C3 amino-substituted chalcone derivative with selective adenosine rA1 receptor affinity in the micromolar range

Chemical Papers

https://doi.org/10.1007/s11696-020-01414-9

ORIGINAL PAPER

C3 amino‑substituted chalcone derivative with selective adenosine

rA receptor afnity in the micromolar range

1

Helena D. Janse van Rensburg¹ · Lesetja J. Legoabe¹ · Gisella Terre’Blanche¹ ^,²

Received: 10 March 2020 / Accepted: 3 November 2020

©

Institute of Chemistry, Slovak Academy of Sciences 2020

Abstract

To identify novel adenosine receptor (AR) ligands based on the chalcone scaꢀold, herein the synthesis, characterization and

in vitro and in silico evaluation of 33 chalcones (15–36 and 37–41) and structurally related compounds (42–47) are reported.

These compounds were characterized by radioligand binding and GTP shift assays to determine the degree and type of bind-

ing aꢁnity, respectively, against rat (r) A and A ARs. The chalcone derivatives 24, 29, 37 and 38 possessed selective

1

2A

A aꢁnity below 10 µM, and thus, are the most active compounds of the present series; compound 38 was the most potent

1

selective A AR antagonist (K (r)=1.6 µM). The structure–aꢁnity relationships (SAR) revealed that the NH -group at posi-

1

i

2

tion C3 of ring A of the chalcone scaꢀold played a key role in aꢁnity, and also, the Br-atom at position C3′ on benzylidene

ring B. Upon in vitro and in silico evaluation, the novel C3 amino-substituted chalcone derivative 38—that contains an α,ß-

unsaturated carbonyl system and easily allows structural modiꢂcation—may possibly be a synthon in future drug discovery.

Graphic abstract

C3 amino-substituted chalcone derivative (38) with C3′ Br substitution on benzylidene ring B possesses selective adenosine

rA receptor aꢁnity in micromolar range.

1

O

increased A AR affinity

1

1'

1

1'

1

1'

A

B

A

B

A

B

2

2'

2

2'

2

Br

2'

3

H

3'

Br

3

NH₂

3'

Br

3

NH₂

27

38

A K (r) = 1.559 µM

37

A K (r) = 7.069 µM

specific binding >20%

1

i

1 i

Keywords Chalcone · Schiꢀ base · Base- and acid-catalysed Claisen–Schmidt condensation reactions · Selective adenosine

A receptor antagonist · Neurological conditions

1

Electronic supplementary material The online version of this

Introduction

article (https://doi.org/10.1007/s11696-020-01414-9) contains

supplementary material, which is available to authorized users.

In the human body, adenosine takes part in both physiologic

*

Lesetja J. Legoabe

and pathophysiologic processes (Boison 2018). Most, if not

all, of these actions are mediated by four cell surface recep-

Lesetja.Legoabe@nwu.ac.za

1

tors, denoted A , A , A and A (Fredholm et al. 1994,

1 2A 2B 3

Centre of Excellence for Pharmaceutical Sciences, North-

West University, Private Bag X6001, Potchefstroom 2520,

South Africa

2001, 2011). Ensuing almost 100 years of research on adeno-

sine and its receptors as well as the ligands that bind to these

adenosine receptors (ARs), the potential of the adenosine

2

Pharmaceutical Chemistry, School of Pharmacy, North-West

University, Private Bag X6001, Potchefstroom 2520,

South Africa

Vol.:(0

1

123456789)

3

Chemical Papers

system as a drug discovery target is evident (de Lera Ruiz

et al. 2013).

Apart from learning and memory, adenosine and its

receptors—speciꢂcally the A AR—also modulate anxiety

1

The A AR has been cloned from diꢀerent mammalian

where blockade of the A AR results in anxiolytic actions

1

species, including humans (Müller 2001) and show struc-

tural homology among diverse mammalian species (Ralevic

and Burnstock 1998) (although lower aꢁnity for human than

rat receptors have been reported) (Klotz et al. 1997). A mem-

ber of the seven transmembrane-spanning G-protein-coupled

receptor superfamily (that preferentially couples to inhibi-

(Maemoto et al. 2004). The A AR agonist R-PIA exac-

1

erbated the eꢀects of ethanol withdrawal, whereas the A

1

AR antagonist CPT improved these anxiogenic eꢀects in

the elevated plus-maze and light/dark test, relevant behav-

ioural animal models of anxiety (Gatch et al. 1999). These

results suggest that A AR antagonists, at some doses, may

1

tory G heterotrimeric G-proteins) (Freissmuth et al. 1991;

be useful for ameliorating the anxiogenic eꢀects produced

by ethanol withdrawal, although it does not appear useful for

reducing ethanol consumption (Gatch et al. 1999). Further-

more, the widely used anxiolytic agents, benzodiazepines,

i/o

Munshi et al. 1991; Ralevic and Burnstock 1998), the A

1

AR inhibits adenylate cyclase and decreases cyclic adeno-

sine monophosphate (Londos et al. 1980; Van Calker et al.

1

978). Other second messenger systems may also be coupled

block adenosine uptake (Noji et al. 2004) and decreased A

1

to the A AR, such as phospholipase C and several types

AR binding capacity in vivo at doses of clinical relevance

(Kaplan et al. 1992). As with the adenosine system and

its eꢀects on learning and memory, there is controversy:

DPCPX did not aꢀect the anxiety state of mice in the ele-

1

of calcium and potassium channels (Ralevic and Burnstock

1

998). A ARs are widely distributed in diꢀerent mamma-

1

lian species (Ralevic and Burnstock 1998) and ubiquitous

within the central nervous system, with the highest density

in the cerebral cortex, cerebellum, hippocampus, thalamus,

brainstem and spinal cord (Dixon et al. 1996; Reppert et al.

vated plus-maze test (Jain et al. 1995) and A AR knockout

1

mice showed signs of increased anxiety in the light/dark test

(Johansson et al. 2001).

1

991). These receptors are localized in the active zone of

Adenosine and its analogues have been known to cause

behavioural despair in animal models relevant to depression.

The A , rather than the A , AR is involved in depression;

the presynaptic nerve terminal (Rebola et al. 2003; Swanson

et al. 1995), a highly specialized region of the cytoplasm

that directly faces the synaptic cleft (Sankaranarayanan and

Ryan 2007).

2

A

1

based on evidence from pharmacology and A AR knock-

2

A

out mice (Yacoubi et al. 2001). (Additionally, the selective

A AR antagonist istradefylline not only improves motor

2A

At presynaptic nerve terminals, A ARs play a role in the

1

release of neurotransmitters (Dunwiddie 1985). Adenosine

acts by inhibiting cholinergic transmission, among other,

ꢃuctuations but also some non-motor symptoms of Parkin-

son’s disease (PD); such as the mood disorder depression—

the most common non-motor symptom of PD (Aarsland

et al. 2012; Nagayama et al. 2019) This is yet to be con-

ꢂrmed by a double-blind placebo-controlled trial (Nagayama

via A ARs (Phillis 1991). The cholinergic system has

1

been associated with a number of cognitive functions, for

example, learning and memory as well as emotion (Jackson

2

011).

et al. 2019). Interestingly, the selective A AR antagonist

1

Interaction between the adenosine and cholinergic system

DPCPX enhanced the anti-depressant eꢀects of selective

serotonin re-uptake inhibitors (SSRIs) imipramine, escitalo-

pram and reboxetine in mice behavioural tests (Szopa et al.

2018); nevertheless, the eꢀects of atypical antidepressants

agomelatine and tianeptine were increased, not by DPCPX,

but by the selective A AR antagonist DMPX (Szopa et al.

is regrettably controversial; on the one hand, administration

of a selective A AR agonist (e.g. CPA) caused learning and

1

memory deꢂcits, which may be prevented by a selective A

1

AR antagonist (e.g. DPCPX) (Normile and Barraco 1991),

and on the other hand, the said antagonist also caused learn-

ing and memory deꢂcits (Vollert et al. 2013)! Moreover, it

2

A

2019).

was found that chronic treatment with A AR modulators

The orally active and brain penetrable pyrazolopyridine

1

result in behavioural eꢀects diꢀerent from those observed

following acute administration; therefore, particular caution

is required in the development of adenosine-based strategies

for the chronic treatment of neurodegenerative or cognitive

disorders (Von Lubitz et al. 1993). Other studies advocated

the use of A AR antagonists and considered the A AR

derivative FR194921 (1) exhibits potent aꢁnity for the A

1

AR (A (h) K = 2.9 nM) without aꢁnity for the A and

1

i

2A

A ARs (Fig. 1). In addition, no species diꢀerences among

3

human, rat and mouse were observed in the binding aꢁn-

ity proꢂle of this compound (Maemoto et al. 2004). After

oral administration of FR194921 (1), hypolocomotion in

1

an interesting drug target for the development of cognitive

rats caused by the A AR agonist CPA was bettered demon-

1

enhancers based on the observation that A AR antagonism

strating A AR antagonism in vivo (Maemoto et al. 2004).

1

positively modulated memory process (Maemoto et al. 2004;

Normile and Barraco 1991; Pitsikas and Borsini 1997;

Suzuki et al. 1993).

Additionally, scopolamine-induced memory deꢂcits (passive

avoidance test) as well as anxiety (social interaction test and

elevated plus-maze test) were also bettered by the said com-

pound (1), without inꢃuencing general behaviour (Maemoto

1

3

Chemical Papers

O

N

S

O

2

N

A

1

& A2A

K

i

(h) >30 µM

N

A K (h) = 5.2 µM

3

i

1

A K (h) = 2.9 nM

1

i

Fig. 2 The chemical structure and A , A and A K (h) values of 2

1

2A

3 i

Fig. 1 The chemical structure and A K (h) value (nM) of FR194921

1

i

(

1)

(

Vazquez‐Rodriguez et al. 2013), the blockade of A ARs

3

et al. 2004). FR194921 (1) showed no anti-depressant activ-

ity (forced swim test)—even at high doses. It may be said

that FR194921 (1) shows promise in the treatment of mem-

ory deꢂcits and anxiety (Maemoto et al. 2004).

may be advantageous in brain ischemia (Fig. 2) (Jacobson

and Gao 2006).

The term chalcone generally refers to chemicals with

an α,ß-unsaturated carbonyl system; thus, the chalcone

family has extensive structural diversity (Zhuang et al.

2017). For example, the chalcone-based benzocycloal-

kanone derivatives are hybrid chalcones with the core

scaꢀold of 1,3-diaryl-2-propen-1-one (Fig. 3). Some of

these compounds structurally related to chalcones include

The role of A AR antagonists in brain functioning is not

1

yet fully understood, and at times, debatable—yet, selective

A AR antagonists have potential for the treatment of neu-

1

rological and psychiatric conditions, as seen with the potent

and selective A AR antagonist FR184921 (1).

1

While diverse classes of A AR antagonists have been

aurone derivatives, which also possess selective A aꢁnity

1

documented since the discovery of the receptor and spe-

ciꢂc radiolabelled ligands, most of these compounds were

derived from xanthine analogues which show poor water

solubility and oral bioavailability, central nervous system

penetration and considerable species diꢀerences in terms of

receptor binding aꢁnity (Maemoto et al. 1997). Due to these

undesirable physiochemical properties of xanthine deriva-

tives, the focus has shifted from xanthine to non-xanthine

[such as hispidol (3)] (Jacobson et al. 2002) and served

as inspiration for the structurally related 2-benzylidene-

1-tetralone (4–8) (Janse van Rensburg et al. 2017; Lego-

abe et al. 2018) and 2-benzylidene-1-indanone derivatives

(9–12) (Janse van Rensburg et al. 2019a, b), leading to

compounds with selective aꢁnity for the A AR in the

1

micromolar range.

The chemistry of chalcones is as attractive today as it

was years ago; due to the open-chain model and the feature

of skeletal modiꢂcation to produce a new class of organic

compounds such as isoxazole-, pyrazole- and indole-

based chalcones. Heterocycles occupy a central position

in medicinal chemistry and a number of both approved and

potential drugs contain at least one heterocyclic nucleus

(Khanam 2015; McGrath et al. 2010). Based on the above

and in continuation of the eꢀorts to obtain heterocycles

as A and/or A AR antagonists, simple chalcone deriva-

based heterocycles as A AR antagonists (de Lera Ruiz et al.

1

2

013).

The chemical structure 1,3-diphenyl-2-propen-1-one—

perhaps better known by the general term “chalcone”—has

attracted attention from both chemical (biosynthesis and

synthesis) and biological standpoints; due to the wide-

ranging pharmacological properties exhibited by these

compounds (Mathew et al. 2019; Zhuang et al. 2017).

These properties include anticancer, antileishmanial, anti-

malarial, antimicrobial, antiviral, antifungal, antioxidant,

antihypertensive and antidiabetic biological activities—

to name a few (Batovska and Todorova 2010; Sahu et al.

1

2A

tives (15–36) with either ring A or ring B substitutions as

well as a series of novel C3 amino-substituted chalcone

derivatives (37–41) with halogen (Br-, Cl- and F-atoms)

substitutions on ring B and their regioisomers (42–47)

were designed containing the basic chalcone scaꢀold as

structural core. Herein the synthesis, characterization and

evaluation, both in vitro and in silico, will be discussed to

ascertain the structure–aꢁnity relationships (SAR) that

govern A and/or A AR aꢁnity as well as the future of

2

012; Karthikeyan et al. 2015; Singh et al. 2014; Zhou and

Xing 2015). Additionally, chalcones show potential in the

treatment of neurological conditions by acting as anxio-

lytics and antidepressants, as well as the modulation of

gamma-aminobutyric acid (GABA) receptors and the inhi-

bition of acetylcholinesterase (AChE), butyrylcholinest-

erase (BChE) and monoamine oxidase (MAO) (Mathew

et al. 2019). Of note, the chalcone–coumarin hybrid (2)

possesses selective A AR aꢁnity (A K (h) = 5.2 µM)

1

2A

the said compounds as synthons by which a range of ana-

logues may be designed for future drug discovery.

3

i

1

3

Chemical Papers

Fig. 3 The chemical structure and A K (r) values of aurone (3), 2-benzylidene-1-tetralone (4–8) and 2-benzylidene-1-indanone (9–12) deriva-

1

i

tives

Results and discussion

highly eꢁcient formation of the carbon–carbon double

bond.

Chemistry

The synthesis of the Schiꢀ base or imine derivatives

4

2–47 by condensation of 3-aminoacetophenone and dif-

The synthesis of the chalcone derivatives 15–36 and 37–41

ferent substituted benzaldehydes using a base catalyst in

a polar solvent (Fig. 4a)—analogous to the reaction con-

ditions of chalcone derivatives 15–36—was not planned.

Initially, it was thought that the said reaction conditions

would yield compounds 37–41 and not the regioisomers

of these C3 amino-substituted chalcone derivatives com-

prised of two aromatic rings linked via an azomethine

(C=N) group. Schiꢀ base or imine compounds are formed

by the reaction of a primary amine (such as 3-aminoaceto-

phenone) and either aldehydes (such as the diꢀerent sub-

stituted benzaldehydes) or ketones with the simultaneous

removal of water (Furniss et al. 1989). When one, or both,

of the reactants are aromatic, the imine is quite stable and

usually known as a Schiꢀ base, additionally, in the case of

wholly aliphatic reactants the imines tend to decompose

or polymerise (Furniss et al. 1989).

was done by a Claisen–Schmidt condensation reaction

(

Claisen and Claparède 1881; Schmidt 1881) of aceto-

phenone and benzaldehyde using either a base or an acid

catalyst in a polar solvent (Fig. 4a, b)—this well-known

synthetic route is deemed a classical organic chemistry

reaction. As stated, the condensing agents are either strong

bases or acids (generally, basic conditions are more com-

mon in chalcone synthesis) (Gaonkar and Vignesh 2017;

Gomes et al. 2017; Rammohan et al. 2020; Zhuang et al.

2

017); in the case of base catalysts (15–36), the chalcone

is generated from the aldol product via dehydration in an

enolate mechanism, while in the case of acid catalysts

(

37–41), the chalcone is generated via an enol mechanism

Nielsen and Houlihan 2004; Noyce and Pryor 1955). The

Claisen–Schmidt condensation reaction is widespread in

the literature because of its experimental simplicity and

1

3

Chemical Papers

Fig. 4 Synthesis of 15–36,

3

7–41 and 42–47 (R substitu-

ents are identiꢂed in Tables 2,

3

, 4). Reagents and conditions:

a EtOH, KOH (10% (w/v) aque-

ous solution), room tempera-

ture; b MeOH, HCl (32 wt. % in

H O, FCC), 120 °C

2

Under the adopted synthetic routes, the test compounds

and two other signals typical of C (121.39 ppm) and C

α

ß

1

5–36, 37–41 and 42–47 were obtained in fair to good

(142.81 ppm).

yields, puriꢂed by recrystallization from a suitable solvent

EtOH), and in the instance of compounds 37–41 and 42–47,

From the coupling constant value of the ethylenic pro-

(

tons H and H (J

=15.7 Hz), it may be deduced that

Hα,Hß

α

ß

the structure, molecular mass and/or purity of these com-

compound 38 exists in the trans (E) conꢂguration (Aksöz

and Ertan 2012; Barros et al. 2004; Jung et al. 2008; Ople-

talova et al. 2000; Rao et al. 2001, 2004). As a result of the

diamagnetic anisotropy (deshielding of proton due to local

diamagnetic current) of the carbonyl functional group, the

ethylenic proton of the (E) isomer gave a signal at a greater

chemical shift than the ethylenic proton of the (Z) isomer, as

the latter is more remote from the carbonyl functional group

(Bayer et al. 1991). Stereochemically, a chalcone might exist

as either a cis (Z)- or trans (E)-isomer, having two aromatic

rings linked via a three carbon α,ß-unsaturated carbonyl sys-

tem (Gomes et al. 2017; Hallgas et al. 2005). The cis (Z)-

conformer is thermodynamically less stable than the trans

(E)-conformer due to the steric eꢀects between the carbonyl

group and ring A (Hallgas et al. 2005; Van der Werten et al.

1995). The more stable trans (E)-isomer is the predominant

conꢂguration among chalcones (Gomes et al. 2017).

1

13

pounds were veriꢂed by H NMR, C NMR, MS and/or

HPLC (Supplementary data). The known chalcone deriva-

1

tives 15–36 were characterized by H NMR only, melting

point (DSC) and HPLC and are in accordance with the lit-

erature values.

Taking the novel 3-amino-substituted chalcone deriva-

2

2′

1

tive 38 (R =NH ; R =Br) as a representative case, the H

2

NMR spectrum displayed two characteristic signals for the

ethylenic protons H (nearer the carbonyl group) and H

α

ß

(

next to the H proton) at 7.73 and 7.97 ppm, respectively,

α

as doublets (J

= 15.7 Hz). Protons on the NH -group

2

Hα,Hß

(

similar to the proton on the OH-group) are not always vis-

1

ible on a H NMR spectrum as protons attached to a N-atom

(

or O-atom) are acidic, and thus, exchangeable. Also, the

1

3

C NMR spectrum displayed three characteristic signals:

a prominent signal for the carbonyl group at 188.36 ppm

1

3

Chemical Papers

The mass spectrum of compound 38 displayed an intense

and expressed as either mean or mean ± standard error of

the mean (SEM), respectively. Only compounds 24, 29, 37

and 38—which displayed speciꢂc binding values < 20%

at a maximum tested concentration of 100 µM—justiꢂed

+

79

[

M + H] molecular ion peak at 302.0164 ( Br isotope)

+

2

81

as well as an intense [M + H] peak at 304.0152 ( Br

isotope)—in accordance with the formulation depicted

(

C H BrNO). Since Bromine has two isotopes (in a ratio of

the determination of inhibition constant values (K , µM),

15

13

i

approximately 1:1), a compound containing a Br-atom (such

as compounds 37–38) will have two peaks of similar height

in the molecular ion region depending on which bromine

isotope the molecular ion contains. Additionally, the two

unlike compounds 15–23, 25–28, 30–36, 39–41 and 42–47

(speciꢂc binding values > 20%). The radioligand binding

assays were validated with CPA (A agonist), DPCPX (A

1

antagonist) and istradefylline (A antagonist) as reference

2

A

+

M molecular ion peaks for compound 38 (C H BrNO)

compounds and results were in accordance with literature

1

5

12

7

9

81

may be seen at 301.0096 ( Br isotope) and 303.0095 ( Br

values (Table 1).

isotope). Of note, chlorine also has two isotopes, namely

3

5

37

Cl and Cl (in a ratio of 3:1) meaning a similar eꢀect may

Structure–afnity relationships (SAR)

be observed on the mass spectrum of an organic compound

containing a Cl-atom (for example, compounds 39–40). The

purity of compound 38 determined by HPLC was 98.0549%.

The melting point of compound 38 determined by DSC was

As depicted in Tables 2, 3 and 4, most of the test compounds

showed poor A and/or A AR aꢁnity upon in vitro evalu-

1

2A

ation—making it diꢁcult to determine SAR; however, some

broad conclusions may be drawn from these results. In brief,

the test compounds were noticeably more active against the

A AR than A AR and the chalcone derivatives 24, 29,

1

76.78 °C.

The word chalcone is derived from the Greek word “chal-

cos”, meaning “bronze”, which results from the colours of

most natural chalcones (Sahu et al. 2012). The bronze colour

of chalcones is most likely due to the reactive keto-ethyl-

enic group CO–CH=CH–; a chromophore responsible for

the colour of chalcones depending on the presence of other

auxochromes (Gaonkar and Vignesh 2017). This bronze col-

our scheme was also observed with most of the synthesised

chalcones, for example, the light brown colour of 38.

1

2A

37 and 38 showed selective A AR aꢁnity below 10 µM—

1

of these compounds, 38 had the best A AR aꢁnity (A K

1

1 i

(r)=1.6 µM). The type of substitution on ring A of the chal-

cone scaꢀold played a key role in aꢁnity, and also, the type

and position of the substitution on benzylidene ring B.

As stated, the chalcone derivatives 24 (A K (r)=5.3 µM)

1

i

and 29 (A K (r) = 6.1 µM) (Table 2) showed selective A

1

i

1

As stated, the 3-amino-substituted chalcones and the

Schiꢀ base derivatives 42–47 are regioisomers (molecules

with the same molecular formula, but diꢀerent bonding pat-

terns and atomic organisations), and as such, dissimilari-

AR aꢁnity below 10 µM, and although, the K (r) values of

i

these compounds were quite similar the substitutions on ring

B were not; 24 was C2′, C4′, C5′-trimethoxy substituted and

29 was C2′-chloro substituted. In the past, the antimicrobial

(Karaman et al. 2010; Ramyashree et al. 2017), anticancer

(Juvale et al. 2012; Mellado et al. 2018) and/or antioxidant

(Shenvi et al. 2013) activities of compounds 24 and 29 were

1

13

ties were detected on the H NMR and C NMR spectra

when comparing these compounds. The absence of the eth-

1

ylenic protons H and H may be observed on the H NMR

α

ß

1

3

spectrum and the signals typical of C and C , on the

C

also explored, and now, selective A AR aꢁnity may be

α

ß

1

NMR. In the place of these signals, the proton adjacent to

added.

1

the azomethine group was visible on the H NMR spectrum

With regard to compound 24 and A AR aꢁnity, it seems

1

3

and the carbon of the azomethine group on the C NMR

that the C2′, C4′, C5′ substitution pattern on ring B was pre-

1

13

3

spectrum. Additionally, on both the H NMR and C NMR

spectra the methyl group from the acetophenone moiety was

clearly visible downꢂeld of all other signals.

ferred to that of compound 25 ([ H]DPCPX-speciꢂc binding

(r)=27%)—interestingly, these compounds diꢀer only at the

C5′ (24: –OCH ; 25: –H) and C6′ (24: –H; 25: –OCH ) posi-

3

tions. However, the radioligand-speciꢂc binding against the

3

A

AR of these compounds were the same (24–25: [ H]

2

A

Biology

NECA-speciꢂc binding (r)=28%). Comparison of 24 to the

structurally related 2-benzylidene-1-indanone compound

13 (Fig. 5) consisting of a fused 6- and 5-membered ring

system (ring A and ring C, respectively) along with C4′-

methoxy substitution on ring A had poor A and A AR

In vitro evaluation

Radioligand binding assays

1

2A

aꢁnity (Janse van Rensburg et al. 2019b). The decreased

The degree of binding affinity that the test compounds

showed toward rat (r) A and A ARs were determined

aꢁnity may be due to the increased number of C-, H- and

O atoms in the form of the C4 OCH -group substitution

1

2A

3

via radioligand binding assays in either duplicate [speciꢂc

on ring A and the CH -group present in ring C, increasing

2

binding (%)] or triplicate [inhibition constant (K , µM)]

the molecular weight from 298.34 g/mol (24) to 340.38 g/

i

1

3

Chemical Papers

Table 1 K values for the binding aꢁnity of reference compounds against rat (r) A and A ARs

i

1

2A

a

SI^g

GTP shift^h

#

K ± SEM (µM)

i

rA₁^bvs [ H]DPCPX

3

d

rA₂_A^cvs [ H]NECA^e

3

rA +GTP vs [ H]DPCPX

c

f

3

d

1

i

CPA (A agonist)

0.0057± 0.0015 (0.0068)

0.40± 0.17 (0.16)

0.099± 0.015 (0.099)

70 (24)

(22)

17 (15)

1

j

(

0.015)

(0.33)

(0.099)

(14)

k

0.0079)

i

DPCPX (A antagonist)

0.0005± 0.00003 (0.0004) 0.23± 0.03 (0.55)

0.0006± 0.00003 (0.0004)

468 (1362) 1.2 (1)

1

j

l

j

(

0.0005)

(0.53)

(0.34)

(0.0004)

(1060)

(1.3)

0.0003)^l

(1133)

m

0.0014± 0.0003 (0.0022)^m0.15± 0.02

Istradefylline (A₂_Aantago-

nist)

0.19± 0.01 (0.23)

7.3 (0.0096) 0.79

a

All inhibition constant (K ) values were determined in triplicate and expressed as mean± standard error of the mean (SEM) in µM

i

b

c

d

e

f

Rat receptors were used (rA : rat whole brain membranes)

1

Rat receptors were used (rA₂_A: rat striatal membranes)

3

0

4

.1 nM [ H]DPCPX

3

nM [ H]NECA

Addition of 100 µM GTP to A AR radioligand binding assay

1

g

Selectivity index (SI) for the A AR isoform calculated as a ratio of A K /A K

1

2A

i

1 i

h

i

GTP shift calculated by dividing K value in the presence of 100 µM GTP by K value in the absence of 100 µM GTP

i

Literature value obtained from (Janse van Rensburg et al. 2017)

j

Literature value obtained from (Van der Walt and Terre’Blanche 2015)

k

l

Literature value obtained from (Bruns et al. 1987)

Literature value obtained from (Lohse et al. 1987)

m

Literature value obtained from (Shimada et al. 1997)

mol (13), and perhaps, the resultant steric hindrance (of the

CH -group present in ring C and C2′ OCH -group on ring

A AR aꢁnity below 10 µM; for example, compound 37

1

H

(A K (r) = 7.1 µM) versus 39 ([3 ]DPCPX-speciꢂc bind-

2

3

1 i

B) also decreased binding aꢁnity (Liu et al. 2014; Vásquez-

Martínez et al. 2019). Interestingly, according to the physi-

ochemical properties calculated by the free web-tool Swis-

sADME, compound 24 will not be orally bioavailable, but

compound 13 will be. Both of these compounds were, unfor-

tunately, not lead-like based on the said parameters. (See “In

silico evaluation” for the complete results and discussion).

ing=26%). The A AR aꢁnity was enhanced almost ꢂve-

1

fold when the Br-atom was moved from the C2′ position

(37) to the C3′ position (38) on ring B. The importance of

the C3 NH -group substitution on ring A to attain A AR

2

1

aꢁnity was demonstrated by comparison of compound 38 to

H

its unsubstituted counterpart 27 ([3 ]DPCPX-speciꢂc bind-

ing=28%). Compound 38 had a K value of 1.6 µM against

i

3

Comparison of 29 (A K (r) = 6.1 µM) to 30–31 ([ H]

the A AR—the best of the evaluated compounds Therefore,

1

i

1

DPCPX-speciꢂc binding > 20%) demonstrated the impor-

it may be said that the A AR favours C3 NH -group sub-

1

2

tance of the position of the Cl-atom on ring B for A AR

stitution on ring A in combination with C3′ Br-atom sub-

stitution on ring B; based on these chalcones (15–41). The

SAR of the chalcone derivatives 27 and 29 and 37–39 are

summarized in Fig. 6.

1

aꢁnity; the C2′ (ortho) position (29) is preferred to the C3′

(

meta) and/or C4′ (para) positions (30–31). Additionally,

at the C2′ (ortho) position on ring B the more electronega-

tive Cl-atom (29) is favoured over the less electronegative

Br-atom (26). (It must be noted that compounds 26–27 and

3

Interestingly, the C3 amino-substituted chalcones 37 ([ H]

3

NECA-speciꢂc binding=30%) and 39 ([ H]NECA-speciꢂc

3

0 retained some aꢁnity against the A AR based on the

binding=23%) with a C2′ substituent [either a Br- (37) or

1

speciꢂc binding of less than 30%).

Cl-atom (39)] on ring B retained some aꢁnity against the

3

These trends were not observed with the C3 amino-sub-

stituted chalcone derivatives 37–41 (Table 3). Compound

A

AR, unlike compounds 38 ([ H]NECA-speciꢂc bind-

2

A

3

ing=75%), 40 ([ H]NECA-speciꢂc binding=72%) and 41

3

2

9 paralleled to its counterpart 39 showed decreased A AR

([ H]NECA-speciꢂc binding = 71%) with a C3′ substitu-

1

3

aꢁnity (39: [ H]DPCPX-speciꢂc binding=26%); this may

ent [either a Br- (38), Cl- (40) or F-atom (41)]. (Again, it

must be noted that compounds 39–41 retained some aꢁnity

be credited to the combination of the NH -group at posi-

2

tion C3 on ring A and the Cl-atom at position C2′. Further-

against the A AR based on the radioligand-speciꢂc binding

1

more, C2′ (ortho) Br-group substitution on ring B led to

of less than 30%). The importance of not only the type of

1

3

Chemical Papers

Table 2 K values for the binding aꢁnity of chalcone derivatives (15–36) against rat (r) A and A ARs

i

1

2A

R⁵^'

O

6

'

_R4'

R³^'

1

2

1'

2'

5'

4'

1

2

1

2

A

B

A

B

R³

4

R¹R¹^'

R³

4

R¹

R³

4

R¹

N

3

3'

3

O

R²

R

2'

R²

O

15-34

35

36

a

#

Ring A

Ring B

K ± SEM (µM) [speciꢂc

i

b

binding (%)]

c

3

e

d

2

R¹

3

R²

4

R³

2′

R¹^′

3′

R²^′

4′

R³^′

5′

R⁴^′

6′

R⁵^′

rA vs [ H]

rA

1

2A

3

DPCPX

vs [ H]

_N_E_C_Af

Structural modiꢂcation of ring A

15

16

17

18

19

H

OH

H

OH

OCH₃

Br

H

(35)

(65)

(56)

(141)

(117)

(79)

(129)

(83)

(106)

(117)

Structural modiꢂcation of ring B

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

H

OCH₃

Br

H

Cl

H

–

OH

OCH₃

H

Br

H

Cl

H

CN

–

H

OCH₃

H

Br

H

Cl

F

CF₃

H

–

H

OCH₃

H

–

H

OCH₃

H

–

(32)

(33)

(45)

(30)

5.3± 1

(27)

(24)

(40)

(106)

(78)

(50)

(28)

(50)

(42)

(91)

(42)

(88)

(77)

(98)

(156)

(155)

(75)

(73)

(28)

(110)

6.1± 1.1

(23)

(114)

(49)

(80)

(52)

(55)

(43)

OCH₃

–

a

All K values were determined in triplicate and expressed as mean± standard error of the mean (SEM) in µM

Speciꢂc binding (%) of the radioligand at a maximum tested concentration of 100 µM were determined in duplicate and expressed as the mean

i

b

in %

c

Rat receptors were used (rA : rat whole brain membranes)

1

d

Rat receptors were used (rA₂_A: rat striatal membranes)

e

f

3

0

.1 nM [ H]DPCPX

3

4

nM [ H]NECA

substituent, but also the position of the substituent on ring B

is clear from these comparisons, for example, a compound

aꢁnity (37 and 39). Previously, it was found that a copla-

nar geometry between the two ring systems (namely, ring A

and benzylidene ring B) in the ꢃavonols (notably, chalcones

may be considered open-chain ꢃavonols) is not required for

residual A and/or A AR aꢁnity; however, the C2′ posi-

with selective A AR aꢁnity may be obtained when a C3

1

NH -group substitution on ring A is combined with a C3′

2

halogen (Br>Cl>F) substitution on ring B of the chalcone

scaꢀold (e.g. 38, 40–41), whereas a C2′ halogen-substituted

ring B could yield a compound with dual A and/or A AR

1

2A

tion on ring B of compounds 37 and 39 was substituted (like

the ꢃavonol MRS 1067 with a planar geometry), and thus,

1

2A

1

3

Chemical Papers

Table 3 K values for the binding aꢁnity of chalcone derivatives (37–

functionality (present in compound 14) may also be respon-

sible for the selectivity of the said compound (as seen with

the triazine virtual screening hits).

i

4

1) against rat (r) A and A ARs

1

2A

O

As seen in Table 4 the Schiꢀ base containing compounds

1

2

1'

2'

4

2–47 showed poor A and A AR affinity. The best

A

B

1

2A

R¹

radioligand-speciꢂc binding at a concentration of 100 µM

3

NH

3'

R

2

against A and/or A AR was demonstrated by compounds

2

1

2A

4

5 and 47; displacing more than 50% of the radioligand at

37-41

A (45 and 47) and A (45) ARs. Comparison of 44 to 45

1

2A

showed that the inclusion of a bromine atom at position C3′

(44), rather than a hydrogen atom (45), in combination with

C2′–OH and C5′–Cl substitution on ring B was detrimental

to both A and A AR aꢁnity as the radioligand-speciꢂc

a

#

Ring B

K ± SEM (µM) [speciꢂc binding

i

b

(

%)]

rA₁^cvs [ H]DPCPX

3

e

rA

d

2

R¹

′

3′

R²

2A

3

1

2A

vs [ H]

f

binding increased more than twofold. The A AR seemed to

NECA

1

be more tolerable toward the said substitution. Schiꢀ base

a

b

3

4

7

8

9

0

1

Br

H

Cl

H

Br

H

Cl

F

7.1± 0.57

(30)

or imine derivatives are important synthetic intermediates

a

b

1.6± 0.02

(75)

(

Furniss et al. 1989); therefore, the synthesised and evalu-

b

(26)

(30)

(26)

(23)

ated compounds 42–47 may be of use in future studies.

b

(72)

b

H

(71)

GTP shiꢀt assays

a

All K_ivalues were determined in triplicate and expressed as

mean± standard error of the mean (SEM) in µM

The type of binding aꢁnity that test compounds 24 and 38

b

Speciꢂc binding (%) of the radioligand at a maximum tested concen-

exhibited at the rat A AR was determined via a GTP shift

1

tration of 100 µM were determined in duplicate and expressed as the

assay, as described previously (Lohse et al. 1987; Van der

mean in %

Walt and Terre’Blanche 2015; Van der Werten et al. 1995).

c

Rat receptors were used (rA : rat whole brain membranes)

1

GTP shifts were calculated by dividing the K values of com-

i

d

Rat receptors were used (rA₂_A: rat striatal membranes)

pounds reported in the presence of GTP by the K values

i

e

f

3

0

.1 nM [ H]DPCPX

obtained in the absence of GTP and the results are sum-

3

4

nM [ H]NECA

marized in Table 5.

Test compounds 24 and 38 were selected as they pos-

there is likely also steric hindrance to free rotation of the

benzylidene ring B of these compounds (37 and 39) (Karton

et al. 1996). Notably, the structurally related 2-benzylidene-

sessed the highest A AR aꢁnity in the three respective

1

series (Tables 2, 3, 4). The results suggested that compounds

24 and 38 acted as A AR antagonists, as the binding curves

1

-indanone 14 (Janse van Rensburg et al. 2019a) that is also

in the presence of GTP were almost unaꢀected and the cal-

culated GTP shifts were approximately 1 (Table 5; Fig. 8)

(Van der Werten et al. 1995; Gütschow et al. 2012). On

account of the structural similarity of the test compounds

(15–23, 25–36, 37 and 39–41), it may be supposed that these

C3′ bromo-substituted on benzylidene ring B has selective

A

AR aꢁnity, unlike compound 38 (Fig. 7). Therefore, the

2A

benzylidene indanone scaꢀold with C4 hydroxy-substitution

on ring A may be essential to selective A AR aꢁnity when

2A

compared to the C3 amino-substituted chalcone scaꢀold.

Compound 14 is structurally related to chromone hits with

selective A AR aꢁnity based on virtual screening, and

chalcone derivatives were all A AR antagonists.

1

In silico evaluation

2

A

perhaps, the conformation of these chromones binding to

the A AR is similar to that of compound 14—leading to

The physiochemical, pharmacokinetic as well as drug-like-

2

A

selectivity of the A AR versus the A AR (Langmead et al.

ness and medicinal chemistry friendliness of compounds 24,

2

A

1

2

012).

29, 37 and 38 (the only test compounds with selective A AR

1

Additionally, SAR demonstrated the importance of,

aꢁnity) were computed via SwissADME and these results

among other, the phenol functionality in triazine virtual

screening hits for selective A AR aꢁnity; possibly due

are summarized in Tables 6, 7 and 8, respectively.

The bioavailability radar (Fig. 9) gave a ꢂrst glance at

the drug-likeness of these compounds; compounds 24, 29,

37 and 38 fall within the optimal range for the parameters

lipophilicity, size, polarity, solubility and ꢃexibility (see

2

A

to the hydrogen bonding between the phenol functionality

6

.55

and Asn253

(Langmead et al. 2012). This key hydrogen

6

.55

bonding residue (Asn253 ) is situated centrally and capa-

ble of high-quality interactions with diverse heterocyclic

compounds (Langmead et al. 2012). Therefore, the phenol

3

Table 6), except for saturation (Csp > 0.25). The fraction

3

of carbon atoms in the sp hybridization of compounds 24

1

3

Chemical Papers

Table 4 K values for the binding aꢁnity of Schiꢀ base derivatives (42–47) against rat (r) A and A ARs

i

1

2A

O

1

2

1

A

2

3

N

_R1

1'

2'

B

R²

3'

5'

R⁴

4

R

'

O

3

O

42-46

47

a

#

Ring B

K ± SEM (µM) [speciꢂc binding

i

b

(

%)]

rA ^cvs [ H]DPCPX^e

3

rA

d

2

R¹

′

3′

R²^′

4′

R³^′

5′

R⁴^′

1

2A

3

vs [ H]

′

_N_E_C_Af

b

(197)^b

42

43

44

45

46

47

OH

–

H

Br

H

–

OCH₃

H

OCH₃

Cl

H

(91)

b

H

(70)

(75)

b

(101)

(95)

b

(43)^b

(44)

(74)

(47)

b

N(CH CH )

(69)

2

3 2

b

(66)^b

–

a

All K values were determined in triplicate and expressed as mean± standard error of the mean (SEM) in µM

Speciꢂc binding (%) of the radioligand at a maximum tested concentration of 100 µM were determined in duplicate and expressed as the mean

i

b

in %

c

Rat receptors were used (rA : rat whole brain membranes)

1

d

Rat receptors were used (rA₂_A: rat striatal membranes)

e

f

3

0

.1 nM [ H]DPCPX

3

4

nM [ H]NECA

Fig. 5 The structure–aꢁnity

relationships (SAR) of com-

pound 24 versus 13

(

0.17), 29 (0), 37 (0) and 38 (0) were smaller than 0.25 and,

the poor solubility of most chalcone-based compounds

[most probably the reason for poor in vivo eꢁcacy in pre-

clinical studies (Zhuang et al. 2017)]. Seeing as solubility

inꢃuences GI absorption (Ottaviani et al. 2010), a soluble

molecule will most probably facilitate drug development

(Ritchie et al. 2013).

thus, out of range. Consequently, compounds 24, 29, 37 and

3

8 were predicted not orally bioavailable.

The qualitative solubility classes of compounds 24, 29,

7 and 38 were moderately soluble to soluble in water [the

predicted values are the decimal logarithm of the molar

solubility in water (logS)]. This was encouraging given

1

3

Chemical Papers

Fig. 6 The structure–aꢁnity

relationships (SAR) of com-

pounds 27 and 29 and 37–39;

highlighting the importance of

C3 NH -substitution on ring A

2

in combination with C3′ (meta)

Br substitution on ring B for

selective rA AR aꢁnity

1

Fig. 7 The structure–aꢁnity

relationships (SAR) of com-

pound 38 versus 14

The BOILED-Egg model (Fig. 10) predicted passive

human gastrointestinal absorption (HIA) and blood–brain-

barrier (BBB) permeation as a function of the position of the

compound in the WLOGP-versus-TPSA referential (Daina

and Zoete 2016). Compounds 24, 29, 37 and 38 were pre-

dicted to have high GI absorption and permeate the BBB

1

3

Chemical Papers

Table 5 A K values (in the absence and presence of GTP) and calcu-

with the exception of 24 and/or 37–38 that did not inhibit

CYP2D6 (29 and 37–38) and CYP3A4 (29).

1

i

lated GTP shifts of 24 and 38

a

GTP shift^e

The drug-likeness of compounds 24, 29, 37 and 38

was assessed by various rule-based ꢂlters (Egan et al.

2000; Ghose et al. 1999; Lipinski et al. 1997; Muegge

et al. 2001; Veber et al. 2002) (Table 8). Compound 29

violated a rule-based ꢂlter from Muegge (Muegge et al.

#

K ± SEM (µM)

i

rA₁^bvs [ H]DPCPX

3

c

rA +GTP vs

b

d

c

1

3

[

H]DPCPX

24

38

5.3± 1^a

1.6± 0.02

7.8± 0.68

1.7± 1.3

1.5

1.1

a

2

001); namely that a compound should contain more than

a_Kvalues were determined in triplicate and expressed as

one heteroatom and the only atom other than carbon and

hydrogen that 29 contained was a chloro atom. Addition-

ally, compounds 24, 29, 37 and 38 all had a bioavailabil-

ity score of 0.55 (the probability that a compound will

have > 10% bioavailability in rat or measurable Caco-2

permeability) (Martin 2005).

i

mean± standard error of the mean (SEM) in µM

b

Rat receptors were used (A : rat whole brain membranes)

1

c

d

e

3

0

.1 nM [ H]DPCPX

Addition of 100 µM GTP to A AR radioligand binding assay

1

GTP shift calculated by dividing K value in the presence of 100 µM

i

GTP by K value in the absence of 100 µM GTP

The medicinal chemistry friendliness of compounds

i

2

4, 29, 37 and 38 was assessed by the identiꢂcation of

potentially problematic fragments; ꢂrst, pan assay interfer-

ence compounds (PAINS) (Baell and Holloway 2010) and,

second, structural alerts (Brenk et al. 2008). Compounds

24, 29, 37 and 38 contained no PAINS; however, Brenk

violations were present (Table 8). All these compounds

contained an α,ß-unsaturated carbonyl system perceived

as a potential Michael acceptor. Additionally, compounds

37–38 contained a potentially unwanted aniline group; as

aniline groups are perhaps inclined toward problems with

genetic toxicity (Clayson 1981).

(

Table 7). Additionally, these compounds were not substrates

for the permeability glycoprotein (Pgp) responsible for eꢄux

through biological membranes, for instance from the gastro-

intestinal wall to the lumen or from the brain (Montanari and

Ecker 2015). Pgp also protects the CNS from xenobiotics

(

Szakács et al. 2008).

The interaction of a compound with cytochromes P450

CYP) is important; seeing as these isoenzymes modulate

(

drug elimination through metabolic transformation (Testa

and Kraemer 2007); probably causing pharmacokinetics-

related drug–drug interactions (Hollenberg 2002; Huang

et al. 2008), leading to adverse or even toxic eꢀects due

to the lower clearance and accumulation of the drug or its

metabolites (Kirchmair et al. 2015). Compounds 24, 29, 37

and 38 were predicted to inhibit the major CYP isoforms

As compounds 24, 29, 37 and 38 did not have pro-

nounced aꢁnity toward the A AR, the present structures

1

need to be optimised, and here, lead-likeness [a molecular

entity suitable for optimization, most probably increasing

size and lipophilicity (Hann and Keserü 2012)] plays a role

(Teague et al. 1999). Accordingly, compounds 24, 37 and

38 (but not compound 29; due to molecular weight value

(

CYP12, CYP2C19, CYP2C9, CYP2D6 and CYP3A4),

a

b

1

50

1

50

00

+

GTP (100 µM)

+

-

GTP (100 µM)

GTP

- GTP

100

50

5

0

-

2

-1

0

1

2

3

-2

-1

0

1

2

3

Log[24] (µM)

Log[38] (µM)

3

Fig. 8 The binding curves of compounds 24 (a) and 38 (b) are exam-

whole brain membranes expressing A ARs with [ H]DPCPX as radi-

1

ples of A AR antagonistic action determined via a GTP shift assay

oligand. Calculated GTP shift of: 1.5 (24) and 1.1 (38)

1

performed in triplicate (with and without 100 μM GTP) using rat

1

3

Chemical Papers

smaller than 250 g/mol and consensus logP value larger

o/w

than 3.5) may be considered lead-like (Tables 6, 8).

Therefore, the optimization of the physiochemical proper-

ties of chalcones and, thus, the pharmacokinetic properties

as well as drug-likeness and medicinal chemistry friendli-

ness is of great importance for medicinal chemistry research

on chalcone-based compounds.

Experimental

Chemistry

Materials

Unless otherwise noted, all starting materials and solvents

were purchased from commercial vendors and used with-

out further puriꢂcation. Thin layer chromatography on TLC

silica gel 60 F aluminium sheets from Merck was used to

2

54

monitor reaction progress. Melting points were determined

by means of diꢀerential scanning calorimetry (DSC) with

a Mettler DSC 3 Star System (Mettler Toledo, Greifensee,

1

13

Switzerland). Proton ( H) and carbon ( C) nuclear magnetic

resonance (NMR) spectra were recorded on a Bruker Avance

III 600 spectrometer at frequencies of 600 and 151 MHz,

respectively, using either CDCl or DMSO-d6 as solvent and

3

TMS as reference. Chemical shifts were reported in parts

per million (ppm) in relation to the solvent peak (CDCl :

3

residual CH at 7.26 ppm and DMSO-d6: residual CH at

3

1

2

.50 ppm for H NMR). Spin multiplicities were indicated

as follows: singlet (s), doublet (d), triplet (t), quartet (q),

doublet of doublets (dd), triplet of doublets (td), double dou-

ble doublet (ddd) and multiplet (m). Coupling constant (J)

values were reported in Hertz (Hz). High-resolution mass

spectra (HRMS) were recorded on a Bruker micrOTOF-Q

II mass spectrometer in atmospheric chemical ionisation

(

APCI) mode. High-performance liquid chromatography

HPLC) analyses were done on an Agilent 1100 HPLC

system.

Synthesis oꢀ 15–36

(

2E)‑1,3‑Diphenylprop‑2‑en‑1‑one (15) A solution of ace-

tophenone (0.50 g, 4.16 mmol) and benzaldehyde (0.44 g,

.16 mmol) in EtOH (5 mL) was mechanically stirred at

4

room temperature for approximately 5 min before the drop-

wise addition of KOH (10% (w/v) aqueous solution, 5 mL).

The subsequent reaction mixture was mechanically stirred

at room temperature and continuously monitored by TLC.

Upon completion, the reaction mixture was quenched with

crushed ice (15 g) and acidiꢂed to pH 2 with HCl (32 wt. %

in H O, FCC). The subsequent precipitate was collected

2

by vacuum ꢂltration, dried (30 °C) and recrystallized from

1

3

Chemical Papers

Table 7 Pharmacokinetic

#

Pharmacokinetic properties

properties of compounds 24, 29,

3

7 and 38

GI absorption BBB

Pgp substrate CYP12

CYP2C19 CYP2C9 CYP2D6 CYP3A4

permea-

tion

inhibitor inhibitor

inhibitor inhibitor inhibitor

24

29

37

38

High

Yes

No

Yes

No

Yes

No

Yes

Table 8 Drug-likeness

#

Drug-likeness

Num. violations

Lead-likeness

and medicinal chemistry

friendliness of compounds 24,

2

9, 37 and 38

Lipinski^a

Ghose^b

Veber^c

Egan^d

Muegge^e

PAINS^f

Brenk^g

Teague^h

24

29

37

38

0

1

0

1

2

0

2

0

a

Lipinski: MW<500, MLOGP<4.15, N or O<10, NH or OH<5 (Lipinski et al. 1997)

Ghose: 160<MW<480, −04<WLOGP<5.6, 40<MR<130, 20<atoms<70 (Ghose et al. 1999)

Veber: Num. rotatable bonds<10, TPSA<140 (Veber et al. 2002)

Egan: WLOGP<5.88, TPSA<131.6 (Egan et al. 2000)

Muegge: 200<MW<600, −2<XLOGP<5, TPSA<150, num. rings<7, num. carbon>4, num. het-

b

c

d

e

eroatoms>1, num. rotatable bonds<15, num. H-bond acceptors<10, num. H-bond donors<5 (Muegge

et al. 2001)

f

Pan assay interference compounds (PAINS) implemented from Baell and Holloway (2010)

g

Structural alert implemented from Brenk et al. (2008)

Teague: 250<MW<350, num. rotatable bonds<7, XLOGP3<3.5 (Teague et al. 1999)

h

EtOH to yield the title compound 15 as light yellow crystals

DMSO) δ 10.46 (d, J = 7.9 Hz, 1H), 8.10–8.04 (m, 2H),

7.90 (d, J = 15.6 Hz, 1H), 7.86 (dd, J = 7.5, 1.7 Hz, 2H),

7.68 (d, J = 15.6 Hz, 1H), 7.45 (d, J = 6.9 Hz, 3H), 6.93–

6.89 (m, 2H) (Xie et al. 2017). Purity (HPLC): 98.9%.

1

(

0.43 g, 49%): mp: 57.87 °C (EtOH); H NMR (600 MHz,

DMSO) δ 8.16 (d, J=7.7 Hz, 2H), 7.95 (d, J=15.6 Hz, 1H),

.89 (d, J=4.8 Hz, 2H), 7.76 (d, J=15.6 Hz, 1H), 7.68 (t,

J=7.3 Hz, 1H), 7.58 (t, J=7.5 Hz, 2H), 7.46 (d, J=4.4 Hz,

H) (Xie et al. 2017). Purity (HPLC): 99.8%.

7

3

(2E)‑1‑(4‑Methoxyphenyl)‑3‑phenylprop‑2‑en‑1‑one

(

18) Prepared as for 15 from 4′-methoxyacetophenone

(

2E)‑1‑(2‑Hydroxyphenyl)‑3‑phenylprop‑2‑en‑1‑one

16) Prepared as for 15 from 2′-hydroxyacetophenone

(0.50 g, 3.33 mmol) and benzaldehyde (0.35 g, 3.33 mmol)

to yield the title compound 18 as white crystals (0.79 g,

1

(

0.50 g, 3.67 mmol) and benzaldehyde (0.39 g, 3.67 mmol)

52%): mp: 105.91 °C (EtOH); H NMR (600 MHz,

to yield the title compound 16 as dark yellow crystals

DMSO) δ 8.17 (d, J = 7.7 Hz, 2H), 7.94 (d, J = 15.6 Hz,

1H), 7.88 (d, J = 6.8 Hz, 2H), 7.71 (d, J = 15.6 Hz, 1H),

7.45 (d, J = 5.5 Hz, 3H), 7.09 (d, J = 7.7 Hz, 2H), 3.87 (s,

3H) (Zhang et al. 2015). Purity (HPLC): 97.2%.

1

(

0.05 g, 6%): mp: 87.21 °C (EtOH); H NMR (600 MHz,

CDCl ) δ 12.82 (s, 1H), 7.97–7.90 (m, 2H), 7.71–7.64 (m,

3

H), 7.51 (t, J=7.7 Hz, 1H), 7.45 (d, J=2.6 Hz, 3H), 7.04

d, J=8.3 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H) (Xie et al. 2017).

Purity (HPLC): 99%.

(

(2E)‑1‑(4‑Bromophenyl)‑3‑phenylprop‑2‑en‑1‑one

(

19) Prepared as for 15 from 4′-bromoacetophenone

(

2E)‑1‑(4‑Hydroxyphenyl)‑3‑phenylprop‑2‑en‑1‑one

17) Prepared as for 15 from 4′-hydroxyacetophenone

(0.50 g, 2.51 mmol) and benzaldehyde (0.27 g, 2.51 mmol)

to yield the title compound 19 as light yellow crystals

1

(

0.50 g, 3.67 mmol) and benzaldehyde (0.39 g, 3.67 mmol)

(0.72 g, 63%): mp: 103.26 °C (EtOH); H NMR (600 MHz,

to yield the title compound 17 as beige crystals (0.15 g,

CDCl ) δ 7.92–7.87 (m, 2H), 7.82 (d, J = 15.7 Hz, 1H),

3

1

8%): mp: 171.29 °C (EtOH); H NMR (600 MHz,

1

3

Chemical Papers

Fig. 9 The pink area rep-

resents the optimal range

for lipophilcity (LIPO:

−

0.7<XLOGP3<+5.0), size

(

SIZE: 150<MW<500), polar-

ity (POLAR: 20<TPSA<130),

solubility (INSOLU: logS<6),

saturation (INSATU: frac-

tion Csp3>0.25) and ꢃex-

ibility (FLEX: num. rotat-

able bonds<9). The red lines

represent the said parameters

of compounds 24, 29, 37 and

3

8. The red lines must fall com-

pletely within the pink area for

a compound to be considered

drug-like; therefore, compounds

2

4, 29, 37 and 38 are predicted

not orally bioavailable

7

.69–7.60 (m, 4H), 7.48 (d, J = 15.7 Hz, 1H), 7.44–7.40

J=1.7 Hz, 1H), 7.07 (dd, J=8.2, 2.4 Hz, 1H), 3.96 (s, 3H)

(

m, 3H) (Zhou et al. 2016). Purity (HPLC): 98%.

(Unoh et al. 2013). Purity (HPLC): 98.2%.

(

2E)‑3‑(3‑Hydroxyphenyl)‑1‑phenylprop‑2‑en‑1‑one

(2E)‑3‑(4‑Methoxyphenyl)‑1‑phenylprop‑2‑en‑1‑one

(22) Prepared as for 15 from acetophenone (0.50 g,

4.16 mmol) and 4-methoxybenzaldehyde (0.57 g,

4.16 mmol) to yield the title compound 22 as light yel-

(

4

20) Prepared as for 15 from acetophenone (0.50 g,

.16 mmol) and 3-hydroxybenzaldehyde (0.51 g,

4

.16 mmol) to yield the title compound 20 as light yellow

1

crystals (0.51 g, 55%): mp: 163.81 °C (EtOH); H NMR

low crystals (0.06 g, 6%): mp: 72.02 °C (EtOH); H NMR

(

600 MHz, DMSO) δ 9.63 (s, 1H), 8.17–8.09 (m, 2H), 7.83

(600 MHz, DMSO) δ 8.17–8.08 (m, 2H), 7.88–7.83 (m,

2H), 7.80 (d, J=15.6 Hz, 1H), 7.72 (d, J=15.6 Hz, 1H),

7.66 (t, J=7.4 Hz, 1H), 7.57 (t, J=7.7 Hz, 2H), 7.06–6.97

(m, 2H), 3.83 (s, 3H) (Zhang et al. 2015). Purity (HPLC):

100%.

d, J=15.6 Hz, 1H), 7.69–7.63 (m, 2H), 7.57 (t, J=7.7 Hz,

2

H), 7.31 (d, J=7.7 Hz, 1H), 7.26 (t, J=7.8 Hz, 1H), 7.23

(

s, 1H), 6.88 (dd, J=7.9, 1.7 Hz, 1H) (Xie et al. 2017).

Purity (HPLC): 99.9%.

(

4

2E)‑3‑(3‑Methoxyphenyl)‑1‑phenylprop‑2‑en‑1‑one

21) Prepared as for 15 from acetophenone (0.50 g,

(2E)‑3‑(2,4‑Dimethoxyphenyl)‑1‑phenylprop‑2‑en‑1‑one

(23) Prepared as for 15 from acetophenone (0.50 g,

4.16 mmol) and 2,4-dimethoxybenzaldehyde (0.69 g,

4.16 mmol) to yield the title compound 23 as dark yel-

.16 mmol) and 3-methoxybenzaldehyde (0.57 g,

4

.16 mmol) to yield the title compound 21 as dark yel-

1

low crystals (0.19 g, 19%): mp: 60.43 °C (EtOH); H

low crystals (0.18 g, 16%): mp: 69.63 °C (EtOH); H

NMR (600 MHz, CDCl ) δ 8.14–8.10 (m, 2H), 7.88 (d,

NMR (600 MHz, DMSO) δ 8.08 (d, J=7.5 Hz, 2H), 7.99

(d, J=15.7 Hz, 1H), 7.91 (d, J=8.6 Hz, 1H), 7.74 (d,

J=15.7 Hz, 1H), 7.64 (t, J=7.3 Hz, 1H), 7.56 (t, J=7.6 Hz,

3

J=15.7 Hz, 1H), 7.69 (t, J=7.4 Hz, 1H), 7.64–7.58 (m,

3

H), 7.44 (t, J=7.9 Hz, 1H), 7.38–7.32 (m, 1H), 7.26 (d,

1

3

Chemical Papers

Fig. 10 Compounds 24, 29,

7 and 38, which are not a

3

substrate for Pgp (PGP-), is

represented by the red circles

in the yellow region. The white

region is for high probability of

passive absorption by the gas-

trointestinal tract (HIA), and the

yellow region (yolk) is for high

probability of brain penetra-

tion (BBB). White and yellow

(

yolk) regions are not mutually

exclusive

1

2

H), 6.67–6.60 (m, 2H), 3.90 (s, 3H), 3.84 (s, 3H) (Suwito

(0.90 g, 75%): mp: 47.76 °C (EtOH); H NMR (600 MHz,

et al. 2014). Purity (HPLC): 94.8%.

DMSO) δ 8.24–8.12 (m, 3H), 8.01 (d, J = 15.5 Hz, 1H),

7

.95 (d, J = 15.5 Hz, 1H), 7.75 (dd, J = 8.0, 0.9 Hz, 1H),

(

4

2E)‑1‑Phenyl‑3‑(2,4,5‑trimethoxyphenyl)prop‑2‑en‑1‑one

24) Prepared as for 15 from acetophenone (0.50 g,

7.69 (t, J = 7.4 Hz, 1H), 7.59 (t, J = 7.7 Hz, 2H), 7.50 (t,

J = 7.5 Hz, 1H), 7.40 (td, J = 7.9, 1.6 Hz, 1H) (Wu et al.

2017). Purity (HPLC): 97.1%.

.16 mmol) and 2,4,5-trimethoxybenzaldehyde (0.82 g,

4

.16 mmol) to yield the title compound 24 as dark yellow

1

crystals (0.95 g, 79%): mp: 102.97 °C (EtOH); H NMR

(2E)‑3‑(3‑Bromophenyl)‑1‑phenylprop‑2‑en‑1‑one

(27) Prepared as for 15 from acetophenone (0.50 g,

4.16 mmol) and 3-bromobenzaldehyde (0.77 g, 4.16 mmol)

to yield the title compound 27 as light yellow crystals

(

600 MHz, CDCl ) δ 8.09 (d, J=15.8 Hz, 1H), 8.03–7.97

3

m, 2H), 7.55 (t, J=7.3 Hz, 1H), 7.47 (dd, J=20.6, 11.8 Hz,

3

H), 7.13 (s, 1H), 6.52 (s, 1H), 3.94 (s, 3H), 3.90 (s, 6H)

1

(

Shenvi et al. 2013). Purity (HPLC): 97.6%.

(0.62 g, 52%): mp: 84.50 °C (EtOH); H NMR (600 MHz,

DMSO) δ 8.24–8.16 (m, 3H), 8.03 (d, J = 15.6 Hz, 1H),

7.87 (d, J = 7.8 Hz, 1H), 7.74–7.62 (m, 3H), 7.58 (dd,

J = 10.7, 4.7 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H) (Wang et al.

2019). Purity (HPLC): 86.5%.

(

2E)‑1‑Phenyl‑3‑(2,4,6‑trimethoxyphenyl)prop‑2‑en‑1‑one

25) Prepared as for 15 from acetophenone (0.50 g,

4

.16 mmol) and 2,4,6-trimethoxybenzaldehyde (0.82 g,

.16 mmol) to yield the title compound 25 as bright yellow

1

crystals (0.43 g, 35%): mp: 109.17 °C (EtOH); H NMR

(2E)‑3‑(4‑Bromophenyl)‑1‑phenylprop‑2‑en‑1‑one

(28) Prepared as for 15 from acetophenone (0.50 g,

4.16 mmol) and 4-bromobenzaldehyde (0.77 g,

4.16 mmol) to yield the title compound 28 as light yel-

(

600 MHz, CDCl ) δ 8.26 (d, J=15.9 Hz, 1H), 8.03–7.98

3

m, 2H), 7.88 (d, J=15.9 Hz, 1H), 7.53 (t, J=7.3 Hz, 1H),

7

3

.47 (t, J=7.5 Hz, 2H), 6.14 (s, 2H), 3.90 (s, 6H), 3.86 (s,

1

H) (Sawle et al. 2008). Purity (HPLC): 88%.

low crystals (0.58 g, 49%): mp: 119.66 °C (EtOH); H

NMR (600 MHz, DMSO) δ 8.19–8.12 (m, 2H), 7.98

(d, J = 15.7 Hz, 1H), 7.87 (d, J = 8.5 Hz, 2H), 7.72 (d,

J = 15.7 Hz, 1H), 7.69–7.64 (m, 3H), 7.58 (t, J = 7.7 Hz,

2H) (Wu et al. 2017). Purity (HPLC): 98.3%.

(

2E)‑3‑(2‑Bromophenyl)‑1‑phenylprop‑2‑en‑1‑one

26) Prepared as for 15 from acetophenone (0.50 g,

4

.16 mmol) and 2-bromobenzaldehyde (0.77 g, 4.16 mmol)

to yield the title compound 26 as dark yellow crystals

1

3

Chemical Papers

(

2E)‑3‑(2‑Chlorophenyl)‑1‑phenylprop‑2‑en‑1‑one

29) Prepared as for 15 from acetophenone (0.50 g,

to yield the title compound 34 as light yellow crystals

1

(0.63 g, 65%): mp: 113.82 °C (EtOH); H NMR (600 MHz,

4

.16 mmol) and 2-chlorobenzaldehyde (0.58 g, 4.16 mmol)

DMSO) δ 8.51 (s, 1H), 8.20 (dd, J = 8.1, 1.0 Hz, 3H),

8.12 (d, J = 15.7 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.77

(d, J = 15.7 Hz, 1H), 7.67 (dd, J = 12.7, 4.7 Hz, 2H), 7.59

(t, J = 7.7 Hz, 2H) (Nagarajan and Shechter 1984). Purity

(HPLC): 94.7%.

to yield the title compound 29 as light yellow crystals

1

(

0.32 g, 32%): mp: 50.30 °C (EtOH); H NMR (600 MHz,

DMSO) δ 8.23 (dd, J=7.5, 1.9 Hz, 1H), 8.20–8.15 (m, 2H),

8

3

9

.03 (q, J=15.6 Hz, 2H), 7.72–7.66 (m, 1H), 7.62–7.55 (m,

H), 7.52–7.43 (m, 2H) (Wu et al. 2017). Purity (HPLC):

7.5%.

( 2 E) ‑ 3 ‑ [ 4 ‑ ( M o r p h o l i n ‑ 4 ‑ y l ) p h e n y l ] ‑ 1 ‑ p h e n y l ‑

prop‑2‑en‑1‑one (35) Prepared as for 15 from acetophe-

none (0.50 g, 4.16 mmol) and 4-(4-morpholinyl)benzal-

dehyde (0.80 g, 4.16 mmol) to yield the title compound

35 as bright yellow crystals (0.15 g, 13%): mp: 149.99 °C

(

2E)‑3‑(3‑Chlorophenyl)‑1‑phenylprop‑2‑en‑1‑one(30) Pre-

pared as for 15 from acetophenone (0.50 g, 4.16 mmol) and

3

-chlorobenzaldehyde (0.58 g, 4.16 mmol) to yield the title

1

compound 30 as light yellow crystals (0.32 g, 32%): mp:

(EtOH); H NMR (600 MHz, DMSO) δ 8.14–8.09 (m,

1

7

5.30 °C (EtOH); H NMR (600 MHz, DMSO) δ 8.19 (d,

2H), 7.78–7.61 (m, 5H), 7.55 (t, J = 7.7 Hz, 2H), 6.99 (d,

J = 8.9 Hz, 2H), 3.77–3.71 (m, 4H), 3.28–3.22 (m, 4H) (Li

et al. 2017). Purity (HPLC): 99.2%.

J=7.3 Hz, 2H), 8.09 (s, 1H), 8.04 (d, J=15.7 Hz, 1H),

.83 (d, J=7.2 Hz, 1H), 7.73 (d, J=15.7 Hz, 1H), 7.69 (t,

7

J=7.4 Hz, 1H), 7.58 (t, J=7.7 Hz, 2H), 7.53–7.46 (m, 2H)

(

Robinson et al. 2015). Purity (HPLC): 96%.

(2E)‑3‑(2H‑1,3‑benzodioxol‑5‑yl)‑1‑(3‑methoxyphenyl)

prop‑2‑en‑1‑one (36) Prepared as for 15 from 3-meth-

oxyacetophenone (0.50 g, 3.33 mmol) and 3,4-(methyl-

enedioxy)benzaldehyde (0.50 g, 3.33 mmol) to yield the

(

2E)‑3‑(3,4‑Dichlorophenyl)‑1‑phenylprop‑2‑en‑1‑one

(

4

31) Prepared as for 15 from acetophenone (0.50 g,

.16 mmol) and 3,4-dichlorobenzaldehyde (0.73 g,

title compound 36 as bright yellow crystals (0.92 g, 98%):

1

4

.16 mmol) to yield the title compound 31 as light yellow

mp: 77.10 °C (EtOH); H NMR (600 MHz, CDCl ) δ 7.73

3

1

crystals (0.35 g, 30%): mp: 108.62 °C (EtOH); H NMR

(d, J = 15.5 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.53 (s,

1H), 7.43–7.31 (m, 2H), 7.16 (s, 1H), 7.12 (d, J = 7.9 Hz,

2H), 6.84 (d, J = 7.5 Hz, 1H), 6.02 (s, 2H), 3.88 (s, 3H)

(Ruparelia et al. 2018). Purity (HPLC): 99.1%.

(

600 MHz, DMSO) δ 8.30 (d, J=2.0 Hz, 1H), 8.21–8.17

m, 2H), 8.07 (d, J=15.7 Hz, 1H), 7.89 (dd, J=8.4, 1.9 Hz,

1

H), 7.75–7.66 (m, 3H), 7.59 (t, J=7.7 Hz, 2H) (Choi et al.

2

016). Purity (HPLC): 95.9%.

(

2E)‑3‑(4‑Fluorophenyl)‑1‑phenylprop‑2‑en‑1‑one (32) Pre-

Synthesis oꢀ 37–41

pared as for 15 from acetophenone (0.50 g, 4.16 mmol) and

4

-ꢃuorobenzaldehyde (0.52 g, 4.16 mmol) to yield the title

( 2 E) ‑ 1 ‑ ( 3 ‑ A m i n o p h e n y l ) ‑ 3 ‑ ( 2 ‑ b r o m o p h e n y l )

prop‑2‑en‑1‑one (37) 3′-Aminoacetophenone (0.50 g,

3.70 mmol) and 2-bromobenzaldehyde (0.68 g, 3.70 mmol)

compound 32 as light yellow crystals (0.32 g, 34%): mp:

1

8

6.71 °C (EtOH); H NMR (600 MHz, DMSO) δ 8.15 (dd,

J=8.2, 1.1 Hz, 2H), 8.03–7.94 (m, 2H), 7.91 (d, J=15.6 Hz,

H), 7.75 (d, J=15.7 Hz, 1H), 7.70–7.64 (m, 1H), 7.57

dd, J=10.7, 4.7 Hz, 2H), 7.34–7.26 (m, 2H) (Stroba et al.

009). Purity (HPLC): 100%.

were suspended in MeOH (4 mL) and HCl (32 wt.% in H O,

2

1

FCC, 6 mL). The subsequent reaction mixture was mechani-

cally stirred at 120 °C under reꢃux while being continuously

monitored by TLC. Upon completion, the reaction mixture

was cooled to room temperature, ice (15 g) was added and the

resulting precipitate was ꢂltered, dried (30 °C) and recrys-

tallized from a suitable solvent to yield the title compound

37 as dark brown powder (1.10 g, 99%): mp: 189.86 °C

(

2

(

2 E) ‑ 1 ‑ P h e n y l ‑ 3 ‑ [ 4 ‑ ( t r i ꢀ l u o r o m e t h y l ) p h e n y l ]

prop‑2‑en‑1‑one (33) Prepared as for 15 from acetophe-

none (0.50 g, 4.16 mmol) and 4-(triꢃuoromethyl)benzalde-

hyde (0.72 g, 4.16 mmol) to yield the title compound 33 as

light yellow crystals (0.41 g, 36%): mp: 126.59 °C (EtOH);

1

(EtOH); H NMR (600 MHz, DMSO) δ 8.21–8.12 (m, 2H),

8.01 (d, J=15.5 Hz, 1H), 7.95 (s, 1H), 7.91 (d, J=15.5 Hz,

1H), 7.75 (d, J=7.9 Hz, 1H), 7.64 (t, J=7.8 Hz, 1H), 7.58

(dd, J=8.1, 0.8 Hz, 1H), 7.50 (t, J=7.5 Hz, 1H), 7.44–7.37

1

H NMR (600 MHz, DMSO) δ 8.20–8.16 (m, 2H), 8.11

(

dd, J=21.5, 11.9 Hz, 3H), 7.81 (dd, J=11.9, 8.8 Hz, 3H),

1

3

7

.73–7.66 (m, 1H), 7.59 (dd, J=10.6, 4.8 Hz, 2H) (Downey

(m, 1H); C NMR (151 MHz, DMSO) δ 188.30, 141.78,

138.30, 133.80, 133.34, 132.35, 130.19, 128.76, 128.26,

et al. 2018). Purity (HPLC): 94.4%.

1

26.55, 126.49, 125.44, 124.70, 121.31. APCI-HRMS m/z

3

(

4

‑[(1E)‑3‑Oxo‑3‑phenylprop‑1‑en‑1‑yl]benzonitrile

34) Prepared as for 15 from acetophenone (0.50 g,

.16 mmol) and 3-cyanobenzaldehyde (0.55 g, 4.16 mmol)

calculated for C H BrNO [M+H]+: 302.0175, found:

15 13

302.0176. Purity (HPLC): 99.8%.

1

3

Chemical Papers

1

3

(

2 E) ‑ 1 ‑ ( 3 ‑ A m i n o p h e n y l ) ‑ 3 ‑ ( 3 ‑ b r o m o p h e n y l )

2.4 Hz, 1H); C NMR (151 MHz, DMSO) δ 188.43,

163.28, 161.67, 143.14, 138.43, 137.12, 137.07, 135.17,

130.93, 130.88, 130.19, 126.74, 126.66, 125.61, 123.29,

121.54, 117.54, 117.40, 114.83, 114.69. APCI-HRMS m/z

calculated for C H FNO [M+H]+: 242.0976, found:

prop‑2‑en‑1‑one (38) Prepared as for 37 from 3′-aminoace-

tophenone (0.50 g, 3.70 mmol) and 3-bromobenzaldehyde

(

0.68 g, 3.70 mmol) to yield the title compound 38 as light

1

brown powder (0.80 g, 72%): mp: 176.78 °C (EtOH); H

NMR (600 MHz, DMSO) δ 8.26–8.13 (m, 2H), 7.97 (d,

J=15.7 Hz, 1H), 7.95 (s, 1H), 7.87 (d, J=7.8 Hz, 1H),

1

5

13

242.0956. Purity (HPLC): 96.4%.

7

.73 (d, J=15.7 Hz, 1H), 7.64 (t, J=7.8 Hz, 2H), 7.58

Synthesis oꢀ 42–47

1

3

(

d, J=7.8 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H); C NMR

151 MHz, DMSO) δ 188.36, 142.82, 138.42, 137.04,

1‑(3‑{(E)‑[(2‑Hydroxy‑4‑methoxyphenyl)methylidene]

amino}phenyl)ethan‑1‑one (42) A solution of 3′-aminoace-

tophenone (0.50 g, 3.70 mmol) and 2-hydroxy-4-methoxy-

benzaldehyde (0.56 g, 3.70 mmol) in EtOH (5 mL) was

mechanically stirred at room temperature for approximately

1

35.23, 133.22, 130.98, 130.91, 130.17, 128.27, 126.72,

26.60, 123.32, 122.40, 121.45. APCI-HRMS m/z cal-

culated for C H BrNO [M+H]+: 302.0175, found:

1

5

13

3

02.0164. Purity (HPLC): 98.1%.

5

min before the dropwise addition of KOH (10% (w/v)

(

2 E) ‑ 1 ‑ ( 3 ‑ A m i n o p h e n y l ) ‑ 3 ‑ ( 2 ‑ c h l o r o p h e n y l )

aqueous solution, 5 mL). The subsequent reaction mixture

was mechanically stirred at room temperature and continu-

ously monitored by TLC. Upon completion, the reaction

mixture was quenched with crushed ice (15 g) and acidiꢂed

prop‑2‑en‑1‑one (39) Prepared as for 37 from 3′-ami-

noacetophenone (0.50 g, 3.70 mmol) and 2-chlorobenza-

ldehyde (0.52 g, 3.70 mmol) to yield the title compound

3

9 as light brown powder (0.94 g, 99%): mp: 188.04 °C

to pH 2 with HCl (32 wt. % in H O, FCC). The subsequent

2

1

(

EtOH); H NMR (600 MHz, DMSO) δ 8.23–8.13 (m, 2H),

precipitate was collected by vacuum ꢂltration, dried (30 °C)

8

.05 (d, J=15.6 Hz, 1H), 7.95 (d, J=15.6 Hz, 2H), 7.65 (t,

and recrystallized from EtOH to yield the title compound 42

1

3

1

J=7.8 Hz, 1H), 7.62–7.56 (m, 2H), 7.53–7.43 (m, 2H);

C

as dark green crystals (0.08 g, 8%): mp: 94.63 °C (EtOH); H

NMR (151 MHz, DMSO) δ 188.30, 139.05, 138.31, 134.43,

NMR (600 MHz, CDCl ) δ 13.47 (d, J=2.0 Hz, 1H), 8.58

3

1

32.20, 132.12, 130.20, 130.08, 128.61, 127.73, 126.63,

(s, 1H), 7.83 (s, 2H), 7.54–7.41 (m, 2H), 7.30 (d, J=8.3 Hz,

26.58, 124.56, 121.39. APCI-HRMS m/z calculated for

1H), 6.51 (d, J=8.0 Hz, 2H), 3.85 (s, 3H), 2.64 (s, 3H);

1

3

C H ClNO [M+H]+: 258.0680, found: 258.0673. Purity

C NMR (151 MHz, CDCl ) δ 197.84, 164.45, 163.95,

3

1

5

13

(

HPLC): 99.8%.

162.75, 149.21, 138.47, 133.96, 129.76, 126.32, 126.21,

20.41, 113.11, 107.54, 101.24, 55.65, 26.85. APCI-HRMS

1

(

2 E) ‑ 1 ‑ ( 3 ‑ A m i n o p h e n y l ) ‑ 3 ‑ ( 3 ‑ c h l o r o p h e n y l )

m/z calculated for C H NO [M+H]+: 270.1125, found:

16 16 3

prop‑2‑en‑1‑one (40) Prepared as for 37 from 3′-aminoace-

270.1116. Purity (HPLC): 99.8%.

tophenone (0.50 g, 3.70 mmol) and 3-chlorobenzaldehyde

(

0.52 g, 3.70 mmol) to yield the title compound 40 as light

1‑(3‑{(Z)‑[(2‑Hydroxy‑5‑methoxyphenyl)methylidene]

amino}phenyl)ethan‑1‑one (43) Prepared as for 42 from

3′-aminoacetophenone (0.50 g, 3.70 mmol) and 2-hydroxy-

5-methoxybenzaldehyde (0.56 g, 3.70 mmol) to yield com-

1

brown powder (0.89 g, 93%): mp: 175.73 °C (EtOH); H

NMR (600 MHz, DMSO) δ 8.17 (d, J=7.6 Hz, 1H), 8.06

(

s, 1H), 7.97 (d, J=15.7 Hz, 1H), 7.95 (s, 1H), 7.83 (d,

J=7.3 Hz, 1H), 7.74 (d, J=15.7 Hz, 1H), 7.64 (t, J=7.8 Hz,

pound 43 as dark red crystals (0.59 g, 59%): mp: 92.81 °C

1

3

1

H), 7.58 (d, J=7.9 Hz, 1H), 7.54–7.45 (m, 2H); C NMR

(EtOH); H NMR (600 MHz, CDCl ) δ 12.53 (s, 1H), 8.63

3

(

151 MHz, DMSO) δ 188.39, 142.86, 138.41, 136.78,

(s, 1H), 7.86 (d, J=11.7 Hz, 2H), 7.52 (t, J=7.6 Hz, 1H),

7.47 (d, J=7.8 Hz, 1H), 7.02 (d, J=9.0 Hz, 1H), 6.97 (d,

J=8.9 Hz, 1H), 6.91 (s, 1H), 3.81 (s, 3H), 2.65 (s, 3H);

1

33.81, 130.73, 130.32, 130.16, 128.05, 127.90, 126.61,

26.56, 123.36, 121.40. APCI-HRMS m/z calculated for

1

3

C H ClNO [M+H]+: 258.0680, found: 258.0658. Purity

C NMR (151 MHz, CDCl ) δ 197.73, 163.63, 155.57,

3

1

5

13

(

HPLC): 98.1%.

152.50, 149.20, 138.48, 129.86, 126.84, 126.37, 121.20,

20.44, 118.63, 118.32, 115.52, 56.08, 26.91. APCI-HRMS

1

(

2E)‑1‑(3‑Aminophenyl)‑3‑(3‑ꢁuorophenyl)prop‑2‑en‑1‑one

41) Prepared as for 37 from 3′-aminoacetophenone (0.50 g,

m/z calculated for C H NO [M+H]+: 270.1125, found:

16 16 3

270.1112. Purity (HPLC): 94.4%.

3

.70 mmol) and 3-ꢃuorobenzaldehyde (0.46 g, 3.70 mmol)

to yield the title compound 41 as dark brown powder

1‑(3‑{(E)‑[(3‑Bromo‑5‑chlorophenyl)methylidene]amino}

phenyl)ethan‑1‑one (44) Prepared as for 42 from 3′-ami-

noacetophenone (0.50 g, 3.70 mmol) and 3-bromo-5-chlo-

rosalicylaldehyde (0.87 g, 3.70 mmol) to yield the title

1

(

0.19 g, 21%): mp: 206.07 °C (EtOH); H NMR (600 MHz,

DMSO) δ 8.17 (d, J=7.7 Hz, 1H), 7.99–7.93 (m, 2H),

.85 (d, J=10.3 Hz, 1H), 7.76 (d, J=15.7 Hz, 1H), 7.70

d, J=7.8 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.63–7.57 (m,

H), 7.55–7.47 (m, J=7.9, 6.3 Hz, 1H), 7.30 (td, J=8.5,

7

(

compound 44 as light orange crystals (0.42 g, 32%): mp:

1

183.31 °C (EtOH); H NMR (600 MHz, CDCl ) δ 14.07

3

1

3

Chemical Papers

(

s, 1H), 8.61 (s, 1H), 7.95–7.84 (m, 2H), 7.64 (s, 1H),

Biology

7

1

.56 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.38 (s,

1

3

H), 2.65 (s, 3H); C NMR (151 MHz, CDCl ) δ 197.38,

In vitro evaluation

3

61.58, 156.92, 147.57, 138.65, 136.12, 130.85, 130.11,

27.76, 126.39, 124.20, 120.40, 120.01, 112.03, 26.90.

Materials

APCI-HRMS m/z calculated for C H rClNO [M+ H]+:

1

5

13

2

3

51.9734, found: 351.9714. Purity (HPLC): 99.7%.

All reagents were commercially available and purchased

3

from various manufacturers. Radioligands [ H]DPCPX

3

1

‑(3‑{(E)‑[(5‑Chloro‑2‑hydroxyphenyl)methylidene]

(speciꢂc activity 120 Ci/mmol) and [ H]NECA (speciꢂc

amino}phenyl)ethan‑1‑one (45) Prepared as for 42 from

activity 21.1 Ci/mmol) were obtained from PerkinElmer.

Radioactivity was counted by a Packard Tri-CARB 2810

liquid scintillation counter.

3

′-aminoacetophenone (0.50 g, 3.70 mmol) and 5-chlo-

rosalicylaldehyde (0.58 g, 3.70 mmol) to yield the title

compound 45 as light orange crystals (0.18 g, 18%):

1

mp: 118.02 °C (EtOH); H NMR (600 MHz, CDCl ) δ

3

Ethics

1

2.97 (s, 1H), 8.61 (s, 1H), 7.92–7.82 (m, 2H), 7.54 (t,

J = 7.7 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.39 (s, 1H), 7.34

The collection of tissue samples for the A and A AR

1

2A

(

d, J = 8.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 2.65 (s, 3H);

1

3

radioligand binding assays were approved by the Health

Sciences Ethics Oꢁce for Research, Training and Support,

North-West University (application number NWU-00260-

C NMR (151 MHz, CDCl ) δ 197.56, 162.59, 159.84,

3

1

48.66, 138.57, 133.51, 131.60, 129.94, 127.23, 126.22,

24.01, 120.58, 119.86, 119.08, 26.91. APCI-HRMS m/z

1

7-A5) and were performed in accordance with the guide-

calculated for C H ClNO [M+ H]+: 274.0629, found:

1

5

13

2

lines of the South African National Standard (SANS) docu-

ment (The care and use of animals for scientiꢂc purposes).

2

74.0629. Purity (HPLC): 100%.

1

‑{3‑[(E)‑{[4‑(Diethylamino)‑2‑hydroxyphenyl]methyl‑

idene}amino]phenyl}ethan‑1‑one (46) Prepared as for

Tissue samples

4

2 from 3′-aminoacetophenone (0.50 g, 3.70 mmol) and

4

-(diethylamino)salicylaldehyde (0.71 g, 3.70 mmol) to

Male Sprague–Dawley rats were dissected to attain rat whole

brain membranes (excluding cerebellum and brain stem) and

rat striatal membranes for the A and A AR radioligand

yield the title compound 46 as gold crystals (0.46 g, 42%):

1

mp: 117.85 °C (EtOH); H NMR (600 MHz, CDCl ) δ

3

1

2A

1

3.52 (s, 1H), 8.47 (s, 1H), 7.84–7.73 (m, 2H), 7.50–7.38

binding assays, respectively. Tissue samples were prepared

and stored as described in literature (Van der Walt and

Terre’Blanche 2015). Protein concentrations were deter-

mined according to the Bradford assay, using bovine serum

albumin as reference standard (Bradford 1976).

(

m, 2H), 7.18 (d, J = 8.7 Hz, 1H), 6.26 (d, J = 8.8 Hz, 1H),

.20 (s, 1H), 3.41 (q, J = 7.0 Hz, 4H), 2.63 (s, 3H), 1.21 (t,

6

1

3

J = 7.0 Hz, 6H); C NMR (151 MHz, CDCl ) δ 197.89,

3

1

2

63.87, 161.38, 152.00, 149.49, 138.15, 133.95, 129.39,

25.85, 125.17, 120.03, 108.90, 103.90, 97.61, 44.55,

6.72, 12.63. APCI-HRMS m/z calculated for C H N O

1

9

23

2

Adenosine A and A receptor radioligand binding assays

1

2A

[

M + H] + : 311.1754, found: 311.1746. Purity (HPLC):

1

00%.

The degree of binding aꢁnity the test compounds possess

towards rat A and A ARs were determined via radio-

1

2A

1

‑(3‑{(E)‑[(2H‑1,3‑benzodioxol‑5‑yl)methylidene]amino}

ligand binding assays, as described previously (Bradford

phenyl)ethan‑1‑one (47) Prepared as for 42 from 3′-ami-

noacetophenone (0.50 g, 3.70 mmol) and 3,4-(methylen-

edioxy)benzaldehyde (0.56 g, 3.70 mmol) to yield the title

1

976; Bruns 1987; Bruns and Watson 2012; Van der Walt

and Terre’Blanche 2015). The A AR radioligand binding

1

assay used rat whole brain membranes (expressing A ARs)

1

compound 47 as light green crystals (0.98 g, 99%): mp:

3

and 0.1 nM 1,3-[ H]-dipropyl-8-cyclopentylxanthine ([ H]

1

27.64 °C (EtOH); H NMR (600 MHz, CDCl ) δ 7.81 (d,

3

DPCPX) as radioligand (Bruns 1987) and, in turn, the A

2

A

J=15.6 Hz, 1H), 7.49–7.32 (m, 4H), 7.21 (d, J=7.9 Hz,

AR radioligand binding assay used rat striatal membranes

1

H), 6.99 (d, J=8.0 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.13

3

(

expressing A ARs) and 4 nM 5′-N-ethylcarboxamido[ H]

1

3

2A

(

s, 2H), 3.93 (s, 2H), 3.82 (q, J=6.9 Hz, 1H); C NMR

3

adenosine ([ H]NECA) as radioligand (Bruns et al. 1986).

151 MHz, CDCl ) δ 190.69, 149.97, 148.53, 146.93,

3

6

N -Cyclopentyladenosine (CPA) was also added to the A

2

A

1

44.50, 139.67, 129.59, 129.54, 125.28, 120.54, 119.41,

AR radioligand binding assay (in order to eliminate the A

1

18.91, 114.52, 108.79, 106.79, 101.75, 58.61, 18.58.

3

component of binding exhibited by the non-selective [ H]

APCI-HRMS m/z calculated for C H NO [M+H]+:

1

6

14

3

NECA) as well as MgCl (in order to increase radioligand

2

68.0968, found: 268.0951. Purity (HPLC): 90.4%.

1

3

Chemical Papers

binding and decrease non-speciꢂc binding) (Bruns et al.

relevant computational methods, and thus, do not focus on

just one speciꢂc property or model (Daina et al. 2017).

1

5

986). The ꢂnal volume of all incubations contained 1 mL

0 mM Tris.HCl buꢀer and 1% DMSO (Van der Walt and

3

Terre’Blanche 2015). Non-speciꢂc binding of [ H]DPCPX

3

and [ H]NECA for the radioligand binding assays were

deꢂned as binding in the presence of 100 µM CPA (Bruns

et al. 1986; Van der Walt and Terre’Blanche 2015). Speciꢂc

binding was deꢂned as the total binding minus the non-spe-

ciꢂc binding (Van der Walt and Terre’Blanche 2015).

Conclusions

A total of 33 chalcones (15–36 and 37–41) and structurally

related compounds (42–47) with diꢀerent substitutions on

ring A and/or benzylidene ring B were synthesised, char-

acterized and evaluated in vitro to determine the degree

and type of A and A receptor binding. While most com-

Guanosine triphosphate (GTP) shiꢀt assays

1

2A

pounds were not novel, the application of all compounds

The type of binding aꢁnity test compounds exhibited at

is original. The chalcone derivatives 24, 29, 37 and 38

the rat A AR was determined via a guanosine triphos-

1

possessed selective A aꢁnity below 10 µM; compound

1

phate (GTP) shift assay, as described previously (Lohse

et al. 1987; Van der Walt and Terre’Blanche 2015; Van der

3

8 was the most potent selective A AR antagonist (K

1

i

(

r)=1.6 µM). Most of the test compounds showed poor A

1

Werten et al. 1995). A GTP shift assay resembles the A AR

1

and/or A AR aꢁnity upon in vitro evaluation—making it

2

A

radioligand binding assay. However, it requires the addition

of 100 µM GTP. Non-speciꢂc binding was deꢂned as bind-

ing in the presence of 10 µM DPCPX (Van der Werten et al.

diꢁcult to determine SARs; however, some broad conclu-

sions were drawn from these results. The type of substitu-

tion on ring A of the chalcone scaꢀold played a key role in

aꢁnity, and the position of the substitution on benzylidene

1

995; Lohse et al. 1984).

ring B; the NH -group at position C3 of ring A of the

2

Statistical data analyses

chalcone scaꢀold, and the Br-atom at position C3′ on ben-

zylidene ring B were essential to selective A AR aꢁnity

1

In short, all statistical data analyses were done using

Microsoft Excel and GraphPad Prism Software. Sigmoi-

dal dose response curves, from which IC values were

(

exempliꢂed by compound 27 versus 38 and 37 versus 38).

Selective A AR aꢁnity and antagonistic activity may be

1

5

0

added to the known biological activities of compounds 24

and 29. The physiochemical and pharmacokinetic proper-

ties (based on in silico evaluation) proved the chalcone

derivatives 24, 29, 37 and 38, although drug-like, not at

all lead-like (29). Thus far, the chalcone chemical structure

was a promising scaꢀold in medicinal chemistry; due to

the diverse chemistry and biology of this α,ß-unsaturated

carbonyl system. The said system may be troublesome (it

is perceived as a potential Michael acceptor); however, it

easily allows structural modiꢂcation and introduction of

a heterocyclic ring system (such as isoxazole, pyrazole,

calculated, were obtained by plotting the speciꢂc binding

against the logarithm of the test compounds’ concentra-

tions. Subsequently, the IC values were used to calculate

5

0

3

the K values for the competitive inhibition of [ H]DPCPX

i

3

(

K =0.36 nM) against rat whole brain membranes and [ H]

d

NECA (K =15.3 nM) against rat striatal membranes by the

d

test compounds by means of the Cheng–Prusoꢀ equation.

All calculated K values were determined in triplicate and

i

given as mean ± standard error of the mean (SEM). Spe-

ciꢂc binding (%) of the radioligand at a maximum tested

concentration of 100 µM were determined in duplicate and

expressed as the mean in %. SI index values were calculated

pyrrole etcetera) which may just be beneꢂcial to A and/

1

or A AR binding aꢁnity; thus, leading to the discovery

2

A

as a ratio of the A and A AR K values of test compounds.

1

2A

i

of new pharmacophores from this classes of compounds.

GTP shifts were calculated by dividing the K values of com-

i

pounds reported in the presence of GTP by the K values

Acknowledgements This study was funded by the National Research

Foundation (NRF) of South Africa (Grant number 111814) and the

North-West University (NWU). The authors wish to thank Dr D. Otto

for NMR analyses and Dr J. Jordaan for MS analyses both from Chemi-

cal Research Beneꢂciation at NWU, as well as Prof. W. Liebenberg

for DSC analyses, Prof F. Van der Kooy for HPLC analyses and Ms S.

Lowe for assistance with biological assays from the Centre of Excel-

lence for Pharmaceutical Sciences (Pharmacen), NWU.

i

obtained in the absence of GTP.

In silico evaluation

SwissADME (https://www.swissadme.ch ), a free web tool,

was used to evaluate key parameters of small molecules;

such as pharmacokinetics, drug-likeness and medicinal

chemistry friendliness. Pharmacokinetic parameters (absorp-

tion, distribution, metabolism and excretion), among others,

were predicted from molecular structures using the most

Compliance with ethical standards

Conꢀlict oꢀ interest The authors declare no conꢃict of interest.

1

3

Chemical Papers

Press, Washington D.C. https://scholar.google.com/schol

ar?hl=en&as_sdt=0%2C5&q=Clays on+DB+%28198

References

1

%29+Aromatic+amines%3A+an+assessment+of+the+biolo

Aarsland D, Påhlhagen S, Ballard CG, Ehrt U, Svenningsson P (2012)

Depression in Parkinson disease—epidemiology, mechanisms

and management. Nat Rev Neurol 8:35. https://doi.org/10.1038/

nrneurol.2011.189

gical+and+environmental+effects.+National+Acade

mies+Press%2C+&btnG=

Daina A, Zoete V (2016) A boiled-egg to predict gastrointesti-

nal absorption and brain penetration of small molecules.

ChemMedChem 11:1117–1121. https://doi.org/10.1002/

cmdc.201600182

Aksöz BE, Ertan R (2012) Spectral properties of chalcones II. Fabad J

Pharm Sci 37:205–216. https://www.semanticscholar.org/paper/

Spectral-Properties-of-Chalcones-II-Aks%C3%B6z-Ertan/9c631

Daina A, Michielin O, Zoete V (2017) SwissADME: a free web tool to

evaluate pharmacokinetics, drug-likeness and medicinal chem-

istry friendliness of small molecules. Sci Rep 7:42717. https://

doi.org/10.1038/srep42717

0

4669fa8cd865bd5c65da7a1d78c8cce36c?p2df

Baell JB, Holloway GA (2010) New substructure ꢂlters for removal

of pan assay interference compounds (PAINS) from screen-

ing libraries and for their exclusion in bioassays. J Med Chem

de Lera Ruiz M, Lim Y-H, Zheng J (2013) Adenosine A2A receptor

as a drug discovery target. J Med Chem 57:3623–3650. https://

doi.org/10.1021/jm4011669

5

3:2719–2740. https://doi.org/10.1021/jm901137j

Barros AI, Silva AM, Alkorta I, Elguero J (2004) Synthesis, experi-

mental and theoretical NMR study of 2′-hydroxychalcones bear-

ing a nitro substituent on their B ring. Tetrahedron 60:6513–

Dixon AK, Gubitz AK, Sirinathsinghji DJ, Richardson PJ, Free-

man TC (1996) Tissue distribution of adenosine receptor

mRNAs in the rat. Br J Pharmacol 118:1461–1468. https://doi.

org/10.1111/j.1476-5381.1996.tb15561.x

6

521. https://doi.org/10.1016/j.tet.2004.06.005

Batovska DI, Todorova IT (2010) Trends in utilization of the pharma-

cological potential of chalcones. Curr Clin Pharmacol 5:1–29.

https://doi.org/10.2174/157488410790410579

Downey CW, Glist HM, Takashima A, Bottum SR, Dixon GJ (2018)

Chalcone and cinnamate synthesis via one-pot enol silane for-

mation-Mukaiyama aldol reactions of ketones and acetate esters.

Tetrahedron Lett 59:3080–3083. https://doi.org/10.1016/j.tetle

t.2018.06.066

Bayer H, Batzl C, Hartman RW, Mannschreck A (1991) New aromatase

inhibitors. Synthesis and biological activity of pyridyl-substi-

tuted tetralone derivatives. J Med Chem 34:2685–2691

Boison D (2018) Regulation of extracellular adenosine. In: Borea PA,

Varani K, Gessi S, Merighi S, Vincenzi F (eds) The adenosine

receptors, vol 34. The receptors. Humana Press, Totowa, pp

Dunwiddie TV (1985) The physiological role of adenosine in the cen-

tral nervous system. International review of neurobiology, vol 27.

Elsevier, Amsterdam, pp 63–139. https://doi.org/10.1016/S0074

1

3–58. https://doi.org/10.1007/978-3-319-90808-3

-

7742(08)60556-5

Bradford MM (1976) A rapid and sensitive method for the quantita-

tion of microgram quantities of protein utilizing the principle

of protein-dye binding. Anal Biochem 72:248–254. https://doi.

org/10.1016/0003-2697(76)90527-3

Egan WJ, Merz KM, Baldwin JJ (2000) Prediction of drug absorption

using multivariate statistics. J Med Chem 43:3867–3877. https

:

//doi.org/10.1021/jm000292e

Fredholm BB et al. (1994) VI. Nomenclature and classifica-

tion of purinoceptors. Pharmacol Rev 46:143. https://schol

ar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Fredh

olm+BB+et+al.+%281994%29+VI.+Nomenclature+and+class

ifica tion+of+purin ocept ors+Pharm acolo gical +revie

ws+46%3A143&btnG=

Brenk R, Schipani A, James D, Krasowski A, Gilbert IH, Frearson

J, Wyatt PG (2008) Lessons learnt from assembling screening

libraries for drug discovery for neglected diseases. ChemMed-

Chem Chem Enabling Drug Discov 3:435–444. https://doi.

org/10.1002/cmdc.200700139

Bruns RF et al. (1987) Binding of the A 1-selective adenosine antago-

nist 8-cyclopentyl-1, 3-dipropylxanthine to rat brain membranes.

Naunyn Schmiedeberg’s Arch Pharmacol 335:59–63. https://

scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Bruns

Fredholm BB, IJzerman AP, Jacobson KA, Klotz K-N, Linden J

(

2001) International Union of Pharmacology. XXV. Nomencla-

ture and classiꢂcation of adenosine receptors. Pharmacol Rev

5

3:527–552. https://scholar.google.com/scholar?hl=en&as_

+

RF+et+al.+%281987%29+Binding+of+the+A+1-selec

sdt=0%2C5&q=Fredholm+BB%2C+IJzerman+AP%2C+Jacob

son+KA%2C+Klotz+K-N%2C+Linden+J+%282001%29+Inter

national+Union+of+Pharmacology.+XXV.+Nomenclatu

re+and+classiꢂcation+of+adenosine+receptors+Pharmacolo

gical+reviews+53%3A527-552&btnG=

tive+adenosine+antagonist+8-cyclopentyl-1%2C+3-dipro

pylxanthine+to+rat+brain+membranes+Naunyn-Schmiedebe

rg%27s+archives+of+pharmacology+335%3A59-63&btnG=

Bruns RF, Watson IA (2012) Rules for identifying potentially reactive

or promiscuous compounds. J Med Chem 55:9763–9772. https

Fredholm BB, IJzerman AP, Jacobson KA, Linden J, Müller CE,

:

//doi.org/10.1021/jm301008n

(

2011) International Union of Basic and Clinical Pharmacol-

Bruns RF, Lu GH, Pugsley TA (1986) Characterization of the

A2 adenosine receptor labeled by [3H] NECA in rat stri-

atal membranes. Mol Pharmacol 29:331–34. https://schol

ar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Bruns

ogy. LXXXI. Nomenclature and classification of adenosine

receptors—an update. Pharmacol Rev 63:1–34. https://doi.

org/10.1124/pr.110.003285

Freissmuth M, Schütz W, Linder M (1991) Interactions of

the bovine brain A1-adenosine receptor with recombi-

nant G protein alpha-subunits. Selectivity for rGi alpha-

+

RF%2C+Lu+GH%2C+Pugsley+TA+%281986%29+Chara

cteri zatio n+of+the+A2+adeno sine+recep tor+label

ed+by+%5B3H%5D+NECA+in+rat+stria tal+membr

anes+Molecular+Pharmacology+29%3A331-346&btnG=

Choi D, Yu S, Baek SH, Kang Y-H, Chang Y-C, Cho H (2016) Synthe-

sis and algicidal activity of new dichlorobenzylamine derivatives

against harmful red tides. Biotechnol Bioprocess Eng 21:463–

3

. J Biol Chem 266:17778–17783. https://scholar.googl

e.com/schol ar?hl=en&as_sdt=0%2C5&q=Freis smuth

M%2C+Sch%C3%BCtz+W%2C+Linder+M+%28199

+

1

%29+Interactions+of+the+bovine+brain+A1-adeno

sine+receptor+with+recombinant+G+protein+alpha-subun

its.+Selectivity+for+rGi+alpha-3+Journal+of+Biological

4

76. https://doi.org/10.1007/s12257-016-0175-8

Claisen L, Claparède A (1881) Condensationen von Ketonen mit

Aldehyden. Ber Dtsch Chem Ges 14:2460–2468. https://doi.

org/10.1002/cber.18810140182

+

Chemistry+266%3A17778-17783&btnG=

Furniss B, Hannaford A, Smith P, Tatchell A (1989) Vogel’s textbook

of practical organic chemistry, 5th edn. Longman Group UK

Limited. https://fac.ksu.edu.sa/sites/default/ꢂles/vogel_-_pract

ical_organic_chemistry_5th_edition.pdf

Clayson DB (1981) Aromatic amines: an assessment of the bio-

logical and environmental effects. National Academies

1

3

Chemical Papers

Gaonkar SL, Vignesh U (2017) Synthesis and pharmacological proper-

ties of chalcones: a review. Res Chem Intermed 43:6043–6077.

https://doi.org/10.1007/s11164-017-2977-5

Jung Y, Son K-I, Oh YE, Noh D-Y (2008) Ferrocenyl chalcones con-

taining anthracenyl group: synthesis, X-ray crystal structures

and electrochemical properties. Polyhedron 27:861–867. https

://doi.org/10.1016/j.poly.2007.11.015

Gatch MB, Wallis CJ, Lal H (1999) The eꢀects of adenosine ligands

R-PIA and CPT on ethanol withdrawal. Alcohol 19:9–14. https

Juvale K, Pape VF, Wiese M (2012) Investigation of chalcones and

benzochalcones as inhibitors of breast cancer resistance pro-

tein. Bioorg Med Chem 20:346–355. https://doi.org/10.1016/j.

bmc.2011.10.074

:

//doi.org/10.1016/S0741-8329(99)00009-9

Ghose AK, Viswanadhan VN, Wendoloski JJ (1999) A knowledge-

based approach in designing combinatorial or medicinal chem-

istry libraries for drug discovery. 1 A qualitative and quantita-

tive characterization of known drug databases. J Comb Chem

Kaplan GB, Cotreau MM, Greenblatt DJ (1992) Eꢀects of benzo-

diazepine administration on A1 adenosine receptor binding

in-vivo and ex-vivo. J Pharm Pharmacol 44:700–703. https://

doi.org/10.1111/j.2042-7158.1992.tb05502.x

1

:55–68. https://doi.org/10.1021/cc9800071

Gomes MN et al (2017) Chalcone derivatives: promising starting points

for drug design. Molecules 22:1210. https://doi.org/10.3390/

molecules22081210

Karaman İ, Gezegen H, Gürdere MB, Dingil A, Ceylan M (2010)

Screening of biological activities of a series of chalcone

derivatives against human pathogenic microorganisms. Chem

Biodivers 7:400–408. https://doi.org/10.1002/cbdv.200900027

Karthikeyan C, SH Narayana Moorthy N, Ramasamy S, Vanam U,

Manivannan E, Karunagaran D, Trivedi P (2015) Advances

in chalcones with anticancer activities. In: Recent patents on

anti-cancer drug discovery, vol 10. pp 97–115. https://www.

ingentaconnect.com/content/ben/pra/2015/00000010/00000

001/art00006

Gütschow M et al (2012) Benzothiazinones: a novel class of adeno-

sine receptor antagonists structurally unrelated to xanthine and

adenine derivatives. J Med Chem 55:3331–3341. https://doi.

org/10.1021/jm300029s

Hallgas B et al (2005) Characterization of lipophilicity and antipro-

liferative activity of E-2-arylmethylene-1-tetralones and their

heteroanalogues. J Chromatogr B 819:283–291. https://doi.

org/10.1016/j.jchromb.2005.02.014

Hann MM, Keserü GM (2012) Finding the sweet spot: the role of

nature and nurture in medicinal chemistry. Nat Rev Drug Discov

Karton Y, Jiang J-l, Ji X-D, Melman N, Olah ME, Stiles GL, Jacob-

son KA (1996) Synthesis and biological activities of ꢃavonoid

derivatives as A3 adenosine receptor antagonists. J Med Chem

39:2293–2301. https://doi.org/10.1021/jm950923i

1

1:355. https://doi.org/10.1038/nrd3701

Hollenberg PF (2002) Characteristics and common properties of inhibi-

tors, inducers, and activators of CYP enzymes. Drug Metab Rev

Khanam H (2015) Bioactive Benzofuran derivatives: a review. Eur

J Med Chem 97:483–504. https://doi.org/10.1016/j.ejmec

h.2014.11.039

3

4:17–35. https://doi.org/10.1081/DMR-120001387

Huang SM et al (2008) New era in drug interaction evaluation: US

Food and Drug Administration update on CYP enzymes, trans-

porters, and the guidance process. J Clin Pharmacol 48:662–670.

https://doi.org/10.1177/0091270007312153

Kirchmair J et al (2015) Predicting drug metabolism: experiment

and/or computation? Nat Rev Drug Discov 14:387. https://doi.

org/10.1038/nrd4581

Jackson CE (2011) Cholinergic system. In: Kreutzer JS, DeLuca J,

Caplan B (eds) Encyclopedia of clinical neuropsychology.

Springer, New York, pp 562–564. https://doi.org/10.1007/978-

Klotz K-N, Hessling J, Hegler J, Owman C, Kull B, Fredholm B,

Lohse M (1997) Comparative pharmacology of human adeno-

sine receptor subtypes–characterization of stably transfected

receptors in CHO cells. Naunyn Schmiedeberg’s Arch Phar-

macol 357:1–9. https://scholar.google.com/scholar?hl=en&as_

sdt=0%2C5&q=Klotz+K-N%2C+Hessling+J%2C+Hegle

r + J % 2 C + O w m a n + C % 2 C + K u l l + B % 2 C + F r e d h

olm+B%2C+Lohse +M+%28199 7%29+Compa rativ

e+pharmacology+of+human+adenosine+receptor+subty

pes%E2%80%93characterization+of+stably+transfecte

d+recep tors+in+CHO+cells +Nauny n-Schmi edebe

rg%27s+archives+of+pharmacology+357%3A1-9&btnG=

Langmead CJ et al (2012) Identiꢂcation of novel adenosine A2A

receptor antagonists by virtual screening. J Med Chem

55:1904–1909. https://doi.org/10.1021/jm201455y

0

-387-79948-3_1113

Jacobson KA, Gao Z-G (2006) Adenosine receptors as therapeutic

targets. Nat Rev Drug Discov 5:247. https://doi.org/10.1038/

nrd1983

Jacobson KA, Moro S, Manthey JA, West PL, Ji X-d (2002) Interac-

tions of ꢃavones and other phytochemicals with adenosine recep-

tors. Flavonoids in cell function. Springer, Berlin, pp 163–171.

https://doi.org/10.1007/978-1-4757-5235-9_15

Jain N, Kemp N, Adeyemo O, Buchanan P, Stone TW (1995) Anxiolytic

activity of adenosine receptor activation in mice. Br J Pharma-

col 116:2127–2133. https://doi.org/10.1111/j.1476-5381.1995.

tb16421.x

Janse van Rensburg H, Terre’Blanche G, van der Walt M, Legoabe

L (2017) 5-Substituted 2-benzylidene-1-tetralone analogues as

A1 and/or A2A antagonists for the potential treatment of neu-

rological conditions. Bioorg Chem 74:251–259. https://doi.

org/10.1016/j.bioorg.2017.08.013

Legoabe LJ, Van der Walt MM, Terre’Blanche G (2018) Evalua-

tion of 2-benzylidene-1-tetralone derivatives as antagonists of

A1 and A2A adenosine receptors. Chem Biol Drug Design

91:234–244. https://doi.org/10.1111/cbdd.13074

Li M, Fang D, Geng F, Dai X (2017) Silver-catalyzed eꢁcient syn-

thesis of enaminones from propargyl alcohols and amines.

Tetrahedron Lett 58:4747–4749. https://doi.org/10.1016/j.

tetlet.2017.09.054

Janse van Rensburg HD, Legoabe LJ, Terre’Blanche G, Van der Walt

MM (2019a) 2-benzylidene-1-indanone analogues as dual adeno-

sine A1/A2a receptor antagonists for the potential treatment of

neurological conditions. Drug Res 69(7):382–391. https://doi.

org/10.1055/a-0808-3993

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experi-

mental and computational approaches to estimate solubility

and permeability in drug discovery and development settings.

Adv Drug Deliv Rev 23:3–25. https://doi.org/10.1016/S0169

-409X(96)00423-1

Janse van Rensburg HD, Legoabe LJ, Terre’Blanche G, Van der Walt

MM (2019b) Methoxy substituted 2-benzylidene-1-indanone

derivatives as A1 and/or A2A AR antagonists for the potential

treatment of neurological conditions. Medchemcomm 10(2):300–

Liu S, Guo C, Guo Y, Yu H, Greenaway F, Sun M-Z (2014) Compara-

tive binding aꢁnities of ꢃavonoid phytochemicals with bovine

serum albumin. Iran J Pharm Res IJPR 13:1019. https://schol

ar.google.com/scholar?q=Liu+S,+Guo+C,+Guo+Y,+Yu+

H,+Greenaway+F,+Sun+M-Z+(2014)+Comparative+bindi

ng+affinities+of+flavonoid+phytochemicals+with+bovin

3

09. https://doi.org/10.1039/C8MD00540K

Johansson B et al (2001) Hyperalgesia, anxiety, and decreased hypoxic

neuroprotection in mice lacking the adenosine A1 receptor. Proc

Natl Acad Sci 98:9407–9412. https://doi.org/10.1073/pnas.16129

2

398

1

3

Chemical Papers

e+serum+albumin+Iranian+journal+of+pharmaceutical+resea

Nielsen AT, Houlihan WJ (2004) The aldol condensation. Org React

16:1–438. https://doi.org/10.1002/0471264180.or016.01

Noji T, Karasawa A, Kusaka H (2004) Adenosine uptake inhibitors.

Eur J Pharmacol 495:1–16. https://doi.org/10.1016/j.ejpha

r.2004.05.003

rch:+IJPR+13:1019&hl=en&as_sdt=0,5

Lohse MJ, Lenschow V, Schwabe U (1984) Interaction of barbitu-

rates with adenosine receptors in rat brain. Naunyn Schmiede-

berg’s Arch Pharmacol 326:69–74. https://scholar.google.com/

scholar?hl=en&as_sdt=0%2C5&q=Lohse+MJ%2C+Lensc

how+V%2C+Schwa be+U+%28198 4%29+Inter actio

n+of+barbiturates+with+adenosine+receptors+in+rat+brain

Normile H, Barraco RA (1991) N6-cyclopentyladenosine impairs

passive avoidance retention by selective action at A1 recep-

tors. Brain Res Bull 27:101–104. https://doi.org/10.1016/0361-

9230(91)90288-U

+

Naunyn-Schmiedeberg%27s+archives+of+pharmacolo

gy+326%3A69-74&btnG=

Noyce DS, Pryor WA (1955) Carbonyl reactions. I. Kinetics and mech-

anism of the acid-catalyzed aldol condensation of benzaldehyde

and acetophenone1. J Am Chem Soc 77:1397–1401. https://doi.

org/10.1021/ja01611a001

Lohse MJ, Klotz K-N, Lindenborn-Fotinos J, Reddington M, Schwabe

U, Olsson RA (1987) 8-Cyclopentyl-1, 3-dipropylxanthine

(

DPCPX)—a selective high aꢁnity antagonist radioligand for A

1

3

adenosine receptors. Naunyn Schmiedeberg’s Arch Pharmacol

36:204–210. https://doi.org/10.1007/BF00165806

Opletalova V, Hartl J, Palát K Jr, Patel A (2000) Conformational analy-

sis of 2-hydroxy-2 ′, 5 ′-diazachalcones. J Pharm Biomed Anal

23:55–59. https://doi.org/10.1016/S0731-7085(00)00263-6

Ottaviani G, Gosling DJ, Patissier C, Rodde S, Zhou L, Faller B

(2010) What is modulating solubility in simulated intestinal

ꢃuids? Eur J Pharm Sci 41:452–457. https://doi.org/10.1016/j.

ejps.2010.07.012

Londos C, Cooper D, Wolꢀ J (1980) Subclasses of external adeno-

sine receptors. Proc Natl Acad Sci 77:2551–2554. https://doi.

org/10.1073/pnas.77.5.2551

Maemoto T, Finlayson K, Olverman HJ, Akahane A, Horton RW,

Butcher SP (1997) Species diꢀerences in brain adenosine A1

receptor pharmacology revealed by use of xanthine and pyrazo-

lopyridine based antagonists. Br J Pharmacol 122:1202–1208.

https://doi.org/10.1038/sj.bjp.0701465

Phillis JW (1991) Adenosine and adenine nucleotides as regulators of

cellular function. CRC Press Incorporated. https://scholar.googl

e.com/scholar?hl=en&as_sdt=0%2C5&q=Phillis+JW+%28199

1%29+Adenosine+and+adenine+nucleotides+as+regulators

+of+cellular+function.+CRC+press%2C+&btnG=

Maemoto T et al (2004) Pharmacological characterization of

FR194921, a new potent, selective, and orally active antagonist

for central adenosine A1 receptors. J Pharmacol Sci 96:42–52.

https://doi.org/10.1254/jphs.FP0040359

Pitsikas N, Borsini F (1997) The adenosine A1 receptor antagonist

BIIP 20 counteracts scopolamine-induced behavioral deꢂcits in

the passive avoidance task in the rat. Eur J Pharmacol 328:19–22.

https://doi.org/10.1016/S0014-2999(97)83021-X

Martin YC (2005) A bioavailability score. J Med Chem 48:3164–3170.

https://doi.org/10.1021/jm0492002

Mathew B et al (2019) Perspective design of chalcones for the manage-

ment of CNS disorders: a mini-review. CNS Neurol Disord Drug

Targets. https://doi.org/10.2174/1871527318666190610111246

McGrath NA, Brichacek M, Njardarson JT (2010) A graphical journey

of innovative organic architectures that have improved our lives.

J Chem Educ 87:1348–1349. https://doi.org/10.1021/ed1003806

Mellado M et al (2018) Synthesis of chalcones with antiproliferative

activity on the SH-SY5Y neuroblastoma cell line: quantitative

structure–activity relationship models. Med Chem Res 27:2414–

Ralevic V, Burnstock G (1998) Receptors for purines and pyrimidines.

Pharmacol Rev 50:413–492. https://doi.org/10.1007/978-3-642-

28863-0_5

Rammohan A, Reddy JS, Sravya G, Rao CN, Zyryanov GV (2020)

Chalcone synthesis, properties and medicinal applications: a

review. Environ Chem Lett 18:1–26. https://doi.org/10.1007/

s10311-019-00959-w

Ramyashree D, Raghavendra K, Kumar AD, Vagish C, Kumar KA

(2017) Synthesis, characterization and antimicrobial activities

of chalcones and their post transformation to pyrazole deriva-

tives. Asian J Chem 29:1538–1542. https://scholar.google.com/

scholar?hl=en&as_sdt=0%2C5&q=Ramyashree+D%2C+Ragha

vendra+K%2C+Kumar+AD%2C+Vagish+C%2C+Kumar

+KA+%28201 7%29+Synth esis%2C+chara cteri zatio

n+and+antimicrobial+activities+of+chalcones+and+their

+post+transformation+to+pyrazole+derivatives+Asian

+J+Chem+29%3A1538-1542&btnG=

2

425. https://doi.org/10.1007/s00044-018-2245-2

Montanari F, Ecker GF (2015) Prediction of drug–ABC-transporter

interaction—recent advances and future challenges. Adv Drug

Deliv Rev 86:17–26. https://doi.org/10.1016/j.addr.2015.03.001

Muegge I, Heald SL, Brittelli D (2001) Simple selection criteria for

drug-like chemical matter. J Med Chem 44:1841–1846. https://

doi.org/10.1021/jm015507e

Müller CE (2001) A1 adenosine receptors and their ligands: overview

and recent developments. Il Farmaco 56:77–80. https://doi.

org/10.1016/S0014-827X(01)01005-9

Rao ML, Houjou H, Hiratani K (2001) Novel synthesis of macrocy-

cles with chalcone moieties through mixed aldol reaction. Tet-

rahedron Lett 42:8351–8355. https://doi.org/10.1016/S0040

-4039(01)01793-2

Munshi R, Pang I-H, Sternweis PC, Linden J (1991) A1 adenosine

receptors of bovine brain couple to guanine nucleotide-binding

proteins Gi1, Gi2, and Go. J Biol Chem 266:22285–22289. https://

scholar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Munsh

i+R%2C+Pang+I-H%2C+Stern weis+PC%2C+Linde

n+J+%281991%29+A1+adenosine+receptors+of+bovin

e+brain+couple+to+guanine+nucleotide-binding+prote

ins+Gi1%2C+Gi2%2C+and+Go+Journal+of+Biological

Rao YK, Fang S-H, Tzeng Y-M (2004) Diꢀerential eꢀects of synthe-

sized 2′-oxygenated chalcone derivatives: modulation of human

cell cycle phase distribution. Bioorg Med Chem 12:2679–2686.

https://doi.org/10.1016/j.bmc.2004.03.014

Rebola N, Pinheiro PC, Oliveira CR, Malva JO, Cunha RA (2003) Sub-

cellular localization of adenosine A1 receptors in nerve terminals

and synapses of the rat hippocampus. Brain Res 987:49–58. https

://doi.org/10.1016/S0006-8993(03)03247-5

+

Chemistry+266%3A22285-22289&btnG=

Nagarajan M, Shechter H (1984) The diverse carbenic and cationic

chemistry of 3-diazo-2, 5-diphenylpyrrole. J Org Chem 49:62–

Reppert SM, Weaver DR, Stehle JH, Rivkees SA (1991) Molecular

cloning and characterization of a rat A1-adenosine receptor that

is widely expressed in brain and spinal cord. Mol Endocrinol

5:1037–1048. https://doi.org/10.1210/mend-5-8-1037

Ritchie TJ, Macdonald SJ, Peace S, Pickett SD, Luscombe CN (2013)

Increasing small molecule drug developability in sub-optimal

chemical space. MedChemComm 4:673–680. https://doi.

org/10.1039/C3MD00003F

74. https://scholar.google.com/scholar?q=Nagarajan+M,+Shech

ter+H+(1984)+The+diverse+carbenic+and+cationic+chemi

stry+of+3-diazo -2,+5-diphe nylpy rrole +The+Journ

al+of+Organic+Chemistry+49:62-74&hl=en&as_sdt=0,5

Nagayama H et al (2019) Eꢀect of istradefylline on mood disorders

in Parkinson’s disease. J Neurol Sci 396:78–83. https://doi.

org/10.1016/j.jns.2018.11.005

1

3

Chemical Papers

Robinson SJ, Petzer JP, Terre’Blanche G, Petzer A, Van der Walt

MM, Bergh JJ, Lourens AC (2015) 2-Aminopyrimidines

as dual adenosine A1/A2A antagonists. Eur J Med Chem

Naunyn Schmiedeberg’s Arch Pharmacol 391:1361–1371.

https://doi.org/10.1007/s00210-018-1551-z

Szopa A et al (2019) Agomelatine and tianeptine antidepressant activ-

ity in mice behavioral despair tests is enhanced by DMPX, a

selective adenosine A2A receptor antagonist, but not DPCPX,

a selective adenosine a1 receptor antagonist. Pharmacol Rep

71:676–681. https://doi.org/10.1016/j.pharep.2019.03.007

Teague SJ, Davis AM, Leeson PD, Oprea T (1999) The design

of leadlike combinatorial libraries. Angew Chem Int Ed

38:3743–3748. https://doi.org/10.1002/(SICI)1521-3773(19991

216)38:24%3c3743::AID-ANIE3743%3e3.0.CO;2-U

1

04:177–188. https://doi.org/10.1016/j.ejmech.2015.09.035

Ruparelia KC et al (2018) The synthesis of chalcones as anti-

cancer prodrugs and their bioactivation in CYP1 express-

ing breast cancer cells. Med Chem 14:322–332. https://doi.

org/10.2174/1573406414666180112120134

Sahu NK, Balbhadra S, Choudhary J, Kohli DV (2012) Exploring

pharmacological signiꢂcance of chalcone scaꢀold: a review.

Curr Med Chem 19:209–225. https://doi.org/10.2174/09298

6

712803414132

Testa B, Kraemer S (2007) The biochemistry of drug metabolism—an

introduction-testa-2007-chemistry and biodiversity-Wiley Online

Library. Chem Biodivers. https://doi.org/10.1002/cbdv.20089

0199

Sankaranarayanan S, Ryan TA (2007) Neuronal exocytosis. Protein

traꢁcking in neurons. Elsevier, Amsterdam, pp 97–124. https

:

//doi.org/10.1016/B978-012369437-9/50010-4

Sawle P, Moulton BE, Jarzykowska M, Green CJ, Foresti R, Fair-

lamb IJ, Motterlini R (2008) Structure−activity relationships

of methoxychalcones as inducers of heme oxygenase-1. Chem

Res Toxicol 21:1484–1494. https://doi.org/10.1021/tx800115g

Schmidt JG (1881) Ueber die Einwirkung von Aceton auf Furfurol

und auf Bittermandelöl bei Gegenwart von Alkalilauge. Ber

Dtsch Chem Ges 14:1459–1461. https://doi.org/10.1002/

cber.188101401306

Unoh Y, Hirano K, Satoh T, Miura M (2013) Palladium-catalyzed

decarboxylative arylation of benzoylacrylic acids toward the

synthesis of chalcones. J Org Chem 78:5096–5102. https://doi.

org/10.1021/jo400716e

Van Calker D, Müller M, Hamprecht B (1978) Adenosine inhib-

its the accumulation of cyclic AMP in cultured brain cells.

Nature 276:839. https://scholar.google.com/scholar?hl=en&as_

sdt=0%2C5&q=Van+Calke r+D%2C+M%C3%BClle

r+M%2C+Hamprecht+B+%281978%29+Adenosine+inhib

its+the+accumulation+of+cyclic+AMP+in+cultured+brain

+cells+Nature+276%3A839&btnG=

Shenvi S, Kumar K, Hatti KS, Rijesh K, Diwakar L, Reddy GC

(

2013) Synthesis, anticancer and antioxidant activities of 2, 4,

5

-trimethoxy chalcones and analogues from asaronaldehyde:

structure–activity relationship. Eur J Med Chem 62:435–442.

https://doi.org/10.1016/j.ejmech.2013.01.018

Van der Walt MM, Terre’Blanche G (2015) 1, 3, 7-Triethyl-substi-

tuted xanthines—possess nanomolar aꢁnity for the adenosine

A1 receptor. Bioorg Med Chem 23:6641–6649. https://doi.

org/10.1016/j.bmc.2015.09.012

Shimada J et al (1997) Adenosine A2A antagonists with potent anti-

cataleptic activity. Bioorg Med Chem Lett 7:2349–2352. https

:

//doi.org/10.1016/S0960-894X(97)00440-X

Van der Werten EM et al (1995) 8-Substituted adenosine and theo-

phylline-7-riboside analogues as potential partial agonists for

the adenosine A1 receptor. Eur J Pharmacol Mol Pharmacol

290:189–199. https://doi.org/10.1016/0922-4106(95)00064-X

Vásquez-Martínez YA et al (2019) Antimicrobial, anti-inꢃamma-

tory and antioxidant activities of polyoxygenated chalcones. J

Braz Chem Soc 30:286–304. https://doi.org/10.21577/0103-

5053.20180177

Singh P, Anand A, Kumar V (2014) Recent developments in biologi-

cal activities of chalcones: a mini review. Eur J Med Chem

8

5:758–777. https://doi.org/10.1016/j.ejmech.2014.08.033

Stroba A et al (2009) 3, 5-Diphenylpent-2-enoic acids as allosteric

activators of the protein kinase PDK1: structure−activity rela-

tionships and thermodynamic characterization of binding as

paradigms for PIF-binding pocket-targeting compounds. J Med

Chem 52:4683–4693. https://doi.org/10.1021/jm9001499

Suwito H et al (2014) Design and synthesis of chalcone derivatives

as inhibitors of the ferredoxin—ferredoxin-NADP+ reduc-

tase interaction of plasmodium falciparum: pursuing new

antimalarial agents. Molecules 19:21473–21488. https://doi.

org/10.3390/molecules191221473

Vazquez-Rodriguez S, Matos MJ, Santana L, Uriarte E, Borges F,

Kachler S, Klotz KN (2013) Chalcone-based derivatives as new

scaꢀolds for h A 3 adenosine receptor antagonists. J Pharm Phar-

macol 65:697–703. https://doi.org/10.1111/jphp.12028

Veber DF, Johnson SR, Cheng H-Y, Smith BR, Ward KW, Kopple KD

(2002) Molecular properties that inꢃuence the oral bioavailabil-

ity of drug candidates. J Med Chem 45:2615–2623. https://doi.

org/10.1021/jm020017n

Suzuki F et al. (1993) Adenosine A1 antagonists. 3. Structure-

activity relationships on amelioration against scopolamine-

or N6-[(R)-phenylisopropyl] adenosine-induced cogni-

tive disturbance. J Med Chem 36:2508–2518. https://schol

ar.google.com/scholar?hl=en&as_sdt=0%2C5&q=Suzuk

i+F+et+al.+%281993%29+Adenosine+A1+antagonist

s.+3.+Structure-activity+relationships+on+ameliorati

on+against+scopolamine-or+N6-%5B%28R%29-phenylisop

ropyl%5D+adenosine-induced+cognitive+disturbance+Journ

al+of+medicinal+chemistry+36%3A2508-2518&btnG=

Swanson TH, Drazba JA, Rivkees SA (1995) Adenosine A1 receptors

are located predominantly on axons in the rat hippocampal for-

mation. J Comp Neurol 363:517–531. https://doi.org/10.1002/

cne.903630402

Vollert C, Forkuo GS, Bond RA, Eriksen JL (2013) Chronic treatment

with DCPCX, an adenosine A1 antagonist, worsens long-term

memory. Neurosci Lett 548:296–300. https://doi.org/10.1016/j.

neulet.2013.05.052

Von Lubitz DK, Paul IA, Bartus RT, Jacobson KA (1993) Eꢀects of

chronic administration of adenosine A1 receptor agonist and

antagonist on spatial learning and memory. Eur J Pharmacol

249:271. https://doi.org/10.1016/0014-2999(93)90522-J

Wang T, Chen G, Lu YJ, Chen Q, Huo Y, Li X (2019) Intermolecu-

lar multiple dehydrogenative cross-couplings of ketones with

boronic acids and amines via copper catalysis. Adv Synth Catal

361:3886–3892. https://doi.org/10.1002/adsc.201900419

Wu S, Yu H, Hu Q, Yang Q, Xu S, Liu T (2017) Silver-catalyzed decar-

boxylative cross-coupling of α-keto acids with alkenes giving

approach to chalcones. Tetrahedron Lett 58:4763–4765. https://

doi.org/10.1016/j.tetlet.2017.11.005

Szakács G, Váradi A, Özvegy-Laczka C, Sarkadi B (2008) The role

of ABC transporters in drug absorption, distribution, metabo-

lism, excretion and toxicity (ADME–Tox). Drug Discov Today

1

3:379–393. https://doi.org/10.1016/j.drudis.2007.12.010

Szopa A et al (2018) DPCPX, a selective adenosine A1 receptor

antagonist, enhances the antidepressant-like eꢀects of imipra-

mine, escitalopram, and reboxetine in mice behavioral tests.

Xie Z et al (2017) Synthesis and evaluation of hydroxychalcones as

multifunctional non-purine xanthine oxidase inhibitors for the

treatment of hyperuricemia. Bioorg Med Chem Lett 27:3602–

3

606. https://doi.org/10.1016/j.bmcl.2017.01.053

1

3

Chemical Papers

Yacoubi ME, Ledent C, Parmentier M, Bertorelli R, Ongini E, Costen-

tin J, Vaugeois JM (2001) Adenosine A2A receptor antagonists

are potential antidepressants: evidence based on pharmacology

and A2A receptor knockout mice. Br J Pharmacol 134:68–77.

https://doi.org/10.1038/sj.bjp.0704240

aromatic alkynes with aldehydes aꢀording chalcones in an oil/

water two-phase system. Synthesis 48:231–237. https://doi.

org/10.1055/s-0035-1560832

Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z (2017) Chal-

cone: a privileged structure in medicinal chemistry. Chem Rev

117:7762–7810. https://doi.org/10.1021/acs.chemrev.7b00020

Zhang N, Yang D, Wei W, Yuan L, Nie F, Tian L, Wang H (2015)

Silver-catalyzed double-decarboxylative cross-coupling of

α-keto acids with cinnamic acids in water: a strategy for the

preparation of chalcones. J Org Chem 80:3258–3263. https://

doi.org/10.1021/jo502642n

Publisher’s Note Springer Nature remains neutral with regard to

jurisdictional claims in published maps and institutional aꢁliations.

Zhou B, Xing C (2015) Diverse molecular targets for chalcones

with varied bioactivities. Med Chem 5:388. https://doi.

org/10.4172/2161-0444.1000291

Zhou Y, Li Z, Yang X, Chen X, Li M, Chen T, Yin S-F (2016)

Phosphorous acid promoted hydration–condensation of

1

3

Article Doi

C3 amino-substituted chalcone derivative with selective adenosine rA1 receptor affinity in the micromolar range

DOI: 10.1007/s11696-020-01414-9

Source and publish data:

Authors:

Article abstract of DOI:10.1007/s11696-020-01414-9

Full text of DOI:10.1007/s11696-020-01414-9

Products guided by the article

R&D Labs maybe for 1155-23-3

Relevant to this article

Hot Product