Substituted Benzenesulfonyl Chlorides Research Articles

New Antioxidant Agents Bearing Carboxamide Moiety: Synthesis, Molecular Docking and in Vitro Studies of New Benzenesulfonamide Derivatives

Oxidative stress occurs when oxygen radical formation and levels exceed those of antioxidants, potentiating cell responses such as apoptosis, tumorigenesis, and immune response. In an event of microbial invasion, there is a production of Reactive-Oxygen-Species (ROS), which when in excess can lead to oxidative stress. Some of these microorganisms are opportunistic pathogens implicated in chronic inflammatory conditions including cystic fibrosis. The synthesis, anti-inflammatory, antimicrobial and antioxidant activities of ten new derivatives of benzenesulfonamide bearing carboxamide functionality are herein reported. The base promoted reactions of the appropriate amino acids with substituted benzenesulfonyl chlorides gave the benzene sulphonamides (3a-j) in excellent yields. Palladium mediated amidation of the benzenesulfonamide (3a-j) and ethylamine gave the new carboxamides (4a-j) in excellent yield.All the compounds possessed good antioxidant activity but only compound 4e (IC50 0.3586 mg/mL) had comparable activity with vitamin C (IC50 0.2090 mg/mL). Compound 4e inhibited carrageenan-induced rat-paw edema at 95.58, 88.79, and 86.96 % each at 1 h, 2 h, and 3 h respectively. In the antimicrobial activity study, compound 4f (MIC 7.23 mg/mL) was most potent against E.coli, compound 4j (MIC7.11, 6.42 and 6.32 mg/mL) was the most active against S.aureus, P.aeruginosa and B.subtilis, compound 4h (MIC 7.12 and 6.48 mg/mL) was most active against S.typhi and C.albicans respectively, compound 4c (MIC 6.63 mg/mL) was the most active against A.niger.

Sulfonamide-Based Azaheterocyclic Schiff Base Derivatives as Potential Carbonic Anhydrase Inhibitors: Synthesis, Cytotoxicity, and Enzyme Inhibitory Kinetics.

A series of sulfonamide-bearing azaheterocyclic Schiff base derivatives 3(a-j) were synthesized as carbonic anhydrase inhibitors. The substituted benzene sulfonyl chlorides 1(a-d) were reacted with N2H4 to get aromatic sulfonyl hydrazides 2(a-d). The intermediate hydrazides 2(a-d) were treated with substituted aldehydes to afford azaheterocyclic sulfonamide Schiff bases 3(a-j). The spectral data of synthesized compounds confirmed the formation of the final products. The inhibitory effects of 3(a-j) on carbonic anhydrase activity were determined, and it was found that derivative 3c exhibited the most potent activity with IC500.84 ± 0.12 μM among all other derivatives and is also more active than standard acetazolamide (IC500.91 ± 0.12). The enzyme inhibitory kinetics results determined by Lineweaver-Burk plots revealed that compound 3c inhibits the enzyme by noncompetitive mode of inhibition with Ki value 8.6 μM. The molecular docking investigations of the synthesized analogues 3(a-j) were evaluated which assured that synthesized compounds bind well inside the active binding site of the target enzyme. Cytotoxicity on human keratinocyte (HaCaT) and MCF-7 cell lines was performed, and it was found that most of the synthesized analogues were nontoxic on these cell lines and the toxic effects follow the dose-dependent manner. Based on our investigations, it was suggested that analogue 3c may serve as core structure to project carbonic anhydrase inhibitors with greater potency.

Synthesis, biological screening, in silico study and fingerprint applications of novel 1, 2, 4‐triazole derivatives

AbstractA series of novel 1,2,4 triazole derivatives were synthesized by treating 4‐bromo‐2‐(4H‐1,2,4‐triazole‐3‐yl)aniline (4) with different substituted benzene sulfonyl chlorides 5(a‐f) and benzyl bromides 7(a‐e). IR, 1H‐NMR, 13C‐NMR, and mass analysis confirmed the structures of the newly synthesized compounds. All derivatives were screened for their in vitro antibacterial activity against two bacterial strains viz Escherichia coli and Staphylococcus aureus, antifungal activity against Aspergillus flavus and Candida albicans, anthelmintic activity against Pheretima posthuma and also cytotoxicity activity against MDA‐MB 231 and A375 cancer cell lines. It was found that some of the derivatives showed significant antibacterial, antifungal, anthelmintic, and cytotoxic activities when compared to respective standard drugs. Molecular docking studies have assisted the theoretical binding mode of the target molecules. Compounds were also explored for fingerprint application.

Synthesis and evaluation of novel S-benzyl- and S-alkylphthalimide- oxadiazole -benzenesulfonamide hybrids as inhibitors of dengue virus protease.

Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9μM and 15.1μM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.

Sulfonylpiperazines based on a flavone as antioxidant and cytotoxic agents.

Chrysin-based sulfonylpiperazines 7a-k were synthesized and investigated for their in vitro free radical scavenging potential as well as cytotoxic efficacies against selected cancer cell lines. Cytotoxicity of the new compounds toward noncancer cells was confirmed using the SRB assay against Madin-Darby Canine Kidney cells. Reaction of piperazine with different substituted benzenesulfonyl chlorides in triethylamine furnished sulfonylpiperazines (3a-k), which were then allowed to react with 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one (6) prepared reacting chrysin with 1,4-dibromobutane to give the final derivatives 7a-k. The results concluded that chrysin-sulfonylpiperazines exerted better antioxidant and anticancer efficacies than previously studied chrysin-piperazine precursors. For example, compounds 7h, 7j, and 7k with 4-OCF3 , 4-OCH3 , and 2,4-diOCH3 groups exhibited the best antioxidant potential against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) radicals. Moreover, halogenated analogues (7b, 7c, 7g, and 7h) demonstrated promising anticancer potential against SK-OV3, HeLa, and HT-29 cell lines, whereas those bearing a methoxy functional group (7j and 7k) had beneficial effects against the cell lines A-549 and HT-29. Thus, it can be confirmed from the bioassay results that the overall structural design as well as proper substitution is crucial to deliver the anticipated biological effects. Spectroscopic techniques such as FT-IR, 1 H NMR, 13 C NMR, mass and elemental analysis (CHN) were carried out to confirm the final structures.

BIO-POTENT SULFONAMIDES

Some 4-(substituted phenylsulfonamido)benzoic acids have been synthesized by fly-ash:H3PO3 nano catalyst catalyzed condensation of substituted benzenesulfonyl chlorides and 4-aminobenzoic acid in ultrasound irradiation conditions. The yields of the sulfonamides are more than 90%. The synthesized 4-(substituted phenylsulfonamido) benzoic acid derivatives were characterized by their physical constants, analytical and spectroscopic data. Antimicrobial activities of all sulfonamides were measured by Bauer-Kirby disc diffusion method.

Synthesis of proline derived benzenesulfonamides: A potent anti-Trypanosoma brucei gambiense agent

Thousands of death in Africa and other developing nations are still attributed to trypanosomiasis. Excessive sleep has been associated with increased inflammation. We report herein, the synthesis, antitrypanosomal and anti-inflammatory activities of eight new carboxamide derivatives bearing substituted benzenesulfonamides. The base promoted reactions of l-proline and L-4-hydroxyproline with substituted benzenesulfonyl chlorides gave the benzenesulfonamides (11a-h) in excellent yields. Boric acid mediated amidation of the benzenesulfonamides (11a-h) and p-aminobenzoic acid (12) gave the new carboxamides (13a-h) in excellent yields. The new carboxamides were tested for their antitrypanosomal and anti-inflammatory activities against Trypanosome brucei gambiense and inhibition of carrageenan-induced rat paw edema. Compound 13f was the most potent antitrypanosomal agent with an IC50 value of 2 nM as against 5 nM for melarsoprol; whereas compound 13a was the most potent anti-inflammatory agent with percentage inhibition of carrageenan-induced rat paw edema of 58, 60, 67 and 84% after 0.5 h, 1 h, 2 h and 3 h administration respectively. The structure-activity relationship study revealed that substitution at the para position in the benzenesulfonamide ring increased both the antitrypanosomal and anti-inflammatory activities. The 4-hydroxyprolines (13a-d) showed higher anti-inflammatory activity than the prolines (13e-h). In contrast, the prolines (13e-h) had higher antitrypanosomal activities than the 4-hydroxyprolines. The link between excessive sleep and inflammation makes the report of this class of compounds possessing both antitrypanosomal and anti-inflammatory activity worthwhile. The pharmacokinetic studies showed that the compounds would not pose oral bioavailability, transport and permeability problems.

Synthesis, Spectral Characterization and Antioxidant Activity of Novel Zafirlukast Sulfonyl Derivatives

AbstractA new series of cyclopentyl 3‐(2‐methoxy‐4‐(piperazine‐1‐carbonyl)benzyl)‐1‐methyl‐1H‐indol‐5‐ylcarbamate sulfonyl derivatives were synthesized by the reaclion of 4‐((5‐(cyclopentyloxycarbonylamino)‐1‐methyl‐1H‐indol‐3‐yl)methyl)‐3‐methoxybenzoic acid (ZAK drug intermediate) with Boc piperazine in the presence of EDC⋅HCl, HOBt, TEA in DMF followed by deboxylation by using 2N HCl or 35 % HCl in acetone to get an intermediate compound. Further, this compound was treated with various substituted benzene sulfonyl chlorides in the presence of TEA in THF to afford title compounds. All the title compounds were characterized by 1HNMR, 13CNMR, IR and mass spectral data. The title compounds and starting material were evaluated for their antioxidant activity by using the DPPH, H2O2 and NO methods. The results revealed that some of the compounds have shown significant antioxidant activity.

Synthesis of new oxadiazole derivatives as anti-inflammatory, analgesic, and antimicrobial agents

In search of pharmalogically active molecules in the class of oxadiazoles, the present article deals with the synthesis of 5-(5′-fluoro-2′-methoxybiphenyl-3-yl)-1,3,4-oxadiazol-2(3H)-one 2 from its hydrazide analog 1. The compound 2 was regioselectively N-alkylated with alkyl halides and produced the compounds 3a–f. Compound 3f was further functionalized with substituted benzenesulfonyl chlorides to give compounds 3g–j. The synthesized compounds were characterized by elemental and spectral analysis. Newly synthesized compounds were tested for their in vivo anti-inflammatory, analgesic, and in vitro antimicrobial activities. The compounds 3a–c were found to have promising anti-inflammatory and analgesic activities. Compounds 3b, 3f, and 3g showed significant antibacterial and antifungal activities.

Synthesis and DPPH radical-scavenging effect of novel heterocyclic derivatives of 2-amino-4-(1-benzoylindol-3-yl)selenophene-3-carbonitrile

Background and objectivesSelenophene moiety is one of the heterocyclic compounds with a selenium atom that plays a vital role in biological fields such as antioxidant, antidepressant, anticonvulsant, antimicrobial, and anticancer activities. The aim of this study was to describe the synthesis of some new heterocycles derived from 2-amino-4-(1-benzoylindol-3-yl)selenophene-3-carbonitrile derivatives and to evaluate their 2,2Ͳ-diphenyl-1-picrylhydrazyl radical-scavenging activity.Materials and methods2-Amino-4-(1-benzoylindol-3-yl)selenophene-3-carbonitrile ( 3 ) was prepared and allowed to react with each of formic acid, formamide, carbon disulfide, urea, thiourea, malononitrile, or ethyl cyanoacetate to yield selenolo[2,3-d]pyrimidines 4-7 and selenolo[2,3-b]pyridine derivatives 8 and 9 , respectively. Moreover, reaction of compound 3 with hydrochloric acid or acetic anhydride in glacial acetic acid yielded selenolo[2,3-d]pyrimidin-4-one 10 and selenoacetamide derivative 11 , respectively. In contrast, reaction of Schiff base 12 with thioglycolic acid, phenacyl bromide, or chloroacetyl chloride yielded thiazolidine 13 and azidatine derivatives 14 and 15 , respectively. Reaction of compound 3 with some substituted benzenesulfonyl chlorides yielded sulfonamide derivatives 16a, b, c , respectively. Moreover, 2-amino-1,3,4-thiadiazole 19 and 4-oxo-2-iminothiazolidine derivatives 21 were prepared through cyclization of hydrazinecarbothioamide 18 or chloroacetamido derivative 20, respectively. The fusion of 3 with succinic anhydride yielded pyrrolidine-2,5-dione 23 , whereas heating of 3 with succinic anhydride in ethanol yielded succinamic acid derivative 24 . The newly synthesized compounds were screened for their 2,2Ͳ-diphenyl-1-picrylhydrazyl radical-scavenging activity.Results and conclusionCompound 8 showed promising activity with a radical-scavenging effect (IC 50 ) of 166.40 μg/ml compared with ascorbic acid (an IC 50 of 129.64 μg/ml) as a reference standard.

Synthesis and characterization of a novel series of benzenesulfonylurea and thiourea derivatives of 2H-pyran and 2H-pyridine-2-ones as antibacterial, antimycobacterial and antifungal agents

Arylhydrazines reacted with dehydroacetic acid ( 1 ) to give the corresponding 2 H -pyran-2-one hydrazones ( 2 ), which on treatment with hydrazine hydrate afforded the corresponding 1-amino-2 H -pyridin-2-ones ( 3 ). Reaction of 3 with nitrous acid, aromatic aldehyde and substituted benzenesulfonyl chlorides yielded the corresponding 2 H -pyridine-2-one derivatives. A series of urea and thiourea derivatives were also prepared. Some of these compounds have shown significant antibacterial and mild to moderate antimycobacterial and antifungal activities.

Micellar charge effects as mechanistic criteria in spontaneous hydrolyses of acid chlorides

AbstractReaction rates in aqueous micelles, treated in terms of a pseudophase model, depend on transfer equilibria between water and micelles and rate constants in each pseudophase. Rate constants of spontaneous reactions of fully micellar‐bound substrates are independent of transfer and are those in the micellar pseudophase. They depend on its properties as a reaction region and the sensitivity of the reaction to medium effects. For a wide range of spontaneous reactions there are simple relationships between rate constants and properties of the micellar interfacial region, e.g. apparent polarity and head‐group charge, which depend on the reaction mechanism. Aqueous micelles inhibit nucleophilic substitutions at alkyl centers, but rate constants, k+, in cationic micelles are higher than those, k−, in anionic micelles for SN2 reactions and lower for SN1 reactions. Except for nitro derivatives, hydrolyses of substituted benzoyl chlorides are micellar inhibited and k+/k−≈18 for nitro derivative and ca 0.04 for 4‐OMe and Me derivatives, indicating different extents of bond making and breaking in the transition state, but there is no evidence of rate‐limiting dissociation in hydrolyses of the latter. For hydrolyses of substituted benzenesulfonyl chlorides, values of k+/k− decrease from 21 for the 4‐NO2 derivative to 1.1 for the 4‐OMe derivative, indicating dominant bond making. These mechanism‐related charge effects are ascribed to charge asymmetries at micelle–water interfaces and zwitterionic sulfobetaine micelles behave very similarly to cationic micelles in these hydrolyses. Copyright © 2004 John Wiley & Sons, Ltd.

Reactions of Sodium Enolates Derived from 6-Aryl-3,5,5-trimethyl-2,3,5,6-tetrahydropyrane-2,4-diones with Substituted Benzenesulfonyl Chlorides and Arenediazonium Salts

Sodium enolates derived from 6-aryl-3,5,5-trimethyl-2,3,5,6-tetrahydropyrane-2,4-diones react with substituted benzenesulfonyl chlorides to give the corresponding O-sulfonation products, 6-aryl-4-(4-R-phenylsulfonyloxy)-3,5,5-trimethyl-5,6-dihydropyrane-2-ones. Reactions of the title compounds with arenediazonium tetrafluoroborates afford 6-aryl-3-arylazo-3,5,5-trimethyl-2,3,5,6-tetrahydropyran-2,4-diones as mixtures of syn and anti isomers.

SOME CHLOROHYDROXYBENZENESULFONYL DERIVATIVES

Abstract 2,4-; 2,6-; 2,3-; 3,4-; 2,5-; and 3,5-dichlorophenols by reaction with chlorosulfonic acid were converted to the following substituted benzenesulfonyl chlorides: 3,5-dichloro-2-hydroxy-; 3,5-dichloro-4-hydroxy-; 2,3-dichloro-4-hydroxy-; 4,5-dichloro-2-hydroxy-; 2,5-dichloro-4-hydroxy-; and 2,6-dichloro-4-hydroxy-respectively. In addition o-chlorophenol gave 5-chloro-4-hydroxybenzene-1,3-bis-sulfonyl chloride. The various sulfonyl chlorides have been condensed with nucleophilic reagents, e.g. ammonia, amines, hydrazine, phenylhydrazine, N, N-dimethylhydrazine, and sodium azide. 3,5-Dichloro-2-hydroxybenzenesulfonyl azide has been reacted with norbornene, triphenylphosphine, dimethylsulfoxide, and cyclohexene. 3,5-Dichloro-2-hydroxybenzenesulfonyl chloride with phenylisocyanate gave the 2-(N-phenyl-carbamoyloxy) derivative which on heating gave a heterocyclic compound. The chlorohydroxybenzenesulfonyl derivatives are of interest as potential herbicides and their ir and nmr spectral characteristics are briefly discussed.

The chemistry of ethyleneimine

The reaction of N-aminoethyleneimine (I) with substituted benzenesulfonyl chlorides (II) has been studied. The main products of the heterolysis of the ring are substituted N′-(Β-chloroethyl)benzenesulfonohydrazides (V). The structure of V has been shown by IR, UV, and PMR spectroscopy, and also by independent synthesis.

Rearrangement of tertiary amine N-oxides—XXVII : Mechanism of the reaction of isoquinoline N-oxide with substituted benzenesulfonyl chlorides

Kinetic experiments have been carried out on the reactions of isoquinoline N-oxide with p-toluenesulfonyl and other substituted benzenesulfonyl chlorides, varying solvent and salt compositions. The rate was correlated by the second-order equation, i.e., v = [N → O] × [ArSO 2Cl], and was found to be accelerated in polar media. The addition of chloride ion was found to increase the rate considerably, while the rates of the over-all reaction became greater with arenesulfonyl chlorides bearing stronger electron-withdrawing substituents (ϱ = +2·0). By the use of 1-deuterated isoquinoline N-oxide a small kinetic isotope effect ( k H/ k D = 1·2) was observed for this reaction. Based on these kinetic observations the rate-determining step of this reaction is considered to be the cleavage of NO bond. Meanwhile, from the 18O-tracer experiments in several solvents using uniformly 18O-labelled p-toluenesulfonyl or p-bromobenzenesulfonyl chloride the migration of arenesulfonate was found to proceed mainly via oxygen-bridged ion pair pathway.