Phenylsulfonyl Moiety Research Articles

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach. One-pot multicomponent reactions between phenyl vinyl sulfone, substituted isatins, and amines afforded highly stereoselective anti-SARS-CoV-2 therapeutics spirooxindoles with three stereogenic centers. Herein, the newly synthesized spirooxindoles were assessed individually against the highly pathogenic human coronaviruses and proved to be highly potent and safer. Interestingly, the synergistic effect by combining the potent, tested spirooxindoles resulted in an improved antiviral activity as well as better host-cell safety. Compounds 4i and 4d represented the most potent activity against MERS-CoV with IC50 values of 11 and 23 µM, respectively. Both compounds 4c and 4e showed equipotent activity with the best IC50 against SARS-CoV-2 with values of 17 and 18 µM, respectively, then compounds 4d and 4k with IC50 values of 24 and 27 µM, respectively. Then, our attention oriented to perform a combination protocol as anti-SARS-CoV-2 for the best compounds with a different binding mode and accompanied with different pharmacophores. Combination of compound 4k with 4c and combination of compounds 4k with 4i proved to be more active and safer. Compounds 4k with 4i displayed IC50 = 3.275 µM and half maximal cytotoxic-concentration CC50 = 11832 µM. MD simulation of the most potential compounds as well as in silico ADMET properties were investigated. This study highlights the potential drug-like properties of spirooxindoles as a cocktail anti-coronavirus protocol.

Synthesis and Antimicrobial Evaluation of Novel Pyrazolopyrimidines Incorporated with Mono- and Diphenylsulfonyl Groups.

A novel series of pyrazolo[1,5-a]pyrimidine ring systems containing phenylsulfonyl moiety have been synthesized via the reaction of 2-(phenylsulfonyl)-1-(4-(phenylsulfonyl) phenyl)ethan-1-one, 2-benzenesulfonyl-1-(4-benzenesulfonyl-phenyl)-3-dimethylamino-propenone and 3-(dimethylamino)-1-(4-(phenylsulfonyl)phenyl)prop-2-en-1-one each with various substituted aminoazopyrazole derivatives in one pot reaction strategy. The proposed structure as well as the mechanism of their reactions were discussed and proved with all possible spectral data. The results of antimicrobial activities of the new sulfone derivatives revealed that several derivatives showed activity exceeding the activity of reference drug. Contrary to expectations, we found that derivatives containing one sulfone group are more effective against all bacteria and fungi used than those contain two sulfone groups.

Discovery of 4-amino-3-arylsulfoquinolines, a novel non-acetylenic chemotype of metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulators

Negative allosteric modulators of metabotropic glutamate receptor 5 (mGlu5) showed efficacy in a number of animal models of different CNS diseases including anxiety and depression. Virtually all of the compounds which reached the clinic belong to the same chemotype having an acetylenic linker that connects (hetero)cyclic moieties. Searching for new chemotypes we identified a morpholino-sulfoquinoline derivative (1) by screening our corporate compound deck. The HTS hit showed reasonable affinity and selectivity towards mGlu5 receptors, however, its inferior metabolic stability prevented its testing in vivo. In a chemical program we aimed to improve the affinity, physicochemical properties and metabolic stability exploring three regions of the hit. Systematic variation of different amines at position 4 (region I) led to the identification of 4-methyl-piperidinyl analogues. Substituents of the quinoline core (region II) and the phenylsulfonyl moiety (region III) were mapped by parallel synthesis. Evaluation of both morpholino- and 4-methyl-piperidinyl-sulfoquinoline libraries of about 270 derivatives revealed beneficial substituent combinations in regions II and III. Blood levels of optimized 4-methyl-piperidinyl-sulfoquinolines, however, were still insufficient for robust in vivo efficacy. Finally, introducing 4-hydoxymethyl-piperidinyl substituent to region I resulted in new sulfoquinolines with greatly improved solubility and reasonable affinity coupled with affordable metabolic stability. The most promising analogues (24 and 25) showed high blood levels and demonstrated significant efficacy in the experimental model of anxiety.

Enantioselective Formal α‐Methylation and α‐Benzylation of Aldehydes by Means of Photo‐organocatalysis

AbstractDetailed herein is the photochemical organocatalytic enantioselective α‐alkylation of aldehydes with (phenylsulfonyl)alkyl iodides. The chemistry relies on the direct photoexcitation of enamines to trigger the formation of reactive carbon‐centered radicals from iodosulfones, while the ground‐state chiral enamines provide effective stereochemical control over the radical trapping process. The phenylsulfonyl moiety, acting as a redox auxiliary group, facilitates the generation of radicals. In addition, it can eventually be removed under mild reducing conditions to reveal methyl and benzyl groups.

Enantioselective Formal α-Methylation and α-Benzylation of Aldehydes by Means of Photo-organocatalysis.

Detailed herein is the photochemical organocatalytic enantioselective α‐alkylation of aldehydes with (phenylsulfonyl)alkyl iodides. The chemistry relies on the direct photoexcitation of enamines to trigger the formation of reactive carbon‐centered radicals from iodosulfones, while the ground‐state chiral enamines provide effective stereochemical control over the radical trapping process. The phenylsulfonyl moiety, acting as a redox auxiliary group, facilitates the generation of radicals. In addition, it can eventually be removed under mild reducing conditions to reveal methyl and benzyl groups.

Crystal structures of three carbazole derivatives: 12-ethyl-7-phenyl-sulfonyl-7H-benzofuro[2,3-b]carbazole, (1), 2-(4,5-dimeth-oxy-2-nitro-phen-yl)-4-hy-droxy-9-phenyl-sulfonyl-9H-carbazole-3-carbaldehyde, (2), and 12-phenyl-7-phenyl-sulfonyl-7H-benzofuro[2,3-b]carbazole, (3).

The three title compounds, C26H19NO3S, (1), C27H20N2O8S, (2), and C30H19NO3S, (3), are carbazole derivatives, where (1) and (3) are heterocycle-containing carbazoles with a benzo-furan moiety fused to a carbazole unit. In (2), a di-meth-oxy-nitro-phenyl ring is attached to the carbazole moiety. In the three derivatives, a phenyl-sulfonyl group is attached to the N atom of the carbazole unit. Compound (1) crystallizes with two independent mol-ecules in the asymmetric unit (A and B). The carbazole skeleton in the three compounds is essentially planar. In compound (1), the benzene ring of the phenyl-sulfonyl moiety is almost orthogonal to the carbazole moiety, with dihedral angles of 85.42 (9) and 84.52 (9)° in mol-ecules A and B, respectively. The benzene ring of the phenyl-sulfonyl group in compounds (2) and (3) are inclined to the carbazole moiety, making dihedral angles of 70.73 (13) and 81.73 (12)°, respectively. The S atom has a distorted tetra-hedral configuration in all three compounds. In the crystals, C-H⋯O hydrogen bonds give rise to R22(12) inversion dimers for compound (1), and to R22(24) inversion dimers and R44(40) ring motifs for compound (2). The crystal packing in (1) also features C-H⋯π and π-π inter-actions [shortest inter-centroid distance = 3.684 (1) Å], leading to supra-molecular three-dimensional aggregation. In the crystal of compound (2), the combination of the various C-H⋯O hydrogen bonds leads to the formation of a three-dimensional network. In the crystal of compound (3), mol-ecules are linked by C-H⋯O hydrogen bonds, forming chains running parallel to the a axis, and the chains are linked by C-H⋯π inter-actions, forming corrugated sheets parallel to the ab plane.

Synthesis of novel tetrazole derivatives and evaluation of their antifungal activity

With the appearance of the antifungal resistance, novel antifungal agents need to be identified. In this context new 2,5-disubstituted tetrazole derivatives containing benzothiazole, benzoxazole or phenylsulfonyl moiety were synthesized by N-alkylation of aryltetrazole with 2-[(3-chloropropyl)sulfanyl]-1,3-benzothiazole or 2-[(3-chloropropyl)sulfanyl]-1,3-benzoxazole and Michael-type addition of aryltetrazole to phenyl vinyl sulfone. The chemical structures of the synthesized compounds were confirmed by means of 1H NMR, 13C NMR, IR and HRMS spectral data. The compounds were tested against the moulds: Fusarium sambucinum, Fusarium oxysporum, Colletotrichum coccodes, Aspergillus niger, and the yeast Candida albicans. The results showed that among the moulds only C. coccodes was significantly sensitive to all the structures examined. All the tetrazole derivatives acted at the same level against C. albicans and demonstrated a high cell growth inhibition (97–99%) at the concentrations ranging from 16 to 0.0313μg/mL. The mode of action of 2-({3-[5-(4-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5c) and 2-({3-[5-(2-chlorophenyl)-2H-tetrazol-2-yl]propyl}sulfanyl)-1,3-benzoxazole (5d) was established by verifying fungal growth in the presence of osmotic protector-sorbitol. The effect of compound 5c or 5d combined with Fluconazole was determined using the checkerboard method. The calculated fractional inhibitory concentration index (FIC) indicated antagonism (FIC >1). Additionally, survival experiments with lepidopteran Galleria mellonella treated with compounds 5c and 5d were performed and demonstrated the lack of toxicity of these compounds.

Regioselective synthesis and ab initio calculations of fused heterocycles thermally and under microwave irradiation

Pyrazolo[1,5-a]pyrimidine, triazolo[1,5-a]pyrimidine, and pyrimido[1,2-a]benzimidazole, pyrido[1,2-a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-(N,N-dimethylamino)-1-(thiophen-2-yl)-2-(phenylsulfonyl)prop-2-en-1-one derivatives with the appropriate aminoazoles as 1,3-binucleophiles and 1H-benzimidazol-2-ylacetonitrile using conventional methods as well as microwave irradiation. The regioselectivity of the cyclocondensation reactions was confirmed both experimentally by alternative synthesis of reaction products and theoretically using ab initio quantum chemical calculations namely the Density Functional Theory (DFT). The theoretical work was carried out using the Becke, three parameter, Lee–Yang–Parr hybrid functional (B3LYP) combined with the 6-311++G(d,p) basis set. It was found that the final cyclocondensation reaction product depends mainly on the initial addition to the activated double bond by the nitrogen atom of the 1,3-binucleophiles that has the higher electron density.

Synthesis of Novel Thiazole and 1,3,4-Thiadiazole Derivatives Incorporating Phenylsulfonyl Moiety

Synthesis of Novel Thiazole and 1,3,4-Thiadiazole Derivatives Incorporating Phenylsulfonyl Moiety

Synthesis and biological evaluation of novel coumarin–pyrazoline hybrids endowed with phenylsulfonyl moiety as antitumor agents

Two groups of coumarin–pyrazoline hybrids were synthesized. The target compounds were obtained by cyclization of the coumarin chalcones with various substituted hydrazines to produce the corresponding pyrazolines through 1,4-addition on α,β-unsaturated carbonyl system. Selected compounds were investigated for their anticancer activity toward 60 cancer cell lines according to US NCI protocol where breast cancer MCF7 and colon cancer HCT-116 were the most susceptible to the influence of compounds 7d, 8c and 9c. Encouraged by this, all final compounds were screened against colorectal cell line HCT-116. The tested compounds exhibited high potency with IC50 ranging from 0.01 μM to 2.8 μM. Moreover, compound 9c which possessed the highest cytotoxicity proved to have weak enzyme inhibitory activity against PI3K (p110α/p85α).

A Robust Yellow‐Emitting Metallophosphor with Electron‐Injection/‐Transporting Traits for Highly Efficient White Organic Light‐Emitting Diodes

With the aim of endowing triplet emitters in the development of organic light-emitting devices (OLEDs) with electron-injection/-transporting (EI/ET) features, the phenylsulfonyl moiety was introduced into the phenyl ring of a 2-phenylpyridine (Hppy) ligand and the yellow phosphorescent heteroleptic iridium(III) complex 1 was developed. It was shown that the SO(2)Ph unit could provide EI/ET character to 1, as indicated from both electrochemical and computational data. Complex 1 is a promising yellow-emitting material for both monochromatic OLEDs and white OLEDs (WOLEDs). The outstanding electronic traits associated with 1, coupled with careful device design, afforded very attractive electroluminescent performances for two-element WOLEDs, including a low turn-on voltage of less than 3.7 V, a maximum brightness of 48,000 cd m(-2), an external quantum efficiency of 13.0%, a luminance efficiency of 34.7 cd A(-1), and a power efficiency of 24.3 Lm W(-1). In addition, a good color rendering index (CRI) of about 74, a stable white color with a Commission Internationale de L'Eclairage (CIE(x,y)) variation of Δ(x, y) < ±(0.02, 0.02), and a correlated color temperature higher than 5130 K were obtained. These encouraging results indicate the potential of these WOLEDs as good candidates for warm indoor lighting sources, as well as the critical contribution of such key EI/ET properties to triplet emitters to advance new OLED research.

Single step synthesis of new fused pyrimidine derivatives and their evaluation as potent Aurora-A kinase inhibitors

A simple, facile, efficient and one pot three-component procedure for the synthesis of pyrazolo[1,5- a]pyrimidines, triazolo[1,5- a]pyrimidines and pyrimido[1,2- a]benzimidazoles ring systems incorporating phenylsulfonyl moiety was developed via the reaction of 1-aryl-2-(phenylsulfonyl)ethanone derivatives 1a– d with the appropriate heterocyclic amine and triethyl orthoformate and evaluated as Aurora-A kinase inhibitors. The cytotoxic activity of the newly synthesized compounds against HST116 colon tumor cell line was investigated. 2,7-Diphenyl-6-(phenylsulfonyl)pyrazolo[1,5- a]pyrimidine ( 4b) and its p-methoxy analogue 4c were found to be equipotent to Doxorubicin as a reference drug. Molecular modeling study was carried out in order to rationalize the in vitro anti-tumor results.

Synthesis and analgesic/anti-inflammatory evaluation of fused heterocyclic ring systems incorporating phenylsulfonyl moiety

A series of pyrazolo[1,5- a]pyrimidine, triazolo[1,5- a]pyrimidine, and pyrimido[1,2- a]benzimidazole ring systems incorporating phenylsulfonyl moiety were synthesized via the reaction of 3-( N,N-dimethylamino)-1-aryl-2-(phenylsulfonyl)prop-2-en-1-one derivatives 2a, b with appropriate nitrogen nucleophiles. The analgesic and anti-inflammatory activities of the newly synthesized compound were investigated in vivo. 3-Bromo-2-phenyl-6-(phenylsulfonyl)-7-(4-methylphenyl)pyrazolo[1,5- a]pyrimidine ( 5e) was found to have an excellent analgesic activity in comparison with indomethacin as a reference drug, while the highest anti-inflammatory effect was observed in the case of 2-(4-bromophenyl)-6-(phenylsulfonyl)-5-(4-methylphenyl)pyrazolo[1,5- a]pyrimidine ( 5d). From the structure–activity relationship (SAR) point of view, the analgesic/anti-inflammatory activity of pyrazolo[1,5- a]pyrimidine derivatives was found to be much higher than triazolo[1,5- a]pyrimidine and pyrimido[1,2- a]benzimidazole derivatives.

Discovery of heteroaryl sulfonamides as new EP1 receptor selective antagonists

4-({2-[Isobutyl(phenylsulfonyl)amino]-5-(trifluoromethyl)phenoxy}methyl)benzoic acid (1) is a functional PGE2 antagonist selective for EP1 receptor subtype. Analogs of 1, in which the phenyl-sulfonyl moiety has been replaced with more hydrophilic heteroarylsulfonyl moieties, exhibited more optimized antagonist activity, while some of them showed in vivo antagonist activity. Structure–activity relationship (SAR) studies are also presented.

The application of intramolecular radical cyclizations of acylsilanes in the regiospecific formation of cyclic silyl enol ethers.

Acylsilanes with terminal alpha-stannyl bromide or xanthate functionalities are prepared. Alpha-stannyl radicals generated from these acylsilanes undergo intramolecular cyclizations to give cyclic silyl enol ethers regiospecifically. The radical processes involve radical cyclization, Brook rearrangement, and beta-fragmentation in sequence. A tributylstannyl group serves as the radical leaving group. The newly formed sigma-bond and pi-bond are located between the same two carbon atoms. This approach is limited to the formation of five-membered rings. In another route, omega-bromo-alpha-phenylsulfonylacylsilanes are synthesized. The radical cyclizations of these alpha-sulfonylacylsilanes also give cyclic silyl enol ethers. The phenylsulfonyl moiety is the radical leaving group in this system. Furthermore, the newly formed sigma-bond and pi-bond are located at adjacent positions sharing a single carbon atom. The latter approach is effective for both five- and six-membered ring formation.

Regio- and stereocontrol elements in Rh(II)-catalyzed intramolecular C-H insertion of alpha-diazo-alpha-(phenylsulfonyl)acetamides.

[reaction: see text]. Intramolecular C-H insertion reaction of alpha-diazo-alpha-(phenylsulfonyl)acetamides proceeded with high regio- and stereoselectivities to afford highly functionalized gamma-lactams predominantly or exclusively. The high regioselectivity was attributed to the use of the phenylsulfonyl moiety, which altered electron density at the carbenoid center and exerted a steric effect during the insertion reaction. Also described herein are three control elements to determine regioselectivity, which are amide conformational, stereoelectronic, and substituent effects.

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones as antihyperglycemic agents.

Novel 5-(3-aryl-2-propynyl)-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-(3-aryl-2-propynyl)-5-(arylsulfanyl)thiazolidine-2,4-diones were prepared and evaluated as oral antihyperglycemic agents in the obese, insulin resistant db/db mouse model at 100 mg/kg and, if the analogue had sufficient potency, 20 mg/kg. The sulfonylthiazolidinediones, 2, were more potent than the corresponding sulfanylthiazolidinedione congeners, 1. With regard to substituent effects on the 3-propynyl phenyl ring (Ar') of 2, 4-halogen substitution generally resulted in the more potent analogues. Substituent effects on the phenylsulfonyl moiety (Ar) of 2 were less clear, although para-halogen substitution on Ar generally was preferable. 2-Pyridinesulfonyl derivatives (Ar = 2-pyridine in 2) also had good potency. Several compounds from series 2 were effective at lowering glucose and insulin in the obese, insulin resistant ob/ob mouse at the 50 mg/kg oral dose. Compound 20 significantly improved the glucose tolerance of obese, insulin resistant Zucker rats at the 20 mg/kg dose level and had no effect on plasma glucose or on glucose tolerance in normal rats fasted for 18 h at the 100 mg/kg level.

Structure-activity relationship study of TXA2 receptor antagonists. 4-[2-(4-substituted phenylsulfonylamino)ethylthio]phenoxyacetic acids and related compounds.

We have recently reported that 4-[2-(4-substituted phenylsulfonylamino) ethylthio]phenoxyacetic acids and related compounds showed potent thromboxane A2 (TXA2) receptor antagonist activity. To understand how substituents affect the biological activity, the quantitative structure-activity relationship (QSAR) was analyzed by using the Hansch-Fujita method for 36 compounds, including newly synthesized compounds. The positive coefficient for pi R and FR in the results of the QSAR study suggested that a hydrophobic an sigma electron-withdrawing substituent R at the para-position of the phenylsulfonyl moiety is required to improve the activity. Further, a substituent R which is long and moderately wide, was suggested to be preferable for the activity. The positive coefficients for pi X,Y,W-COOH and sigma Q(1)-(6) may indicate that the introduction of a hydrophobic and electron-withdrawing group on the benzene ring of the phenoxy acetic acid moiety enhances the activity. The length of the W-COOH moiety may also be important. On the other hand, the effect of the presence of methylene (n = 1) was not clear.

The Synthesis of Amidine Acetals as Intermediates for the Preparation of Naturally Occurring Cyclic Amidine Antibiotics

Abstract Regioselective 1,3-dipolar cycloaddition of (phenylsulfonyl)nitrile oxide to acrolein dimethylacetal gave the isoxazole 3. Nucleophilic displacement of the phenylsulfonyl moiety followed by reductive N-O bond cleavage gave the amidine acetal 6.