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Review

N-Pyrrylarylsulfones with High Therapeutic Potential

by
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
2
Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, I-84084 Fiscano, Salerno, Italy
*
Author to whom correspondence should be addressed.
Molecules 2017, 22(3), 434; https://doi.org/10.3390/molecules22030434
Submission received: 12 February 2017 / Revised: 1 March 2017 / Accepted: 3 March 2017 / Published: 9 March 2017
(This article belongs to the Special Issue Sulfonamides)
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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.

Graphical Abstract

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 Nowadays, sulfonamides have been replaced by other antibacterial drugs such as β-lactam antibiotics, with some important exception; for example, sulfamethoxazole (2) is used for treatment of urinary and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 [14,15,16,17,18], 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).
Pyrrole ring is a well-known privileged scaffold that exhibits a wide variety of biological activities [23]. Including the pyrrole into different pharmacophores has resulted in non-cyclic and polycyclic pyrrole-containing systems with potential therapeutic effects such as anticancer (leukemia and lymphoma), anti-microbic (bacteria, malaria, protozoa, and fungi) and central nervous system agents (antipsychotic and anxiolytic) (for example, pyrrolnitrin (8) [24], tolmetin (9) [25], isamoltane (CGP-361A) (10) [26], porphobilinogen (11) [27], and atorvastatin (12) [28]). Recently, VU0410150 (13), a pyrrylarylsulfone containing compound, has been discovered as mGluR4-positive allosteric modulator and evaluated as potential drug for treatment for Parkinson’s disease [29,30]. In the past decades, numerous N-pyrrylarylsulfones have been synthesized by our research group in several drug discovery projects. In this work, attempt has been made to review various N-pyrrylarylsulfone 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 and bretazenil, have been widely investigated as psychotic drugs. The synthesis of pyrrolobenzothiadiazepine anellated with azole ring started as a development of a previous research project on tetra-anellated heterocycles [31,32,33]. Pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine 5,5-dioxide (14) was synthesized by reaction of 2-nitrobenzensulfonyl chloride with ethyl pyrrole-2-carboxylate in the presence of potassium tert-butoxide and 18-crown-6 to provide 2-ethoxycarbonyl-1-(2-nitrobenzenesulfony)-1H-pyrrole (15). After reduction of 15 to amino derivative 16, the product was cyclized to lactam 17 in the presence of 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].

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

Studies on tetracyclic analogs of mianserin as antidepressant drugs led to the development of the pyrrole analog aptazepine and the strictly related isoaptazepine and 10-methyl-10-azaaptazepine (20). Pursuing this research project, 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 10,10-dioxide (21) (tiaaptazepine) was designed as new putative core for central nervous system (CNS) active drugs. The synthesis of 21 is depicted in Scheme 2. Reaction of 1-(2-aminobenzenesulfonyl)pyrrole with ethyl glyoxylate via a Pictet-Spengler type condensation gave 11-ethoxycarbonyl-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide (22). Reaction of 22 with bromoacetyl bromide afforded the corresponding bromoacetyl derivative 23 which reacted with benzylamine (24) and subsequently thermally cycled to 25. Compound 25 was reduced with lithium aluminum hydride (26) and debenzylated to 27 with hydrogen over Pd/C. Finally, 27 was converted to 21 via reductive amination using formaldehyde in the presence of hydrogen (Scheme 2) [35].
It is worthwhile mentioning that direct cyclization of 24 in the presence of excess of methylamine via diketo intermediate 28, failed due the formation 11-carboxy-10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic acid bis methylamide 5,5-dioxide (29). Intramolecular cyclization of 29 in the presence of 2-hydroxypyridine led exclusively to the spiro derivative 30. It should be noted that 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].
Compounds 21 and 22 were enantioseparated by enantioselective HPLC, and the absolute configuration of the pure enantiomers was established by circular dichroism (CD) spectroscopy.
The in vitro binding affinities for several CNS receptors (DA1, DA2, DA3, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, α1NA, α2NA and muscarinic receptors) showed that both enantiomers of derivative 21, (−)-(R)-21 and (+)-(S)-21, showed higher affinities than the (−)-(R)-22 and (+)-(S)-22 counterparts, with exception of α1NA for which (+)-(S)-22 was superior. Compound (+)-(S)-21 showed good affinities for 5-HT1A, 5-HT2A, 5-HT2C, and α1NA receptors but only moderate affinities for DA1, DA2 and 5-HT3 receptors. Compared to the reference compounds mirtazepine, mianserine and 5-methoxymianserin, this compound showed higher affinity of the 5-HT1A subtype, and different general pharmacological profile [37].

4. Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide

Imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothia-diazepine 9,9-dioxide (32) was synthesized as a new benzothiadiazepine tetracyclic ring of pharmaceutical interest. The synthesis of 32 was achieved by a simple procedure involving the anellation of pyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide (33) at the 10,11-azomethine bond by cycloaddition with tosylmethyl isocyanide (TosMIC) in the presence of buthyl lithium. Alternatively, 32 could be prepared starting from addition reaction of nitromethane 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 furnished the dihydro derivative 36 which was oxidized to 32 with manganese dioxide (Scheme 4) [38].

5. 5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one 5,5-dioxide

5H-pyrrolo[1,2-b][1,2,5]benzothiadiazepin-11(10H)-one 5,5-dioxide (PBTD) derivatives, analogs of compound 17 described in Scheme 1, were synthesized as a novel class of HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs). In general, the newly synthesized compounds were non cytotoxic for MT-4 cells at concentrations up to 300 μM. Maximum antiviral activity was obtained with compounds 37a–h bearing the chlorine atom at position 7 and the alkyl/alkenyl group at position 10 of the pyrrolo[1,2-b][1,2,5]benzothiadiazepine ring (Table 1). Compounds 37a and 37b (EC50 = 1.0 and 0.5 μM, respectively) showed the highest potency and selectivity (SI of >300 and >600, respectively) [39].
Crystal structure [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 Schaefer’s model [41].

6. Pyrrolo[1,2-b][1,2,5]benzothiadiazepine Acetic Acid 5,5,-dioxide

The PBTD scaffold has been exploited in several antiviral research programs. A series of pyrrolo[1,2-b][1,2,5]benzothiadiazepine acetic acid derivatives was synthesized by reaction of 1-(2-aminobenzenesulfonyl)pyrrole with ethyl 3,3-diethoxypropionate in aqueous acetic acid to furnish ethyl 10,11-dihydro-pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic acetate 5,5-dioxide (38). Ester 38 was N-acylated in the presence of triisobutylamine to afford ethyl 10,11-dihydro-10-(4-methylbenzoyl)pyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetate 5,5-dioxide (39) which was hydrolyzed into the corresponding acetic acid 40. Alternatively, alkaline hydrolysis of 38 furnished acid 41 which was transformed into azetidone 42 by treatment with trifluoroacetic anhydride (Scheme 5). Derivatives 38 and 42 showed significant inhibition of HIV-1 with EC50 = 19.5 and 18 μM, respectively) [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 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 synthesized as new heterocyclic systems mimicking the structural features of the PBTDs scaffold (Chart 2).

7. PBTDs as Chronic Myelogenous Leukemia (CML) Agents

The antitumor activity of pyrrolo[2,1-c][1,4]benzodiazepines (PBDs, e.g., 48) related to anthramycin was extensively studied, as it was documented in Thurston’s review [46]. Given the high structural similarity between PBTD and PBD compounds, two PBTDs, 23 and its 10-(4-methylbenzoyl) derivative 49, were selected for screening of pro-apoptotic and anti-leukemia activity (Chart 3, Table 2 and Table 3) [47]. PBTD 23 was prepared by an improved procedure using dimethoxyacetal of ethyl glyoxylate in absolute ethanol in the presence of 4-toluenesulfonic acid (PTSA). Compound 23, prepared as described in Scheme 2, was N-acylated to 49 with 4-methylbenzoyl by refluxing in 1-bromo-3-chloropropane in the presence of sodium hydrogen carbonate. PBTDs 23 and 49 induced apoptosis in K562 cells and caused cell death in BCR-ABL-positive leukemia cells obtained from chronic myeloid leukemia patients who were at onset or were IM-resistant. Apoptotic mechanism studies showed that PBTDs 23 and 49 activated the caspase activity through two different pathways: both compounds activated caspase-3; 23 significantly reduced the procaspase-8; in contrast 49 evidenced a decrease of procaspase-9 band. The apoptosis was observed before the expression of BCR-ABL protein and the tyrosine phosphorylation. 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].

8. Pyrryl Aryl Sulfones

Diarylsulfones emerged as a chemical class of HIV-1 NNRTIs. The presence of the nitro group at position 2 of the phenyl ring and the sulfur bridging atom as sulfur dioxide are fundamental structural characteristics for their activity. The antiviral activity of 2-nitrophenyl phenyl sulfone (50, NPPS) [52] prompted the synthesis of a series of 41 pyrryl aryl sulfones (PAS) and some related derivatives [53]. Pyrryl 2-nitrophenyl sulfone (51) was straightforwardly prepared by nucleophilic substitution reaction between 2-nitrobenzenesulfonyl chloride and pyrrole in the presence of n-tetrabutylammonium hydrogen sulfate (TBAS) as a phase transfer catalyst. On the other hand, alkaline hydrolysis of 2-ethoxycarbonylpyrrole (16) [34] afforded the acid 52 which was transformed into 53 by reaction with ethyl chloroformate in the presence of 4-methylmorpholine followed by treatment of the intermediate mixed anhydride with glycine ethyl ester (Scheme 6).
Ester 55 was prepared by treating the corresponding acid 54 [54] with oxalyl chloride and then 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 (Scheme 6). Compound 16, a 2-nitrophenyl 1-pyrryl sulfone bearing the 2-ethoxycarbonyl function, showed the highest anti HIV-1 activity (Table 4).
The importance of the diaryl sulfone moiety for the design of new anti-HIV-1 agents was further confirmed by the synthesis of new series of PAS and indolyl aryl sulfones [55,56]. The amino-PAS 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 HIV-1 NNRTIs, for example 8-Cl-TIBO [57], 7-Cl-PBTD (37) [39] (Table 1), 3,3-dialkyl-3,4-dihydroquinoxaline-2-(1H)thione [58], oxoquinoline [59], and PETT [60]. In the case of PAS derivatives, the 4-chloroaniline moiety worked as a pharmacophore only when the sulfonyl group was near to the amino group. The nature of the pharmacophore could not be modified without affecting the anti-HIV-1 activity. The highest anti-HIV-1 activity of compounds 59a and 59b was also associated with the presence of the alkoxycarbonyl group at position 2 of the pyrrole ring. Alkylation of aniline nitrogen completely abolished the activity (data not shown), whereas acylation led to weakly active compounds (Table 5). The ability to inhibit the recombinant reverse transcriptase (rRT) of HIV-1 is depicted in Table 6. When tested against the rRT form HIV-1 mutants resistant to nevirapine (Y181C) and TIBO (L1001I), the compounds showed activity at 10-fold higher concentrations.
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 R90385 [61] served as basis to select conformations of 59b for docking studies. By scanning the rotatable bonds of the crystal structure of 59b, a low energy conformation was identified and this compound superimposable on α-APA R95845 about the aromatic rings and the COOEt/COMe and SO2/CONH2 groups. Inspection of the RT/59b complex revealed a region of the HIV-1 NNBS (non-nucleoside binding site) delimited by Tyr181, Tyr188 and Trp229 side chains, which could be filed by substituents at position 4 of the pyrrole ring. Among the compounds synthesized, 60 (EC50 = 42 nM; IC50 = 50 nM) was the most potent PAS derivative (Table 7). Compared with 59b, it showed three- and eight-fold improvement in cell-based and enzyme assays, respectively [62].
Further studies were conducted to improve the activity of PAS 59b [63]. New PAS derivatives were synthesized by introduction of different alkyl, alkenyl or cycloalkyl substituents at the 2-ester function, along with a small series of 2-carboxamide derivatives, in order to explore the effects of substituents a position of the pyrrole ring. The new derivatives were less potent and sometimes more toxic than the previously reported 59a and 59b. This study confirmed the key role of the 4-chloroanilino moiety and the substituent at the ester function.
Compound 60 was synthesized as depicted in Scheme 7. 5-Chloro-2-nitrobenzenesulfonyl chloride was reacted with 2-ethoxycarbonyl-1H-pyrrole-4-carboxaldehyde in the presence of potassium tert-butoxide and 18-crown-6 to give 61. Sodium borohydride reduction of aldehyde 61 afforded alcohol 62, and the nitro group reduction with iron in glacial acetic acid to provide the amino derivative 60 (Scheme 7).
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-2-carboxylate (65), were designed as novel HIV-1 NNRTIs using structure based computational methods (Chart 4) [64]. These compounds inhibited the HIV-1 RT at micromolar concentrations, but were found inactive in the MT-4 cells assay.

9. Acylamino Pyrryl Aryl Sulfones

A series of PAS related compounds bearing acylamino moieties at position 2 of the benzene ring were synthesized as truncated analogs of PBTDs [39]. Furthermore, potent HIV-1 NNRTIs, such as PETT (67) [65] and truncated-TIBO (68) [66] compounds, were designed and synthesized based on the structure of 8-Cl-TIBO (66) [67,68] using a ring-opening strategy. Based on these findings, the same strategy was applied to 7-Cl-PBTD (37a) by breaking the 11,11b bond. The drug design strategy conceived a series of acylamino-PAS (APAS) derivatives, which were synthetized and characterized for their antiviral properties [69] (Chart 5).
Several APAS derivatives inhibited the HIV-1 replication in MT-4 cells in the 1–2 μM range. Two compounds, 69 and 70, showed activity at submicromolar concentrations with EC50 of 0.4 and 0.5 μM, respectively. Both compounds failed to inhibit the HIV-1 K103N and Y181C mutant strains, similar to that observed for structurally correlated 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile [70]. Although structurally related to the previously reported PAS family, the APAS derivatives were investigated for binding mode in the non-nucleoside binding site of the HIV-1 RT [71]. Derivative 69, the most active among the test APASs, was modeled from the X-ray coordinates of 59b and docked into the HIV-1 NNBS of the RT using the 2-amino-6-[(3,5-dimethyl)sulfonylbenzonitrile/RT complex [70]. The binding mode of 69 shared similarities with previously reported PASs [62,64]: the ethoxycarbonyl filled the highly hydrophobic region of NNBS, and the 4-chloro-2-methoxycarbonyl moiety took up the H-bond region.
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 derivative 71. Treatment of 71 with sodium methoxide or thiomethoxide afforded APASs 69 or 70, respectively (Scheme 8).

10. Smiles Rearrangement

In the search for novel tetracyclic ring systems containing the benzothiadiazepine ring, a multistep synthesis was planned starting from 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide (72) [72]. Reduction of 72 with iron powder in glacial acetic acid did not afford the expected 7-chloro-11-hydrazinopyrrolo[1,2-b][1,2,5]benzothiadiazepine (73), but only a bicyclic derivative that was identified as 1-amino-6-chloro-(1H-pyrrol-yl)benzimidazole (74). Structure of 74 was established by NMR spectroscopy and elemental analysis, and was confirmed by crystallographic data. Formation of 74 was hypothesized by extrusion of the sulfur dioxide followed by Smiles rearrangement [73] of 75 to 76. Reduction of nitro group to amino underwent with concomitant cyclization of the intermediate amino derivative 77 to form 74 (Scheme 9). The structure of 74 was confirmed by direct synthesis of 75 and subsequent treatment with iron in acetic acid to provide 74. It is interesting to note that any attempt to obtain 73 from 1-[(5-chloro-2-aminophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide (the corresponding amino derivative of 72), by heating in the presence of 2-hydroxypyridine, failed, 37a being the only product of reaction.

11. Structurally Related Compounds

The highly potent anti-HIV-1 activity displayed by Merck carboxamide L-737,126 (78) [74,75,76] (HIV-1 WTIIIB EC50 = 1 nM; HIV-1 RT IC50 = 25 nM) prompted the design of new indolylarylsulfone (IAS) analogs. Due to the lack of SAR information, the design of first IAS derivatives was based on PASs’ structural features. In general, 2-ethoxycarbonyl-1-benzenesulfonyl-1H-indoles showed weak antiretroviral activity, with the exception of derivative 79 (HIV-1 WTIIIB EC50 = 8.3 μM) bearing the 4-chloroaniline moiety [77]. Indoles bearing the carbethoxy group at position 3 of the indole were inactive. Moving the 1-benzenesulfonyl group of 79 to position 3 of the indole gave IAS 80 (HIV-1 WTIIIB 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 WTIIIB EC50 = 0.04 μM) led to a notably increase of both potency and selectivity. SAR studies led to partition the IAS scaffold in three regions: (A) the activity of 78 against HIV-1 mutant strains significantly improved by the presence of two methyl groups at positions 3 and 5 of the 3-phenylsulfonyl moiety (82) [78]; (B) coupling the indole-2-carboxamide with either natural or unnatural amino acids provided potent HIV-1 inhibitors, for example 83–85, against the HIV-1 L100I, K103N, and Y181C strains in CEM cells, with potency comparable to the fist line HIV-1 NNRTI efavirenz [79,80]; and (C) the 5-chloro-4-fluoro substitution pattern at the indole ring, compound 86, afforded potent inhibitors of HIV-1 RT WT and RTs carrying the K103N, Y181I, and L100I mutations [81] (Chart 6).

12. Conclusions

N-pyrrylarylsulfones display a variety of biological activities. This review illustrates the various studies made to investigate the N-pyrrylarylsulfone scaffold as privileged structure to discover putative antiviral, anticancer and SNC drugs. A number of synthetic approaches to obtain tetracyclic pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine 5,5-dioxide, 2-methyl-1,3,4,14b-tetrahydro-2H-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)-one 5,5-dioxide (PBTD), and non-cyclic pyrryl aryl sulfone and acylamino-PAS (APAS) 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.

Acknowledgments

This work was supported by Institute Pasteur Italy—Fondazione Cenci Bolognetti.

Dedication

Dedicated with respect and gratitude to Giorgio Stefancich, medicinal chemistry teacher.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Gerald, M.C. The Drug Book; Sterling Education: New York, NY, USA, 2013. [Google Scholar]
  2. Dogmagk, G. Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Deutsch. Med. Wochenschr. 1935, 61, 250–253. [Google Scholar] [CrossRef]
  3. Dogmagk, G. Eine neue Klasse von Desinfectionsmitteln. Deutsch. Med. Wochenschr. 1935, 61, 829–832. [Google Scholar] [CrossRef]
  4. Henry, R.J. The mode of action of sulfonamides. Bacteriol. Rev. 1943, 7, 175–262. [Google Scholar] [PubMed]
  5. Sulfamethoxazole. DrugBank. Available online: http://www.drugbank.ca (accessed on 17 August 2016).
  6. Fromm, E.; Wittmann, J. Derivate des p-nitrophenols. Ber. Deutsch. Chem. Ges. 1908, 41, 2264–2273. [Google Scholar] [CrossRef]
  7. Goulart, I.M.; Reis, A.C.; de Rezende, T.M.; Borges, A.S.; Ferreira, M.S.; Nishioka, S.A. Aplastic anaemia associated with multidrug therapy (dapsone, rifampicin and clofazimine) in a patient with lepromatous leprosy. Lepr. Rev. 2005, 76, 167–169. [Google Scholar] [PubMed]
  8. Brown, A.; Captain, B. 50 years of thiazides: Should thiazide diuretics be considered third-line hypertension treatment? Am. J. Ther. 2011, 18, e244–e254. [Google Scholar] [CrossRef] [PubMed]
  9. Fregly, M.J. Effect of chlorothiazide and hydrochlorothiazide on blood pressure and thyroid activity of hypertensive rats. Am. J. Cardiol. 1961, 8, 890–898. [Google Scholar] [CrossRef]
  10. Maxwell, R.A.; Eckhardt, S.B. Furosemide in “Drug Discovery”; The Humana Press Inc.: New York, NY, USA, 1990; pp. 67–77. [Google Scholar]
  11. Stumvoll, M.; Goldstein, B.J.; van Haeften, T.W. Type 2 diabetes: Principles of pathogenesis and therapy. Lancet 2005, 365, 1333–1346. [Google Scholar] [CrossRef]
  12. Tzoulaki, I.; Molokhia, M.; Curcin, V.; Little, M.P.; Millett, C.J.; Ng, A.; Hughes, R.I.; Khunti, K.; Wilkins, M.R.; Majeed, A.; et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: Retrospective cohort study using UK general practice research database. BMJ 2009, 339, b4731. [Google Scholar] [CrossRef] [PubMed]
  13. Tyrrell, P.N.; Kandasamy, R.A.; Crotty, C.M.; Espie, G.S. Ethoxyzolamide Differentially Inhibits CO2 Uptake and Na+-Independent and Na+-Dependent HCO3− Uptake in the Cyanobacterium Synechococcus sp. UTEX 625. Plant Physiol. 1996, 112, 79–88. [Google Scholar] [CrossRef] [PubMed]
  14. De Clercq, E. Dancing with chemical formulae of antivirals: A personal account. Biochem. Pharmacol. 2013, 86, 711–725. [Google Scholar] [CrossRef] [PubMed]
  15. De Clercq, E. Dancing with chemical formulae of antivirals: A panoramic view. Biochem. Pharmacol. 2013, 86, 1397–1410. [Google Scholar] [CrossRef] [PubMed]
  16. Mehellou, Y.; De Clercq, E. Twenty-six years of anti-HIV drug discovery: Where do we stand and where do we go? J. Med. Chem. 2010, 53, 521–538. [Google Scholar] [CrossRef] [PubMed]
  17. Vere Hodge, R.A. Meeting report: 28th International conference on antiviral research in Rome, Italy. Antivir. Res. 2015, 123, 172–187. [Google Scholar] [CrossRef] [PubMed]
  18. Zhan, P.; Pannecouque, C.; De Clercq, E.; Liu, X. Anti-HIV drug discovery and development: Current innovations and future trends. J. Med. Chem. 2015, 59, 2849–2878. [Google Scholar] [CrossRef] [PubMed]
  19. López-Labrador, F.X. Hepatitis C Virus NS3/4A protease inhibitors. Recent Pat. Antiinfect. Drug Discov. 2008, 3, 157–167. [Google Scholar] [CrossRef] [PubMed]
  20. Gerber, L.; Welzel, T.M.; Zeuzem, S. New therapeutic strategies in HCV: Polymerase inhibitors. Liver Int. 2013, 3 (Suppl. 1), 85–92. [Google Scholar] [CrossRef] [PubMed]
  21. Bandmann, H.J.; Breit, R. The mafenide story. Br. J. Dermatol. 1973, 89, 219–221. [Google Scholar] [CrossRef] [PubMed]
  22. McCormack, P.L. Celecoxib: A review of its use for symptomatic relief in the treatment of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis. Drugs 2011, 71, 2457–2489. [Google Scholar] [CrossRef] [PubMed]
  23. Bhardwaj, V.; Gumber, D.; Abbot, A.; Dhimana, S.; Sharma, P. Pyrrole: A resourceful small molecule in key medicinal hetero-aromatics. RCS Adv. 2015, 5, 15233–15266. [Google Scholar] [CrossRef]
  24. Gordee, R.S.; Matthews, T.R. Systemic antifungal activity of pyrrolnitrin. Appl. Microbiol. 1969, 17, 690–694. [Google Scholar] [PubMed]
  25. Cordrey, L.J. Tolmetin sodium, a new anti-arthritis drug: Double-blind and long-term studies. J. Am. Geriatr. Soc. 1976, 24, 440–446. [Google Scholar] [CrossRef] [PubMed]
  26. Rényi, L.; Larsson, L.G.; Berg, S.; Svensson, B.E.; Thorell, G.; Ross, S.B. Biochemical and behavioural effects of isamoltane, a beta-adrenoceptor antagonist with affinity for the 5-HT1B receptor of rat brain. Naunyn Schmiedebergs Arch. Pharmacol. 1991, 343, 1–6. [Google Scholar] [CrossRef] [PubMed]
  27. Aarsand, A.K.; Petersen, P.H.; Sandberg, S. Estimation and application of biological variation of urinary-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria. Clin. Chem. 2006, 52, 650–656. [Google Scholar] [CrossRef] [PubMed]
  28. Roth, B.D. The discovery and development of atorvastatin, a potent novel hypolipidemic agent. Prog. Med. Chem. 2002, 40, 1–22. [Google Scholar] [PubMed]
  29. Hopkins, C.R.; Lindsley, C.W.; Niswender, C.M. mGluR4-positive allosteric modulation as potential treatment for Parkinson’s disease. Future Med. Chem. 2009, 1, 501–513. [Google Scholar] [CrossRef] [PubMed]
  30. Gogliotti, R.D.; Blobaum, A.L.; Morrison, R.M.; Daniels, J.S.; Salovich, J.M.; Cheung, Y.Y.; Rodriguez, A.L.; Loch, M.T.; Conn, P.J.; Lindsley, C.W.; et al. Discovery and characterization of a novel series of N-phenylsulfonyl-1H-pyrrole picolinamides as positive allosteric modulators of the metabotropic glutamate receptor 4 (mGlu4). Bioorg. Med. Chem. Lett. 2016, 26, 2984–2987. [Google Scholar] [CrossRef] [PubMed]
  31. Stefancich, G.; Silvestri, R. Research on nitrogen containing heterocyclic compounds. XVI. Synthesis of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino-[2,1-d]pyrrolo[1,2-b][1,2,5]benzotriazepine (1:1) maleate (10-methyl-10-azaaptazepine). J. Heterocycl. Chem. 1989, 26, 745–746. [Google Scholar] [CrossRef]
  32. Stefancich, G.; Artico, M.; Silvestri, R.; Pantaleoni, G.C.; Giorgi, R.; Palumbo, G. Research on psycotropic agents. III. Antidepressant activity and neuropsycobehavioural effects of new 5H-pyrrolo[1,2-b][1,2,5]benzotriazepine derivatives. Farmaco 1990, 45, 7–27. [Google Scholar] [PubMed]
  33. Stefancich, G.; Artico, M.; Silvestri, R.; Prosini, P.P.; Pantaleoni, G.C.; Giorgi, R.; Palumbo, G. Non-steroidal antiinflammatory agents. VII. Synthesis and antiinflammatory activity of 5-methyl-10,11-dihydro-5H-pyrrolo[1,2-b][1,2,5]-benzotriazepine-11-acetic acid and its 10-aroyl derivatives. Farmaco 1990, 45, 817–831. [Google Scholar] [PubMed]
  34. Artico, M.; Silvestri, R.; Stefancich, G. Heterocycles with a benzothiadiazepine moiety. 1. Synthesis of pyrrolo[1,2-b]-s-triazolo[3,4-d][1,2,5]benzothiadiazepine 5,5-dioxide. Synth. Commun. 1992, 22, 1433–1439. [Google Scholar] [CrossRef]
  35. Stefancich, G.; Silvestri, R.; Pagnozzi, E.; Artico, M. Heterocycles with a benzothiadiazepine moiety. 2. Synthesis of 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 10,10-dioxide (Tiaatpazepine). J. Heterocycl. Chem. 1994, 31, 867–869. [Google Scholar]
  36. Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Artico, M. Heterocycles with a benzothiadiazepine moiety. 4. Synthesis of novel tetracyclic rings by intramolecular cyclization of 10-bromoacetyl-10,11-dihydro-11-ethoxycarbonylpyrrolo[1,2-b][1,2,5]benzothiadiazepine 5,5-dioxide and its derivatives. Synth. Commun. 1994, 24, 2685–2695. [Google Scholar] [CrossRef]
  37. Silvestri, R.; Artico, M.; La Regina, G.; di Pasquali, A.; de Martino, G.; la Torre, F.; Cirilli, R.; Cagnotto, A.; Mennini, T. Chiral resolution and binding study of 1,3,4,14b-tetrahydro-2,10-dimethyl-2H,10H-pyrazino[2,1-d]pyrrolo[1,2-b][1,2,5]benzotriazepine (10-methyl-10-azaaptazeine) and 2-methyl-1,3,4,14b-tetrahydro-2H-pyrazino-[2,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 10,10-dioxide (tiaaptazepine). Farmaco 2005, 60, 931–937. [Google Scholar]
  38. Silvestri, R.; Artico, M.; Pagnozzi, E.; Stefancich, G. Heterocycles with a benzothiadiazepine moiety. 3. Synthesis of imidazo[5,1-d]pyrrolo[1,2-b][1,2,5]benzothiadiazepine 9,9-dioxide. J. Heterocycl. Chem. 1994, 31, 1033–1036. [Google Scholar] [CrossRef]
  39. Artico, M.; Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Massa, S.; Loi, A.G.; Scano, P.; Corrias, S.; Spiga, M.G.; La Colla, P. 5H-Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A novel class of HIV-1-specific non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 1996, 4, 837–885. [Google Scholar] [CrossRef]
  40. Ettorre, A.; Silvestri, R.; Artico, M.; Massa, S.; La Colla, P. Crystal structure of 7-chloro[1,2-b][1,2,5]benzothiadiazepin-10(11H)-one-5,5-dioxide, C11H7N2O3ClS. Z. Kristallogr. NCS 2001, 216, 57–58. [Google Scholar]
  41. Schäfer, W.; Friebe, W.G.; Leinert, H.; Mertens, A.; Poll, T.; von der Saal, W.; Zilch, H.; Nuber, B.; Ziegler, M.L. Non-nucleoside inhibitors of HIV-1 reverse transcriptase: Molecular modeling and X-ray structure investigations. J. Med. Chem. 1993, 36, 726–732. [Google Scholar] [CrossRef] [PubMed]
  42. Artico, M.; Silvestri, R.; Pagnozzi, E.; Stefancich, G.; Massa, S.; La Colla, P. Synthesis and anti-HIV activity of 10,11-dihydropyrrolo[1,2-b][1,2,5]benzothiadiazepine-11-acetic acid 5,5-dioxide derivatives and related compounds. Farmaco 1996, 51, 425–430. [Google Scholar]
  43. Silvestri, R.; Artico, M.; Bruno, B.; Massa, S.; Novellino, E.; Greco, G.; Marongiu, M.E.; Pani, A.; de Montis, A.; La Colla, P. Synthesis and biological evaluation of 5H-indolo[3,2-b][1,5]benzothiazepine derivatives, designed as conformationally constrained analogues of the human immunodeficiency virus type 1 reverse transcriptase inhibitor L-737,126. Antivir. Chem. Chemother. 1998, 9, 139–148. [Google Scholar] [CrossRef] [PubMed]
  44. Artico, M.; Stefancich, G.; Silvestri, R.; Massa, S.; Pagnozzi, E.; Loi, A.G.; Musu, D.; Doa, M.; Scano, P.; La Colla, P. Pyrrolobenzothiazepines: A new class of non-nucleoside HIV-1 reverse transcriptase inhibitors. Med. Chem. Res. 1994, 4, 283–290. [Google Scholar]
  45. Silvestri, R.; Pagnozzi, E.; Artico, M.; Stefancich, G.; Massa, S.; La Colla, P. Synthesis of 9H-pyrrolo[2,1-b][1,3,6]benzothiadiazocin-10(11H)-one 4,4-dioxide, potential anti-HIV agent. J. Heterocycl. Chem. 1995, 32, 683–685. [Google Scholar] [CrossRef]
  46. Thurston, D.E.; Bose, D.S. Synthesis of DNA-interactive pyrrolo-[2,1-c][1,4]benzodiazepines. Chem. Rev. 1994, 94, 433–465. [Google Scholar] [CrossRef]
  47. Silvestri, R.; Marfè, G.; Artico, M.; La Regina, G.; De Martino, G.; Lavecchia, A.; Novellino, E.; Morgante, E.; di Stefano, C.; Catalano, G.; et al. Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs): A new class of agents endowed with high apoptotic activity in chronic myelogenous leukemia K562 cells and in cells from patients at onset and imatinib-resistant. J. Med. Chem. 2006, 49, 5840–5844. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Marfè, G.; di Stefano, C.; Silvestri, R.; Abruzzese, E.; Catalano, G.; Di Renzo, L.; Filomeni, G.; Giorda, E.; La Regina, G.; Morgante, E.; et al. Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) induce apoptosis in chronic myelogenous leukemic K562 cells. BMC Cancer 2007, 7, 207–218. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  49. Di Stefano, C.; Marfe, G.; Trawinska, M.M.; Sinibaldi-Salimei, P.; Silvestri, R.; Amadori, S.; Abruzzese, E. Pyrrolo[1,2-b][1,2,5]benzothiadiazepines (PBTDs) exert their anti-proliferative activity by interfering with Akt-mTOR signaling and bax:bcl-2 ratio modulation in cells from chronic myeloid leukemic patients. Cancer Sci. 2010, 101, 991–1000. [Google Scholar] [CrossRef] [PubMed]
  50. Silvestri, R.; Marfè, G.; Di Stefano, C.; Sinibaldi Salimei, P.; De Martino, M.G.; La Regina, G.; Abruzzese, E.; Catalano, G. Derivati delle Benzodiazepine e loro uso in Campo Medico. Patent IT2006/000401, 3 August 2005. [Google Scholar]
  51. Silvestri, R.; Marfè, G.; Abruzzese, E.; Catalano, G.; Di Stefano, C.; Novellino, E.; Sinibaldi Salimei, P.; La Regina, G.; Lavecchia, A. Benzodiazepine Derivatives and Uses Thereof in Medical Field. Patent WO 2007/015280, 8 February 2007. [Google Scholar]
  52. McMahon, J.B.; Gulakowski, R.J.; Weislow, O.S.; Schultz, R.J.; Narayanan, V.L.; Clanton, D.J.; Pedemonte, R.; Wassmundt, F.W.; Buckheit, R.W., Jr.; Decker, W.D.; et al. Diarylsulfones, a new chemical class of nonnucleoside antiviral inhibitors of human immunodeficiency virus type 1 reverse transcriptase. Antimicrob. Agents Chemother. 1993, 37, 754–760. [Google Scholar] [CrossRef] [PubMed]
  53. Artico, M.; Silvestri, R.; Stefancich, G.; Massa, S.; Pagnozzi, E.; Musu, D.; Scintu, F.; Pinna, E.; Tinti, E.; La Colla, P. Synthesis of pyrryl aryl sulfones targeted at the HIV-1 reverse transcriptase. Arch. Pharm. (Weinheim) 1995, 328, 223–229. [Google Scholar] [CrossRef] [PubMed]
  54. Langlois, N.; Andriamialisoa, R.Z. Synthesis of sulfonamide analogs of the pyrrolo[1,4]benzodiazepine antibiotic abbeymycin. Heterocycles 1989, 8, 1529–1536. [Google Scholar] [CrossRef]
  55. Artico, M.; Silvestri, R.; Massa, S.; Loi, A.G.; Corrias, S.; Piras, G.; La Colla, P. 2-Sulfonyl-4-chloroanilino moiety: A potent pharmacophore for the anti-human immunodeficiency virus type 1 activity of pyrrolyl aryl sulfones. J. Med. Chem. 1996, 39, 522–530. [Google Scholar] [CrossRef] [PubMed]
  56. Silvestri, R.; Artico, M.; Massa, S.; Stefancich, G.; Congeddu, E.; Putzolu, M.; La Colla, P. Sulfone derivatives with anti-HIV activity. Farmaco 1997, 52, 323–329. [Google Scholar] [PubMed]
  57. Pawels, R. Discovery of TIBO, a new family of HIV-1 specific reverse transcriptase inhibitors. In The Search for Antiviral Drugs; Adams, J., Merluzzi, V.J., Eds.; Birkhäuser: Boston, MA, USA, 1993; Chapter 4; pp. 71–104. [Google Scholar]
  58. De Clercq, E. Antiviral therapy for human immunodeficiency virus infections. Clin. Microbiol Rev. 1995, 8, 200–239. [Google Scholar] [PubMed]
  59. Baba, M.; Okamoto, M.; Makino, M.; Kimura, Y.; Ikeuchi, T.; Sakaguchi, T.; Okamoto, T. Potent and selective inhibition of human immunodeficiency virus type 1 transcription by piperazinyloxoquinoline derivatives. Antimicrob. Agents Chemother. 1997, 41, 1250–1255. [Google Scholar] [PubMed]
  60. Högberg, M.; Sahlberg, C.; Engelhardt, P.; Noréen, R.; Kangasmetsä, J.; Johansson, N.G.; Oberg, B.; Vrang, L.; Zhang, H.; Sahlberg, B.L.; et al. Urea-PETT compounds as a new class of HIV-1 reverse transcriptase inhibitors. 3. Synthesis and further structure-activity relationship studies of PETT analogues. J. Med. Chem. 1999, 20, 4150–4160. [Google Scholar] [CrossRef]
  61. Ren, J.; Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.; Keeling, J.; Darby, G.; Jones, Y.; Stuart, D.; et al. High resolution structures of HIV-1 RT from four RT-inhibitor complexes. Nat. Struct. Biol. 1995, 2, 293–302. [Google Scholar] [CrossRef] [PubMed]
  62. Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B.; Novellino, E.; Greco, G.; Massa, S.; Ettorre, A.; Loi, A.G.; Scintu, F.; et al. Structure-based design, synthesis and biological evaluation of novel pyrrolyl aryl sulfones (PASs), HIV-1 non-nucleoside reverse transcriptase inhibitors active at nanomolar concentrations. J. Med. Chem. 2000, 43, 1886–1891. [Google Scholar] [CrossRef] [PubMed]
  63. Silvestri, R.; Artico, M.; La Regina, G.; De Martino, G.; La Colla, M.; Loddo, R.; La Colla, P. Anti-HIV-1 activity of pyrryl aryl sulfone (PAS) derivatives. Synthesis and SAR studies of novel esters and amides at the position 2 of the pyrrole nucleus. Farmaco 2004, 59, 201–210. [Google Scholar] [CrossRef] [PubMed]
  64. Silvestri, R.; Artico, M.; De Martino, G.; Novellino, E.; Greco, G.; Lavecchia, A.; Massa, S.; Loi, A.G.; Doratiotto, S.; La Colla, P. Computer-assisted design, synthesis and biological evaluation of novel pyrrolyl heteroaryl sulfones targeted at HIV-1 reverse transcriptase as non-nucleoside inhibitors. Bioorg. Med. Chem. 2000, 8, 2305–2309. [Google Scholar] [CrossRef]
  65. Cantrell, A.S.; Engelhardt, P.; Högberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kangasmetsä, J.; Kinnick, M.D.; Lind, P.; Morin, J.M., Jr.; et al. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure-activity relationship studies of PETT analogs. J. Med. Chem. 1996, 39, 4261–4274. [Google Scholar] [CrossRef] [PubMed]
  66. Breslin, H.J.; Kukla, M.J.; Kromis, T.; Cullis, H.; de Knaep, F.; Pauwels, R.; Andries, K.; De Clercq, E.; Janssen, M.A.; Janssen, P.A. Synthesis and anti-HIV activity of 1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one (TBO) derivatives. Truncated 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-on es (TIBO) analogues. Bioorg. Med. Chem. 1999, 7, 2427–2436. [Google Scholar] [CrossRef]
  67. Pauwels, R.; Andries, K.; Desmyter, J.; Schols, D.; Kukla, M.J.; Breslin, H.J.; Raeymaeckers, A.; van Gelder, J.; Woestenborghs, R.; Heykants, J.; et al. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 1990, 343, 470–474. [Google Scholar] [CrossRef] [PubMed]
  68. Das, K.; Ding, J.; Hsiou, Y.; Clark, A.D., Jr.; Moereels, H.; Koymans, L.; Andries, K.; Pauwels, R.; Janssen, P.A.; Boyer, P.L.; et al. Crystal structures of 8-Cl and 9-Cl TIBO complexed with wild-type HIV-1 RT and 8-Cl TIBO complexed with the Tyr181Cys HIV-1 RT drug-resistant mutant. J. Mol. Biol. 1996, 26, 1085–1100. [Google Scholar] [CrossRef]
  69. Silvestri, R.; De Martino, G.; Artico, M.; La Regina, G.; Ragno, R.; Loddo, R.; La Colla, P.; Marongiu, M.E.; La Colla, M.; Pani, A. Anti-HIV-1 NNRT agents: Acylamino pyrryl aryl sulfones (APASs) as truncated analogues of tricyclic PBTDs. Med. Chem. Res. 2002, 11, 195–218. [Google Scholar]
  70. Chan, J.H.; Hong, J.S.; Hunter, R.N., 3rd; Orr, G.F.; Cowan, J.R.; Sherman, D.B.; Sparks, S.M.; Reitter, B.E.; Andrews, C.W., 3rd; Hazen, R.J.; et al. 2-Amino-6-arylsulfonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1. J. Med. Chem. 2001, 44, 1866–1882. [Google Scholar] [CrossRef] [PubMed]
  71. Titmuss, S.J.; Keller, P.A.; Griffith, R. Docking experiments in the flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase. Bioorg. Med Chem. 1999, 7, 1163–1170. [Google Scholar] [CrossRef]
  72. Silvestri, R.; Pifferi, A.; De Martino, G.; Saturnino, C.; Artico, M. Reductive Smiles rearrangement of 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide to 1-amino-6-chloro-2-(1H-pyrrol-2-yl)benzimidazole. Heterocycles 2000, 53, 2163–2174. [Google Scholar]
  73. Skarżewski, J.; Skrowaczewska, Z. The smiles rearrangement: Mechanism of unusual acyl and 2,4-dinitrophenyl migrations in aryl acylamino ethers. Tetrahedron 1976, 32, 1221–1224. [Google Scholar] [CrossRef]
  74. Williams, T.A.; Ciccarone, T.M.; Saari, W.S.; Wai, J.S.; Greenlee, W.J.; Balani, S.K.; Goldman, M.E.; Theoharides, A.D. Indoles as Inhibitors of HIV Reverse Transcriptase. Patent Application EP 0 530 907 A1, 28 August 1992. [Google Scholar]
  75. Williams, T.A.; Ciccarone, T.M.; Greenlee, W.J.; Balani, S.K.; Goldman, M.E.; Hoffman, J.M., Jr.; Lumma, W.C.; Huff, J.R.; Rooney, C.S.; Sanderson, P.E.; Theoharides, A.D. Patent Application WO 94/19321 A1, 01 September 1994.
  76. Williams, T.M.; Ciccarone, T.M.; MacTough, S.C.; Rooney, C.S.; Balani, S.K.; Condra, J.H.; Emini, E.A.; Goldman, M.E.; Greenlee, W.J.; Kauffman, L.R.; et al. 5-Chloro-3-(phenylsulfonyl)indole-2-carboxamide: A novel, non-nucleoside inhibitor of HIV-1 reverse transcriptase. J. Med. Chem. 1993, 36, 1291–1294. [Google Scholar] [CrossRef] [PubMed]
  77. Silvestri, R.; Artico, M. Indolyl aryl sulfones (IASs): Development of highly potent NNRTIs active against wt-HIV-1 and clinically relevant drug resistant mutants. Curr. Pharm. Des. 2005, 11, 3779–3806. [Google Scholar] [CrossRef]
  78. Silvestri, R.; De Martino, G.; La Regina, G.; Artico, M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A.G.; Marceddu, T.; La Colla, P. Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI resistance mutations: Synthesis and SAR studies. J. Med. Chem. 2003, 46, 2482–2493. [Google Scholar] [CrossRef] [PubMed]
  79. Silvestri, R.; Artico, M.; De Martino, G.; La Regina, G.; Loddo, R.; La Colla, M.; La Colla, P. Simple, short peptide derivatives of a sulfonylindolecarboxamide (L-737,126) active in vitro against HIV-1 wild-type and variants carrying non-nucleoside reverse transcriptase inhibitor resistance mutations. J. Med. Chem. 2004, 47, 3892–3896. [Google Scholar] [CrossRef] [PubMed]
  80. Piscitelli, F.; Coluccia, A.; Brancale, A.; La Regina, G.; Sansone, A.; Giordano, C.; Balzarini, J.; Maga, G.; Zanoli, S.; Samuele, A.; et al. Indolylarylsulfon bearing natural and unnatural amino acids. Discovery of potent inhibitors of HIV-1 non-nucleoside wild type and resistant mutant strains reverse transcriptase and coxsackie B4 virus. J. Med. Chem. 2009, 52, 1922–1934. [Google Scholar] [CrossRef] [PubMed]
  81. La Regina, G.; Coluccia, A.; Piscitelli, F.; Bergamini, A.; Sinistro, A.; Cavazza, A.; Maga, G.; Samuele, A.; Zanoli, S.; Novellino, E.; et al. Indolyl aryl sulfones as HIV-1 non-nucleoside reverse transcriptase inhibitors: Role of two halogen atoms at the indole ring in developing new analogues with improved antiviral activity. J. Med. Chem. 2007, 50, 5034–5038. [Google Scholar] [CrossRef] [PubMed]
Molecules 22 00434 ch001 550
Chart 1. Examples of sulfa and pyrrole containing drugs.
Chart 1. Examples of sulfa and pyrrole containing drugs.
Molecules 22 00434 ch001
Molecules 22 00434 sch001 550
Scheme 1. Synthesis of 14.
Scheme 1. Synthesis of 14.
Molecules 22 00434 sch001
Molecules 22 00434 sch002 550
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).
Molecules 22 00434 sch002
Molecules 22 00434 sch003 550
Scheme 3. Chemical transformation of 24.
Scheme 3. Chemical transformation of 24.
Molecules 22 00434 sch003
Molecules 22 00434 sch004 550
Scheme 4. Synthesis of 32.
Scheme 4. Synthesis of 32.
Molecules 22 00434 sch004
Molecules 22 00434 sch005 550
Scheme 5. Synthesis of 38 and 42.
Scheme 5. Synthesis of 38 and 42.
Molecules 22 00434 sch005
Molecules 22 00434 ch002 550
Chart 2. Heterocyclic compounds structurally correlated to PBTD HIV-1 NNRTIs.
Chart 2. Heterocyclic compounds structurally correlated to PBTD HIV-1 NNRTIs.
Molecules 22 00434 ch002
Molecules 22 00434 ch003 550
Chart 3. PBTDs as CML agents.
Chart 3. PBTDs as CML agents.
Molecules 22 00434 ch003
Molecules 22 00434 sch006 550
Scheme 6. Synthesis of PAS 51–58.
Scheme 6. Synthesis of PAS 51–58.
Molecules 22 00434 sch006
Molecules 22 00434 sch007 550
Scheme 7. Synthesis of PAS 60.
Scheme 7. Synthesis of PAS 60.
Molecules 22 00434 sch007
Molecules 22 00434 ch004 550
Chart 4. Structure of pyrryl heteroaryl sulfones 63–65.
Chart 4. Structure of pyrryl heteroaryl sulfones 63–65.
Molecules 22 00434 ch004
Molecules 22 00434 ch005 550
Chart 5. Design of APAS derivatives.
Chart 5. Design of APAS derivatives.
Molecules 22 00434 ch005
Molecules 22 00434 sch008 550
Scheme 8. Synthesis of APASs 69 and 70.
Scheme 8. Synthesis of APASs 69 and 70.
Molecules 22 00434 sch008
Molecules 22 00434 sch009 550
Scheme 9. Smile rearrangement of 72 to 74.
Scheme 9. Smile rearrangement of 72 to 74.
Molecules 22 00434 sch009
Molecules 22 00434 ch006 550
Chart 6. Structure of indolylsulfones 78–86.
Chart 6. Structure of indolylsulfones 78–86.
Molecules 22 00434 ch006
Table
Table 1. Anti-HIV-1 activity of 7-Cl-PBTDs 37a–h a.
Table 1. Anti-HIV-1 activity of 7-Cl-PBTDs 37a–h a.
Molecules 22 00434 i001
CompoundRHIV-1 IIIB
CC50 b (μM)EC50 c (μM)SI d
37aH>3001.0>300
37bMe>3000.5>600
37cEt2832.4118
37dPropyl126149
37eIsopropyl>300Nd e-
37fAllyl>3003.7>81
37gCrotyl>3004.1>73
37hDimethylallyl>300129>2
a Data are mean values of two to three independent experiments each one in triplicate. b CC50: cytotoxic concentration (μM) to induce 50% death of noninfected cells, as evaluated with the MTT 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 evaluated with the MTT method in MT-4 cells. d SI: selectivity index calculated as CC50/EC50 ratio. e nd, no data.
Table
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].
PatientSexAgeSource a% of Apoptosis
2349
24 h48 h24 h48 h
1M45PB a64707785
2M60BM b50707085
3F73PB65796682
4M83BM50705075
5F46PB50706080
6F27PB50706080
7F45PB60806480
8M35PB60806585
9M66PB60806080
10F38PB50707080
11F65PB52715578
12F27PB52735578
a PB: peripheral blood cells. b BM: bone marrow cells.
Table
Table 3. Apoptotic activity of 23 and 49 in cells from CML patients in blast crisis and Imatinib-resistant at onset at 10 μM.
Table 3. Apoptotic activity of 23 and 49 in cells from CML patients in blast crisis and Imatinib-resistant at onset at 10 μM.
PatientSexAgeSource aPercent Apoptosis
2349
24 h48 h24 h48 h
13M38PB a60804060
14F70PB55785070
a PB: peripheral blood cells.
Table
Table 4. Anti-HIV-1 Activity of PASs 16 and 51–58 a.
Table 4. Anti-HIV-1 Activity of PASs 16 and 51–58 a.
CompoundHIV-1 IIIB
CC50 b (μM)EC50 c (μM)SI d
16>30815.08>20
5136.55>36.55-
52>337.5>337.5-
53>262.2>262.2-
54>333>333-
55255>255-
56>37063>5.8
57>279>279-
58>285>285-
NPPS-1.4-
a Data are mean values of two to three independent experiments each one in triplicate; b CC50: cytotoxic concentration (μM) to induce 50% death of non-infected cells, as evaluated with the MTT 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 evaluated with the MTT method in MT-4 cells; d SI: selectivity index calculated as CC50/EC50 ratio.
Table
Table 5. Anti-HIV-1 activity of amino-PAS 59a–h against the WT strain a.
Table 5. Anti-HIV-1 activity of amino-PAS 59a–h against the WT strain a.
Molecules 22 00434 i002
CompoundR1R2HIV-1 IIIB
CC50 b (μM)EC50 c (μM)SI d
59a2-NH2-5-Cl2-COOMe>3000.18>2140
59b2-NH2-5-Cl2-COOEt>3000.14>2140
59c2-NO22-COOEt>30015>20
59d2-Cl2-COOEt141255
59e2-NH2-5-Cl2-COOCH2CHC=CH21000.40250
59f2-NHCHO-5-Cl2-COOEt>3001.0>300
59g2-NHCOMe-5-Cl2-COOEt≥3001.0≥300
59h2-NHCOOEt2-COOEt>3001.0>300
NVP e>100000.60>167
a Data are mean values of two to three independent experiments each one in triplicate; b CC50: cytotoxic concentration (μM) to induce 50% death of non-infected cells, as evaluated with the MTT 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 evaluated with the MTT method in MT-4 cells; d SI: selectivity index calculated as CC50/EC50 ratio; e NVP: nevirapine.
Table
Table 6. Anti-HIV-1 activity of PAS 59a–h against the rRT.
Table 6. Anti-HIV-1 activity of PAS 59a–h against the rRT.
CompoundIC50 ± SD (μM) a
WT IIIBY181CL100I
59a0.45 ± 0.096.9 ± 2.37.4 ± 1.2
59b0.40 ± 0.057.5 ± 1.48.5 ± 1.0
59c0.40 ± 0.145.0 ± 1.510 ± 3.1
59d0.27 ± 0.108.0 ± 2.014 ± 1.2
59e0.90 ± 0.1214 ± 2.5>20
59f>20>20>20
59g>20>20>20
59h>20>20>20
NVP0.60 ± 0.1>203.5 ± 0.18
a Compound concentration required to inhibit the HIV rRT activity by 50%. SD: standard deviation.
Table
Table 7. Anti-HIV-1 activity of PAS 60 in MT-4 cells and against rRT a.
Table 7. Anti-HIV-1 activity of PAS 60 in MT-4 cells and against rRT a.
Molecules 22 00434 i003
CompoundCC50 b (μM)HIV-1 IIIBIC50 e (μM)
EC50 c (μM)SI d
602400.04253330.05
NVP f>2000.35>5710.64
a Data are mean values of two to three independent experiments each one in triplicate; b CC50: cytotoxic concentration (μM) to induce 50% death of non-infected cells, as evaluated with the MTT 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 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.

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Famiglini, V.; Castellano, S.; Silvestri, R. N-Pyrrylarylsulfones with High Therapeutic Potential. Molecules 2017, 22, 434. https://doi.org/10.3390/molecules22030434

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Famiglini V, Castellano S, Silvestri R. N-Pyrrylarylsulfones with High Therapeutic Potential. Molecules. 2017; 22(3):434. https://doi.org/10.3390/molecules22030434

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Famiglini, Valeria, Sabrina Castellano, and Romano Silvestri. 2017. "N-Pyrrylarylsulfones with High Therapeutic Potential" Molecules 22, no. 3: 434. https://doi.org/10.3390/molecules22030434

APA Style

Famiglini, V., Castellano, S., & Silvestri, R. (2017). N-Pyrrylarylsulfones with High Therapeutic Potential. Molecules, 22(3), 434. https://doi.org/10.3390/molecules22030434

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