pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-

1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities.

Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was

identified as a potent and selective inhibitor of COX-2 (COX-2 IC₅₀) 0.1 µM; SI ) 300), being 5-fold

more potent than rofecoxib (COX-2 IC₅₀) 0.5 µM; SI > 200). In a rat carrageenan-induced paw edema

assay 13h exhibited moderate antiinflammatory activity (26% inhibition of inflammation) at 3 h after

administration of a 30 mg/kg oral dose. A related dual COX-1/2 and 5/15-LOX inhibitor 3-(4-

methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g, COX-1 IC₅₀) 31.5 µM; COX-2 IC₅₀

)

1.0 µM; SI ) 31.5; 5-LOX IC₅₀) 1.0 µM; 15-LOX IC₅₀) 3.2 µM) exhibited more potent antiinflammatory

activity (ED₅₀) 90 mg/kg), being superior to the reference drug aspirin (ED₅₀) 129 mg/kg). Within this

group of compounds 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) emerged as

having an optimal combination of in vitro COX-1/2 and 5/15-LOX inhibitory effects (COX-1 IC₅₀) 9.2

µM; COX-2 IC₅₀) 0.32 µM; SI ) 28; 5-LOX IC₅₀) 0.32 µM; 15-LOX IC₅₀) 0.36 µM) in conjunction

with a good antiinflammatory activity (ED₅₀) 35 mg/kg) compared to the reference drug celecoxib (ED₅₀

) 10.8 mg/kg) when administered orally. A molecular modeling study where 13e was docked in the COX-2

binding site indicated the C-1 p-i-Pr group was positioned within a hydrophobic pocket (Phe205, Val344,

Val349, Phe381 and Leu534), and that this positioning of the i-Pr group facilitated orientation of the C-3

p-SO₂Me COX-2 pharmacophore such that it inserted into the COX-2 secondary pocket (His90, Arg513,

Ile517 and Val523). A related docking study of 13e in the 15-LOX binding site indicates that the C-3

p-SO₂Me COX-2 pharmacophore was positioned in a region closer to the catalytic iron site where it undergoes

a hydrogen bonding interaction with His541 and His366, and that the C-1 p-i-Pr substituent is buried deep

in a hydrophobic pocket (Ile414, Ile418, Met419 and Ile593) near the base of the 15-LOX binding site.

Chart 1. Representative Examples of COX and LOX Inhibitors

Introduction

Introduction of selective cyclooxygenase-2 (COX-2) inhibitors

(see structures in Chart 1) such as celecoxib (Celebrex, 1) and

rofecoxib (Vioxx, 2) in the late 1990s heralded the start of a

new era for the treatment of inflammatory conditions such as

rheumatoid arthritis (RA) and osteoarthritis (OA).^1,2However,

the recent withdrawal of rofecoxib, and subsequently valdecoxib

(Bextra), due to their adverse cardiovascular side effects clearly

delineates the need to develop antiinflammatory agents exhibit-

ing reduced gastrointestinal (GI) and cardiovascular side ef-

fects.^3,4It is well established that conventional nonsteroidal

antiinflammatory drugs (NSAIDs) and selective COX-2 inhibi-

tors decrease the bioconversion of arachidonic acid (AA) to

proinflammatory prostaglandins (PGs) by inhibiting the COX

pathway.⁵Alternatively, arachidonic acid can also undergo

bioconversion to proinflammatory lipid mediators through the

lipoxygenase (LOX) pathway. For example, leukotrienes (LTs)

produced via the 5-LOX enzyme catalyzed pathway are known

to play a role in the pathogenesis of inflammatory and allergic

disorders.⁶Zileuton was the first 5-LOX inhibitor used in the

chronic treatment of asthma.⁷The related isozyme 15-LOX is

linked to cardiovascular complications since it is known to

participate in oxidative modification of low-density lipoproteins

(LDL) leading to the development of atherosclerosis.⁸

Accordingly, development of dual inhibitors of cyclooxyge-

nases (COXs) and lipoxygenases (LOXs) have shown promising

results.^9,10In this regard, the dual COX/LOX inhibitor dihy-

drodimethylbenzofuran (DHDMBF, 3) showed excellent anti-

inflammatory activity with reduced GI side effects, whereas

licofelone (4) a dual COX/LOX inhibitor has been effective in

* To whom correspondence should be addressed. Phone: 780-492-5993.

Fax: 780-492-1217. Email: eknaus@pharmacy.ualberta.ca.

Published on Web 02/10/2006

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1669

Scheme 2^a

Scheme 1^a

^aReagents and conditions: (a) THF, -78 °C, n-BuLi, -78 °C to 25 °C

overnight; (b) acetone, MnO₂, 25 °C, 2-3 h; (c) 1,4-dioxane, aqueous

Oxone, 25 °C, 3-4 h.

strategies used in this study to prepare the target 1,3-diarylprop-

2-yn-1-ones (13a-p, 17a-c, 23a,b, 26a-c and 28) are il-

lustrated in Schemes 1-4. Sonogashira coupling of 4-bro-

mothioanisole (7) with 2-methyl-3-butyn-1-ol in the presence

of triethylamine (Et₃N), CuI and a Pd(0) catalyst [PdCl₂(PPh₃)₂]

afforded the protected p-methylsulfanylphenylacetylene (8) in

70-75% yield (Scheme 1). Subsequent removal of the 2-pro-

panol moiety was effected using NaH to afford 1-ethynyl-4-

methylsulfanylbenzene (9) in 40-55% yield. The 1,3-diphe-

nylprop-2-yn-1-ols (11) were synthesized by the condensation

of 9 with a substituted-benzaldehyde (10) in the presence of

n-butyllithium (40-58%).²⁰Subsequent oxidation of 11 using

activated manganese dioxide (MnO₂) afforded the corresponding

1,3-diphenylprop-2-yn-1-one (12) in 44-56% yield as shown

in Scheme 1. Subsequent oxidation of 12 using an aqueous

solution of Oxone afforded the target 1,3-diphenylprop-2-yn-

1-ones (13a-j, 13l and 13n-p) possessing a C-3 p-SO₂Me

substituent in good yield (60-90%). Compounds 13k and 13m

possessing a C-1 hydroxyl substituent were prepared by the

O-demethylation of 13j and 13l in the presence of boron

tribromide (50-55%) as shown in Scheme 1. Compounds

17a-c possessing a R¹furanyl (17a), naphthyl (17b) or a

methoxynaphthyl (17c) substituent were prepared as shown in

Scheme 2, where the respective aldehydes (14a-c) were

condensed with 9 in the presence of n-butyllithium to prepare

15a-c (58-62%). Subsequent oxidation of the alcohols 15a-c

using MnO₂afforded the ketones 16a-c (52-65%). Oxidation

of the SMe moiety in 16a-c using an aqueous solution of Oxone

afforded the target SO₂Me products 17a-c (81-88%).

^aReagents and conditions: (a) triethylamine, 2-methyl-3-butyn-1-ol,

PdCl₂(PPh₃)₂, CuI, 70-75 °C, 6 h; (b) benzene, NaH, 105-110 °C, 1 h;

(c) THF, -78 °C, n-BuLi, and then at -78 °C to 25 °C overnight; (d)

acetone, MnO₂, 25 °C, 2-3 h; (e) 1,4-dioxane, aqueous Oxone, 25 °C,

3-4 h; (f) BBr₃, CH₂Cl₂, -5-0 °C, 1 h.

the treatment of OA exhibiting reduced GI toxicity compared

to conventional NSAIDs.^11,12In addition, recent studies have

also shown that dual inhibitors of COX/LOX could be useful

as tumor suppressor agents in the treatment of prostate and colon

cancers.^13,14

Other studies have shown that compounds possessing a

propenone moiety as represented by 5 exhibit dual COX/LOX

inhibition,¹⁵and that a novel class of 1,3-diphenylprop-2-yn-

1-ones (6) reported previously possessing a central propynone

moiety constitutes a suitable template for the design of dual

COX/LOX inhibitors.¹⁶As part of our ongoing research

program, we describe herein the design, synthesis and more

extensive structure-activity relationship (SAR) studies for this

new class of 1,3-diarylprop-2-yn-1-ones as dual inhibitors of

COX/LOX enzymes exhibiting in vivo antiinflammatory and

analgesic activities.

Compounds 23a and 23b possessing a C-1 methoxyphenol

substituent were prepared as shown in Scheme 3. The tert-

butyldimethylsilyl ethers (19a and 19b) were prepared by the

reaction of the respective phenols (18a and 18b) with tert-

Chemistry

A variety of synthetic approaches have been used successfully

for the preparation of acetylenic ketones

17-19

The synthetic

1670 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

Scheme 3^a

Scheme 4^a

^aReagents and conditions: (a) THF, 25 °C, PdCl₂(PPh₃)₂, CuI, triethy-

lamine 25 °C, 2-3 h; (b) 1,4-dioxane, aqueous Oxone, 25 °C, 3-4 h.

Scheme 5^a

^aReagents and conditions: (a) THF, NaH, TBDMSCl, 25 °C, 2-3 h;

(b) 9, THF, -78 °C, n-BuLi, -78 °C to 25 °C overnight; (c) acetone, MnO₂,

25 °C, 2-3 h; (d) EtOH, KOH, 25 °C, 1 h; (e) 1,4-dioxane, aqueous Oxone,

25 °C, 3-4 h.

^aReagents and conditions: (a) 1,4-dioxane, aqueous Oxone, 25 °C,

3-4 h.

butyldimethylsilyl chloride (TBDMSCl) in the presence of NaH

in good yield (65-70%).²¹Subsequent condensation of 19a or

19b with 9 in the presence of n-BuLi, and then oxidation of

the intermediate alcohol using activated MnO₂, afforded the 1,3-

diphenylprop-2-yn-1-ones (21a and 21b; 45-54%). The phe-

nolic derivatives 22a and 22b were obtained by removal of the

tert-butyldimethylsilyl protecting group present in 21a and 21b

using KOH in EtOH (45-52%).²²Subsequent oxidation of 21a

and 21b using aqueous Oxone afforded the target SO₂Me

products 23a and 23b (80-85%) as illustrated in Scheme 3.

The 1,3-diarylprop-2-yn-1-ones 26a-c were prepared using

the reactions shown in Scheme 4. The Sonogashira coupling of

the terminal alkyne 9 with an acid chloride (24a-c) using a

Pd(0) catalyst [PdCl₂(PPh₃)₂], CuI and Et₃N at room temperature

afforded the respective product 25a-c (18-25%)²³possessing

a C-3 methylthiophenyl substituent which was subsequently

oxidized to the corresponding methanesulfonylphenyl derivatives

(26a-c) in good yield (80-84%) using an aqueous solution of

Oxone. Compound 28 was prepared by the oxidation of 1,3-

diphenylprop-2-yn-1-one (27) using an aqueous solution of

Oxone (75%) as shown in Scheme 5.

>10 µM range; Table 1). Compound 13a, having an unsubsti-

tuted C-1 phenyl ring was a 10-fold less potent inhibitor of

COX-2 (COX-2 IC₅₀) 10 µM) than COX-1, and it did not

inhibit either 5- or 15-LOX at a concentration of 10 µM.

Introduction of an alkyl substituent (13b, R²) Me) provided

weak COX-2 inhibition and modest COX-2 selectivity (COX-2

IC₅₀) 33.0 µM; SI > 3.0) with no gain in either 5- or 15-

LOX inhibition. In contrast, increasing the alkyl chain length

13c (R²) n-Pr) provided dual COX and LOX inhibition with

a gain in both COX and 5/15-LOX inhibitory potency (COX-1

IC₅₀) 3.2 µM; COX-2 IC₅₀) 1.0 µM; 5-LOX IC₅₀) 3.2

µM; 15-LOX IC₅₀) 3.2 µM). Compound 13c exhibited LOX

inhibitory activity comparable to the reference drugs caffeic acid

(5-LOX IC₅₀) 3.0 µM) and luteolin (15-LOX IC₅₀) 3.2 µM),

respectively. A further increase in alkyl chain length from n-Pr

to n-Bu (13d, R²) n-Bu), provided a gain in both COX-2

(COX-1 IC₅₀> 100 µM; COX-2 IC₅₀) 10.0 µM; SI > 10)

and 5-LOX (5-LOX IC₅₀) 4.5 µM; 15-LOX IC₅₀> 10 µM)

selectivity albeit with a loss in COX-2 and 5-LOX inhibitory

potency compared to 13c. It is notable that introduction of an

i-Pr substituent at the para-position of the C-1 phenyl ring (13e,

R²) i-Pr) provided dual inhibition of both COX and LOX

enzymes. Compound 13e exhibited moderate COX-2 selectivity

(COX-1 IC₅₀) 9.2 µM; COX-2 IC₅₀) 0.32 µM; SI ) 28)

and an equipotent inhibition of 5/15-LOX (5-LOX IC₅₀) 0.32

µM; 15-LOX IC₅₀) 0.36 µM). Compound 13e was a 1.5-fold

more potent inhibitor of COX-2 than the reference drug

rofecoxib (COX-2 IC₅₀) 0.50 µM), and it was a 9-fold more

potent inhibitor of both 5 and 15-LOX compared to the reference

drugs caffeic acid (5-LOX IC₅₀) 3.0 µM) and luteolin (15-

Results and Discussion

The 1,3-diarylprop-2-yn-1-ones (13a-p, 17a-c, 23a,b, 26a-

c, 27 and 28) possessing a p-SO₂Me COX-2 pharmacophore

on the C-3 phenyl ring were evaluated in vitro to determine

their COX-1/2 and 5/15-LOX inhibitory activities. The structure-

activity relationship (SAR) data acquired for these 1,3-diaryl-

prop-2-yn-1-ones showed that they exhibit a broad range (potent-

to-inactive) of COX/LOX inhibitory activities (COX-2 IC₅₀

)

0.1 to >100 µM range; COX-1 IC₅₀) 0.2 to >100 µM range;

5-LOX IC₅₀) 0.1 to >10 µM range; 15-LOX IC₅₀) 0.1 to

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1671

Table 1. COX-1/2 and 5/15-LOX Inhibitory Activities of the 1,3-Diarylprop-2-yn-1-ones (13a-p, 17a-c, 23a,b, 26a-c, 27 and 28)

^aValues are means of two determinations and deviation from the mean is <10% of the mean value (Catalog No. 560101, 760700 and 60401 Cayman

Chemicals Inc., Ann Arbor, MI). ^bIn vitro COX-2 selectivity index (IC₅₀COX-1/IC₅₀COX-2). ^cThe volume of the molecule after minimization using the

PM3 force field was calculated using the Alchemy 2000 program.

LOX IC₅₀) 3.2 µM). In contrast 13f, possessing a C-1 p-CF₃-

phenyl moiety (R²) CF₃), exhibited COX-1 selectivity (COX-1

IC₅₀) 3.1 µM; COX-2 IC₅₀> 100 µM).

µM; COX-1 IC₅₀) 31.5 µM) and LOX inhibition with moderate

COX-2 selectivity (SI ) 31.5). In addition, 13g exhibited a more

potent inhibition of 5-LOX (5-LOX IC₅₀) 1.0 µM) compared

to 15- LOX (15-LOX IC₅₀) 3.2 µM) as shown in Table 1.

Within this class of compounds, 13h possessing a C-1 p-

It is also of interest that introduction of a C-1 p-CN-phenyl

ring (13g, R²) CN) provided dual COX (COX-2 IC₅₀) 1.0

1672 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

fluorophenyl substituent, was a potent and selective inhibitor

of COX-2 (COX-2 IC₅₀) 0.1 µM; SI ) 300), being 5-fold

more potent than rofecoxib (COX-2 IC₅₀) 0.5 µM; SI > 200)

although it was less potent than celecoxib (COX-2 IC₅₀) 0.07

µM; SI ) 474). On the other hand, introduction of a C-1 3,4-

difluorophenyl substituent (13i, R¹) R²) F) decreased both

COX-2 inhibitory potency and selectivity (COX-2 IC₅₀) 0.5

µM; SI ) 6.0) but provided a gain in 5-LOX inhibition (5-

LOX IC₅₀) 0.4 µM). Incorporating a C-1 p-MeO-phenyl

substituent (13j provided weak COX but potent 15-LOX

inhibition (COX-1/2 IC₅₀) 31.5 µM; 15-LOX IC₅₀) 3.5 µM),

whereas incorporation of a p-SMe substituent (27, R²) SMe)

resulted in a large increase in COX-2 inhibitory potency and

the C-1 meta or para-position provided compounds (26b, R²)

NO₂; 26c, R¹) NO₂) that showed contrasting LOX inhibitory

activities with compound 26b (R²) NO₂) exhibiting 5-LOX

selectivity (5-LOX IC₅₀) 6.2 µM), whereas 26c exhibited 15-

LOX selectivity (5-LOX IC₅₀) 3.5 µM) as shown in Table 1.

Incorporation of a naphthyl substituent at the C-1 position

(17b) provided a COX-2 selective compound although 17b

(COX-2 IC₅₀) 2.6 µM; COX-1 IC₅₀> 100 µM; SI > 38),

was not as potent as the reference drug rofecoxib, and it did

not inhibit 5/15-LOX up to a concentration of 10 µM (see data

in Table 1). However, introduction of a methoxy substituent at

the 4-position of the naphthyl ring (17c) led to a dramatic gain

in both COX-2 (COX-2 IC₅₀) 0.6 µM; COX-1 IC₅₀> 100

µM; SI > 166) and 15-LOX (5-LOX IC₅₀> 10 µM; 15-LOX

IC₅₀) 0.3 µM) inhibitory potency. Introduction of a hetero-

cyclic furanyl ring at the C-1 position (17a), provided a COX-1

and 5-LOX selective compound. Compound 17a was a 30-fold

more potent inhibitor of 5-LOX (IC₅₀) 0.1 µM) than the

reference drug caffeic acid (5-LOX IC₅₀) 3.0 µM). In contrast,

introduction of an isoxazole ring at the C-1 position (26a)

selectivity (COX-2 IC₅₀) 0.32 µM; SI ) 28), 5-LOX (IC₅₀

)

0.32 µM) and 15-LOX (IC₅₀) 0.36 µM) inhibitions. In contrast,

incorporation of a p-SO₂Me substituent on both the C-1 and

C-2 phenyl ring (28) led to a complete loss in both COX and

LOX inhibitory activity. Introduction of a C-1 m-MeO-phenyl

substituent (13l) increased both COX-2 inhibitory potency and

selectivity (COX-2 IC₅₀) 10 µM; SI > 10) with a moderate

gain in 5-LOX (5-LOX IC₅₀) 9.0 µM) inhibition compared to

the regioisomer 13j. On the other hand, introduction of a 3,4-

dimethoxyphenyl group (13n, R¹) R²) OMe) provided a gain

in both COX-1 (COX-1 IC₅₀) 3.3 µM) and 5-LOX (5-LOX

IC₅₀) 1.0 µM) inhibitory potency and selectivity. However,

incorporation of a C-1 3,4,5-trimethoxyphenyl moiety (13o, R¹

) R²) R³) OMe) resulted in a complete loss of COX

inhibitory activity, but 13o did exhibit selective inhibition of

5-LOX (5-LOX IC₅₀) 7.0 µM) albeit was less potent than

compared to 13n. Within this sub group of C-1 methoxy

substituted compounds (13j, 13l, 13n and 13o) the COX-2

potency order was 3-OMe > 4-OMe > inactive 3,4-di-OMe

and 3,4,5-tri-OMe, and the 5-LOX potency order was 3,4-di-

OMe > 3,4,5-tri-OMe > 3-OMe > inactive 4-OMe. The

potency order for 15-LOX was 4-OMe > inactive 3-OMe, 3,4-

di-OMe₂and 3,4,5-tri-OMe₃. The C-1 4-hydroxyphenyl com-

pound (13k R²) OH) exhibited dual inhibition of COX and

LOX. However, 13k was not a potent inhibitor of either COX-1

(COX-1 IC₅₀) 3.5 µM) or COX-2 (COX-2 IC₅₀) 10.0 µM).

On the other hand, 13k exhibited equipotent inhibition of both

5- and 15-LOX (5-LOX IC₅₀) 0.3 µM; 15-LOX IC₅₀) 0.32

µM), and it was a 9-fold more potent inhibitor of 5-LOX than

the reference drug caffeic acid (5-LOX IC₅₀) 3.0 µM). In

contrast, introduction of a hydroxy substituent at the meta-

position of the C-1 phenyl ring (13m, R¹) OH) led to a

complete abolition of COX inhibitory potency (COX-1/2 IC₅₀

> 100 µM) while retaining 5/15-LOX inhibitory potency (5-

LOX IC₅₀) 0.3 µM; 15-LOX IC₅₀) 0.5 µM). Introduction of

a methoxyphenol moiety at the C-1 position provided com-

pounds 23a (R¹) OMe, R²) OH) and 23b (R¹) OH, R²)

OMe) that exhibited moderate COX-1 selectivity, with prefer-

ential inhibition of 15-LOX (Table 1). Compound 23a, which

is a potent inhibitor of 15-LOX (15-LOX IC₅₀) 0.1 µM), is

35-fold more potent than the reference drug nordihydroguiarectic

acid (NDGA, 15-LOX IC₅₀) 3.5 µM).

provided a moderate gain in COX-2 selectivity (COX-2 IC₅₀

)

10.0 µM; COX-1 IC₅₀) 32.3 µM; SI ) 3.2) while retaining

5-LOX selectivity (IC₅₀) 1.5 µM) even though it was less

potent compared to 17a.

The in vitro data acquired for this class of 1,3-diarylprop-2-

yn-1-ones (13a-p, 17a-c, 23a,b, 26a-c, 27 and 28) show that

COX and LOX inhibition can be manipulated by varying the

electronic and steric properties of substituents attached to the

C-1 phenyl ring. For example, compounds possessing an n-Pr,

i-Pr, CN, 3,4-di-F₂or p-OH substituents at the para-position of

the C-1 phenyl ring (13c, 13e, 13g, 13j and 13k) exhibited dual

inhibition of both COX-1/2 and 5/15-LOX enzymes. The COX-2

inhibitory potency order for these compounds was p-F > p-i-

Pr > 3,4-di-F₂> p-COOMe > 4-MeO-naphthyl > p-n-Pr ≈

p-CN > naphthyl ≈ m-NO₂> p-OH ≈ m-OMe ≈ p-SMe ≈

isoxazole, whereas the 5-LOX inhibitory potency was of the

order furanyl > m-OH ≈ p-OH ≈ i-Pr > 3,4-di-F₂> p-CN ≈

3,4-di-OMe₂> isoxazole > n-Bu > p-NO₂> 3,4,5-tri-OMe₃

> m-OMe. It is interesting to note that compounds possessing

a hydroxyl substituent on the C-1 phenyl ring (13k, 13m, 23a

and 23b) generally exhibited potent inhibition of 15-LOX

suggesting that these compounds could act as antioxidants. The

15-LOX inhibitory potency was of the order 3-OMe-4-OH >

3-OH-4-MeO > 4-OMe-naphthyl > p-OH > i-Pr > m-OH >

p-SMe > p-CN ≈ m-NO₂≈ p-OMe > p-COOMe.

The critical difference between the binding sites for COX-1

and COX-2 is at position 523 where COX-2 has a smaller Val

residue in place of the bulkier Ile in COX-1. This difference

produces a secondary pocket extending off the primary binding

site in COX-2 that is absent in COX-1. Consequently, the

combined volume of the primary binding site and the secondary

pocket in COX-2 is about 25% larger (394 Å³) than the volume

of the COX-1 binding site (316 Å³).²⁴This group of 1,3-

diarylprop-2-yn-1-ones (13a-p, 17a-c, 23a,b, 26a-c, 27 and

28) possess a wide range of molecular volumes (224.2-321.7

Å³). Compounds exhibiting COX-2 selectivity have volumes

in the range of 290-314.6 Å³with the exception of compound

13h (R²) F) that has a volume of 250.3 Å³. It is known that

the various LOX isoforms also differ in their binding site

volumes. For example, the volume of the 5-LOX binding site

(470 Å³) is much larger than that of 15-LOX (390 Å³).²⁵In

this study, compounds exhibiting 5-LOX inhibitory potency have

molecular volumes in the range of 253.8.-321.7 Å³, with the

exception of compounds possessing a C-1 heterocyclic sub-

It was interesting to note that introduction of an electron

withdrawing group at the para-position of the C-1 phenyl ring

(13p, R²) COOCH₃) provided dual inhibition of COX-2 and

15-LOX (15-LOX IC₅₀) 5.0 µM). Compound 13p exhibited

good COX-2 inhibitory potency and selectivity (COX-2 IC₅₀

) 0.54 µM; COX-1 IC₅₀> 100 µM; SI > 185) and was an

equipotent inhibitor compared to the reference drug rofecoxib

(COX-2 IC₅₀) 0.50 µM; SI > 200). In contrast, introduction

of an electron withdrawing group such as a nitro substituent at

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1673

Figure 1. Docking 3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e) (ball-and-stick) in the active site of murine COX-2

(E_{intermolecular}) -63.17 kcal/mol). Red dotted line represents hydrogen bonding. Hydrogen atoms are not shown for clarity.

stituent (17a ) 228.3 Å³and 26a ) 224.2 Å³), that are only

marginally larger than compounds exhibiting 15-LOX inhibitory

potency with molecular volumes in the range of 253.8-314.6

Å³.

Molecular modeling (docking) studies were carried out to

investigate the binding interactions of certain 1,3-diphenylprop-

2-yn-1-ones within the COX and LOX binding sites. The

binding interaction of 3-(4-methanesulfonylphenyl)-1-(4-iso-

propylphenyl)prop-2-yn-1-one (13e, COX-2 IC₅₀) 0.32 µM;

SI ) 28) within the COX-2 binding site is illustrated in Figure

1. The most stable enzyme-ligand complex shows that the C-3

p-MeSO₂-phenyl moiety is oriented within the vicinity of the

COX-2 secondary pocket where it undergoes interaction with

the amino acid residues Val523, Phe518, Ile517, Ser353, Leu352

and His90. The distance between the center of C-3 p-MeSO₂-

phenyl ring and that of Phe518 is about 6.53 Å. One of the

oxygen atoms of SO₂Me undergoes a hydrogen bonding

interaction with the backbone NH of Ile517 (distance ) 3.33

Å), and it is positioned about 4.27 Å from the NH₂of Arg513.

The other O-atom of the SO₂Me substituent is about 5.23 Å

away from the backbone NH of Phe518. The methyl group of

Figure 2. Docking 3-(4-methanesulfonylphenyl)-1-(4-isopropylphe-

SO₂Me, located in the vicinity of Ala516, Thr94 and Ser353,

is about 3.96 Å from the methyl side chain of Thr94. It is

interesting to note that the C)O of the central prop-2-yn-1-one

(C≡C-CdO) participates in a favorable hydrogen bonding

interaction with the OH of Ser121 closer to the mouth of the

COX-2 binding site (distance ) 2.66 Å). In this regard, in a

previous study the most potent and selective COX-2 inhibitor

13h (R²) F) interacted favorably with Tyr355 closer to the

mouth of the COX-2 binding site.¹⁶The C-1 p-i-Pr-phenyl

substituent is oriented toward the apex of the COX-2 active

site in the vicinity of the amino acid residues Ser530, Leu531,

Tyr385, Tyr348 and Phe381. The p-isopropyl substituent is

positioned in the vicinity of a hydrophobic pocket where it is

nyl)prop-2-yn-1-one (13e) (ball-and-stick) in the active site of ovine

COX-1 (E_{intermolecular}) -59.14 kcal/mol). Red dotted line represents

hydrogen bonding. Hydrogen atoms are not shown for clarity.

within van der Waals contact range of the amino acid residues

Phe205, Val344, Val349, Phe381 and Leu534 (distance < 5

Å).

A similar docking study for 13e (COX-1 IC₅₀) 9.2 µM)

was carried out within the COX-1 binding site which shows it

binds in an extended conformation (see Figure 2). It is interesting

to note that the C-3 phenyl ring possessing the p-SO₂Me COX-2

pharmacophore is located in the side pocket, facing Ile517 and

that one of the O-atoms of SO₂Me substituent undergoes a

favorable hydrogen bonding interaction with the backbone NH

1674 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

substituent is within van der Waals contact range of hydrophobic

amino acid residues such as Val116, Leu117, Leu357 (Phe357

in COX-2) and Leu535 (Met535 in COX-2) (distance < 5 Å).

These observations suggests that the steric hindrance arising

from the presence of a bulkier Ile523 is not enough to prevent

binding of 13e within the COX-1 binding site.

The most stable enzyme-ligand complex for 13e (15-LOX

IC₅₀) 0.36 µM) within the 15-LOX binding site is shown in

Figure 3. The substrate binding site for mammalian 15-LOX is

a boot shaped cavity (volume ) 390 Å³)²⁵with the hydrophobic

amino acid residues Phe353, Ile418, Met419 and Ile593 located

at the base of the binding site. A charged Arg403 is present at

the mouth of (opening to) the binding site. It is of interest that

the linear C≡C (of the central C≡C-CdO) of 13e orients the

C-3 p-SO₂Me-phenyl moiety toward a region that is closer to

the catalytic iron site (His361, Gly365, His366, Ile400, His541,

Ile544 and His545). The His361 is positioned directly behind

the plane of C-3 p-MeSO₂-phenyl moiety with which it

undergoes a π-π interaction. One of the O-atoms of the p-SO₂-

Me COX-2 pharmacophore forms a hydrogen bond with the

NH of His541 (distance ) 3.43 Å) while the other O-atom forms

a hydrogen bond with the backbone NH of His366 (distance )

2.78 Å). The Me of the SO₂Me moiety is within van der Waals

contact range of Gly365 and Ile544 (distance < 5 Å). The C)O

of the central CtC-CdO undergoes a hydrogen bonding

interaction with the backbone NH of Gly598 (distance ) 2.03

Å) closer to the entrance of the 15-LOX binding site, and the

distance between the charged NH₂(guanidino group) of Arg403

and C)O is about 13.22 Å. The C-1 p-i-Pr-phenyl substituent

is buried deep inside a hydrophobic pocket at the base of 15-

LOX binding site. The p-i-Pr group is positioned such that it

can undergo van der Waals interactions with the amino acid

residues Ile414, Ile418, Met419 and Ile593 (distance < 5 Å).

Figure 3. Docking 3-(4-methanesulfonylphenyl)-1-(4-isopropylphe-

nyl)prop-2-yn-1-one (13e) (ball-and-stick) in the active site of rabbit

15-LOX (E_{intermolecular}) -54.41 kcal/mol). Red dotted line represents

hydrogen bonding. Hydrogen atoms are not shown for clarity.

of Ile517 (distance ) 2.15 Å). The C)O of the central prop-

2-yn-1-one (C≡C-CdO) that, in contrast to COX-2, does not

participate in hydrogen bonding with Ser121, and it is far

removed from either Tyr355 or Arg120 present at the mouth

of the COX-1 binding site. It was also observed that the C-1

i-Pr-phenyl ring is oriented toward a hydrophobic pocket close

to the mouth of the COX-1 binding site, and that it is not

oriented toward the apex of the COX-1 binding site as for the

interaction of 13e within COX-2 binding site. The C-1 p-i-Pr

A similar docking experiment to determine the binding

interaction of 3-(4-methanesulfonylphenyl)-1-(4-hydroxy-3-

Figure 4. Docking 3-(4-methanesulfonylphenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-yn-1-one (23a) (ball-and-stick) in the active site of rabbit

15-LOX (E_{intermolecular}) -63.57 kcal/mol). Red dotted line represents hydrogen bonding. Hydrogen atoms are not shown for clarity.

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1675

COX-2 pharmacophore is positioned within van der Waals

contact range (<5 Å) of the amino acid residues Ile418, Met419,

Leu597 and Ile593. It is noteworthy that one of the oxygen-

atoms of the p-SO₂Me substituent forms a hydrogen bond with

the NH₂of Gln599 (distance ) 2.40 Å). The linear CtC is

surrounded by Gln357 and Ala404, whereas the C)O of the

central prop-2-yn-1-one (CtC-CdO) is oriented toward the

catalytic iron where it interacts with His361, His366 and Ala404.

The C)O of prop-2-yn-1-one forms a hydrogen bond with the

NH of His366 (distance ) 2.74 Å). The C)O is much closer

to the NH₂(guanidino) group of Arg403 (distance ) 8.86 Å)

located at the opening of the 15-LOX binding site compared to

13e. The C-1 methoxyphenol substituent is oriented in the

direction of the catalytic iron site where it is positioned in a

region comprised of the hydrophobic amino acid residues

Leu362, Ile400, Val402, Ala 404 and Val409. The C-1 3-OMe

substituent is within van der Waals contact range of the amino

acid residues Ala404, Leu408 and Val409 (distance < 5 Å).

The C-1 4-OH substituent can interact with Leu362, Ile385 and

the polar Asn401. The distance between the C-1 4-OH sub-

stituent and the NH₂of Asn401 is about 4.81 Å. It should be

noted that 13e and 23a possessing a C-3 p-SO₂Me COX-2

pharmacophore display contrasting binding conformations within

Figure 5. Over lay of the binding modes of 3-(4-methanesulfonylphe-

nyl)-1-(4-isopropylphenyl)prop-2-yn-1-one (13e, blue) and 3-(4-meth-

anesulfonylphenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-yn-1-one (23a,

green) in the active sites of 15-LOX. Hydrogen atoms are not shown

for clarity.

methoxyphenyl)prop-2-yn-1-one (23a, 15-LOX IC₅₀) 0.1 µM)

within the 15-LOX binding site indicates a different picture

compared to that of 13e (Figure 4 and Figure 5). In this regard,

compound 23a is oriented in a reverse conformation where the

C-3 p-SO₂Me-phenyl moiety is oriented toward the base of the

active site, and the C-1 methoxyphenol terminus of the molecule

is located near the catalytic iron (Figure 4). The p-SO₂Me

Table 2. Antiinflammatory and Analgesic Activities of the 1,3-Diarylprop-2-yn-1-ones (13e-l, 13o,p, 17a-c and 23a)

^aInhibitory activity in a carrageenan-induced rat paw edema assay. The results are expressed as mean ( SEM (n ) 4-6) following a 30 mg/kg oral dose

of the test compound or as the ED₅₀values when it was determined. ^bInhibitory activity in the rat 4% NaCl-induced abdominal constriction assay. The

results are expressed as mean ( SEM (n ) 4-6) following a 30 mg/kg oral dose of the test compound. ^c5 mg/kg oral dose.

1676 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

the 15-LOX binding site, suggesting that the electronic and steric

properties at the C-1 phenyl ring also contributes to the binding

of these ligands to 15-LOX (Figure 5).

Conclusions

The strucureactivity relationship (SAR) data acquired show

that (i) the 1,3-diarylprop-2-yn-1-one structure is a suitable

template to design dual inhibitors of COX and LOX; (ii) COX-2

selectivity requires a p-SO₂Me COX-2 pharmacophore on the

C-3 phenyl ring; (iii) optimal dual COX-1/2 and 5/15-LOX

inhibition can be achieved by varying the electronic and steric

properties at the C-1 phenyl ring substitution pattern (eg: 13e,

R²) i-Pr; 13g, R²) CN); (iv) molecular modeling studies

show, for this class of compounds, that the C-3 p-SO₂Me COX-2

pharmacophore can adopt contrasting binding modes within the

15-LOX binding site; (v) dual inhibitors of both COX-1/2 and

5/15-LOX possess clinically relevant oral antiinflammatory and

analgesic activities (eg: 13e, R²) i-Pr; 13g, R²) CN).

In vivo pharmacological studies were carried out to evaluate

the antiinflammatory and analgesic activity potential for the 1,3-

diarylprop-2-yn-1-ones (13e-l, 13o-p, 17a-c and 23a) and

the results are listed in Table 2. In a rat carrageenan-induced

paw edema assay these 1,3-diarylprop-2-yn-1-ones exhibited

weak to good antiinflammatory activities (6.8-48% inhibition

of inflammation) at 3 h after administration for a 30 mg/kg oral

dose. The dual COX-1/2 and 5/15-LOX inhibitor compound

3-(4-methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-

1-one (13e, COX-1 IC₅₀) 9.2 µM; COX-2 IC₅₀) 0.32 µM;

SI ) 28; 5-LOX IC₅₀) 0.32 µM; 15-LOX IC₅₀) 0.36 µM)

was the most potent antiinflammatory agent in this series

exhibiting 48% inhibition of inflammation at 3 h after admin-

istration of a 30 mg/kg oral dose. Compound 13e is about 5.8-

fold and 3.2-fold more potent than the respective reference drugs

nordihydroguiaretic acid (NDGA) and caffeic acid (15 and 8%

inhibition of inflammation for a 30 mg/kg oral dose). However,

13e was not as potent (ED₅₀) 35 mg/kg) as the reference drug

celecoxib (10.8 mg/kg) as an antiinflammatory agent. Accord-

ingly, the dual COX-1/2 and 5/15-LOX inhibitor 3-(4-meth-

anesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-one (13g,

COX-1 IC₅₀) 31.5 µM; COX-2 IC₅₀) 1.0 µM; SI ) 31.5;

5-LOX IC₅₀) 1.0 µM; 15-LOX IC₅₀) 3.2 µM) exhibited

respectable antiinflammatory activity (ED₅₀) 90 mg/kg) since

it is more potent than the reference drug aspirin (ED₅₀) 129

mg/kg). The most potent and selective COX-2 inhibitor 3-(4-

methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h,

COX-2 IC₅₀) 0.1 µM; SI > 300) exhibited moderate

antiinflammatory activity (26% inhibition of inflammation) at

3 h after administration of a 30 mg/kg oral dose. The selective

5-LOX inhibitor 13o (R¹) R²) R³) OMe) exhibited good

antiinflammatory activity (ED₅₀) 112.8 mg/kg) since it is about

Experimental Section

General. Melting points were determined using a Buchi capillary

apparatus and are uncorrected. All other reagents were purchased

from Aldrich (Milwaukee, WI). Silica gel column chromatography

was performed using Merck silica gel 60 ASTM (70-230 mesh).

Infrared (IR) spectra were recorded using a Nicolet 550 Series II

Magna FT-IR spectrometer. Nuclear magnetic resonance (¹H NMR)

spectra were recorded on a Bruker AM-300 spectrometer and

chemical shifts are expressed in parts per million (ppm, δ) relative

to tetramethylsilane as internal standard. Spin multiplets are given

as s (singlet), d (doublet), dd (doublet of doublets), t (triplet), q

(quartet) and m (multiplet). Coupling constants (J) are given in

Hertz (Hz). Microanalyses were performed for C, H and N (Micro

Analytical Service Laboratory, Department of Chemistry, University

of Alberta) and were within ( 0.4% of the theoretical values.

Celecoxib and rofecoxib were synthesized according to the literature

procedures.^1,26Luteolin, caffeic acid and nordihydroguaiaretic acid

(NDGA) were purchased from Cayman Chemicals Inc. Ann Arbor,

MI. Acetyl salicylic acid (aspirin) was purchased from Sigma

Chemical Company. 3-(4-Methylsulfanylphenyl)-1-phenylprop-2-

yn-1-ol (11a) and other derivatives possessing a C-1 p-Me, OMe,

F or CF₃substituent (compounds 11b-e) and 3-(4-methylsulfa-

nylphenyl)-1-phenylprop-2-yn-1-one (12a) and other derivatives

possessing a C-1 p-Me, OMe, F or CF₃substituent (compounds

12b-e), 3-(4-methanesulfonylphenyl)-1-phenylprop-2-yn-1-one (13a)

and 3-(4-methanesulfonylphenyl)-1-(4-methylsulfanylphenyl)prop-

2-yn-1-one (27) were prepared according to a previously reported

method.²⁰Male Sprague-Dawley rats, used in the antiinflammatory

and analgesic screens, were purchased from Animal Health Services

at the University of Alberta, and experiments were carried out using

protocols approved by the Animal Welfare Committee, University

of Alberta.

2-Methyl-4-(4-methylsulfanylphenyl)but-3-yn-2-ol (8). 4-Bro-

mothioanisole (7, 49.2 mmol) was added slowly under an argon

atmosphere to a stirred solution of freshly dried EtN₃(100 mL,

730.6 mmol) at 25 °C. To this solution, PdCl₂(PPh₃)₂(0.14 g, 0.19

mmol), 2-methyl-3-butyn-2-ol (5.06 mL, 52.1 mmol) and CuI (40

mg, 0.21 mmol) were added successively, and the reaction mixture

was refluxed under an argon atmosphere for 6 h at 70-75 °C. The

cooled reaction mixture was filtered and excess TEA was evapo-

rated in vacuo to furnish a dark brown mixture that was purified

by silica gel column chromatography using hexanes-ethyl acetate

(3:1, v/v) as eluent to afford 8 as a pale yellow solid (75%, 7.6 g).

mp 70-72 °C; IR (film): 3655 (OH), 2130 (CtC) cm^-1; ¹H NMR

(CDCl₃): δ 1.61 [s, 6H, C(CH₃)₂], 2.01 (br s, 1H, OH), 2.48 (s,

3H, SCH₃), 7.14 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-3,

H-5), 7.30 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-2, H-6).

1-Ethynyl-4-methylsulfanylbenzene (9). 2-Methyl-4-(4-meth-

ylsulfanylphenyl)but-3-yn-2-ol (8, 48.5 mmol) was dissolved in

benzene (40 mL), NaH (0.16 g, 6.45 mmol) was added, and the

reaction mixture was heated at 105-110 °C for 1 h. Removal of

the solvent in vacuo gave a dark brown oil which was purified by

silica gel column chromatography using hexanes-ethyl acetate (3:

1, v/v) as eluent to afford 9 as a yellowish brown oil (55%, 3.9 g).

1.8-fold more potent than the reference drug NDGA (ED₅₀

)

205 mg/kg). In this regard, the most potent 15-LOX inhibitor

3-(4-methanesulfonylphenyl)-1-(4-hydroxy-3-methoxyphenyl)-

prop-2-yn-1-one (23a, 15-LOX IC₅₀) 0.1 µM) exhibited a 26%

inhibition of inflammation at 3 h after administration of a 30

mg/kg oral dose. Further studies are required to determine the

most ideal COX-2/COX-1 and/or 5-LOX/15-LOX values. The

in vivo antiinflammatory data for compounds 13 (see Table 2)

appear to suggest that compounds showing the most potent

inhibition of both 5-LOX and 15-LOX in conjunction with

nonselective inhibition of the COX isozymes are among the

most potent antiinflammatory agents in this group of 1,3-

diarylprop-2-yn-1-ones.

In vivo analgesic activity was determined using the rat 4%

NaCl-induced abdominal constriction assay. These compounds

(13e-l, 13o-p, 17a-c and 23a) exhibited moderate to good

analgesic activities (36-84% inhibition of writhing) at different

time intervals after administration of a 30 mg/kg oral dose.

Among this series of compounds 13i (R¹) R²) F, R³) H)

exhibited excellent analgesic activity where a 30 mg/kg oral

dose reduced writhing by 84 and 72% at 30 and 60 min postdrug

administration since it showed superior analgesic activity

compared to the reference drug NDGA (46 and 62.5% inhibition

of writhing at 30 and 60 min postdrug administration). The most

potent antiinflammatory agent 13e exhibited 41 and 54%

inhibition of writhing at 30 and 60 min postdrug administration

(30 mg/kg oral dose).

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1677

50%): IR (film) 3219 (OH), 2228 (CtC) cm^-^{1 1}H NMR

1

IR (film): 2112 (CtC) cm^-1; H NMR (CDCl₃): δ 2.49 (s, 3H,

;

SCH₃), 3.07 (s, 1H, -CtCH), 7.16 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.39 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6).

(CDCl₃): δ 2.34 (d, J ) 5.8 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

5.64 (d, J ) 5.8 Hz, 1H, CHOH), 7.14-7.23 (m, 3H, methylsul-

fanylphenyl H-3, H-5; difluorophenyl H-5), 7.31-7.35 (m, 1H,

difluorophenyl H-2), 7.36 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl

H-2, H-6), 7.42 (dddd, J ) 8.5, 5.5, 3.0, 1.8 Hz, 1H, difluorophenyl

H-6). Anal. (C₁₆H₁₂F₂OS): C, H.

General Procedure for the Synthesis of 1,3-Diarylprop-2-yn-

1-ols (11 and 15a-c). 1-Ethynyl-4-methylsulfanylbenzene (9, 9.75

mmol) was added slowly under an argon atmosphere to a stirred

solution of freshly dried THF (10 mL) at -78 °C. A solution of

n-BuLi (4 mL of 2.5 M in hexane) was added slowly. After 3 min

a solution of the respective substituted-benzaldehyde (10, R¹) H,

OMe, F, NO₂; R²) H, OMe, F, NO₂, CN, n-Pr, n-Bu, i-Pr,

COOMe; R³) H, OMe or 14a-c (R¹) furanyl, naphthyl or

methoxynaphthyl; 9.75 mmol) in dry THF (5 mL) was added slowly

while maintaining the temperature at -78 °C, and the reaction was

allowed to proceed overnight with stirring after warming to room

temperature. The reaction mixture was washed with saturated

aqueous NH₄Cl (10 mL), extracted with EtOAc (2 × 20 mL), the

organic phase was separated, dried over Na₂SO₄, and the solvent

was evaporated in vacuo to give a crude oil which was purified by

silica gel column chromatography using hexanes-ethyl acetate (3:

1, v/v) as eluent to afford the respective title compound 11f-n

and 15a-c in 40-62% yield. Some physical and spectroscopic data

for 11f-n and 15a-c are listed below.

3-(4-Methylsulfanylphenyl)-1-(3,4-dimethoxyphenyl)prop-2-

yn-1-ol (11l). The product was obtained as a yellow oil (1.96 g,

64%): IR (film) 3211 (OH), 2213 (C≡C) cm^-1

;

¹H NMR

(CDCl₃): δ 2.24 (d, J ) 6.1 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

3.88 (s, 3H, 4-OMe), 3.91 (s, 3H, 3-OMe), 5.63 (d, J ) 6.1 Hz,

1H, CHOH), 6.85 (d, J ) 7.9 Hz, 1H, dimethoxyphenyl H-5), 7.17-

7.20 (m, 4H, methylsulfanylphenyl H-3, H-5; dimethoxyphenyl H-2,

H-6), 7.36 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-2, H-6).

Anal. (C₁₈H₁₈O₃S): C, H.

3-(4-Methylsulfanylphenyl)-1-(3,4,5-trimethoxyphenyl)prop-

2-yn-1-ol (11m). The product was obtained as a pale yellow oil

(1.94 g, 58%): IR (film) 3308 (OH), 2224 (CtC) cm^-1; ¹H NMR

(CDCl₃): δ 2.29 (d, J ) 5.8 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

3.90 [s, 9H, (OCH₃)₃], 5.62 (d, J ) 5.8 Hz, 1H, CHOH), 6.86 (s,

2H, trimethoxyphenyl H-2, H-6), 7.17 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.37 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6). Anal. (C₁₉H₂₀O₄S): C, H.

4-[3-(4-Methylsulfanylphenyl)prop-2-yn-1-ol]benzoic acid meth-

yl ester (11n). The product was obtained as a brown oil (1.21 g,

40%): IR (film) 3221 (OH), 2218 (C≡C), 1640 (CdO) cm^-1; ¹H

NMR (CDCl₃): δ 2.43 (br s, 1H, CHOH), 2.48 (s, 3H, SCH₃),

3.98 (s, 3H, COOCH₃), 5.73 (1H, CHOH), 7.16 (d, J ) 8.2 Hz,

2H, methylsulfanylphenyl H-3, H-5), 7.35 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.66 (d, J ) 8.5 Hz, 2H, benzoic

acid methyl ester H-2, H-6), 8.06 (d, J ) 8.5 Hz, 2H, benzoic acid

methyl ester H-3, H-5). Anal. (C₁₈H₁₆O₃S): C, H.

3-(4-Methylsulfanylphenyl)-1-(3-methoxyphenyl)prop-2-yn-

1-ol (11f). The product was obtained as a pale yellow oil (1.52 g,

55%): IR (film) 3223 (OH), 2218 (C≡C) cm^-1

;

¹H NMR

(CDCl₃): δ 2.24 (d, J ) 6.1 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

3.85 (s, 3H, OCH₃), 5.66 (d, J ) 6.1 Hz, 1H, CHOH), 6.88 (dd, J

) 7.9, 2.4 Hz, 1H, methoxyphenyl H-4), 7.15-7.35 (m, 5H,

methylsulfanylphenyl H-3, H-5; methoxyphenyl H-2, H-5, H-6),

7.37 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl H-2, H-6). Anal.

(C₁₇H₁₆O₂S): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-propylphenyl)prop-2-yn-1-

ol (11g). The product was obtained as a brownish oil (1.15 g,

3-(4-Methylsulfanylphenyl)-1-furan-3-yl-prop-2-yn-1-ol (15a).

40%): IR (film) 3256 (OH), 2221 (CtC) cm^-^{1 1}H NMR

;

The product was obtained as a dark brown oil (1.47 g, 62%): IR

(CDCl₃): δ 0.95 (t, J ) 7.0 Hz, 3H, CH₂CH₂CH₃), 1.59-1.71 (m,

2H, CH₂CH₂CH₃), 2.19 (br s, 1H, CHOH), 2.49 (s, 3H, SCH₃),

2.58 (t, J ) 7.0 Hz, 2H, CH₂CH₂CH₃), 5.65 (br s, 1H, CHOH),

7.16 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl H-3, H-5), 7.19 (d,

J ) 8.8 Hz, 2H, propylphenyl H-3, H-5), 7.37 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.51 (d, J ) 8.8 Hz, 2H,

propylphenyl H-2, H-6). Anal. (C₁₉H₂₀OS): C, H.

1

(film) 3220 (OH), 2218 (C≡C) cm^-1; H NMR (CDCl₃): δ 2.17

(d, J ) 6.7 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃), 5.62 (d, J ) 6.7

Hz, 1H, CHOH), 6.58 (br s, 1H, furanyl H-4), 7.17 (d, J ) 8.5 Hz,

2H, methylsulfanylphenyl H-3, H-5), 7.36 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.43 (br s, 1H, furanyl H-2), 7.60

(br s, 1H, furanyl H-5). Anal. (C₁₄H₁₂O₂S): C, H.

3-(4-Methylsulfanylphenyl)-1-naphthalen-1-yl-prop-2-yn-1-

3-(4-Methylsulfanylphenyl)-1-(4-butylphenyl)prop-2-yn-1-

ol (11h). The product was obtained as a brownish oil (1.69 g,

ol (15b). The product was obtained as a yellowish brown oil (1.82

1

g, 61.6%): IR (film) 3218 (OH), 2211 (C≡C) cm^-1; H NMR

56%): IR (film) 3215 (OH), 2209 (CtC) cm^-^{1 1}H NMR

;

(CDCl₃): δ 2.38 (d, J ) 6.1 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

6.35 (d, J ) 6.1 Hz, 1H, CHOH), 7.16 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.37 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.48-7.90 (m, 6H, naphthyl H-2,

H-3, H-4, H-5, H-6, H-7), 8.37-8.40 (m, 1H, naphthyl H-8). Anal.

(C₂₀H₁₆OS): C, H.

(CDCl₃): δ 0.87 (t, J ) 7.0 Hz, 3H, CH₂CH₃), 1.24-1.63 [m, 4H,

(CH₂)₂], 2.22 (br s, 1H, CHOH), 2.49 (s, 3H, SCH₃), 2.58 (t, J )

7.0 Hz, 2H, aromatic-CH₂), 5.66 (br s, 1H, CHOH), 7.15 (m, 4H,

methylsulfanylphenyl H-3, H-5; butylphenyl H-3, H-5), 7.37 (d, J

) 8.2 Hz, 2H, methylsulfanylphenyl H-2, H-6), 7.51 (d, J ) 7.9

Hz, 2H, butylphenyl H-2, H-6). Anal. (C₂₀H₂₂OS): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-methoxynaphthalen-1-yl)-

prop-2-yn-1-ol (15c). The product was obtained as a yellowish

3-(4-Methylsulfanylphenyl)-1-(4-isopropylphenyl)prop-2-yn-

1-ol (11i). The product was obtained as a yellow oil (1.85 g,

brown oil (1.89 g, 58%): IR (film) 3232 (OH), 2211 (C≡C) cm^-1

;

64%): IR (film) 3217 (OH), 2211 (CtC) cm^-^{1 1}H NMR

;

¹H NMR (CDCl₃): δ 2.28 (d, J ) 6.1 Hz, 1H, CHOH), 2.49

(s, 3H, SCH₃), 4.03 (s, 3H, OCH₃), 6.27 (d, J ) 6.1 Hz, 1H,

CHOH), 6.80 (d, J ) 7.9 Hz, 1H, methoxynaphthyl H-3), 7.16 (d,

J ) 8.5 Hz, 2H, methylsulfanylphenyl H-3, H-5), 7.38 (d, J ) 8.5

Hz, 2H, methylsulfanylphenyl H-2, H-6), 7.52-7.61 (m, 2H,

methoxynaphthyl H-6, H-7), 7.83 (d, J ) 7.9 Hz, 1H, methoxy-

naphthyl H-2), 8.33-8.36 (m, 2H, methoxynaphthyl H-5, H-8).

Anal. (C₂₁H₁₈O₂S): C, H.

(CDCl₃): δ 1.27-1.29 [d, J ) 6.7 Hz, 6H, CH(CH₃)₂], 2.19 (br s,

1H, CHOH), 2.49 (s, 3H, SCH₃), 2.89-2.98 [m, 1H, CH(CH₃)₂],

5.65 (br s, 1H, CHOH), 7.16-7.32 (m, 4H, methylsulfanylphenyl

H-3, H-5; isopropylphenyl H-3, H-5), 7.37 (d, J ) 8.8 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.53 (d, J ) 8.2 Hz, 2H,

isopropylphenyl H-2, H-6). Anal. (C₁₉H₂₀OS): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-

ol (11j). The product was obtained as a brown oil (1.22 g, 45%):

1

IR (film) 3382 (OH), 2221 (CtN), 2206 (CtC) cm^-1; H NMR

General Procedure for the Synthesis of 1,3-Diarylprop-2-yn-

1-ones (12 and 16a-c). To a stirred solution of the respective 1,3-

diarylprop-2-yn-1-ol (11 and 15a-c; 4.5 mmol) in acetone (25 mL)

was added activated manganese IV oxide (7.8 g, 90 mmol), and

the reaction mixture was stirred for 2-3 h at 25 °C after which

MnO₂was filtered off, and the organic solvent was removed in

vacuo to give the title compound (12f-n and 16a-c) in good yield

(44-65%). Some physical and spectroscopic data for 12f-n and

16a-c are listed below.

(CDCl₃): δ 2.41 (d, J ) 5.8 Hz, 1H, CHOH), 2.49 (s, 3H, SCH₃),

5.74 (d, J ) 5.8 Hz, 1H, CHOH), 7.17 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.35 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.69 (d, J ) 8.5 Hz, 2H,

cyanophenyl H-2, H-6), 7.73 (d, J ) 8.5 Hz, 2H, cyanophenyl H-3,

H-5). Anal. (C₁₇H₁₃NOS): C, H, N.

3-(4-Methylsulfanylphenyl)-1-(3,4-difluorophenyl)prop-2-yn-

1-ol (11k). The product was obtained as a brown oil (1.45 g,

1678 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

3-(4-Methylsulfanylphenyl)-1-(3-methoxyphenyl)prop-2-yn-

1-one (12f). The product was obtained as a yellow solid by the

oxidation of 11f in the presence of MnO₂(0.76 g, 60.4%): mp

(CDCl₃): δ 2.53 (s, 3H, SCH₃), 3.96 [s, 9H, (OCH₃)₃], 7.25 (d, J

) 8.2 Hz, 2H, methylsulfanylphenyl H-3, H-5), 7.50 (s, 2H,

trimethoxyphenyl H-2, H-6), 7.55 (d, J ) 8.2 Hz, 2H, methylsul-

fanylphenyl H-2, H-6). Anal. (C₁₉H₁₈O₄S): C, H.

1

53-55 °C; IR (film) 2209 (C≡C), 1625 (CdO) cm^-1; H NMR

(CDCl₃): δ 2.50 (s, 3H, SCH₃), 3.90 (s, 3H, OCH₃), 7.17 (dd, J )

7.9, 2.4 Hz, 1H, methoxyphenyl H-4), 7.24 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.40 (t, J ) 8.5 Hz, 1H, meth-

oxyphenyl H-5), 7.58 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl

H-2, H-6), 7.70 (br s, 1H, methoxyphenyl H-2), 7.83 (br, d, J )

7.6 Hz, methoxyphenyl H-6). Anal. (C₁₇H₁₄O₂S): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-propylphenyl)prop-2-yn-1-

one (12g). The product was obtained as an oil by the oxidation of

11g in the presence of MnO₂(0.71 g, 54%): IR (film) 2205 (C≡C),

1629 (CdO) cm^-1; ¹H NMR (CDCl₃): δ 0.97 (t, J ) 7.3 Hz, 3H,

CH₂CH₂CH₃), 1.65-1.73 (m, 2H, CH₂CH₂CH₃), 2.53 (s, 3H,

SCH₃), 2.66 (t, J ) 7.3 Hz, 2H, CH₂CH₂CH₃), 7.23 (d, J ) 8.8

Hz, 2H, methylsulfanylphenyl H-3, H-5), 7.31 (d, J ) 8.2 Hz, 2H,

propylphenyl H-3, H-5), 7.57 (d, J ) 8.8 Hz, 2H, methylsulfa-

nylphenyl H-2, H-6), 8.12 (d, J ) 8.2 Hz, 2H, propylphenyl H-2,

H-6). Anal. (C₁₉H₁₈OS): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-butylphenyl)prop-2-yn-1-

one (12h). The product was obtained as an oil by the oxidation of

11h in the presence of MnO₂(0.70 g, 51%): IR (film) 2202 (C≡C),

1623 (CdO) cm^-1; ¹H NMR (CDCl₃): δ 0.95 (t, J ) 7.3 Hz, 3H,

CH₂CH₃), 1.26-1.69 [m, 4H, (CH₂)₂CH₃], 2.53 (s, 3H, SCH₃), 2.65

(t, J ) 7.3 Hz, 2H, aromatic-CH₂), 7.21 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.30 (d, J ) 8.5 Hz, 2H,

butylphenyl H-3, H-5), 7.58 (d, J ) 8.2 Hz, 2H, methylsulfa-

nylphenyl H-2, H-6), 8.13 (d, J ) 8.5 Hz, 2H, butylphenyl H-2,

H-6). Anal. (C₂₀H₂₀OS): C, H.

4-[3-(4-Methylsulfanylphenyl)prop-2-yn-1-one]benzoic Acid

Methyl Ester (12n). The product was obtained as a yellow solid

by the oxidation of 11n in the presence of MnO₂(0.81 g, 58%):

1

mp 143-145 °C; IR (film) 2208 (C≡C), 1642 (CdO) cm^-1; H

NMR (CDCl₃): δ 2.54 (s, 3H, SCH₃), 3.98 (s, 3H, COOCH₃), 7.25

(d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-3, H-5), 7.59 (d, J )

8.5 Hz, 2H, methylsulfanylphenyl H-2, H-6), 8.17 (d, J ) 8.2 Hz,

2H, benzoic acid methyl ester H-2, H-6), 8.26 (d, J ) 8.2 Hz, 2H,

benzoic acid methyl ester H-3, H-5). Anal. (C₁₈H₁₄O₃S): C, H.

3-(4-Methylsulfanylphenyl)-1-furan-3-yl-prop-2-yn-1-one (16a).

The product was obtained as a brown solid by the oxidation of

15a in the presence of MnO₂(0.57 g, 52.6%): mp 83-85 °C; IR

(film) 2213 (C≡C), 1625 (CdO) cm^-1; ¹H NMR (CDCl₃): δ 2.50

(s, 3H, SCH₃), 6.88 (br d, J ) 1.8 Hz, 1H, furanyl H-4), 7.23 (d,

J ) 8.5 Hz, 2 H, methylsulfanylphenyl H-3, H-5), 7.47-7.49 (m,

1H, furanyl H-5), 7.52 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl

H-2, H-6), 8.23 (br s, 1H, furanyl H-2). Anal. (C₁₄H₁₀O₂S): C, H.

3-(4-Methylsulfanylphenyl)-1-naphthalen-1-yl-prop-2-yn-1-

one (16b). The product was obtained as a yellow solid by the

oxidation of 15b in the presence of MnO₂(0.88 g, 65%): mp 113-

115 °C; IR (film) 2206 (C≡C), 1628 (CdO) cm^-1

;

¹H NMR

(CDCl₃): δ 2.52 (s, 3H, SCH₃), 7.22 (d, J ) 8.8 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.56-7.72 (m, 5H, methylsulfa-

nylphenyl H-2, H-6; naphthyl H-3, H-6, H-7), 7.91-7.94 (m, 1H,

naphthyl H-5), 8.09-8.12 (m, 1H, naphthyl H-4), 8.62-8.65 (m,

1H, naphthyl H-2), 9.21-9.24 (m, 1H, naphthyl H-8). Anal. (C₂₀H₁₄-

OS): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-isopropylphenyl)prop-2-yn-

1-one (12i). The product was obtained as a yellowish oil by the

oxidation of 11i in the presence of MnO₂(0.75 g, 57%): IR (film)

2208 (C≡C), 1632 (CdO) cm^-1; ¹H NMR (CDCl₃): δ 1.28-1.31

[d, J ) 6.7 Hz, 6H, CH(CH₃)₂], 2.53 (s, 3H, SCH₃), 2.89-2.98

[m, 1H, CH(CH₃)₂], 7.24 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl

H-3, H-5), 7.36 (d, J ) 8.8 Hz, 2H, isopropylphenyl H-3, H-5),

7.57 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl H-2, H-6), 8.13 (d,

J ) 8.8 Hz, 2H, isopropylphenyl H-2, H-6). Anal. (C₁₉H₁₈OS): C,

H.

3-(4-Methylsulfanylphenyl)-1-(4-methoxynaphthalen-1-yl)-

prop-2-yn-1-one (16c). The product was obtained as a yellow solid

by the oxidation of 15c in the presence of MnO₂(0.88 g, 59%):

1

mp 105-107 °C; IR (film) 2218 (CtC) 1614 (CdO) cm^-1; H

NMR (CDCl₃): δ 2.51 (s, 3H, SCH₃), 4.12 (s, 3H, OCH₃), 6.91

(d, J ) 8.2 Hz, 1H, methoxynaphthyl H-3), 7.24 (d, J ) 8.2 Hz,

2H, methylsulfanylphenyl H-3, H-5), 7.54-7.73 (m, 4H, methyl-

sulfanylphenyl H-2, H-6; methoxynaphthyl H-6, H-7), 8.34-8.36

(m, 1H, methoxynaphthyl H-5), 8.68 (d, J ) 8.2 Hz, 1H,

methoxynaphthyl H-2), 9.37-9.39 (m, 1H, methoxynaphthyl H-8).

Anal. (C₂₁H₁₆O₂S): C, H.

3-(4-Methylsulfanylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-

one (12j). The product was obtained as a yellow solid by the

oxidation of 11j in the presence of MnO₂(0.50 g, 40%): mp 149-

General Procedure for the Synthesis of 1,3-Diarylprop-2-yn-

1-ones (13b-j, 13l, 13n-p and 17a-c). An aqueous solution of

Oxone (50% w/v, 3.24 mmol) was added dropwise to a stirred

solution of a 1,3-diarylprop-2-yn-1-one (12 and 16a-c, 1.08 mmol)

possessing a 4-methylsulfanyl substituent on the C-3 phenyl ring

in 1,4-dioxane (10 mL) at 0 °C. The reaction was allowed to proceed

with stirring at 25 °C for 3-4 h. The reaction mixture was diluted

with water (15 mL), extracted with EtOAc (3 × 25 mL), the EtOAc

fraction was washed successively with brine solution and water

(15 mL each), the organic phase was separated, dried over Na₂-

SO₄, and the solvent was removed in vacuo to give a crude product.

This crude product was purified by silica gel column chromatog-

raphy using ethyl acetate-hexanes (2:1, v/v or 3:1, v/v) as eluent

to afford the respective title compound 13b-j, 13l, 13n-p and

17a-c in 60-90% yield. Some physical and spectroscopic data

for 13b-p and 17a-c are listed below.

151 °C; IR (film) 2201 (C≡N), 2193 (C≡C), 1640 (CdO) cm^-1

;

¹H NMR (CDCl₃) δ 2.54 (s, 3H, SCH₃), 7.26 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.59 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.82 (d, J ) 8.2 Hz, 2H,

cyanophenyl H-3, H-5), 8.29 (d, J ) 8.2 Hz, 2H, cyanophenyl H-2,

H-6). Anal. (C₁₇H₁₁NOS): C, H, N.

3-(4-Methylsulfanylphenyl)-1-(3,4-difluorophenyl)prop-2-yn-

1-one (12k). The product was obtained as an oil by the oxidation

of 11k in the presence of MnO₂(0.68 g, 52.6%): IR (film) 2186

1

(C≡C), 1633 (CdO) cm^-1; H NMR (CDCl₃): δ 2.53 (s, 3H,

SCH₃), 7.25-7.36 (m, 3H, methylsulfanylphenyl H-3, H-5; dif-

luorophenyl H-5), 7.58 (d, J ) 8.2 Hz, 2H, methylsulfanylphenyl

H-2, H-6), 7.98-8.05 (m, 2H, difluorophenyl H-2, H-6). Anal.

(C₁₆H₁₀F₂OS): C, H.

3-(4-Methylsulfanylphenyl)-1-(3,4-dimethoxyphenyl)prop-2-

yn-1-one (12l). The product was obtained as an oil by the oxidation

of 11l in the presence of MnO₂(0.76 g, 54%): IR (film) 2195

3-(4-Methanesulfonylphenyl)-1-(4-tolyl)prop-2-yn-1-one (13b).

The product was obtained as a white solid by oxidation of 12b in

the presence of aqueous Oxone solution (0.27 g, 85%): mp 116-

118 °C; IR (film) 2204 (CtC), 1620 (CdO), 1317, 1160 (SO₂)

1

(C≡C), 1638 (CdO) cm^-1; H NMR (CDCl₃): δ 2.52 (s, 3H,

SCH₃), 3.95 (s, 3H, 4-OMe), 3.97 (s, 3H, 3-OMe), 6.91 (d, J )

8.5 Hz, 1H, dimethoxyphenyl H-5), 7.23 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.55 (d, J ) 8.2 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.67 (br s, 1H, dimethoxyphenyl

H-2), 7.91 (d, J ) 8.5 Hz, 1H, dimethoxyphenyl H-6). Anal.

(C₁₈H₁₆O₃S): C, H.

cm^-^{1 1}H NMR (CDCl₃): δ 2.47 (s, 3H, CH₃), 3.10 (s, 3H,

;

SO₂CH₃), 7.32 (d, J ) 7.9 Hz, 2H, tolyl H-3, H-5), 7.85 (d, J )

8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.00 (d, J ) 8.5

Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.09 (d, J ) 7.9 Hz,

2H, tolyl H-2, H-6). Anal. (C₁₇H₁₄O₃S): C, H.

3-(4-Methylsulfanylphenyl)-1-(3,4,5-trimethoxyphenyl)prop-

2-yn-1-one (12m). The product was obtained as a white solid by

the oxidation of 11m in the presence of MnO₂(0.66 g, 43.4%):

mp 88-90 °C; IR (film) 2206 (C≡C), 1612 (CdC) cm^-1; ¹H NMR

3-(4-Methanesulfonylphenyl)-1-(4-propylphenyl)prop-2-yn-1-

one (13c). The product was obtained as a yellow oil by oxidation

of 12g in the presence of aqueous Oxone solution (0.27 g, 78%):

1

IR (film) 2232 (CtC), 1636 (CdO), 1317, 1150 (SO₂) cm^-1; H

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1679

NMR (CDCl₃): δ 0.95 (t, J ) 7.3 Hz, 3H, CH₂CH₂CH₃), 1.60-

1.73 (m, 2H, CH₂CH₂CH₃), 2.67 (t, J ) 7.3 Hz, 2H, CH₂CH₂-

CH₃), 3.10 (s, 3H, SO₂CH₃), 7.31 (d, J ) 8.2 Hz, 2H, propylphenyl

H-3, H-5), 7.85 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2,

H-6), 8.00 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5),

8.11 (d, J ) 8.2 Hz, 2H, propylphenyl H-2, H-6). Anal.

(C₁₉H₁₈O₃S): C, H.

3H, OCH₃), 7.00 (d, J ) 8.8 Hz, 2H, methoxyphenyl H-3, H-5),

7.84 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.00

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.17 (d, J

) 8.8 Hz, 2H, methoxyphenyl H-2, H-6). Anal. (C₁₇H₁₄O₄S): C,

H.

3-(4-Methanesulfonylphenyl)-1-(3-methoxyphenyl)prop-2-yn-

1-one (13l). The product was obtained as a white solid by oxidation

of 12f in the presence of aqueous Oxone solution (0.26 g, 77%):

mp 134-136 °C; IR (film) 2199 (C≡C), 1632 (CdO), 1333, 1150

3-(4-Methanesulfonylphenyl)-1-(4-butylphenyl)prop-2-yn-1-

one (13d). The product was obtained as a yellow oil by oxidation

of 12h in the presence of aqueous Oxone solution (0.28 g, 76%):

1

(SO₂) cm^-1; H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃), 3.90 (s,

1

IR (film) 2198 (CtC), 1624 (CdO), 1314, 1154 (SO₂) cm^-1; H

3H, OCH₃), 7.20 (dd, J ) 8.5, 2.7 Hz, 1H, methoxyphenyl H-4),

7.44 (t, J ) 8.5 Hz, 1H, methoxyphenyl H-5), 7.68 (br, s, 1H,

methoxyphenyl H-2), 7.83-7.88 (m, 3H, methoxyphenyl H-6,

methanesulfonylphenyl H-2, H-6), 8.01 (d, J ) 8.2 Hz, 2H,

methanesulfonylphenyl H-3, H-5). Anal. (C₁₇H₁₄O₄S): C, H.

3-(4-Methanesulfonylphenyl)-1-(3,4-dimethoxyphenyl)prop-

2-yn-1-one (13n). The product was obtained as a white solid by

oxidation of 12l in the presence of aqueous Oxone solution (0.31

g, 85%): mp 144-146 °C; IR (film) 2187 (C≡C), 1626 (CdO),

1310, 1154 (SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃),

3.95 (s, 3H, 4-OMe), 3.98 (s, 3H, 3-OMe), 6.97 (d, J ) 8.5 Hz,

1H, dimethoxyphenyl H-5), 7.66 (br s, 1H, dimethoxyphenyl H-2),

7.83 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 7.91

(d, J ) 8.5 Hz, 1H, dimethoxyphenyl H-6), 8.00 (d, J ) 8.5 Hz,

2H, methanesulfonylphenyl H-3, H-5). Anal. (C₁₈H₁₆O₅S): C, H.

3-(4-Methanesulfonylphenyl)-1-(3,4,5-trimethoxyphenyl)prop-

2-yn-1-one (13o). The product was obtained as a white solid by

oxidation of 12m in the presence of aqueous Oxone solution (0.31

g, 78%): mp 154-155 °C; IR (film) 2197 (C≡C), 1622 (CdO),

1320, 1158 (SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃),

3.98 [s, 9H, (OCH₃)₃], 7.48 (s, 2H, trimethoxyphenyl H-2, H-6),

7.83 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.01

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5). Anal.

(C₁₉H₁₈O₆S): C, H.

4-[3-(4-Methanesulfonylphenyl)prop-2-yn-1-one]benzoic Acid

Methyl Ester (13p). The product was obtained as a white solid by

oxidation of 12n in the presence of aqueous Oxone solution (0.31

g, 85%): mp 189-191 °C; IR (film) 2211 (C≡C), 1645 (CdO),

1317, 1150 (SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.11 (s, 3H, SO₂CH₃),

3.98 (s, 3H, COOCH₃), 7.85 (d, J ) 8.2 Hz, 2H, methanesulfo-

nylphenyl H-2, H-6), 8.02 (d, J ) 8.2 Hz, 2H, methanesulfonylphe-

nyl H-3, H-5), 8.19 (d, J ) 8.5 Hz, 2H, benzoic acid methyl ester

H-2, H-6), 8.25 (d, J ) 8.5 Hz, 2H, benzoic acid methyl ester H-3,

H-5). Anal. (C₁₈H₁₄O₅S): C, H.

NMR (CDCl₃): δ 0.98 (t, J ) 7.3 Hz, 3H, CH₂CH₃), 1.32-1.39

(m, 2H, CH₂CH₃), 1.57-1.59 (m, 2H, CH₂CH₂CH₃), 2.69 (t, J )

7.3 Hz, 2H, aromatic-CH₂), 3.10 (s, 3H, SO₂CH₃), 7.33 (d, J )

8.2 Hz, 2H, butylphenyl H-3, H-5), 7.85 (d, J ) 8.5 Hz, 2H,

methanesulfonylphenyl H-2, H-6), 8.00 (d, J ) 8.5 Hz, 2H,

methanesulfonylphenyl H-3, H-5), 8.11 (d, J ) 8.2 Hz, 2H,

butylphenyl H-2, H-6). Anal. (C₂₀H₂₀O₃S): C, H.

3-(4-Methanesulfonylphenyl)-1-(4-isopropylphenyl)prop-2-yn-

1-one (13e). The product was obtained as pale yellow solid by

oxidation of 12i in the presence of aqueous Oxone solution (0.30

g, 85%): mp 182-184 °C; IR (film) 2186 (CtC), 1630 (CdO),

1310, 1145 (SO₂) cm^-1; ¹H NMR (CDCl₃): δ 1.29 [d, J ) 6.7 Hz,

6H, CH(CH₃)₂], 2.97-3.04 [m, 1H, CH(CH₃)₂], 3.10 (s, 3H,

SO₂CH₃), 7.38 (d, J ) 8.2 Hz, 2H, isopropylphenyl H-3, H-5),

7.85 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.00

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.12 (d, J

) 8.2 Hz, 2H, isopropylphenyl H-2, H-6). Anal. (C₁₉H₁₈O₃S): C,

H.

3-(4-Methanesulfonylphenyl)-1-(4-trifluoromethylphenyl)-

prop-2-yn-1-one (13f). The product was obtained as a yellow solid

by oxidation of 12e in the presence of aqueous Oxone solution

(0.29 g, 78%): yellow solid; mp 151-153 °C; IR (film) 2191

1

(C≡C), 1632 (CdO), 1322, 1154 (SO₂) cm^-1; H NMR (CDCl₃):

δ 3.11 (s, 3H, SO₂CH₃), 7.81 (d, J ) 8.2 Hz, 2H, trifluorometh-

ylphenyl H-3, H-5), 7.87 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl

H-2, H-6), 8.03 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-3,

H-5), 8.31 (d, J ) 8.2 Hz, 2H, trifluoromethylphenyl H-2, H-6).

Anal. (C₁₇H₁₁F₃O₃S): C, H.

3-(4-Methanesulfonylphenyl)-1-(4-cyanophenyl)prop-2-yn-1-

one (13g). The product was obtained as a white solid by oxidation

of 12j in the presence of aqueous Oxone solution (0.28 g, 85%):

mp 183-185 °C; IR (film) 2220 (C≡N), 2200 (C≡C), 1640 (Cd

1

O), 1311, 1150 (SO₂) cm^-1; H NMR (CDCl₃): δ 3.11 (s, 3H,

SO₂CH₃), 7.84 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-2,

H-6), 7.88 (d, J ) 8.5 Hz, 2H, cyanophenyl H-3, H-5), 8.03 (d, J

) 8.2 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.29 (d, J ) 8.5

Hz, 2H, cyanophenyl H-2, H-6). Anal. (C₁₇H₁₁NO₃S): C, H, N.

3-(4-Methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-

one (13h). The product was obtained by oxidation of 12d in the

presence of aqueous Oxone solution (0.26 g, 81%): yellow solid;

mp 142-144 °C; IR (film) 2200 (C≡C), 1647 (CdO), 1309, 1154

(SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃), 7.19 (dd,

J ) 8.5, 8.5 Hz, 2H, fluorophenyl H-3, H-5), 7.85 (d, J ) 8.2 Hz,

2H, methanesulfonylphenyl H-2, H-6), 8.01 (d, J ) 8.2 Hz, 2H,

methanesulfonylphenyl H-3, H-5), 8.23 (dd, J ) 8.5, 5.5 Hz, 2H,

fluorophenyl H-2, H-6). Anal. (C₁₆H₁₁FO₃S): C, H.

3-(4-Methanesulfonylphenyl)-1-(3,4-difluorophenyl)prop-2-

yn-1-one (13i). The product was obtained as a yellow solid by

oxidation of 12k in the presence of aqueous Oxone solution (0.26

g, 76%): mp 149-151 °C; IR (film) 2190 (C≡C), 1633 (CdO),

1318, 1152 (SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.11 (s, 3H, SO₂CH₃),

7.30-7.39 (m, 1H, difluorophenyl H-5), 7.86 (d, J ) 8.2 Hz,

2H, methanesulfonylphenyl H-2, H-6), 7.98-8.05 (m, 4H, meth-

anesulfonylphenyl H-3, H-5; difluorophenyl H-2, H-6). Anal.

(C₁₆H₁₀F₂O₃S): C, H.

3-(4-Methanesulfonylphenyl)-1-furan-3-yl-prop-2-yn-1-one

(17a). The product was obtained as a yellow solid by oxidation of

16a in the presence of aqueous Oxone solution (0.26 g, 88%): mp

155-157 °C; IR (film) 2218 (C≡C), 1622 (CdO), 1311, 1154

(SO₂) cm^-1; ¹H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃), 6.89 (br

d, J ) 1.8 Hz, 1H, furanyl H-4), 7.50-7.51 (m, 1H, furanyl H-5),

7.81 (d, J ) 8.2 Hz, 2 H, methanesulfonylphenyl H-2, H-6), 8.00

(d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.26 (br s,

1H, furanyl H-2). Anal. (C₁₄H₁₀O₄S): C, H.

3-(4-Methanesulfonylphenyl)-1-naphthalen-1-yl-prop-2-yn-1-

one (17b). The product was obtained as a white solid by oxidation

of 16b in the presence of aqueous Oxone solution (0.29 g, 81%):

mp 132-134 °C; IR (film) 2218 (C≡C), 1613 (CdO), 1317, 1150

1

(SO₂) cm^-1; H NMR (CDCl₃): δ 3.11 (s, 3H, SO₂CH₃), 7.61-

7.75 (m, 3H, naphthyl H-3, H-6, H-7), 7.86 (d, J ) 8.5 Hz, 2H,

methanesulfonylphenyl H-2, H-6), 7.89-7.93 (m, 1H, naphthyl

H-5), 8.01 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5),

8.13-8.16 (m, 1H, naphthyl H-4), 8.62-8.65 (m, 1H, naphthyl

H-2), 9.23-9.26 (m, 1H, naphthyl H-8). Anal. (C₂₀H₁₄O₃S): C,

H.

3-(4-Methanesulfonylphenyl)-1-(4-methoxynaphthalen-1-yl)-

prop-2-yn-1-one (17c). The product was obtained as a white solid

by oxidation of 16c in the presence of aqueous Oxone solution

(0.32 g, 82%): mp 175-177 °C; IR (film) 2218 (C≡C), 1622 (Cd

3-(4-Methanesulfonylphenyl)-1-(4-methoxyphenyl)prop-2-yn-

1-one (13j). The product was obtained as a white solid by oxidation

of 12c in the presence of aqueous Oxone solution (0.29 g, 86%):

mp 151-153 °C; IR (film) 2195 (C≡C), 1634 (CdO), 1315, 1154

1

O), 1311, 1150 (SO₂) cm^-1; H NMR (CDCl₃): δ 3.11 (s, 3H,

SO₂CH₃), 4.13 (s, 3H, OCH₃), 6.92 (d, J ) 8.2 Hz, 1H, methox-

ynaphthyl H-3), 7.56-7.76 (m, 2H, methoxynaphthyl H-6, H-7),

1

(SO₂) cm^-1; H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃), 3.92 (s,

1680 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

7.85 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.00

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.35-8.38

(m, 1H, methoxynaphthyl H-5), 8.66 (d, J ) 8.2 Hz, 1H,

methoxynaphthyl H-2), 9.36-9.39 (m, 1H, naphthyl H-8). Anal.

(C₂₁H₁₆O₄S): C, H.

are listed below, were prepared using a procedure similar to

that described previously for the synthesis of compounds 11 and

15a-c.

3-(4-Methylsulfanylphenyl)-1-[4-(tert-butyldimethylsilyloxy)-

3-methoxyphenyl]prop-2-yn-1-ol (20a). The product was obtained

as an oil by the reaction of 9 with 19a (1.53 g, 38%): IR (film)

3220 (OH), 2218 (C≡C) cm^-1; ¹H NMR (CDCl₃): δ 0.16 [s, 6H,

Si(CH₃)₂], 1.00 [s, 9H, C(CH₃)₃], 2.20 (d, J ) 6.1 Hz, 1H, CHOH),

2.49 (s, 3H, SCH₃), 3.84 (s, 3H, OCH₃), 5.62 (d, J ) 6.1 Hz, 1H,

CHOH), 6.85 (d, J ) 8.2 Hz, 1H, tert-butyldimethylsilyloxyphenyl

H-5), 7.00-7.13 (m, 2H, tert-butyldimethylsilyloxyphenyl H-2,

H-6), 7.17 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-3, H-5),

7.37 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-2, H-6). Anal.

(C₂₃H₃₀O₃SSi): C, H.

3-(4-Methylsulfanylphenyl)-1-[3-(tert-butyldimethylsilyloxy)-

4-methoxyphenyl]prop-2-yn-1-ol (20b). The product was obtained

as an oil by the reaction of 9 with 19b (1.25 g, 31%): IR (film)

3210 (OH), 2208 (C≡C) cm^-1; ¹H NMR (CDCl₃): δ 0.16 [s, 6H,

Si(CH₃)₂], 1.01 [s, 9H, C(CH₃)₃], 2.15 (d, J ) 6.1 Hz, 1H, CHOH),

2.49 (s, 3H, SCH₃), 3.82 (s, 3H, OCH₃), 5.57 (d, J ) 6.1 Hz, 1H,

CHOH), 6.85 (d, J ) 8.2 Hz, 1H, tert-butyldimethylsilyloxyphenyl

H-5), 7.11-7.24 (m, 4H, methylsulfanylphenyl H-3, H-5; tert-

butyldimethylsilyloxyphenyl H-2, H-6), 7.36 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6). Anal. (C₂₃H₃₀O₃SSi): C, H.

General Procedure for the Synthesis of 3-(4-Methylsulfa-

nylphenyl)-1-[4-(tert-butyldimethylsilyloxy)-3-methoxyphenyl]-

prop-2-yn-1-one (21a) and 3-(4-Methylsulfanylphenyl)-1-[3-(tert-

butyldimethylsilyloxy)-4-methoxyphenyl]prop-2-yn-1-one (21b).

Compounds 21a,b for which the physical and spectroscopic data

are listed below, were prepared using a procedure similar to that

described previously for the synthesis of compounds 12 and 16a-

c.

3-(4-Methylsulfanylphenyl)-1-[4-(tert-butyldimethylsilyloxy)-

3-methoxyphenyl]prop-2-yn-1-one (21a). The product was ob-

tained as an oil by the oxidation of 20a in the presence of MnO₂

(0.83 g, 45%): IR (film) 2215 (C≡C), 1660 (CdO) cm^-1; ¹H NMR

(CDCl₃): δ 0.20 [s, 6H, Si(CH₃)₂], 1.00 [s, 9H, C(CH₃)₃], 2.52 (s,

3H, SCH₃), 3.89 (s, 3H, OCH₃), 6.93 (d, J ) 8.2 Hz, 1H, tert-

butyldimethylsilyloxyphenyl H-5), 7.22 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.55 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.66 (d, J ) 1.8 Hz, 1H, tert-

butyldimethylsilyloxyphenyl H-2), 7.81-7.85 (m, 1H, tert-bu-

tyldimethylsilyloxyphenyl H-6). Anal. (C₂₃H₂₈O₃SSi): C, H.

3-(4-Methylsulfanylphenyl)-1-[3-(tert-butyldimethylsilyloxy)-

4-methoxyphenyl]prop-2-yn-1-one (21b). The product was ob-

tained as an oil by the oxidation of 20b in the presence of MnO₂

(1.0 g, 54%): IR (film) 2214 (C≡C), 1666 (CdO) cm^-1; ¹H NMR

(CDCl₃): δ 0.19 [s, 6H, Si(CH₃)₂], 1.01 [s, 9H, C(CH₃)₃], 2.51 (s,

3H, SCH₃), 3.90 (s, 3H, OCH₃), 6.94 (d, J ) 7.9 Hz, 1H, tert-

butyldimethylsilyloxyphenyl H-5), 7.22 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.54 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.68 (d, J ) 2.1 Hz, 1H, tert-

butyldimethylsilyloxyphenyl H-2), 7.86-7.89 (m, 1H, tert-bu-

tyldimethylsilyloxyphenyl H-6). Anal. (C₂₃H₂₈O₃SSi): C, H.

General Procedure for the Synthesis of 3-(4-Methylsulfa-

nylphenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-yn-1-one (22a)

and 3-(4-Methylsulfanylphenyl)-1-(3-hydroxy-4-methoxyphen-

yl)prop-2-yn-1-one (22b). To a solution of KOH (0.045 g, 0.80

mmol) in ethanol (4 mL), the TBDMS protected 1,3-diphenylprop-

2-yn-1-one (21a or 21b, 0.53 mmol) was added and the reaction

was allowed to proceed with stirring at 25 °C for 45 min. Addition

of water (10 mL), extraction with EtOAc (3 × 20 mL), drying the

extract (Na₂SO₄), and removal of the solvent in vacuo gave an oil.

This oil was purified by silica gel column chromatography using

ethyl acetate-hexanes (1:3, v/v) as eluent to afford the respective

product 22a and 22b. Some physical and spectroscopic data for

22a and 22b are listed below.

General Procedure for the Synthesis of 3-(4-Methanesulfo-

nylphenyl)-1-(4-hydroxyphenyl)prop-2-yn-1-one (13k) and 3-(4-

Methanesulfonylphenyl)-1-(3-hydroxyphenyl)prop-2-yn-1-one

(13m). To a stirred solution of 13j or 13l (1.1 mmol) in freshly

dried CH₂Cl₂under an argon atmosphere at 0 °C, boron tribromide

(0.40 mL, 4.3 mmol) was added dropwise and the reaction was

stirred at -5 to 0 °C for 1 h, after which the reaction mixture was

quenched with crushed ice, extracted with EtOAc (3 × 20 mL),

dried over Na₂SO₄and the solvent was removed in vacuo to afford

a dark brown oil. This oil was purified by silica gel column

chromatography using CH₂Cl_2-ethyl acetate (5:1, v/v or 4:1, v/v)

as eluent, using two consecutive column separations, to afford the

respective title compound 13k and 13m in 50-55% yield. Some

physical and spectroscopic data for 13k and 13m are listed below.

3-(4-Methanesulfonylphenyl)-1-(4-hydroxyphenyl)prop-2-yn-

1-one (13k). The product was obtained as a yellow solid from 13j

(0.18 g, 56%): mp 211-213 °C; IR (film) 3205 (OH), 2204 (C≡C),

1642 (CdO), 1323, 1170 (SO₂) cm^-1; ¹H NMR (CDCl₃+ DMSO-

d₆): δ 3.05 (s, 3H, SO₂CH₃), 6.77 (d, J ) 8.5 Hz, 2H, hydrox-

yphenyl H-3, H-5), 7.29 (s, 1H, OH), 7.68 (d, J ) 8.2 Hz, 2H,

methanesulfonylphenyl H-2, H-6), 7.83 (d, J ) 8.2 Hz, 2H,

methanesulfonylphenyl H-3, H-5), 7.89 (d, J ) 8.5 Hz, 2H,

hydroxyphenyl H-2, H-6). Anal. (C₁₆H₁₂O₄S): C, H.

3-(4-Methanesulfonylphenyl)-1-(3-hydroxyphenyl)prop-2-yn-

1-one (13m). The product was obtained as a yellow solid from 13l

(0.17 g, 52%): mp 178-180 °C; IR (film) 3207 (OH), 2185 (C≡C),

1635 (CdO), 1313, 1156 (SO₂) cm^-1; ¹H NMR (CDCl₃+ DMSO-

d₆): δ 3.06 (s, 3H, SO₂CH₃), 7.00 (dd, J ) 7.9, 2.4 Hz, 1H,

hydroxyphenyl H-4), 7.21 (t, J ) 7.9 Hz, 1H, hydroxyphenyl H-5),

7.34-7.37 (m, 2H, hydroxyphenyl H-2, H-6), 7.56 (s, 1H, OH),

7.83 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-2, H-6), 7.91

(d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-3, H-5). Anal.

(C₁₆H₁₂O₄S): C, H.

General Procedure for the Synthesis of 4-(tert-Butyldimeth-

ylsilyloxy)-3-methoxybenzaldehyde (19a) and 3-(tert-Butyldi-

methylsilyloxy)-4-methoxybenzaldehyde (19b). To a stirred solu-

tion of the aldehyde (18a or 18b; 6.1 mmol) in freshly dried THF

(15 mL) kept under an argon atmosphere at 25 °C, NaH (0.29 g,

12.0 mmol) was slowly added, immediately after which tert-

butyldimethylsilyl chloride (TBDMSCl, 1.1 g, 6.7 mmol) was added

and the reaction mixture was stirred at 25 °C for 2-3 h. The

reaction mixture was washed with 1N HCl (10 mL), extracted with

EtOAc (3 × 20 mL), the organic phase was separated, dried over

Na₂SO₄, and the organic solvent was removed in vacuo to afford

the respective title compounds 19a and 19b in 65-70% yield. Some

physical and spectroscopic data for 19a and 19b are listed below.

4-(tert-Butyldimethylsilyloxy)-3-methoxybenzaldehyde (19a).

The product was obtained as an oil from 18a (1.90 g, 65%): IR

1

(film) 1689 (CdO) cm^-1; H NMR (CDCl₃): δ 0.18 [s, 6H, Si-

(CH₃)₂], 1.00 [s, 9H, C(CH₃)₃], 3.90 (s, 3H, OCH₃), 6.95 (d, J )

8.5 Hz, 1H, benzaldehyde H-5), 7.37 (d, J ) 2.1 Hz, 1H,

benzaldehyde H-2), 7.46-7.50 (m, 1H, benzaldehyde H-6), 9.83

(s, 1H, CHO).

3-(tert-Butyldimethylsilyloxy)-4-methoxybenzaldehyde (19b).

The product was obtained as a yellow solid from 18b (2.05 g,

70%): IR (film) 1693 (CdO) cm^-1; ¹H NMR (CDCl₃): δ 0.18 [s,

6H, Si(CH₃)₂], 1.00 [s, 9H, C(CH₃)₃], 3.89 (s, 3H, OCH₃), 6.94 (d,

J ) 8.5 Hz, 1H, benzaldehyde H-5), 7.37 (d, J ) 1.8 Hz, 1H,

benzaldehyde H-2), 7.46-7.49 (m, 1H, benzaldehyde H-6), 9.82

(s, 1H, CHO).

General Procedure for the Synthesis of 3-(4-Methylsulfa-

nylphenyl)-1-[4-(tert-butyldimethylsilyloxy)-3-methoxyphenyl]-

prop-2-yn-1-ol (20a) and 3-(4-Methylsulfanylphenyl)-1-[3-(tert-

butyldimethylsilyloxy)-4-methoxyphenyl]prop-2-yn-1-ol (20b).

Compounds 20a,b for which the physical and spectroscopic data

3-(4-Methylsulfanylphenyl)-1-(4-hydroxy-3-methoxyphenyl)-

prop-2-yn-1-one (22a). The product was obtained as a yellow solid

from 21a (0.08 g, 52%): mp 109-111 °C; IR (film) 3102 (OH),

1

2215 (C≡C), 1661 (CdO) cm^-1; H NMR (CDCl₃): δ 2.52 (s,

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1681

3H, SCH₃), 3.99 (s, 3H, OCH₃), 6.16 (br s, 1H, OH), 7.01 (d, J )

8.2 Hz, 1H, hydroxyphenyl H-5), 7.23 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.55 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.67 (d, J ) 1.8 Hz, 1H,

hydroxyphenyl H-2), 7.88-7.92 (m, 1H, hydroxyphenyl H-6). Anal.

(C₁₇H₁₄O₃S): C, H.

methylsulfanylphenyl H-2, H-6), 8.35-8.40 (m, 4H, nitrophenyl

H-2, H-3, H-5, H-6). Anal. (C₁₆H₁₁NO₃S): C, H, N.

3-(4-Methylsulfanylphenyl)-1-(3-nitrophenyl)prop-2-yn-1-

one (25c). The product was obtained as a yellow solid by the

coupling of 9 with 24c (0.20 g, 25%): mp 154-156 °C; IR (film)

2191 (C≡C), 1644 (CdO), 1535, 1348 (NO₂) cm^-1

;

¹H NMR

3-(4-Methylsulfanylphenyl)-1-(3-hydroxy-4-methoxyphenyl)-

prop-2-yn-1-one (22b). The product was obtained as an oil from

21b (0.07 g, 48%): IR (film) 3102 (OH), 2207 (C≡C), 1602 (Cd

(CDCl₃): δ 2.52 (s, 3H, SCH₃), 7.24 (d, J ) 8.8 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.63 (d, J ) 8.8 Hz, 2H,

methylsulfanylphenyl H-2, H-6), 7.72 (t, J ) 8.2 Hz, 1H, nitro-

phenyl H-5), 8.47-8.54 (m, 2H, nitrophenyl H-4, H-6), 9.05 (d, J

) 1.8 Hz, 1H, nitrophenyl H-2). Anal. (C₁₆H₁₁NO₃S): C, H, N.

General Procedure for the Synthesis of 1,3-Diarylprop-2-yn-

1-ones (26a-c). An aqueous solution of Oxone (50% w/v, 1.62

mmol) was added dropwise to a stirred solution of a 1,3-diarylprop-

2-yn-1-one (25a-c, 0.54 mmol) possessing a p-methylsulfanyl

substituent on the C-3 phenyl ring in 1,4-dioxane (10 mL) at 0 °C.

The reaction was allowed to proceed with stirring at 25 °C for 4-5

h. The reaction mixture was diluted with water (10 mL), extracted

with EtOAc (2 × 20 mL), the EtOAc fraction was washed

successively with brine solution and water (10 mL each), the organic

phase was separated, dried over Na₂SO₄, and the solvent was

removed in vacuo to give a crude oil. This oil was purified by

silica gel column chromatography using ethyl acetate-hexanes (2:

1, v/v or 3:1, v/v) as eluent to afford the respective title compound

26a-c in 80-84% yield. Some physical and spectroscopic data

for 26a-c are listed below.

1

O) cm^-1; H NMR (CDCl₃): δ 2.51 (s, 3H, SCH₃), 4.00 (s, 3H,

OCH₃), 5.70 (br s, 1H, OH), 6.96 (d, J ) 8.2 Hz, 1H, hydrox-

yphenyl H-5), 7.23 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-3,

H-5), 7.57 (d, J ) 8.5 Hz, 2H, methylsulfanylphenyl H-2, H-6),

7.76 (d, J ) 1.8 Hz, 1H, hydroxyphenyl H-2), 7.81-7.85 (m, 1H,

hydroxyphenyl H-6). Anal. (C₁₇H₁₄O₃S): C, H.

General Procedure for the Synthesis of 3-(4-Methanesulfo-

nylphenyl)-1-(4-hydroxy-3-methoxyphenyl)prop-2-yn-1-one (23a)

and 3-(4-Methanesulfonylphenyl)-1-(3-hydroxy-4-methoxyphen-

yl)prop-2-yn-1-one (23b). Compounds 23a,b for which the physical

and spectroscopic data are listed below, were prepared using a

procedure similar to that described previously for the synthesis of

compounds 13b-j, 13l, 13n-p and 17a-c.

3-(4-Methanesulfonylphenyl)-1-(4-hydroxy-3-methoxyphenyl-

)prop-2-yn-1-one (23a). The product was obtained as a white solid

by oxidation of 22a in the presence of aqueous Oxone solution

(0.28 g, 81%): mp 194-196 °C; IR (film) 3102 (OH), 2215 (C≡C),

1660 (CdO), 1317, 1150 (SO₂) cm^-1; ¹H NMR (CDCl₃+ DMSO-

d₆): δ 3.10 (s, 3H, SO₂CH₃), 3.97 (s, 3H, OCH₃), 7.00 (d, J ) 8.2

Hz, 1H, hydroxyphenyl H-5), 7.63 (d, J ) 1.8 Hz, 1H, hydrox-

yphenyl H-2), 7.81-7.86 (m, 3H, methanesulfonylphenyl H-2, H-6;

hydroxyphenyl H-6), 7.99 (d, J ) 8.2 Hz, 2H, methanesulfonylphe-

nyl H-3, H-5), 8.78 (br s, 1H, OH). Anal. (C₁₇H₁₄O₅S): C, H.

3-(4-Methanesulfonylphenyl)-1-(3-hydroxy-4-methoxyphenyl-

)prop-2-yn-1-one (23b). The product was obtained as a white solid

by oxidation of 22b in the presence of aqueous Oxone solution

(0.29 g, 85%): mp 195-197 °C; IR (film) 3105 (OH), 2217 (C≡C),

1660 (CdO), 1315, 1150 (SO₂) cm^-1; ¹H NMR (CDCl₃+ DMSO-

d₆): δ 3.11 (s, 3H, SO₂CH₃), 3.98 (s, 3H, OCH₃), 6.90 (d, J ) 8.2

Hz, 1H, hydroxyphenyl H-5), 7.56 (d, J ) 2.1 Hz, 1H, hydrox-

yphenyl H-2), 7.64-7.67 (m, 1H, hydroxyphenyl H-6), 7.72 (br s,

1H, OH), 7.81 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-2,

H-6), 7.94 (d, J ) 8.2 Hz, 2H, methanesulfonylphenyl H-3, H-5).

Anal. (C₁₇H₁₄O₅S): C, H.

3-(4-Methanesulfonylphenyl)-1-isoxazol-5-yl-prop-2-yn-1-

one (26a). The product was obtained as a yellow solid by oxidation

of 25a in the presence of aqueous Oxone solution (0.11 g, 80%):

mp 163-165 °C; IR (film) 2212 (CtC), 1622 (CdO), 1317, 1154

1

(SO₂) cm^-1; H NMR (CDCl₃): δ 3.10 (s, 3H, SO₂CH₃), 7.12 (d,

J ) 1.8 Hz, 1H, isoxazolyl H-3 or H-4), 7.89 (d, J ) 8.5 Hz, 2H,

methanesulfonylphenyl H-2, H-6), 8.03 (d, J ) 8.5 Hz, 2H,

methanesulfonylphenyl H-3, H-5), 8.46 (d, J ) 1.8 Hz, 1H,

isoxazolyl H-4 or H-3). Anal. (C₁₃H₁₁NO₄S): C, H, N.

3-(4-Methanesulfonylphenyl)-1-(4-nitrophenyl)prop-2-yn-1-

one (26b). The product was obtained as a yellow solid by oxidation

of 25b in the presence of aqueous Oxone solution (0.14 g, 80%):

mp 211-213 °C; IR (film) 2193 (CtC), 1640 (CdO), 1535, 1348

(NO₂), 1317, 1150 (SO₂), cm^-1; ¹H NMR (CDCl₃): δ 3.11 (s, 3H,

SO₂CH₃), 7.88 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2,

H-6), 8.04 (d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5),

8.36-8.42 (m, 4H, nitrophenyl H-2, H-3, H-5, H-6). Anal. (C₁₆H₁₁-

NO₅S): C, H, N.

3-(4-Methanesulfonylphenyl)-1-(3-nitrophenyl)prop-2-yn-1-

one (26c). The product was obtained as a yellow solid by oxidation

of 25c in the presence of aqueous Oxone solution (0.15 g, 84%):

mp 195-197 °C; IR (film) 2188 (CtC), 1643 (CdO), 1531, 1341

(NO₂), 1311, 1150 (SO₂), cm^-1; ¹H NMR (CDCl₃): δ 3.11 (s, 3H,

SO₂CH₃), 7.74 (t, J ) 8.8 Hz, 1H, nitrophenyl H-5), 7.87 (d, J )

8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.05 (d, J ) 8.5

Hz, 2H, methanesulfonylphenyl H-3, H-5), 8.51-8.55 (m, 2H,

nitrophenyl H-4, H-6), 9.04 (d, J ) 1.8 Hz, 1H, nitrophenyl H-2).

Anal. (C₁₆H₁₁NO₅S): C, H, N.

General Procedure for the Synthesis of 1,3-Diarylprop-2-yn-

1-ones (25a-c). To a solution of freshly dried THF (10-15 mL)

under an argon atmosphere, an acid chloride (24a-c, 4.0 mmol)

and 1-ethynyl-4-methylsulfanylbenzene (9, 2.7 mmol) were added.

PdCl₂(PPh₃)₂(18 mg, 25.6 µmol) and CuI (16 mg, 84 µmol) were

added with stirring for 1-2 min. This was immediately followed

by the addition of anhydrous Et₃N (0.5 mL, 3.56 mmol), the reaction

was allowed to proced with stirring for 2-3 h at 25 °C, filtered,

washed with ethyl acetate (20 mL), and the solvent from the organic

layer was removed in vacuo. The residue obtained was purified by

silica gel column chromatography using CH₂Cl_2-ethyl acetate (5:

1, v/v or 4:1, v/v) as eluent by two consecutive column purifications,

to afford the respective title compound 25a-c in 18-25% yield.

Some physical and spectroscopic data for 25a-c are listed below.

3-(4-Methylsulfanylphenyl)-1-isoxazol-5-yl-prop-2-yn-1-one

(25a). The product was obtained as a yellow solid by the coupling

of 9 with 24a (0.11 g, 18%): mp 114-116 °C; IR (film) 2205

Procedure for the Synthesis of 1,3-Bis-(4-methanesulfonyl-

phenyl)prop-2-yn-1-one (28). An aqueous solution of Oxone

(50% w/v, 1.62 mmol) was added dropwise to a stirred solution of

3-(4-methanesulfonylphenyl)-1-(4-methylsulfanylphenyl)prop-2-yn-

1-one (27, 0.54 mmol) in 1,4-dioxane (10 mL) at 0 °C. The reaction

was allowed to proceed with stirring at 25 °C for 3-4 h. The

reaction mixture was diluted with water (10 mL), extracted with

EtOAc (2 × 20 mL), the EtOAc fraction was washed successively

with brine solution and water (10 mL each), the organic phase was

separated, dried over Na₂SO₄, and the solvent was removed in vacuo

to give a crude solid which was purified by silica gel column

chromatography using ethyl acetate-hexanes (3:1, v/v) as eluent

to afford 28 as a white solid (0.14 g, 75%): mp 235-237 °C;

1

(C≡C), 1610 (CdO) cm^-1; H NMR (CDCl₃): δ 2.54 (s, 3H,

SCH₃), 7.08 (d, J ) 1.8 Hz, 1H, isoxazolyl H-3 or H-4), 7.21 (d,

J ) 8.8 Hz, 2 H, methylsulfanylphenyl H-3, H-5), 7.59 (d, J ) 8.8

Hz, 2H, methylsulfanylphenyl H-2, H-6), 8.23 (d, J ) 1.8 Hz, 1H,

isoxazolyl H-4 or H-3). Anal. (C₁₃H₉NO₂S): C, H, N.

3-(4-Methylsulfanylphenyl)-1-(4-nitrophenyl)prop-2-yn-1-

one (25b). The product was obtained as a yellow solid by the

coupling of 9 with 24b (0.16 g, 21%): mp 165-167 °C; IR (film)

1

IR (film) 2218 (CtC), 1622 (CdO), 1317, 1150 (SO₂) cm^-1; H

2193 (C≡C), 1640 (CdO), 1530, 1341 (NO₂) cm^-1

;

¹H NMR

NMR (CDCl₃) δ 3.11 (s, 3H, SO₂CH₃), 3.12 (s, 3H, SO₂CH₃), 7.88

(d, J ) 8.5 Hz, 2H, ethynylmethanesulfonylbenzene H-2, H-6), 8.04

(d, J ) 8.5 Hz, 2H, ethynylmethanesulfonylbenzene H-3, H-5), 8.12

(CDCl₃): δ 2.53 (s, 3H, SCH₃), 7.25 (d, J ) 8.5 Hz, 2H,

methylsulfanylphenyl H-3, H-5), 7.59 (d, J ) 8.5 Hz, 2H,

1682 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5

PraVeen Rao et al.

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-2, H-6), 8.38

(d, J ) 8.5 Hz, 2H, methanesulfonylphenyl H-3, H-5). Anal.

(C₁₇H₁₄O₅S₂): C, H.

Analgesic Assay. Analgesic activity was determined using the

4% sodium chloride-induced writhing (abdominal constriction)

assay as described previously.²⁹

Molecular Modeling (Docking) Studies. Docking experiments

were performed using Insight II software Version 2000.1 (Accelrys

Inc.) running on a Silicon Graphics Octane 2 R14000A workstation.

The coordinates for the X-ray crystal structure of the enzyme COX-

1/2 and 15-LOX were obtained from the RCSB Protein Data Bank

and hydrogens were added. The ligand molecules were constructed

using the Builder module and energy minimized for 1000 iterations

reaching a convergence of 0.01 kcal/mol Å. The docking experiment

on COX-2 was carried out by superimposing the energy minimized

ligand on SC-558 in the PDB file 1cx2 after which SC-558 was

deleted. In the case of COX-1 (PDB file 1prh) the ligand was

suitably positioned in the active site while carefully monitoring

nonbonded interactions of the ligand-enzyme assembly and any

side chain bumps. The coordinates for 15-LOX was obtained from

PDB file1lox and the energy minimized ligand was superimposed

on the inhibitor RS75091 after which RS75091 was deleted. In all

these experiments the resulting ligand-enzyme complex was

subjected to docking using the Affinity command in the Docking

module of Insight II after defining subsets of the enzyme such that

residues within 10 Å of the ligand were allowed to relax, while

the remainder of the enzyme residues were fixed. The consistent

valence force field (CVFF) was employed for all docking purposes.

The ligand-enzyme assembly was then subjected to a molecular

dynamics (MD) simulation using the Discover module Version 2.98

at a constant temperature of 300 K with a 100 step equilibration

for over 1000 iterations and a time step of 1 fs using a distance

dependent dielectric constant 4r. The optimal binding orientation

of the ligand-enzyme assembly obtained after docking was further

minimized for 1000 iterations using the conjugate gradient method

until a convergence of 0.001 kcal/mol Å was reached after which

Cyclooxygenase Inhibition Studies. The ability of the test

compounds 13, 17, 26, 27 and 28 to inhibit ovine COX-1 and

COX-2 ((IC₅₀values, µM) was determined using an enzyme

immuno assay (EIA) kit (catalog number 560101, Cayman Chemi-

cal, Ann Arbor, MI) according to the manufacturer’s instructions.

Cyclooxygenase catalyzes the first step in the biosynthesis of

arachidonic acid (AA) to PGH₂. PGF₂R, produced from PGH₂by

reduction with stannous chloride, is measured by enzyme immu-

noassay (ACE competitive EIA). Stock solutions of test compounds

were dissolved in a minimum volume of DMSO. Briefly, to a series

of supplied reaction buffer solutions (960 µl, 0.1 M Tris-HCl pH

8.0 containing 5 mM EDTA and 2 mM phenol) with either COX-1

or COX-2 (10 µl) enzyme in the presence of heme (10 µl) were

added 10 µl of various concentrations of test drug solutions (0.001,

0.01, 0.1, 1, 10 and 100 µM in a final volume of 1 mL). These

solutions were incubated for a period of 5 min at 37 °C after which

10 µl of AA (100 µM) solution were added and the COX reaction

was stopped by the addition of 50 µl of 1 M HCl after 2 min.

PGF₂R, produced from PGH₂by reduction with stannous chloride

was measured by enzyme immunoassay. This assay is based on

the competition between PGs and a PG-acetylcholinesterase

conjugate (PG tracer) for a limited amount of PG antiserum. The

amount of PG tracer that is able to bind to the PG antiserum is

inversely proportional to the concentration of PGs in the wells since

the concentration of PG tracer is held constant while the concentra-

tion of PGs varies. This antibody-PG complex binds to a mouse

anti-rabbit monoclonal antibody that had been previously attached

to the well. The plate is washed to remove any unbound reagents

and then Ellman’s reagent, which contains the substrate to

acetylcholine esterase, is added to the well. The product of this

enzymatic reaction produces a distinct yellow color that absorbs at

405 nm. The intensity of this color, determined spectrophotometri-

cally, is proportional to the amount of PG tracer bound to the well,

which is inversely proportional to the amount of PGs present in

the well during the incubation: Absorbance R [Bound PG Tracer]

R 1/PGs. Percent inhibition was calculated by the comparison of

compound-treated to various control incubations. The concentration

of the test compound causing 50% inhibition (IC_50,µM) was

calculated from the concentration-inhibition response curve (du-

plicate determinations).

Lipoxygenase Inhibition Studies. The ability of the test

compounds 13, 17, 26, 27 and 28 to inhibit potato 5-LOX (catalog

number 60401, Cayman Chemical, Ann Arbor, MI) and soybean

15-LOX (IC₅₀values, µM) was determined using an enzyme

immuno assay (EIA) kit (catalog number 760700, Cayman Chemi-

cal, Ann Arbor, MI) according to the manufacturer’s instructions.

The Cayman Chemical lipoxygenase inhibitor screening assay

detects and measures the hydroperoxides produced in the lipoxy-

genation reaction using a purified lipoxygenase. Stock solutions

of test compounds were dissolved in a minimum volume of DMSO

and were diluted using the supplied buffer solution (0.1 M, Tris-

HCl pH 7.4). To a 90 µL solution of 5- or 15-LOX enzyme in

0.1 M, Tris-HCl pH 7.4 buffer, 10 µL of various concentrations

of test drug solutions (0.001, 0.01, 0.1, 1and 10 µM in a final

volume of 210 µL) were added and the lipoxygenase reaction

was initiated by the addition of 10 µL (100 µM) of linoleic acid

(LA). After maintaining the 96-well plate on a shaker for 5 min,

100 µL of chromogen was added and the plate was retained on

a shaker for 5 min. The lipoxygenase activity was determined after

measuring absorbance at a wavelength of 490 nm. Percent inhibi-

tion was calculated by the comparison of compound-treated to

various control incubations. The concentration of the test compound

causing 50% inhibition (IC_50,µM) was calculated from the

concentration-inhibition response curve (duplicate determina-

tions).

E

ated.

_{intermolecular}(kcal/mol) of the ligand-enzyme assembly was evalu-

Acknowledgment. We are grateful to the Canadian Institutes

of Health Research (CIHR) (MOP-14712) for financial support

of this research, and to Rx&D-HRF/CIHR for a postdoctoral

fellowship (to Q.H.C.).

Supporting Information Available: A table of microanalytical

data is presented for compounds 11-13, 15-17, 20-23, 25, 26

and 28. This material is available free of charge via the Internet at

http://pubs.acs.org.

References

(1) Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins,

P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.;

Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.; Anderson,

G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.; Koboldt, C.

M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;

Isakson, P. C. Synthesis and biological evaluation of the 1,5-

diarylpyrazole class of cyclooxygenase-2 inhibitors: identification

of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]ben-

zenesulfonamide (SC-58635, celecoxib). J. Med. Chem. 1997, 40,

1347-1365.

(2) De Leval, X.; Julemont, F.; Benoit, V.; Frederich, M.; Pirotte, B.;

Dogne, J. M. First and second generations of COX-2 selective

inhibitors. Mini ReV. Med. Chem. 2004, 4, 597-601.

(3) Dogne´, J. M.; Supuran, C. T.; Pratico, D. Adverse cardiovascular

effects of the coxibs. J. Med. Chem. 2005, 48, 2251-2257.

(4) Solomon D. H.; Selective cyclooxygenase-2 inhibitors and cardio-

vascular events. Arthritis Rheum. 2005 52, 1968-1978.

(5) Vane, J. R.; Botting, R. M. Antiinflammatory drugs and their

mechanism of action. Inflamm Res. 1998, 47, S78-S87.

(6) Funk, C. D. Prostaglandins and leukotrienes: advances in eicosanoids

biology, Science 2001, 294, 1875-1890.

(7) Drazen, J. M.; Israel, E.; O’Byrne, P. M. Treatment of asthma with

drugs modifying the leukotriene pathway. N. Engl. J. Med. 1999,

340, 197-206.

(8) Zhao, L.; Funk, C. D. Lipoxygenase pathways in atherogenesis.

Trends CardioVasc. Med. 2004, 14, 191-195.

Antiinflammatory Assay. The test compounds were evaluated

using the in vivo rat carrageenan-induced foot paw edema model

reported previously.^27,28

(9) Julemont, F.; Dogne, J. M.; Pirotte, B.; de Leval, X. Recent

development in the field of dual COX/5-LOX inhibitors. Mini ReV.

Med. Chem. 2004, 4, 633-638.

Dual Inhibitors of Cyclooxygenases and Lipoxygenases

Journal of Medicinal Chemistry, 2006, Vol. 49, No. 5 1683

(10) Charlier, C.; Michaux, C. Dual inhibition of cyclooxygenase-2 (COX-

2) and 5-lipoxygenase (5-LOX) as a new strategy to provide safer

non-steroidal anti-inflammatory drugs. Eur. J. Med. Chem. 2003, 38,

645-659.

(20) Rao, P. N. P.; Uddin, M. J.; Knaus, E. E. Design, synthesis, and

structure-activity relationship studies of 3,4,6-triphenylpyran-2-ones

as selective cyclooxygenase-2 inhibitors. J. Med. Chem. 2004, 47,

3972-3990.

(21) Weiss, K. L.; Alshafie, G.; Chapman, J. S.; Mershon, S. M.; Abou-

Isaa, H.; Clagett-Dame, M.; Curley, R. W. An unhydrolyzable

analogue of N-(4-hydroxyphenyl)retinamide. synthesis and prelimi-

nary biological studies. Bioorg. Med. Chem. Lett. 2001, 11, 1583-

1586.

(11) Janusz J. M.; Young P. A.; Ridgeway, J. M.; Scherz, M. W.;

Enzweiler, K.; Wu, Li.; Gan, L.; Darolia, R.; Matthews, R. S.;

Hennes, D.; Kellstein, D. E.; Green, S. A.; Tulich, J. L.; Rosario-

Jansen, T.; Magrisso, I. J.; Wehmeyer, K. R.; Kuhlenbeck, D. L.;

Eichhold, T. H.; Dobson, R. L.; Sirko, S. P.; Farmer, R. W. New

cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-butyl-2,3-di-

hydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe

antiinflammatory and analgesic agents: discovery and variation of

the 5-keto substituent. J. Med. Chem. 1998, 41, 1112-1123.

(12) Alvaro-Gracia, J. M. Licofelone-clinical update on a novel LOX/

COX inhibitor for the treatment of osteoarthritis. Rheumatology 2004,

43, i21-i25.

(13) Pommery, N.; Taverne, T.; Telliez, A.; Goossens, L.; Charlier, C.;

Pommery, J.; Goossens, J. F.; Houssin, R.; Durant, F.; Henichart, J.

P. New COX-2/5-LOX inhibitors: apoptosis-inducing agents poten-

tially useful in prostate cancer chemotherapy. J. Med. Chem. 2004,

47, 6195-6206.

(14) Ye, Y. N.; Wu, W. K.; Shin, V. Y.; Bruce, I. C.; Wong, B. C.; Cho,

C. H. Dual inhibition of 5-LOX and COX-2 suppresses colon cancer

formation promoted by cigarette smoke. Carcinogensis 2005, 26,

827-834.

(15) Jahng, Y.; Zhao, L, X.; Moon, Y, S.; Basnet, A.; Kim, E. K.; Chang,

H. W.; Ju, H. K.; Jeong, T. C.; Lee, E. S. Simple aromatic compounds

containing propenone moiety show considerable dual COX/5-LOX

inhibitory activities. Bioorg. Med. Chem. Lett. 2004, 14, 2559-2562.

(16) Rao, P. N. P.; Chen, Q. H.; Knaus, E. E. Synthesis and biological

evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of

cyclooxygenases and lipoxygenases. Bioorg. Med. Chem. Lett. 2005,

15, 4842-4845.

(22) Jiang, Z. Y.; Wang, Y. G. A Mild, Efficient and selective cleavage

of aryl tert-butyldimethysilyl ethers using KOH in ethanol. Chem.

Lett. 2003, 32, 568-569.

(23) Cox, R. J.; Ritson, D. J.; Dane, T. A.; Berge, J.; Charmant, J. P. H.;

Kantacha, A. Room temperature palladium catalyzed coupling of acyl

chlorides with terminal alkynes. Chem. Commun. 2005, 1037-1039.

(24) Luong, C.; Miller, A.; Barnett, J.; Chow, J.; Ramesha, C.; Browner,

M. F. Flexibility of the NSAID binding site in the structure of human

cyclooxygenase-2. Nature Struct. Biol. 1996, 3, 927-933.

(25) Gillmor, S. A.; Villasenor, A.; Fletterick, R.; Sigal, E.; Browner, M.

F. The structure of mammalian 15-lipoxygenase reveals similarity

to the lipases and the determinants of tsubstrate specificity. Nature

Struct. Biol. 1997, 4, 1003-1009.

(26) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C. C.; Charleson, S.;

Cromlish, W.; Ethier, D.; Evans, J. F.; Ford-Hutchinson, A. W.;

Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser, M.; Kargman, S.;

Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O’Neill, G. P.;

Ouellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.;

Zamboni, R.; Boyce, S.; Rupniak, N.; Forrest, M.; Visco, D.; Patrick,

D. The discovery of rofecoxib, [MK 966, VIOXX, 4-(4′-methylsul-

fonylphenyl)-3-phenyl-2(5H)-furanone], an orally active cyclooxy-

genase-2 inhibitor. Bioorg. Med. Chem. Lett. 1999, 9, 1773-1778.

(27) Winter, C. A.; Risley, E. A.; Nuss, G. W.; Carrageenan-induced

edema in hind paw of the rat as an assay for antiinflammatory drugs.

Proc. Soc. Exp. Biol. Med. 1962, 111, 544-552.

(28) Kumar, P.; Knaus, E. E. Synthesis and antiinflammatory activity of

N-substituted dihydropyridylacetic acids, esters and amides. Drug

Des. DeliVery 1987, 2, 145-149.

(29) Fukawa, K.; Kawano, O.; Hibi, M.; Misaka, N.; Ohba, S.; Hatanaka,

Y. Method for evaluating analgesic agents in rats. J. Pharmacol.

Methods 1980, 4, 251-259.

(17) Gavrilov, L. D.; Meshcheryakov, V. I.; Glazunova, N. P.; Kalyagina,

G. F.; Dobronravova, Z. A.; Vereschchagin, L. I. Synthesis of

diarylpropynones and their antibiotic activity. Pharm. Chem. J. 1978,

12, 1146-1149.

(18) Ahmed, M. S. M.; Mori, A. Carbonylative Sonogashira coupling of

terminal alkynes with aqueous ammonia. Org. Lett. 2003, 5, 3057-

3060.

(19) Maeda, Y.; Kakiuchi, N.; Matsumura, S.; Nishimura, T.; Kawamura,

T.; Uemura, S. Oxovanadium complex-catalyzed aerobic oxidation

of propargylic alcohols. J. Org. Chem. 2002, 67, 6718-6724.

JM0510474

Article Doi

Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: Dual inhibitors of cyclooxygenases and lipoxygenases

DOI: 10.1021/jm0510474

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