Molecules: N-Pyrrylarylsulfones With High Therapeutic Potential

molecules
Review
N-Pyrrylarylsulfones with High Therapeutic Potential
Valeria Famiglini 1 , Sabrina Castellano 2 and Romano Silvestri 1, *
1 Department of Drug Chemistry and Technologies, Sapienza University of Rome,
Laboratory affiliated to Istituto Pasteur Italia—Fondazione Cenci Bolognetti, Piazzale Aldo Moro 5,
I-00185 Roma, Italy; valeria.famiglini@uniroma1.it
2 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fiscano, Salerno, Italy;
scastellano@unisa.it
* Correspondence: romano.silvestri@uniroma1.it; Tel.: +39-06-4991-3800
Academic Editor: Claudiu T. Supuran

Received: 12 February 2017; Accepted: 3 March 2017; Published: 9 March 2017
Abstract: This review illustrates the various studies made to investigate the activity of N-pyrrylarylsulfone
containing compounds as potential antiviral, anticancer and SNC drugs. A number of synthetic
approaches to obtain tetracyclic, tricyclic and non-cyclic compounds, and their biological activity
with regard to structure–activity relationships (SARs) have been reviewed. The literature reviewed
here may provide useful information on the potential of N-pyrrylarylsulfone pharmacophore as well
as suggest concepts for the design and synthesis of new N-pyrrylarylsulfone based agents.
Keywords: sulfonamide; heterocycle; polycyclic compound; therapeutic agent
1. Introduction
Sulfonamide is the basis of several groups of drugs [1]. Intense interest focused on sulfonamide
drugs after the discovery in 1935 that the activity of red dye Prontosil [2,3] was attributed to breakdown
product sulfanilamide (1). The antibacterial sulfonamides work as competitive inhibitors of the
dihydropteroate synthase, an enzyme involved in folate synthesis [4]. The simple 1 was cheaper
than Prontosil, had fewer unwanted effects and did not impart the typical red color to the skin.
Nowadays, sulfonamides have been replaced by other antibacterial drugs such as β-lactam antibiotics,
with some important exception; for example, sulfamethoxazole (2) is used for treatment of urinary and
respiratory-tracts infections [5]. Sulfa molecules have been chemically manipulated to obtain drug for
the treatment of leprosy, fluid accumulation and diabetes. The modern era of drug treatment of leprosy
began in 1937 when the sulfa drug dapsone (3) [6] proved to be highly effective. For more than six
decades, 3 remained first line drug to treat leprosy. Since 1980s, 3 has been administered in combination
with rifampicin and clofazimine for treatment of leprosy [7]. Chlorothiazide (4) is a carbonic anhydrase
inhibitor which was introduced in 1958 as a diuretic drug and is used to treat hypertension and
edema [8,9]. Before the discovery of 4, mercurial drugs associated with severe toxicity were the only
available drugs to treat fluid retention. Few years later, in 1962, another sulfonamide, furosemide
(5), was discovered as diuretic drug and is used to treat fluid retention and for the treatment of high
blood pressure [10]. Tolbutamide (6), the first sulfonylurea anti-diabetic drug, was approved in the
United States in 1957 for the treatment of type 2 diabetics [11]. Even though since 1964 there were
concerns that sulfonylurea antidiabetic drugs may increase cardiovascular risk, the current literature
does not confirm the detrimental risk profile of sulphonylureas compared with other anti-diabetic
drugs [12]. Ethoxyzolamide (7) is a carbonic anhydrase inhibitor used in the treatment of glaucoma
and duodenal ulcers, and as a diuretic [13]. Other sulfa drug examples include antivirals agents, such
HIV-1 non-nucleoside reverse transcriptase and protease inhibitors [14–18], HCV NS3/4A protease [19]
and NS5B polymerase inhibitors [20]; antibiotics, such mafenide, approved by the FDA in 1948 [21];
and nonsteroidal anti-inflammatory drug such celecoxib, a COX-2 selective inhibitor [22] (Chart 1).
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Molecules 2017, 22, 434 2 of 17
Molecules
NS5B 2017, 22, 434
polymerase 2 of 18
inhibitors [20]; antibiotics, such mafenide, approved by the FDA in 1948 [21]; and
nonsteroidal anti-inflammatory drug such celecoxib, a COX-2 selective inhibitor [22] (Chart 1).
Chart
Chart 1. 1. Examplesofofsulfa
Examples sulfa and
and pyrrole
pyrrole containing
containingdrugs.
drugs.
Pyrrole ring is a well-known privileged scaffold that exhibits a wide variety of biological activities
Pyrrole
[23]. ring is
Including theapyrrole
well-known privileged
into different scaffold that
pharmacophores has exhibits
resulted ina non-cyclic
wide variety of biological
and polycyclic
activities [23]. Including
pyrrole-containing the pyrrole
systems into different
with potential pharmacophores
therapeutic effects such as hasanticancer
resulted in non-cyclic
(leukemia andand
polycyclic pyrrole-containing
lymphoma), systemsmalaria,
anti-microbic (bacteria, with potential
protozoa, therapeutic
and fungi) effects suchnervous
and central as anticancer
system (leukemia
agents
and (antipsychotic and anxiolytic)
lymphoma), anti-microbic (for example,
(bacteria, malaria, pyrrolnitrin
protozoa,(8)and[24], tolmetin
fungi) (9) [25],
and central isamoltane
nervous system
(CGP-361A) (10) [26], porphobilinogen (11) [27], and atorvastatin (12) [28]). Recently, VU0410150
agents (antipsychotic and anxiolytic) (for example, pyrrolnitrin (8) [24], tolmetin (9) [25], isamoltane (13),
a pyrrylarylsulfone
(CGP-361A) containing compound,
(10) [26], porphobilinogen has and
(11) [27], beenatorvastatin
discovered (12)
as mGluR4-positive
[28]). Recently, allosteric
VU0410150
modulator and evaluated as potential drug for treatment for Parkinson’s
(13), a pyrrylarylsulfone containing compound, has been discovered as mGluR4-positive disease [29,30]. In the past
allosteric
decades, numerous N-pyrrylarylsulfones have been synthesized by our research group in several drug
modulator and evaluated as potential drug for treatment for Parkinson’s disease [29,30]. In the past
discovery projects. In this work, attempt has been made to review various N-pyrrylarylsulfone based
decades, numerous N-pyrrylarylsulfones have been synthesized by our research group in several
compounds to discuss the synthetic approaches and the biological activity with regard to structure–
drug discovery projects. In this work, attempt has been made to review various N-pyrrylarylsulfone
activity relationships (SARs).
based compounds to discuss the synthetic approaches and the biological activity with regard to
structure–activity relationships (SARs).
2. Pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine 5,5-dioxide
Tetracyclic systems, for example mianserin, aptazepine
2. Pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine and bretazenil, have been widely
5,5-dioxide
investigated as psychotic drugs. The synthesis of pyrrolobenzothiadiazepine anellated with azole
Tetracyclic
ring started assystems, for example
a development mianserin,
of a previous researchaptazepine and bretazenil,
project on tetra-anellated have been
heterocycles widely
[31–33].
investigated as psychotic drugs. The synthesis of pyrrolobenzothiadiazepine
Pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine anellated
5,5-dioxide (14) was synthesized with azole
by reaction
ring of 2-nitrobenzensulfonyl
started as a development chloride with ethyl
of a previous pyrrole-2-carboxylate
research in the presence
project on tetra-anellated of potassium
heterocycles [31–33].
tert-butoxide and 18-crown-6 to provide 2-ethoxycarbonyl-1-(2-nitrobenzenesulfony)-1H-pyrrole
Pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine (15).
5,5-dioxide (14) was synthesized by reaction
After reduction of 15 to amino
of 2-nitrobenzensulfonyl derivative
chloride 16, the
with ethyl product was cyclized toinlactam
pyrrole-2-carboxylate 17 in the presence
the presence of
of potassium
2-hydroxypyridine as a bifunctional catalyst. Treatment of 17 with di-4-morpholinylphosphinic
tert-butoxide and 18-crown-6 to provide 2-ethoxycarbonyl-1-(2-nitrobenzenesulfony)-1H-pyrrole (15). chloride
(18) in the presence of sodium hydride afforded phosphinyloxyimine 19 which was transformed into
After reduction of 15 to amino derivative 16, the product was cyclized to lactam 17 in the presence of
14 by reaction with formylhydrazine (Scheme 1) [34].
2-hydroxypyridine as a bifunctional catalyst. Treatment of 17 with di-4-morpholinylphosphinic
chloride (18) in the presence of sodium hydride afforded phosphinyloxyimine 19 which was
transformed into 14 by reaction with formylhydrazine (Scheme 1) [34].
Molecules 2017, 22, 434 3 of 18
Molecules 2017, 22, 434 3 of 17
Molecules 2017, 22, 434 3 of 17
Scheme 1. Synthesis of 14.

3. 2-Methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]benzothiadia-zepine
10,10-dioxide
10,10-dioxide
Studies on tetracyclic analogs of mianserin as antidepressant drugs led to the development of
10,10-dioxide
Studies
the pyrroleon tetracyclic
analog analogs
aptazepine and of
themianserin as antidepressant
strictly related isoaptazepine and drugs led to the development of
10-methyl-10-azaaptazepine
the (20).
pyrrole analog
Studies
Pursuing aptazepine
onthis
tetracyclic and
researchanalogs the strictly related isoaptazepine and 10-methyl-10-azaaptazepine
project,of2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b]
mianserin as antidepressant drugs led to the development of
(20).[1,2,5]benzothiadiazepine
Pursuing
the this research
pyrrole analog project,
aptazepine 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b]
and the
10,10-dioxide strictly related isoaptazepine
(21) (tiaaptazepine) and 10-methyl-10-azaaptazepine
was designed as new putative core for
(20). Pursuing
central nervousthis
[1,2,5]benzothiadiazepine research
system (CNS) project,
active 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b]
10,10-dioxide (21)The
drugs. (tiaaptazepine)
synthesis of 21 was designed
is depicted inas new putative
Scheme 2. Reaction core
of for
[1,2,5]benzothiadiazepine
central
1-(2-aminobenzenesulfonyl)pyrrole10,10-dioxide
nervous system (CNS) activewith (21)
drugs.
ethyl (tiaaptazepine)
The synthesis
glyoxylate viaofwas designed as
21 is depicted type
a Pictet-Spengler new putative
in Scheme core for
2. Reaction
condensation gave of
central nervous system (CNS) active drugs.
ethylThe synthesisvia
11-ethoxycarbonyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine
1-(2-aminobenzenesulfonyl)pyrrole with glyoxylate of a21Pictet-Spengler
is depicted in Scheme
5,5-dioxide 2. Reaction
type(22). Reaction of
condensation of
gave
1-(2-aminobenzenesulfonyl)pyrrole
22 with bromoacetyl bromide afforded with the
ethyl glyoxylate viabromoacetyl
corresponding
11-ethoxycarbonyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine a Pictet-Spengler type condensation
derivative
5,5-dioxide23 which gave of
reacted
(22). Reaction
11-ethoxycarbonyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine
with benzylamine (24) and subsequently 5,5-dioxide (22). Reaction of
22 with bromoacetyl bromide afforded thethermally cycled to
corresponding 25. Compound
bromoacetyl 25 was reduced
derivative 23 which with lithium
reacted with
22 with bromoacetyl
aluminum hydride bromide afforded the corresponding bromoacetyl derivative 23 which reacted
benzylamine (24) and(26) and debenzylated
subsequently to 27 with
thermally hydrogen
cycled over Pd/C. Finally,
to 25. Compound 25 was 27 reduced
was converted
with to 21
lithium
withreductive
via benzylamine (24) and
amination subsequently
using thermally
formaldehyde cycled
in the to 25. Compound
presence of hydrogen25(Scheme
was reduced with lithium
2) [35].
aluminum hydride (26) and debenzylated to 27 with hydrogen over Pd/C. Finally,
aluminum hydride (26) and debenzylated to 27 with hydrogen over Pd/C. Finally, 27 was converted 27 was converted
to 21
to 21via
via reductive
reductive amination
amination using
using formaldehyde
formaldehyde in thein the presence
presence of hydrogen
of hydrogen (Scheme(Scheme
2) [35]. 2) [35].
Scheme 2. Synthesis of 21, and structure of 10-methyl-10-azaaptazepine (20).
Scheme 2. Synthesis of 21, and structure of 10-methyl-10-azaaptazepine (20).

It is worthwhile
Scheme mentioning
2. Synthesis that direct
of 21, cyclization
and structure of of 24 in the presence of excess
10-methyl-10-azaaptazepine of methylamine
(20).
via diketo intermediate 28, failed due the formation 11-carboxy-10,11-dihydropyrrolo[1,2-b][1,2,5]
It is worthwhile mentioning that direct cyclization of 24 in the presence of excess of methylamine
benzothiadiazepine-11-acetic
It isdiketo
worthwhile mentioning acid bisdirect
that methylamide 5,5-dioxide (29).presence
Intramolecular cyclization of 29
via intermediate 28, failed due the cyclization of 24 in the of excess of methylamine
formation 11-carboxy-10,11-dihydropyrrolo[1,2-b][1,2,5]
in the presence of 2-hydroxypyridine led exclusively to the spiro derivative 30. It should be noted that
via diketo intermediate 28, failed
benzothiadiazepine-11-acetic aciddue the formation
bis methylamide 11-carboxy-10,11-dihydropyrrolo[1,2-b][1,2,5]
5,5-dioxide (29). Intramolecular cyclization of 29
in the presence of 2-hydroxypyridine
benzothiadiazepine-11-acetic led exclusively 5,5-dioxide
acid bis methylamide to the spiro derivative 30. It should cyclization
(29). Intramolecular be noted thatof 29
Molecules 2017, 22, 434 4 of 18
in theMolecules
presence2017,of
22,2-hydroxypyridine
434 4 of 17 that
led exclusively to the spiro derivative 30. It should be noted
treatment of 24 with sodium hydrogen carbonate gave lactam 31, which might be the intermediate of
the conversion of 24 to 29 (Scheme 3) [36].
Molecules 2017, 22, 434 4 of 17
Scheme 3. Chemical transformation of 24.

Scheme 3. Chemical transformation of 24.
Compounds 21 and 22 were enantioseparated by enantioselective HPLC, and the absolute
Compounds
configuration of21the and were
pure22enantiomersenantioseparated
Scheme
was established by enantioselective
by circular
3. Chemical transformation
dichroism (CD)
of 24. HPLC, and the absolute
spectroscopy.
The inofvitro
configuration the binding affinities forwas
pure enantiomers several CNS receptors
established (DA1, DA
by circular 2, DA3, 5-HT
dichroism 1A, 5-HT
(CD) 2A, 5-HT2C,
spectroscopy.
5-HTin
The 3, α1NA, α2NA and
Compounds
vitro binding 21 muscarinic
and 22 were
affinities receptors)
for several showed
enantioseparated that
CNS receptorsbyboth enantiomers
enantioselective
(DA , DA , of
DA derivative
HPLC,, 5-HTand ,21,
the
5-HT(−)-(R)-21
absolute
1 2 3 1A 2A , 5-HT2C ,
and (+)-(S)-21, of
configuration showed
the higher
pure aﬃnities was
enantiomers thanestablished
the (−)-(R)-22by and (+)-(S)-22
circular counterparts,
dichroism (CD) with exception
spectroscopy.
5-HT3 , α1NA , α2NA and muscarinic receptors) showed that both enantiomers of derivative 21, (−)-(R)-21
of α1NAThe forinwhich
vitro (+)-(S)-22
binding was superior.
affinities Compound
for than
several (+)-(S)-21 showed good affinities for 5-HT2A 1A,, 5-HT
5-HT2C 2A,,
and (+)-(S)-21, showed higher affinities theCNS receptors
(−)-(R)-22 and 1, DA
(DA(+)-(S)-222, DA 3, 5-HT1A , 5-HT
counterparts, with exception
5-HT2C
5-HT 3, ,αand
1NA, α 2NAreceptors
α1NA but onlyreceptors)
and muscarinic moderateshowed
affinitiesthat
for both
DA1, enantiomers
DA2 and 5-HT3 receptors. Compared
of derivative 21, (−)-(R)-21 to
of α1NA for which compounds
the reference
(+)-(S)-22 was superior. Compound
mirtazepine,
(+)-(S)-21 showed good affinities for 5-HT 1A , 5-HT2A ,
and (+)-(S)-21, showed higher aﬃnities mianserine and 5-methoxymianserin,
than the (−)-(R)-22 this compound
and (+)-(S)-22 counterparts, showed
with exception
5-HThigher
2C , andaffinity
α receptors
the 5-HTbut only moderate affinities for DA 1 , DA2 and 5-HT3 receptors. Compared
of α1NA for 1NA which of(+)-(S)-22 1A subtype,
was superior.and different
Compound general
(+)-(S)-21 pharmacological
showed profile
good affinities for[37].
5-HT1A, 5-HT2A,
to the reference compounds mirtazepine, mianserine and 5-methoxymianserin,
5-HT2C, and α1NA receptors but only moderate affinities for DA1, DA2 and 5-HT3 receptors. Compared to
this compound
4. Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine
showed
the higher affinity
reference compoundsof themirtazepine,
5-HT1A subtype, andand
mianserine different9,9-dioxide
general pharmacological
5-methoxymianserin, this compound profile
showed [37].
higher affinity of the 5-HT1A subtype, and different general9,9-dioxide
Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothia-diazepine pharmacological profile
(32) was [37]. as a new
synthesized
4. Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide
benzothiadiazepine tetracyclic ring of pharmaceutical interest. The synthesis of 32 was achieved by a
4. Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine
simple
Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothia-diazepine 9,9-dioxide
procedure involving the anellation of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide (33)
9,9-dioxide (32) was synthesized as a new
at the 10,11-azomethine
benzothiadiazepine bond by cycloaddition with tosylmethyl
tetracyclic ring of pharmaceutical interest.
Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothia-diazepine isocyanide (TosMIC)
The synthesis
9,9-dioxide in the presence
of 32 was achieved
(32) was synthesized as a new by a
of buthyl
simple lithium.
benzothiadiazepine
procedure Alternatively,
tetracyclic
involving 32 could
ring be
ofprepared
of pharmaceutical
the anellation starting
interest.from addition reaction
The synthesis of 32 was
pyrrolo[1,2-b][1,2,5]benzothiadiazepine of achieved
nitromethane
by a (33)
5,5-dioxide
to the azomethine
simple procedure bond of 33the
involving to anellation
provide 34ofwhich was reduced to amino 35 with of hydrogen
pyrrolo[1,2-b][1,2,5]benzothiadiazepine at high
5,5-dioxide (33)
at the 10,11-azomethine bond by cycloaddition with tosylmethyl isocyanide (TosMIC) in the presence
pressure
at the in the presencebond
10,11-azomethine of nickel/Raney
by as a with
cycloaddition catalyst. Treatment
tosylmethyl of 35 with
isocyanide triethylinorthoformate
(TosMIC) the presence
of buthyl lithium. Alternatively, 32 could be prepared starting from addition reaction of nitromethane
furnished the dihydro
of buthyl lithium. derivative 32
Alternatively, 36 could
whichbewas oxidized
prepared to 32 with
starting frommanganese dioxideof
addition reaction (Scheme 4) [38].
nitromethane
to the azomethine bond of 33 to provide 34 which was reduced to amino 35 with of hydrogen at high
to the azomethine bond of 33 to provide 34 which was reduced to amino 35 with of hydrogen at high
pressure in the presence of nickel/Raney as a catalyst. Treatment of 35 with triethyl orthoformate
pressure in the presence of nickel/Raney as a catalyst. Treatment of 35 with triethyl orthoformate
furnished the dihydro
furnished derivative
the dihydro 3636which
derivative whichwas
was oxidized
oxidized toto3232with
with manganese
manganese dioxide
dioxide (Scheme
(Scheme 4) [38].
4) [38].
Scheme 4.
Scheme 4. Synthesis
Synthesisofof32.
32.
Molecules 2017, 22, 434 5 of 18
Molecules 2017, 22, 434 5 of 17
5.
5. 5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one
5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one5,5-dioxide
5,5-dioxide
5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one
5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one 5,5-dioxide
5,5-dioxide (PBTD)
(PBTD) derivatives,
derivatives, analogs
analogs ofof
compound
compound17 17described
describedininScheme
Scheme1, 1,were
weresynthesized
synthesizedas asaanovel
novelclass
classofofHIV-1-specific
HIV-1-specificnon-nucleoside
non-nucleoside
reverse
reverse transcriptase
transcriptase inhibitors
inhibitors (NNRTIs).
(NNRTIs). InIn general,
general, the
the newly
newly synthesized
synthesized compounds
compounds werewere non
non
cytotoxic MT-4cells
cytotoxic for MT-4 cellsatatconcentrations
concentrationsupup to to
300300
µM.μM. Maximum
Maximum antiviral
antiviral activity
activity was was obtained
obtained with
with compounds
compounds 37a–h37a–h bearing
bearing the chlorine
the chlorine atomatom at position
at position 7 and
7 and the the alkyl/alkenyl
alkyl/alkenyl group
group at position
at position 10
10 of the pyrrolo[1,2-b][1,2,5]benzothiadiazepine ring (Table 1). Compounds 37a and 37b
of the pyrrolo[1,2-b][1,2,5]benzothiadiazepine ring (Table 1). Compounds 37a and 37b (EC50 = 1.0 and (EC 50 = 1.0 and
0.5
0.5μM,
µM, respectively)
respectively) showed
showed thethe highest
highest potency
potency and
and selectivity
selectivity (SI
(SI of
of >300
>300and
and>600,
>600,respectively)
respectively)[39].
[39].
Table Anti-HIV-1 activity of 7-Cl-PBTDs 37a–h aa..

Table 1. Anti-HIV-1
HIV-1 IIIB
Compound R HIV-1 IIIB
Compound R CC b (μM)
50 b EC50 c (μM) SI d d
CC50 (µM) EC50 c (µM) SI
37a H >300 1.0 >300
37a
37b HMe >300
>300 1.0
0.5 >300
>600
37b Me >300 0.5 >600
37c
37c
Et
Et
283
283
2.4
2.4
118
118
37d
37d Propyl
Propyl 126
126 14
14 99
37e
37e Isopropyl
Isopropyl >300
>300 Ndee
Nd --
37f
37f Allyl
Allyl >300
>300 3.7
3.7 >81
>81
37g Crotyl >300 4.1 >73
37g Crotyl >300 4.1 >73
37h Dimethylallyl >300 129 >2
a
37h Dimethylallyl >300 129 b
>2
Data are mean values of two to three independent experiments each one in triplicate. CC50 : cytotoxic
a Data are mean
concentration (µM) values of two
to induce 50%to death
three of independent
noninfected experiments eachwith
cells, as evaluated onethe
in triplicate.
MTT method
b CC50: cytotoxicc
in MT-4 cells.
EC (HIV-1,
concentration
50 III
(μM)
B ): effective concentration (µM) to inhibit by 50% HIV-1
to induce 50% death of noninfected cells, as evaluated (IIIB strain) induced cell death,
with the MTT method as evaluated
in MT-4
with the MTT method in MT-4 cells. d SI: selectivity index calculated as CC /EC ratio. e nd, no data.
50 50
cells. EC50 (HIV-1, IIIB): effective concentration (μM) to inhibit by 50% HIV-1 (IIIB strain) induced cell
c
death, as evaluated with the MTT method in MT-4 cells. d SI: selectivity index calculated as CC50/EC50
Crystal structure ◦
ratio. e nd, no data. [40] of 37a showed that the aromatic moieties adopted a dihedral angle of 114.4 ,
a value that was very near to the optimal value of the butterfly-like conformation reported by the
Crystalmodel
Schaefer’s structure
[41]. [40] of 37a showed that the aromatic moieties adopted a dihedral angle of
114.4°, a value that was very near to the optimal value of the butterfly-like conformation reported by
6. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine
the Schaefer’s model [41]. Acetic Acid 5,5,-dioxide
The PBTD scaffold has been exploited in several antiviral research programs. A series of
6. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine
pyrrolo[1,2-b][1,2,5]benzothiadiazepine acetic Acetic Acid
acid 5,5,-dioxide
derivatives was synthesized by reaction of 1-(2-
aminobenzenesulfonyl)pyrrole with ethyl 3,3-diethoxypropionate
The PBTD scaffold has been exploited in several antiviral research in aqueous acetic acid
programs. A to furnish
series of
ethyl 10,11-dihydro-pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic
pyrrolo[1,2-b][1,2,5]benzothiadiazepine acetate 5,5-dioxide
acetic acid derivatives was synthesized (38). Ester
by reaction 38
of 1-(2-
was N-acylated in the presence of
aminobenzenesulfonyl)pyrrole triisobutylamine
with to afford ethyl 10,11-dihydro-10-(4-methylbenzoyl)
ethyl 3,3-diethoxypropionate in aqueous acetic acid to furnish
pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetate
ethyl 5,5-dioxide (39)acetate
10,11-dihydro-pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic which 5,5-dioxide
was hydrolyzed into the
(38). Ester 38
corresponding
was N-acylated inacetic acid 40. Alternatively,
the presence alkaline
of triisobutylamine hydrolysis
to afford of 38 furnished acid 41 which was
ethyl 10,11-dihydro-10-(4-methylbenzoyl)
transformed into azetidone 42 by treatment with trifluoroacetic
pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetate anhydride
5,5-dioxide (39) which (Scheme 5). Derivatives
was hydrolyzed 38
into the
and 42 showed significant inhibition of HIV-1 with EC
corresponding acetic acid 40. Alternatively, alkaline hydrolysis
50 = 19.5 and 18 µM, respectively) [42].
of 38 furnished acid 41 which was
Replacement
transformed of the pyrrole
into azetidone 42 byring of PBTD
treatment with
with the indole (43)
trifluoroacetic resulted (Scheme
anhydride in weaker5).antiretroviral
Derivatives
compounds [39]. On the other hand, the 5H-indolo[3,2-b][1,5]benzothiazepine isomers
38 and 42 showed significant inhibition of HIV-1 with EC50 = 19.5 and 18 μM, respectively) [42]. (e.g., 44), were
endowed with anti-HIV-1 activity in the low micromolar range of concentrations [43]. In addition,
1H-pyrrolo[2,3-b][1,5]benzothiazepine (e.g., 45), 1H-pyrrolo[3,2-b][1,5]benzothiazepine (e.g., 46) [44]
and 9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one 4,4-dioxide derivatives (47) [45] were
Molecules 2017, 22, 434 6 of 17
Molecules 2017, 22, 434 6 of 18
synthesized as new heterocyclic systems mimicking the structural features of the PBTDs scaffold
(Chart 2).
Molecules 2017, 22, 434 6 of 17
Scheme 5. Synthesis of 38 and 42.
Replacement of the pyrrole ring of PBTD with the indole (43) resulted in weaker antiretroviral
compounds [39]. On the other hand, the 5H-indolo[3,2-b][1,5]benzothiazepine isomers (e.g., 44), were
1H-pyrrolo[2,3-b][1,5]benzothiazepine (e.g., 45), 1H-pyrrolo[3,2-b][1,5]benzothiazepine (e.g., 46) [44] and
9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one
Scheme 5. Synthesis4,4-dioxide derivatives (47) [45] were synthesized
of 38 and 42.
Scheme 5. Synthesis of 38 and 42.
as new heterocyclic systems mimicking the structural features of the PBTDs scaffold (Chart 2).
Replacement of the pyrrole ring of PBTD with the indole (43) resulted in weaker antiretroviral
compounds [39]. On the other hand, the 5H-indolo[3,2-b][1,5]benzothiazepine isomers (e.g., 44), were
1H-pyrrolo[2,3-b][1,5]benzothiazepine (e.g., 45), 1H-pyrrolo[3,2-b][1,5]benzothiazepine (e.g., 46) [44] and
9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one 4,4-dioxide derivatives (47) [45] were synthesized
as new heterocyclic systems mimicking the structural features of the PBTDs scaffold (Chart 2).
Chart
Chart 2.
2. Heterocyclic
Heterocyclic compounds
compounds structurally correlated to
structurally correlated to PBTD
PBTD HIV-1
HIV-1 NNRTIs.
NNRTIs.
7. PBTDs
7. PBTDs as
as Chronic
Chronic Myelogenous
Myelogenous Leukemia
Leukemia (CML)
(CML) Agents
Agents
The antitumor
The antitumor activity
activity of
of pyrrolo[2,1-c][1,4]benzodiazepines
pyrrolo[2,1-c][1,4]benzodiazepines (PBDs, (PBDs, e.g.,
e.g., 48)
48) related
relatedto toanthramycin
anthramycin
was extensively
was extensively studied,
studied, as as it
it was
was documented
documented in in Thurston’s
Thurston’s review
review [46].
[46]. Given
Given the the high
high structural
structural
similarity between PBTD and PBD compounds, two PBTDs, 23
similarity between PBTD and PBD compounds, two PBTDs, 23 and its 10-(4-methylbenzoyl) and its 10-(4-methylbenzoyl) derivative
49, were selectedChartfor2.screening
Heterocyclic compounds structurally correlated activity
to PBTD(Chart
HIV-1 3, NNRTIs.
derivative 49, were selected of forpro-apoptotic
screening ofand anti-leukemia
pro-apoptotic and anti-leukemia Tables
activity2 and 3) [47].
(Chart 3,
PBTD
Tables 23 was
2 and prepared
3) [47]. PBTD by an improved
23 was prepared procedure using dimethoxyacetal of ethyl glyoxylate in
7. PBTDs as Chronic Myelogenous Leukemiaby an improved
(CML) Agents procedure using dimethoxyacetal of
absolute
ethyl ethanol in
glyoxylate inthe presence
absolute of 4-toluenesulfonic
ethanol in the presence acid
of(PTSA). Compoundacid
4-toluenesulfonic 23, prepared
(PTSA). as described
Compound
in Scheme
23, prepared 2, was
The antitumor N-acylated
activityin
as described of to 49 with 2, 4-methylbenzoyl
pyrrolo[2,1-c][1,4]benzodiazepines
Scheme was N-acylated to by49refluxing
(PBDs,
with in 1-bromo-3-chloropropane
e.g., 48) related by
4-methylbenzoyl to anthramycin
refluxing in in
the
was presence
extensivelyof sodium
studied, hydrogen
as it was carbonate.
documented PBTDs
in 23 and
Thurston’s 49 induced
review
1-bromo-3-chloropropane in the presence of sodium hydrogen carbonate. PBTDs 23 and 49 induced apoptosis
[46]. Given in
the K562
high cells and
structural
caused cell
similarity
apoptosis indeath
between in BCR-ABL-positive
K562 PBTD
cells and caused
and PBD compounds, leukemia
cell death two cells obtained
PBTDs, 23 and itsfrom
in BCR-ABL-positive chroniccellsmyeloid
10-(4-methylbenzoyl)
leukemia obtained leukemia
derivative
from
patients
49, were who were
selected forat onset
screening or were
of IM-resistant.
pro-apoptotic and Apoptotic
anti-leukemia mechanism
activity
chronic myeloid leukemia patients who were at onset or were IM-resistant. Apoptotic mechanism studies
(Chart 3,showed
Tables 2 that
and PBTDs
3) [47].
23
PBTDand 2349 activated
was preparedthe caspase
by an activity
improved through
procedure two different
using pathways:
dimethoxyacetal
studies showed that PBTDs 23 and 49 activated the caspase activity through two different pathways: both ofcompounds
ethyl activated
glyoxylate in
caspase-3;
absolute 23 significantly
ethanol in the reduced
presence of the procaspase-8;
4-toluenesulfonic in
acidcontrast
(PTSA). 49 evidenced
Compound
both compounds activated caspase-3; 23 significantly reduced the procaspase-8; in contrast 49 a decrease
23, prepared of procaspase-9
as described
band.
in The 2,
Scheme
evidenced aapoptosis was
was N-acylated
decrease observed
to 49 with
of procaspase-9 before the
Theexpression
4-methylbenzoyl
band. apoptosis of BCR-ABL
by refluxing
was protein andexpression
in 1-bromo-3-chloropropane
observed before the the tyrosine in
of
phosphorylation.
the presence of PBTDs-mediated
sodium hydrogen suppression
carbonate. PBTDsof K562
23 cell
and proliferation
49
BCR-ABL protein and the tyrosine phosphorylation. PBTDs-mediated suppression of K562 cellinduced was
apoptosis characterized
in K562 by
cells the
and
appearance
caused cell of
proliferation DNA
death
was infragmentation
characterized by and
BCR-ABL-positive was associated
leukemia
the appearance with
cells
of DNA the
obtained poly(ADPribose)
from chronic
fragmentation and was polymerase
myeloid
associated (PARP)
leukemia
with
cleavage.
patients PBTDs
who were23 and
at 49
onset treatment
or were resulted
IM-resistant.in caspase-3
Apoptotic activation
mechanism
the poly(ADPribose) polymerase (PARP) cleavage. PBTDs 23 and 49 treatment resulted in caspase-3through down-regulation
studies showed that of Bcl-2
PBTDs
and
23 up-regulation
and 49 activated of
theBax [48].
caspase PBTDs
activity possessed
through two inhibitory
different activity
pathways: against
activation through down-regulation of Bcl-2 and up-regulation of Bax [48]. PBTDs possessed inhibitory both mTOR
compounds and impeded
activated
hyper-phosphorylation
caspase-3;
activity 23 significantly
against mTOR and ofreduced
Akt as athe
impeded feedback of inhibition
procaspase-8; of mTOR
in contrast
hyper-phosphorylation by rapamycin
49ofevidenced
Akt [49].of
a decrease
as a feedback These
of findings
procaspase-9
inhibition of
highlighted
band. The PBTDs
apoptosis as potential
was agents
observed for
before the treatment
the expression of CMLof [50,51].
BCR-ABL
mTOR by rapamycin [49]. These findings highlighted PBTDs as potential agents for the treatment protein and the tyrosineof
phosphorylation.
CML [50,51]. PBTDs-mediated suppression of K562 cell proliferation was characterized by the
appearance of DNA fragmentation and was associated with the poly(ADPribose) polymerase (PARP)
cleavage. PBTDs 23 and 49 treatment resulted in caspase-3 activation through down-regulation of Bcl-2
and up-regulation of Bax [48]. PBTDs possessed inhibitory activity against mTOR and impeded
hyper-phosphorylation of Akt as a feedback of inhibition of mTOR by rapamycin [49]. These findings
highlighted PBTDs as potential agents for the treatment of CML [50,51].
Molecules 2017, 22, 434 7 of 18
Molecules 2017, 22, 434 7 of 17
Chart 3.
Chart 3. PBTDs
PBTDs as
as CML
CML agents.
agents.
Table 2. Apoptotic activity of 23 and 49 in cells from CML patients at onset at 10 μM [46].
Table 2. Apoptotic activity of 23 and 49 in cells from CML patients at onset at 10 µM [46].
% of Apoptosis
Patient Sex Age Source aa % of Apoptosis
23 49
Patient Sex Age Source
24 h 23 48 h 49
24 h 48 h
1 M 45 PB a 64h
24 48 h70 24 h 77 48 h 85
2 1 M M 6045 BM
PB a
b 50
64 7070 77 70 85 85
3 2 F M 7360 PB
BM b 65
50 7079 70 66 85 82
4 3 M F 8373 PB
BM 65
50 7970 66 50 82 75
4 M 83 BM 50 70 50 75
5 F 46 PB 50 70 60 80
5 F 46 PB 50 70 60 80
6 6 F F 2727 PB
PB 50
50 70 70 60 60 80 80
7 7 F F 4545 PB
PB 60
60 80 80 64 64 80 80
8 8 M M 3535 PB
PB 60
60 80 80 65 65 85 85
9 9 M M 6666 PB
PB 60
60 8080 60 60 80 80
10 F 38 PB 50 70 70 80
10 11
F F
3865
PB
PB
50
52 71
70 55
70 78
80
11 12 F F 6527 PB
PB 52
52 7371 55 55 78 78
12 F 27
a PB: peripheral PB b 52 73
blood cells. BM: bone marrow cells. 55 78
a PB: peripheral blood cells. b BM: bone marrow cells.
Table 3.
Table 3. Apoptotic
Apoptotic activity
activity of
of 23 and 49 in cells
cells from
from CML
CML patients
patients in blast
blast crisis
crisis and
and Imatinib-resistant
Imatinib-resistant
μM.
at onset at 10 µM.
Percent Apoptosis
Percent Apoptosis
Patient Sex
Patient Sex Age
Age Source
Source
aa 23 49
23 49
24 h 48 h 24 h 48 h
24 h 48 h 24 h 48 h
13 M 38 PB a 60 80 40 60
13 14 MF 38
70 PB a
PB 5560 78 80 50 40 70 60
14 F 70 PB 55
a PB: peripheral blood cells.
78 50 70
a PB: peripheral blood cells.
8. Pyrryl Aryl Sulfones

Diarylsulfones
8. Pyrryl emerged as a chemical class of HIV-1 NNRTIs. The presence of the nitro group at
Aryl Sulfones
position 2 of the phenyl ring and the sulfur bridging atom as sulfur dioxide are fundamental structural
Diarylsulfones emerged as a chemical class of HIV-1 NNRTIs. The presence of the nitro group at
characteristics for their activity. The antiviral activity of 2-nitrophenyl phenyl sulfone (50, NPPS) [52]
position 2 of the phenyl ring and the sulfur bridging atom as sulfur dioxide are fundamental structural
prompted the synthesis of a series of 41 pyrryl aryl sulfones (PAS) and some related derivatives [53].
characteristics for their activity. The antiviral activity of 2-nitrophenyl phenyl sulfone (50, NPPS) [52]
Pyrryl 2-nitrophenyl sulfone (51) was straightforwardly prepared by nucleophilic substitution reaction
prompted the synthesis of a series of 41 pyrryl aryl sulfones (PAS) and some related derivatives [53].
between 2-nitrobenzenesulfonyl chloride and pyrrole in the presence of n-tetrabutylammonium
Pyrryl 2-nitrophenyl sulfone (51) was straightforwardly prepared by nucleophilic substitution reaction
hydrogen sulfate (TBAS) as a phase transfer catalyst. On the other hand, alkaline hydrolysis of 2-
between 2-nitrobenzenesulfonyl chloride and pyrrole in the presence of n-tetrabutylammonium
ethoxycarbonylpyrrole (16) [34] afforded the acid 52 which was transformed into 53 by reaction with
hydrogen sulfate (TBAS) as a phase transfer catalyst. On the other hand, alkaline hydrolysis of
ethyl chloroformate in the presence of 4-methylmorpholine followed by treatment of the intermediate
2-ethoxycarbonylpyrrole (16) [34] afforded the acid 52 which was transformed into 53 by reaction with
mixed anhydride with glycine ethyl ester (Scheme 6).
ethyl chloroformate in the presence of 4-methylmorpholine followed by treatment of the intermediate
Ester 55 was prepared by treating the corresponding acid 54 [54] with oxalyl chloride and then
mixed anhydride with glycine ethyl ester (Scheme 6).
with anhydrous ethanol. Reaction of 1-(2-aminobenzenesulfonyl)pyrrole [35] with methyl malonyl
chloride in the presence of triethylamine led to amide 56 which in turn was methylated to 57 or 58
with one or two equivalents of methyl chloride, respectively, in the presence of potassium carbonate
Molecules 2017, 22, 434 8 of 17
(Scheme 6). Compound

Molecules 2017, 22, 434 16, a 2-nitrophenyl 1-pyrryl sulfone bearing the 2-ethoxycarbonyl function,
8 of 18
showed the highest anti HIV-1 activity (Table 4).
Scheme 6. Synthesis of PAS 51–58.

Scheme 6. Synthesis of PAS 51–58.
Table 4. Anti-HIV-1 Activity of PASs 16 and 51–58 a.

Ester 55 was prepared by treating the corresponding acid 54 [54] with oxalyl chloride and then
with anhydrous ethanol. HIV-1 IIIB
Reaction of 1-(2-aminobenzenesulfonyl)pyrrole [35] with methyl malonyl
Compound
chloride in the presence of triethylamine led to amide 56 which in turn wasSI
CC (μM) EC
b c (μM) d
50 50 methylated to 57 or 58
16 of methyl chloride,
with one or two equivalents >308 respectively,15.08 in the presence of >20potassium carbonate
(Scheme 6). Compound 51 16, a 2-nitrophenyl36.551-pyrryl sulfone>36.55 -
bearing the 2-ethoxycarbonyl function,
52 >337.5
showed the highest anti HIV-1 activity (Table 4). >337.5 -
53 >262.2 >262.2 -
54 Table 4. Anti-HIV-1
>333 Activity of PASs 16 and 51–58 a .
>333 -
55 255 >255 -
56 >370 HIV-1 III
63 B >5.8
Compound
57 >279 b (µM) EC c (µM)
>279 d-
CC 50 50 SI
5816 >285
>308 >285
15.08 >20-
NPPS51 -
36.55 1.4
>36.55 --
aData are mean values of >337.5 experiments
52two to three independent >337.5 -
each one in triplicate; b CC50: cytotoxic
53 >262.2 >262.2 -
concentration (μM) to induce 50% death of non-infected cells, as evaluated with the MTT method in MT-4
54 >333 >333 -
cells; c EC50 (HIV-1, IIIB): effective concentration (μM) to inhibit by 50% HIV-1 (IIIB strain) induced cell death,
55 255 >255 -
as evaluated with the MTT >370 SI: selectivity index
56method in MT-4 cells;
d
63 calculated as CC50/EC50 ratio.
>5.8
57 >279 >279 -
The importance of the58 diaryl sulfone moiety >285 for the design of new anti-HIV-1
>285 - agents was further
NPPS - 1.4
confirmed by the synthesis of new series of PAS and indolyl aryl sulfones [55,56]. The amino-PAS -
a Data are mean values of two to three independent experiments each one in triplicate; b CC : cytotoxic
derivatives were synthesized as follows. Alkylation of the 2-amino group was achieved50 by reaction of
concentration (µM) to induce 50% death of non-infected cells, as evaluated with the MTT method in MT-4 cells;
59a and 59b withIII
c EC (HIV-1,
50
the appropriate aldehyde in the presence of sodium cyanoborohydride; carboxamides
B ): effective concentration (µM) to inhibit by 50% HIV-1 (IIIB strain) induced cell death, as evaluated
werewith
obtained
the MTTbymethod
heating withcells;
in MT-4 an dacyl chlorideindex
SI: selectivity in pyridine
calculated(Scheme
as CC50 /ECnot shown). It was reported that
50 ratio.
the 4-chloroaniline moiety or the related 5-chloro-2-pyridylamine represented the key feature of
highly
Thepotent HIV-1 NNRTIs,
importance for sulfone
of the diaryl examplemoiety
8-Cl-TIBO [57],
for the 7-Cl-PBTD
design of new(37) [39] (Table
anti-HIV-1 agents1), 3,3-dialkyl-
was further
3,4-dihydroquinoxaline-2-(1H)thione [58], oxoquinoline [59], and PETT
confirmed by the synthesis of new series of PAS and indolyl aryl sulfones [55,56]. The amino-PAS [60]. In the case of PAS
Molecules 2017, 22, 434 9 of 18
derivatives were synthesized as follows. Alkylation of the 2-amino group was achieved by reaction of
59a and 59b with the appropriate aldehyde in the presence of sodium cyanoborohydride; carboxamides
were obtained by heating with an acyl chloride in pyridine (Scheme not shown). It was reported
that the 4-chloroaniline moiety or the related 5-chloro-2-pyridylamine represented the key feature of
highly potent
Molecules 2017, 22,HIV-1
434 NNRTIs, for example 8-Cl-TIBO [57], 7-Cl-PBTD (37) [39] (Table 1), 3,3-dialkyl-3,4- 9 of 17
dihydroquinoxaline-2-(1H)thione [58], oxoquinoline [59], and PETT [60]. In the case of PAS derivatives,
derivatives, the 4-chloroaniline
the 4-chloroaniline moiety worked moiety
as aworked as a pharmacophore
pharmacophore only when the only when the
sulfonyl sulfonyl
group group
was near to
was near to the amino group. The nature of the pharmacophore could not
the amino group. The nature of the pharmacophore could not be modified without affecting the be modified without
affecting
anti-HIV-1 theactivity.
anti-HIV-1Theactivity.
highest The highestactivity
anti-HIV-1 anti-HIV-1 activity of compounds
of compounds 59a and 59b59a wasand 59b
also was also
associated
associated with theofpresence
with the presence of the alkoxycarbonyl
the alkoxycarbonyl group at2 position
group at position 2 of the
of the pyrrole pyrrole
ring. ring. Alkylation
Alkylation of aniline
of
nitrogen completely abolished the activity (data not shown), whereas acylation led to weaklyweakly
aniline nitrogen completely abolished the activity (data not shown), whereas acylation led to active
active compounds
compounds (Table(Table
5). The5).ability
The ability to inhibit
to inhibit the recombinant
the recombinant reverse
reverse transcriptase
transcriptase (rRT)
(rRT) of of HIV-1
HIV-1 is
is depictedininTable
depicted Table6.6.When
Whentested
testedagainst
againstthe
therRT
rRTform
form HIV-1
HIV-1 mutants
mutants resistant
resistant to
to nevirapine
nevirapine(Y181C)
(Y181C)
and
and TIBO
TIBO (L1001I),
(L1001I), the
the compounds
compounds showed
showed activity
activity at
at 10-fold
10-fold higher
higher concentrations.
concentrations.
Table
Table 5. Anti-HIV-1 activity of amino-PAS
amino-PAS 59a–h
59a–h against
against the
the WT strain a.
WT strain
HIV-1 IIIB
Compound R1 R2 HIV-1 IIIB
Compound R1 R2 CC b (μM) EC50 cc (μM)
50 b SI d d
CC50 (µM) EC50 (µM) SI
59a 2-NH2-5-Cl 2-COOMe >300 0.18 >2140
59a 2-NH2 -5-Cl 2-COOMe >300 0.18 >2140
59b
59b
2-NH2-5-Cl
2-NH2 -5-Cl
2-COOEt
2-COOEt
>300
>300
0.14
0.14
>2140
>2140
59c
59c 2-NO
2-NO2 2 2-COOEt
2-COOEt >300
>300 15
15 >20
>20
59d
59d 2-Cl
2-Cl 2-COOEt
2-COOEt 141
141 25
25 55
2-NH2 -5-Cl
59e
59e 2-NH2-5-Cl 2-COOCH 2-COOCH 2 CHC=CH 2
2CHC=CH2
100
100 0.40
0.40 250
250
59f 2-NHCHO-5-Cl 2-COOEt >300 1.0 >300
59f
59g 2-NHCHO-5-Cl
2-NHCOMe-5-Cl 2-COOEt
2-COOEt >300
≥300 1.0
1.0 >300
≥300
59g
59h 2-NHCOMe-5-Cl
2-NHCOOEt 2-COOEt
2-COOEt ≥300
>300 1.0
1.0 ≥300
>300
NVP e >10000 0.60 >167
59h 2-NHCOOEt 2-COOEt >300 1.0 >300
aData b CC : cytotoxic
NVPare e mean values of two to three independent experiments each>10000
one in triplicate; 0.60 50 >167
concentration (µM) to induce 50% death of non-infected cells, as evaluated with the MTT method in MT-4 cells;
Data
ac are mean
EC50 (HIV-1, IIIBvalues of two
): effective to three independent
concentration (µM) to inhibit experiments each
by 50% HIV-1 (III one ininduced
B strain) triplicate; b CC50: cytotoxic
cell death, as evaluated
with the MTT method in MT-4 cells; d e
concentration (μM) to induce 50%SI: selectivity
death index calculated
of non-infected cells,asasCC 50 /EC50 ratio;
evaluated with NVP:
the MTTnevirapine.
method in
MT-4 cells; c EC50 (HIV-1, IIIB): effective concentration (μM) to inhibit by 50% HIV-1 (IIIB strain) induced
cell death, as evaluatedTable 6. Anti-HIV-1
with the MTT method activity of cells;
in MT-4 PAS 59a–h against the
d SI: selectivity rRT.calculated as CC50/EC50
index
ratio; NVP: nevirapine.
e
IC50 ± SD (µM) a
Compound
Table 6. Anti-HIV-1 activity of PAS Y181C
WT IIIB 59a–h against the rRT. L100I
59a 0.45 ± 0.09
IC50 ±6.9
SD± (μM)
2.3 a 7.4 ± 1.2
Compound
59b 0.40 ± 0.05 7.5 ± 1.4 8.5 ± 1.0
59c
WT IIIB
0.40 ± 0.14
Y181C
5.0 ± 1.5
L100I
10 ± 3.1
59a
59d 0.27 ±±0.10
0.45 0.09 6.9 ± 2.3
8.0 ± 2.0 7.4
14±±1.2
1.2
59b
59e 0.40±±0.12
0.90 0.05 7.5±± 2.5
14 1.4 8.5 >20
± 1.0
59f
59c >20
0.40 ± 0.14 5.0>20
± 1.5 10 ±>20
3.1
59g >20 >20 >20
59d 0.27 ± 0.10 8.0 ± 2.0 14 ± 1.2
59h >20 >20 >20
59e
NVP 0.90±± 0.1
0.60 0.12 14 ±
>20 2.5 3.5>20
± 0.18
59f
a Compound concentration required to>20
inhibit the HIV rRT >20
activity by 50%. SD:>20
standard deviation.
59g >20 >20 >20
59h >20 >20
Compound 59b was selected as lead compound for an antiviral project >20 based on molecular
NVP 0.60 ± 0.1 >20 3.5 ± 0.18
modeling studies. Using the three-dimensional structure of HIV-1 RT cocrystallized with α-APA
a Compound concentration required to inhibit the HIV rRT activity by 50%. SD: standard deviation.
Compound 59b was selected as lead compound for an antiviral project based on molecular
modeling studies. Using the three-dimensional structure of HIV-1 RT cocrystallized with α-APA
(alpha-anilinophenyl acetamide) derivative R95845, a model of RT/59b complex was derived using
previously developed SARs. The experimentally determined RT bound conformations of α-APA
Molecules 2017, 22, 434 10 of 18
(alpha-anilinophenyl acetamide) derivative R95845, a model of RT/59b complex was derived using
previously developed SARs. The experimentally determined RT bound conformations of α-APA
R90385 [61] served as basis to select conformations of 59b for docking studies. By scanning the rotatable
bonds of
Molecules the22,crystal
2017, 434 structure of 59b, a low energy conformation was identified and this compound 10 of 17
superimposable on α-APA R95845 about the aromatic rings and the COOEt/COMe and SO2 /CONH2
SO 2/CONH
groups. 2 groups. of
Inspection Inspection
the RT/59b of the RT/59brevealed
complex complexa revealed
region ofatheregion of the
HIV-1 NNBSHIV-1 NNBS (non-
(non-nucleoside
nucleoside
binding site) binding
delimited site)by
delimited by Tyr181,
Tyr181, Tyr188 and Tyr188
Trp229 and
side Trp229
chains, side
whichchains,
couldwhich could
be filed be filed by
by substituents
Molecules 2017, 22, 434 10 of 17
substituents at position 4 of the pyrrole ring. Among the compounds synthesized,
at position 4 of the pyrrole ring. Among the compounds synthesized, 60 (EC50 = 42 nM; IC50 ==42 60 (EC 50 50nM;
nM)
IC 50 =the
was 50 nM)
most was
potent the most
PAS potent
derivative PAS derivative
(Table 7). (Table
Compared 7).
withCompared
59b, it with
showed 59b,
SO2/CONH2 groups. Inspection of the RT/59b complex revealed a region of the HIV-1 NNBS (non- it
three- showed
and three-
eight-fold
and eight-fold
improvement
nucleosidein improvement
cell-based
binding in cell-based
and enzyme
site) delimited and Tyr188
assays,
by Tyr181, enzyme assays,
respectively
and respectively
[62].
Trp229 [62]. could be filed by
side chains, which
substituents at position 4 of the pyrrole ring. Among the compounds synthesized, 60 (EC50 = 42 nM;
Table
IC50 = 50 nM) was Anti-HIV-1
the7.7.most
Table Anti-HIV-1 activity
potent activity
PAS of PAS
of PAS 60
derivative 60 in MT-4
in
(Table cells and against
7). Compared rRT aait.. showed three-
with 59b,
and eight-fold improvement in cell-based and enzyme assays, respectively [62].
Table 7. Anti-HIV-1 activity of PAS 60 in MT-4 cells and against rRT a.
HIV-1 IIIB
Compound CC 50 b (μM) HIV-1 IIIB ICIC
50 e (μM)
e (µM)
Compound CC b (µM)
50 EC c (μM)
50 c SI dd 50
EC50 (µM) SI
60 240 HIV-1 IIIB 5333
0.042 0.05
Compound CC24050 b (μM) IC50 e (μM)
60 f
NVP >200 EC0.042
c (μM)
0.35
50 SI5333
d
>571 0.64 0.05
NVP f >200 0.35 >571 0.64
a Data are mean values 60 of two to three 240 0.042
independent experiments 5333one in triplicate;
each 0.05 b CC50: cytotoxic
a Data are mean values fof two to three independent experiments each one in triplicate; b CC : cytotoxic
concentration NVP
(μM)totoinduce
induce 50% >200
death 0.35
of non-infected cells, >571
as evaluated 0.64 50
concentration
a Data are(µM) 50% death of non-infected cells, as evaluated with thewith
MTTthe MTTin
method method in
MT-4 cells;
c EC cells; mean values of two to three independent experiments each one in triplicate; b CC 50 : cytotoxic
MT-4 c EC50 (HIV-1, IIIB): effective concentration (μM) to inhibit by 50% HIV-1 (IIIB strain) induced
50 (HIV-1, IIIB ): effective concentration (µM) to inhibit by 50% HIV-1 (IIIB strain) induced cell death, as evaluated
concentration
withdeath,
the MTT method (μM) to induce d50%
in MT-4 death of non-infected cells,
asas
CCevaluated withethe MTT method in
cell as evaluated withcells;
the MTT SI: selectivity
method inindex
MT-4 calculated
cells; d SI: 50 /EC50 index
selectivity ratio; Compound
calculated concentration
as CC50/EC50
MT-4
required cells; c EC50 (HIV-1, IIIB): effective concentration
f
to inhibit the HIV rRT activity by 50%; NVP: nevirapine. (μM) to inhibit by 50% HIV-1 (IIIB strain) induced
e Compound
ratio; cell concentration required to inhibit the HIV rRT activity by 50%; f NVP: nevirapine.
death, as evaluated with the MTT method in MT-4 cells; d SI: selectivity index calculated as CC50/EC50
ratio; e Compound concentration required to inhibit the HIV rRT activity by 50%; f NVP: nevirapine.
Furtherstudies
Further studieswerewereconducted
conductedto toimprove
improvethe theactivity
activityofofPAS
PAS 59b [63]. New
59b [63]. NewPAS PAS derivatives
derivatives
were synthesized
were synthesized by introduction
by introduction
Further studies were conducted of different
of different
to improve alkyl,
alkyl, alkenyl
thealkenyl or cycloalkyl
or PAS
activity of cycloalkyl
59b [63]. substituents
substituents at the2-ester
at the
New PAS derivatives 2-ester
function, along
werealong
function, with
synthesized a small
with abysmall series
introduction
series of of 2-carboxamide
of different derivatives,
alkyl, alkenyl
2-carboxamide in
or cycloalkyl
derivatives, order
in order to explore
substituents
to explore the
at the effects
the2-ester
effects ofof
substituents
function,aaalong
substituents position
positionwith ofathe
of the pyrrole
small ring.
seriesring.
pyrrole Thenewnewderivatives
of 2-carboxamide
The derivatives
derivatives,were
were lesspotent
in order
less potent andthe
to explore
and sometimes more
effects ofmore
sometimes
toxic substituents
than the a position
previously of the
reported pyrrole
59a ring.
and The
59b. new
This derivatives
study were
confirmed less
thepotent
key
toxic than the previously reported 59a and 59b. This study confirmed the key role of the 4-chloroanilino and
role sometimes
of the more
4-chloroanilino
moietytoxic
andthan the
the previously reported
substituent at the 59a and
the ester
ester 59b. This study confirmed the key role of the 4-chloroanilino
function.
moiety and the substituent at function.
moiety and
Compound6060 the substituent
was at the
synthesized ester function.
as depicted in Scheme 7. 5-Chloro-2-nitrobenzenesulfonyl
Compound was synthesized as depicted in Scheme 7. 5-Chloro-2-nitrobenzenesulfonyl chloride
Compound 60 was synthesized as depicted in Scheme 7. 5-Chloro-2-nitrobenzenesulfonyl chloride
chloride
was reacted was reacted
withwith with 2-ethoxycarbonyl-1H-pyrrole-4-carboxaldehyde
2-ethoxycarbonyl-1H-pyrrole-4-carboxaldehyde in the presence of potassium
was reacted 2-ethoxycarbonyl-1H-pyrrole-4-carboxaldehyde ininthe thepresence
presence of potassium
of potassium tert- tert-
tert-butoxide
butoxide and and 18-crown-6
18-crown-6 to to give
give 61. 61.
SodiumSodium borohydride
borohydride reduction
reduction of of aldehyde6161afforded
aldehyde affordedalcohol
alcohol
butoxide and 18-crown-6 to give 61. Sodium borohydride reduction of aldehyde 61 afforded alcohol
62, and
62, and the
62,the nitro
andnitro group
group
the nitro reduction
reduction
group reduction with
with iron
withiron in glacial
ironininglacial acetic
glacial acetic acid to provide
acidtotoprovide
acetic acid provide the
thethe amino
amino
amino derivative
derivative
derivative 60 60 60
(Scheme
(Scheme 7).
7). 7).
(Scheme
Scheme 7. Synthesis of PAS 60.

Three pyrryl heteroaryl sulfones, ethyl 1-[(6-amino-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-
yl)sulfonyl]-1H-pyrrole-2-carboxylate (63), ethyl 1-[(5-amino-1H-benzo[d]imidazol-6-yl)sulfonyl]-1H-
Three pyrryl heteroaryl
pyrrole-2-carboxylate sulfones,
(64), and ethyl 1-[(6-amino-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-
ethyl 1-[(6-amino-2H-benzo[d][1,2,3]triazol-5-yl)sulfonyl]-1H-pyrrole-2-
yl)sulfonyl]-1H-pyrrole-2-carboxylate (63),
carboxylate (65), were designed as novel ethyl 1-[(5-amino-1H-benzo[d]imidazol-6-yl)sulfonyl]-1H-
HIV-1 NNRTIs using structure based computational
pyrrole-2-carboxylate (64), and ethyl 1-[(6-amino-2H-benzo[d][1,2,3]triazol-5-yl)sulfonyl]-1H-pyrrole-2-
Molecules 2017, 22, 434 11 of 18
Three pyrryl heteroaryl sulfones, ethyl 1-[(6-amino-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)

sulfonyl]-1H-pyrrole-2-carboxylate (63), ethyl 1-[(5-amino-1H-benzo[d]imidazol-6-yl)sulfonyl]-1H-
pyrrole-2-carboxylate (64), and ethyl 1-[(6-amino-2H-benzo[d][1,2,3]triazol-5-yl)sulfonyl]-1H-pyrrole-
Molecules 2017, 22, 434 11 of 17
Molecules 2017,
2-carboxylate 22, 434
(65), were designed as novel HIV-1 NNRTIs using structure based computational 11 of 17
methods (Chart
methods (Chart 4) 4) [64].
[64]. These
These compounds
compounds inhibited
inhibited the
the HIV-1
HIV-1 RT
RT at
at micromolar
micromolar concentrations,
concentrations, but
methods (Chart 4) [64]. These compounds inhibited the HIV-1 RT at micromolar concentrations, but but
were were
were found
found inactive
inactive
found
in
in the
inactive the MT-4
MT-4
in the
cells
MT-4cells assay.
cellsassay.
assay.
Chart 4. Structure of pyrryl heteroaryl sulfones 63–65.

Chart 4.
Chart Structure of
4. Structure of pyrryl
pyrryl heteroaryl
heteroaryl sulfones
sulfones 63–65.
63–65.
9. Acylamino Pyrryl Aryl Sulfones
9. Acylamino
9. Acylamino Pyrryl
Pyrryl Aryl
Aryl Sulfones
Sulfones
A series of PAS related compounds bearing acylamino moieties at position 2 of the benzene ring
A
A series
series
were of PAS
of PAS related
synthesized related compounds
analogs bearing
compounds
as truncated of PBTDsacylamino
bearing acylamino moieties at position
moietiespotent
[39]. Furthermore, at position 2NNRTIs,
HIV-1 2 of the
of the benzene
benzene ring
such as ring
were PETT
were synthesized
synthesized as
(67) [65] as
andtruncated analogs
truncated-TIBO
truncated analogs of[66]
(68)
of PBTDs [39]. Furthermore,
compounds,
PBTDs [39]. Furthermore,
were designedpotent HIV-1 NNRTIs,
NNRTIs,
and synthesized
potent HIV-1 such
based such
on asas
PETT the structure
(67) [65] andof 8-Cl-TIBO
truncated-TIBO(66) [67,68]
(68) using
[66] a ring-opening
compounds, strategy.
were Based
designed
PETT (67) [65] and truncated-TIBO (68) [66] compounds, were designed and synthesized based on on
and these findings,
synthesized the
based on
the same strategy
the structure
structure of was applied
of 8-Cl-TIBO
8-Cl-TIBO to 7-Cl-PBTD
(66)
(66) [67,68] (37a)a
[67,68] using
using aby breaking the 11,11b
ring-opening
ring-opening bond.
strategy.
strategy. The drug
Based
Based designfindings,
on these
on these strategy the
findings, the
conceived
same strategy
strategy wasa series
was appliedof acylamino-PAS
applied toto 7-Cl-PBTD (APAS)
7-Cl-PBTD (37a) derivatives,
(37a) by
by breaking which
breaking the were
the 11,11bsynthetized
11,11b bond.
bond. The and
The drug characterized
drug design
design strategy
strategy
same
for their antiviral properties [69] (Chart 5).
conceived a series of acylamino-PAS (APAS) derivatives, which were synthetized
conceived a series of acylamino-PAS (APAS) derivatives, which were synthetized and characterized and characterized
for their
for their antiviral
antiviral properties
properties [69][69] (Chart
(Chart 5).
5).
Chart 5. Design of APAS derivatives.
Several APAS derivatives inhibited the HIV-1 replication in MT-4 cells in the 1–2 μM range. Two
compounds, 69 and 70, showed Chart activity at submicromolar concentrations with EC50 of 0.4 and 0.5 μM,
Chart 5.
5. Design
Design of
of APAS
APAS derivatives.
derivatives.
respectively. Both compounds failed to inhibit the HIV-1 K103N and Y181C mutant strains, similar to
that observed
Several APASfor structurallyinhibited
derivatives correlatedthe
2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile
HIV-1 replication in MT-4 cells in the 1–2 [70].
μMAlthough
range. Two
Several APAS
structurally derivatives
related inhibitedreported
to the previously the HIV-1
PASreplication
family, thein MT-4derivatives
APAS cells in the 1–2investigated
were µM range. Two
compounds, 69 and 70, showed activity at submicromolar concentrations with EC50 of 0.4 and 0.5 μM,
compounds, 69 and
for binding mode 70,inshowed activity at submicromolar
the non-nucleoside binding site of theconcentrations
HIV-1 RT [71].with EC50 of69,
Derivative 0.4the
and 0.5 µM,
most
respectively. Both compounds failed to inhibit the HIV-1 K103N and Y181C mutant strains, similar to
active among
respectively. Both the test APASs,
compounds was to
failed modeled
inhibitfrom the X-ray
the HIV-1 coordinates
K103N of 59bmutant
and Y181C and docked intosimilar
strains, the to
that observed
HIV-1 NNBS for structurally correlated 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile [70].
[70].Although
that observed for of the RT using
structurally the 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile/RT
correlated 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile complex [70]. The
Although
structurally
binding related
mode ofto the previously reported PAS family, the APAS derivatives were investigated
structurally related to69the
shared similarities
previously with previously
reported PAS family,reported PASs derivatives
the APAS [62,64]: the ethoxycarbonyl
were investigated
for binding
filled the highly hydrophobic region of NNBS, and the 4-chloro-2-methoxycarbonyl moiety 69,
mode in the non-nucleoside binding site of the HIV-1 RT [71]. Derivative tooktheupmost
for binding mode in the non-nucleoside binding site of the HIV-1 RT [71]. Derivative 69, the most
activethe
among
H-bondthe test APASs, was modeled from the X-ray coordinates of 59b and docked into the
region.
active among the test APASs, was modeled from the X-ray coordinates of 59b and docked into the
HIV-1 NNBS APASofderivatives
the RT using 69 and
the70 were prepared by reacting compound 59b with bromoacetyl
2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile/RT complex bromide
[70]. The
HIV-11-bromo-3-chloropropane
NNBS of the RT using the 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile/RT complex [70].
binding mode of 69 shared in the presence
similarities withsodium hydrogen
previously carbonate
reported to give
PASs 2-bromoacetylamino
[62,64]: the ethoxycarbonyl
The binding mode of 69 shared similarities with previously reported PASsafforded
[62,64]:APASs
the ethoxycarbonyl
filledderivative
the highly 71.hydrophobic
Treatment of region
71 withof
sodium
NNBS, methoxide or thiomethoxide
and the 4-chloro-2-methoxycarbonyl 69 or took
moiety 70, up
filledrespectively
the highly (Scheme
hydrophobic 8). region of NNBS, and the 4-chloro-2-methoxycarbonyl moiety took up
the H-bond region.
the H-bond region.
APAS derivatives 69 and 70 were prepared by reacting compound 59b with bromoacetyl bromide
APAS derivatives 69 and 70 were prepared by reacting compound 59b with bromoacetyl bromide
1-bromo-3-chloropropane in the presence sodium hydrogen carbonate to give 2-bromoacetylamino
1-bromo-3-chloropropane in the presence sodium hydrogen carbonate to give 2-bromoacetylamino
derivative 71. Treatment of 71 with sodium methoxide or thiomethoxide afforded APASs 69 or 70,
derivative 71. Treatment of 71 with sodium methoxide or thiomethoxide afforded APASs 69 or 70,
respectively (Scheme 8).
respectively (Scheme 8).
Molecules 2017, 22, 434 12 of 18
Molecules 2017, 22, 434 12 of 17
Molecules 2017, 22, 434 12 of 17
Scheme 8. Synthesis of APASs 69 and 70.

Scheme 8. Synthesis of APASs 69 and 70.
10. Smiles Rearrangement Scheme 8. Synthesis of APASs 69 and 70.

10. Smiles Rearrangement
In the search for novel tetracyclic ring systems containing the benzothiadiazepine ring, a
10.
InSmiles Rearrangement
the search for novel
multistep synthesis was tetracyclic ring systems
planned starting containing the benzothiadiazepine ring, a multistep
from 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-
synthesis was
carbohydrazide planned
In the search starting
(72) for
[72].novel from
Reduction 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide
of 72 ring
tetracyclic withsystems
iron powder in glacial
containing the acetic acid did not afford
benzothiadiazepine ring, the
a
(72) [72]. Reduction
expected
multistep synthesisofwas with iron
72 planned powder fromin1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-
glacial acetic acid
7-chloro-11-hydrazinopyrrolo[1,2-b][1,2,5]benzothiadiazepine
starting (73),did not aafford
but only bicyclicthe expected
derivative
7-chloro-11-hydrazinopyrrolo[1,2-b][1,2,5]benzothiadiazepine
carbohydrazide
that was identified(72) [72]. Reduction of 72 with iron powder in (73),
as 1-amino-6-chloro-(1H-pyrrol-yl)benzimidazole glacialbut
(74). onlyacid
acetic
Structurea bicyclic
ofdid
74 not
was derivative
afford the that
established
was expected
identified 7-chloro-11-hydrazinopyrrolo[1,2-b][1,2,5]benzothiadiazepine
as 1-amino-6-chloro-(1H-pyrrol-yl)benzimidazole (73),
(74). but only
Structure
by NMR spectroscopy and elemental analysis, and was confirmed by crystallographic data. Formation aofbicyclic
74 was derivative
established
byof that
NMR74 was identified
hypothesized
spectroscopy asand
1-amino-6-chloro-(1H-pyrrol-yl)benzimidazole
by extrusionanalysis,
elemental of the sulfur dioxide
and was followed
confirmed (74).
byby Structure of 74 was
Smiles rearrangement
crystallographic established
data. [73] of
Formation
74byto
of 75 NMR
was spectroscopy
76.hypothesized
Reduction and
of nitro
by elemental
group
extrusion ofanalysis,
to amino anddioxide
the underwent
sulfur waswith
confirmed by by
concomitant
followed crystallographic
cyclization
Smiles ofdata. Formation
the intermediate
rearrangement [73] of 75
of Reduction
to amino
76. 74 was hypothesized
derivative of77 to form
nitro by 74
group extrusion
(Scheme
to amino of9).
the sulfur
The dioxide
structure
underwent followed
withofconcomitant by Smiles
74 was confirmed rearrangement
by direct
cyclization of synthesis[73]ofof75
the intermediate
75 to
and 76. Reduction
subsequent of nitro group
treatment with to amino
iron in underwent
acetic acid with
to concomitant
provide 74. It cyclization
is of the
interesting to intermediate
note that any
amino derivative 77 to form 74 (Scheme 9). The structure of 74 was confirmed by direct synthesis
amino derivative 77 to form 74 (Scheme 9). The structure of 74 was confirmed by direct synthesis of 75
of attempt to obtain 73 treatment
75 and subsequent from 1-[(5-chloro-2-aminophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide
with iron in acetic acid to provide 74. It is interesting to note (thethat
and subsequent
corresponding treatment
amino with of
derivative iron inby
72), acetic acid in
heating tothe
provide 74. Itofis2-hydroxypyridine,
presence interesting to note failed,
that any 37a
any attempt to obtain 73 from 1-[(5-chloro-2-aminophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide
attempt
being to obtain
the only product 73 from 1-[(5-chloro-2-aminophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide (the
of reaction.
(the corresponding
corresponding amino
amino derivative
derivative of 72),
of 72), by heating
by heating in theinpresence
the presence of 2-hydroxypyridine,
of 2-hydroxypyridine, failed, 37afailed,
beingthe
37a being theonly
onlyproduct
product of of reaction.
reaction.
Scheme 9. Smile rearrangement of 72 to 74.

11. Structurally Related Compounds
11. Structurally Related Compounds
The highlyRelated
11. Structurally potent Compounds
anti-HIV-1 activity displayed by Merck carboxamide L-737,126 (78) [74–76]
(HIV-1The WThighly
IIIB EC50 = 1 nM;
potent HIV-1 RT
anti-HIV-1 IC50 =displayed
activity 25 nM) prompted
by Merckthe design of new
carboxamide indolylarylsulfone
L-737,126 (78) [74–76]
Theanalogs.
(HIV-1
(IAS) highly
WTIIIB Duepotent
EC50 to anti-HIV-1
= 1the
nM; HIV-1
lack activity
RT IC
of SAR 50 =displayed
25 nM) the
information, by
promptedMerck
design of carboxamide
the design
first newL-737,126
IASofderivatives was (78)
indolylarylsulfone
based[74–76]
on
(HIV-1
(IAS) WT analogs.
PASs’ structuralIIIB EC Due = 1
to nM;
the HIV-1
lack of RT
SAR IC = 25
information,nM) prompted
the design ofthe design
first
50features. In general, 2-ethoxycarbonyl-1-benzenesulfonyl-1H-indoles
50 IAS of new
derivatives indolylarylsulfone
was based
showed weak on
PASs’
(IAS) analogs.
antiretroviralstructural
Due features.
to the
activity, with Inthe
lack general,
SAR 2-ethoxycarbonyl-1-benzenesulfonyl-1H-indoles
ofexception
information,
of derivativethe 79
design
(HIV-1of WT
firstIIIBIAS
ECderivatives
50 = 8.3 μM) showed
was weak
based
bearing the on
antiretroviral
PASs’ structural activity,
4-chloroaniline moiety with
features. the
In general,
[77]. exception
Indoles of derivative 79 (HIV-1 WT
2-ethoxycarbonyl-1-benzenesulfonyl-1H-indoles
bearing the carbethoxy group EC50 = 8.3
atIIIBposition 3 ofμM)thebearing
showed
indole theweak
were
4-chloroaniline
inactive.
antiretroviral Moving moiety
the with
activity, [77].
theIndoles
1-benzenesulfonyl bearing
exception group theofcarbethoxy
79 to 79
of derivative group
position
(HIV-1 at the
3 of
WT position
EC503 =
IIIBindole
of
gavetheµM)
8.3 indole
IAS 80 were the
(HIV-1
bearing
WTinactive. EC Moving
= 1.9 μM) the 1-benzenesulfonyl
that showed 4.3-fold group of 79
improvement to position
of 3
activity.
4-chloroaniline moiety [77]. Indoles bearing the carbethoxy group at position 3 of the indole
IIIB 50 of the indole
Replacement gave
of theIAS 80 (HIV-1
2-ester groupwere
WT IIIB EC50 = 1.9 μM) that showed 4.3-fold improvement of activity. Replacement of the 2-ester group
with a carboxyamide function, 81 (HIV-1 WTIIIBofEC = 0.04 μM) 3led
inactive. Moving the 1-benzenesulfonyl group 7950to position of tothea indole
notablygave increase
IAS of80 both
(HIV-1
with a and
potency carboxyamide
selectivity.function,
SAR studies 81 (HIV-1 WTIIIB ECthe
led to partition 50 = 0.04 μM) led to a notably increase of both
IAS scaffold in three regions: (A) the activity
WT IIIB EC50 = 1.9 µM) that showed 4.3-fold improvement of activity. Replacement of the 2-ester group
potency and selectivity. SAR studies led to partition the IAS scaffold in three regions: (A) the activity
Molecules 2017, 22, 434 13 of 18
with a carboxyamide function, 81 (HIV-1 WTIIIB EC50 = 0.04 µM) led to a notably increase of both
Molecules 2017, 22, 434 13 of 17
potency and selectivity. SAR studies led to partition the IAS scaffold in three regions: (A) the activity
ofof78
78against
againstHIV-1
HIV-1mutant
mutantstrains
strains significantly
significantly improved
improved by by the
the presence
presence ofof two
two methyl
methylgroups
groupsatat
positions 3 and 5 of the 3-phenylsulfonyl moiety (82) [78]; (B) coupling the indole-2-carboxamide
positions 3 and 5 of the 3-phenylsulfonyl moiety (82) [78]; (B) coupling the indole-2-carboxamide with with
either natural or unnatural amino acids provided potent HIV-1 inhibitors, for example
either natural or unnatural amino acids provided potent HIV-1 inhibitors, for example 83–85, against 83–85, against
the
theHIV-1
HIV-1L100I,
L100I,K103N,
K103N, and
and Y181C
Y181C strains
strains in
in CEM
CEM cells, with potency
cells, with potency comparable
comparableto tothe
thefist
fistline
line
HIV-1 NNRTI efavirenz [79,80]; and (C) the 5-chloro-4-fluoro substitution pattern at the
HIV-1 NNRTI efavirenz [79,80]; and (C) the 5-chloro-4-fluoro substitution pattern at the indole ring, indole ring,
compound
compound86, 86,afforded
afforded potent
potent inhibitors of HIV-1
inhibitors of HIV-1 RT
RT WT
WT and
and RTs
RTs carrying
carrying the
the K103N,
K103N,Y181I,
Y181I,and
and
L100I mutations [81] (Chart
L100I mutations [81] (Chart 6). 6).
Chart 6. Structure of indolylsulfones 78–86.

Chart 6. Structure of indolylsulfones 78–86.
12. Conclusions
12. Conclusions
N-pyrrylarylsulfones display a variety of biological activities. This review illustrates the various
N-pyrrylarylsulfones
studies made to investigatedisplay a variety of biologicalscaffold
the N-pyrrylarylsulfone activities.
as This reviewstructure
privileged illustratestothe various
discover
studies made to investigate the N-pyrrylarylsulfone scaffold as privileged structure
putative antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic to discover
putative antiviral, anticancer and SNC drugs. A number of
pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine synthetic approaches
5,5-dioxide, to obtain tetracyclic
2-methyl-1,3,4,14b-tetrahydro-
pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine
2H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]-benzothiadiazepine 5,5-dioxide, 2-methyl-1,3,4,14b-tetrahydro-2H-
10,10-dioxide, imidazo[5,1-d]pyrrolo[1,2-b]
pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]-benzothiadiazepine 10,10-dioxide, imidazo[5,1-d]pyrrolo[1,2-b]
[1,2,5]benzothia-diazepine 9,9-dioxide, tricyclic 5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-
[1,2,5]benzothia-diazepine
one 5,5-dioxide (PBTD), and 9,9-dioxide,
non-cyclic tricyclic 5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one
pyrryl aryl sulfone and acylamino-PAS (APAS) compounds and
5,5-dioxide (PBTD), and non-cyclic pyrryl aryl sulfone and acylamino-PAS
their biological activity with regard to structure–activity relationships (APAS)
(SARs) have compounds
been reviewed. Theand
their biological activity with regard to structure–activity relationships (SARs) have
literature reviewed here may provide useful information on the potential of N-pyrrylarylsulfone been reviewed.
The literature reviewed
pharmacophore as wellhere may provide
as suggest conceptsuseful information
for the design andon the potential
synthesis of new N-pyrrylarylsulfone
ofN-pyrrylarylsulfone
pharmacophore
based agents. as well as suggest concepts for the design and synthesis of new N-pyrrylarylsulfone
based agents.
Acknowledgments: This work was supported by Institute Pasteur Italy—Fondazione Cenci Bolognetti.
Acknowledgments: This work was supported by Institute Pasteur Italy—Fondazione Cenci Bolognetti.
Dedication: Dedicated with respect and gratitude to Giorgio Stefancich, medicinal chemistry teacher.
Dedication: Dedicated with respect and gratitude to Giorgio Stefancich, medicinal chemistry teacher.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
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© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Molecules: N-Pyrrylarylsulfones With High Therapeutic Potential

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Molecules: N-Pyrrylarylsulfones With High Therapeutic Potential

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molecules

Academic Editor: Claudiu T. Supuran

Keywords: sulfonamide; heterocycle; polycyclic compound; therapeutic agent

Molecules 2017, 22, 434; doi:10.3390/molecules22030434 www.mdpi.com/journal/molecules

Molecules 2017, 22, 434 3 of 17

Scheme 1. Synthesis of 14.

Scheme 2. Synthesis of 21, and structure of 10-methyl-10-azaaptazepine (20).

Scheme 2. Synthesis of 21, and structure of 10-methyl-10-azaaptazepine (20).

Scheme 3. Chemical transformation of 24.

Scheme 4. Synthesis of 32.

Table Anti-HIV-1 activity of 7-Cl-PBTDs 37a–h aa..

Molecules 2017, 22, 434 6 of 18

Scheme 5. Synthesis of 38 and 42.

8. Pyrryl Aryl Sulfones

(Scheme 6). Compound

Scheme 6. Synthesis of PAS 51–58.

Table 4. Anti-HIV-1 Activity of PASs 16 and 51–58 a.

Table 7. Anti-HIV-1 activity of PAS 60 in MT-4 cells and against rRT a.

Scheme 7. Synthesis of PAS 60.

Three pyrryl heteroaryl sulfones, ethyl 1-[(6-amino-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)

Chart 4. Structure of pyrryl heteroaryl sulfones 63–65.

Chart 5. Design of APAS derivatives.

Molecules 2017, 22, 434 12 of 17

Scheme 8. Synthesis of APASs 69 and 70.

10. Smiles Rearrangement Scheme 8. Synthesis of APASs 69 and 70.

Scheme 9. Smile rearrangement of 72 to 74.

Chart 6. Structure of indolylsulfones 78–86.

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