Sulfonamide Moiety Research Articles

In silico and bio assay of juvenile hormone analogs as an insect growth regulator against Galleria mellonella (wax moth) – Part I

Juvenile hormone (JH) analogs are nowadays in use to control harmful pests. In order to develop new bioactive molecules as potential pesticides, we have incorporated different active structural features like sulfonamide, aromatic rings, amide group, and amino acid moiety to the base structure. We have screened a series of designed novel JH analogs against JH receptor protein (jhbpGm-2RCK) of Galleria mellonella in comparison to commercial insect growth regulators (IGRs) – Pyriproxyfen (T1) and Fenoxycarb (T2). All analogs exhibit the binding energy profile comparable to commercial IGRs. Based upon these results, a series of sulfonamide-based JHAs (T3–T8) as IGRs have been synthesized and characterized. Further, the efficacy of synthesized analogs (T3–T8) and commercial IGRs (Pyriproxyfen and Fenoxycarb) has been assessed against fourth instars larvae of G. mellonella under the laboratory conditions. LC50 values of all the analogs (T1–T8) against the fourth instars larvae were 9.99, 10.12, 24.76, 30.73, 38.45, 34.15, 34.14, 19.48 ppm and the LC90 153.27, 131.69, 112.15, 191.46, 427.02, 167.13, 217.10, 172.00 ppm, respectively. Among these analogs, N-(1-isopropyl-2-oxo-3-aza-3-N-ethyl-pentanyl)-p-toluene sulfonamide (T8) and N-(1-isopropyl-2-oxo-3-aza-3-N-ethyl-pentanyl) benzene sulfonamide (T7) exhibited the good pest larval mortality at different exposure periods (in hours) and different concentrations (in ppm) in comparison to in use IGRs- T1 and T2. Bio assay results are supported by docking at higher concentration. The present investigation clearly exhibits that analog T8 could serve as a potential IGR in comparison to in use IGRs (T1 and T2). The results are promising and provide new array of synthetic chemicals that may be utilized as IGRs.

Design and synthesis of some novel 4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide derivatives as anticancer and radiosensitizing agents

A novel series of sulfonamide derivatives 4–21 have been synthesized starting from the strategic starting material (E)-4-Chloro-N-(4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)phenyl) benzenesulfonamide 4. Two series of hydrazone 5–9, and pyridone 10–21 derivatives bearing a sulfonamide moiety were obtained. All the newly synthesized compounds were evaluated for their in vitro cytotoxic activity against human liver cancer cell line (HepG2). Compounds 4–6, 8, 9, 10–14 and 16–18 showed higher activity compared to doxorubicin as a positive control. The radiosensitizing ability of the most promising compounds 4, 10 and 12 was studied which showed an increase in the cell killing effect of γ-radiation after combination with these derivatives. The molecular design was performed to predict the binding mode of the most promising compounds 4, 10 and 12 with the active site of hCA IX, that showed appropriate fitting with the relevant amino acids in the binding pocket on the basis of standard bond lengths, angles, S score and E conformation data.

Synthesis and pharmacological evaluation of pyrazole derivatives containing sulfonamide moiety

A new series of N-[4-[N-[4-[5-[4-(benzyloxy)phenyl]-1-(substituted phenyl)-1H-pyrazol-3-yl]phenyl]sulfamoyl]phenyl]acetamide derivatives were synthesized and elucidated by spectral data. All the compounds were subjected to in vitro evaluation for anti-inflammatory (BSA anti-denaturation assay), antioxidant (DPPH radical scavenging assay) and in vivo screening for anti-inflammatory (carrageenan induced rat paw edema inhibition) activities. Selected active compounds were evaluated for ulcerogenic, lipid peroxidation, and LPS induced TNF-α production inhibition potential. The most active compound in the series showed an in vivo anti-inflammatory efficacy of 83.1 % when compared to diclofenac sodium (81.6 %). Evaluation of ulcer index and biochemical estimation for oxidative stress also revealed that this compound was safe on gastric mucosa and did not induce oxidative stress in tissues. When further tested for LPS induced TNF-α production inhibition in mice, it showed a better inhibition (ID50 = 6.23 mg/kg) when compared to standard inhibitor, SB 203580 (ID50 = 28.40 mg/kg). The p38α MAP kinase docking score of this active compound was also found to be better than that of SB 203580.

Structure-Based Design of Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) Inhibitors using a Virtual Fragment Growing Optimization Scheme.

A small library of 2,3-dihydroxybenzamide- and N-(2,3-dihydroxyphenyl)-4-sulfonamide-based microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors was identified following a step-by-step optimization of small aromatic fragments selected to interact in focused regions in the active site of mPGES-1. During the virtual optimization process, the 2,3-dihydroxybenzamide moiety was first selected as a backbone of the proposed new chemical entities; the identified compounds were then synthesized and biologically evaluated, identifying derivatives with very promising inhibitory activities in the micromolar range. Subsequent structure-guided replacement of the 2,3-dihydroxybenzamide by the N-(2,3-dihydroxyphenyl)sulfonamide moiety led to the identification of N-(2,3-dihydroxyphenyl)-4-biphenylsulfonamide (6), the most potent small molecule of the series (IC50 =0.53 ± 0.04 μM). The simple synthetic procedure and the possibility of enhancing the potency of this class of inhibitors through additional structural modifications pave the way for further development of new molecules with mPGES-1-inhibitory activity, with potential application as anti-inflammatory and anticancer agents.

Novel Ferroptosis Inhibitors with Improved Potency and ADME Properties.

Ferroptosis is a nonapoptotic, iron-catalyzed form of regulated necrosis that is critically dependent on glutathione peroxidase 4 (GPX4). It has been shown to contribute to liver and kidney ischemia reperfusion injury in mice. A chemical inhibitor discovered by high-throughput screening displayed inhibition of ferroptosis with nanomolar activity and was dubbed ferrostatin-1 (fer-1). Ferrostatins inhibit oxidative lipid damage, but suffer from inherent stability problems due to the presence of an ester moiety. This limits the application of these molecules in vivo, due to rapid hydrolysis of the ester into the inactive carboxylic acid. Previous studies highlighted the importance of the ethyl ester and suggested steric modifications of the ester for generating improved molecules. In this study, we report the synthesis of novel ferroptosis inhibitors containing amide and sulfonamide moieties with improved stability, single digit nanomolar antiferroptotic activity, and good ADME properties suitable for application in in vivo disease models.

Role of the sulfonamide moiety of Ru(II) half-sandwich complexes in the asymmetric transfer hydrogenation of 3,4-dihydroisoquinolines

The role of the sulfonamide moiety of Noyori-Ikariya [Ru(II)Cl(η6-p-cymene)(S,S)-(N-arylsulfonyl-DPEN)] (where DPEN = 1,2-diphenylethylene-1,2-diamine) half-sandwich complexes in the asymmetric transfer hydrogenation (ATH) of imines (1-methyl-3,4-dihydroisoquinoline and 6,7-dimethoxy-1-methyl-3,4-dihydroisoquinoline) was investigated. Nine complexes were synthesized and characterized, most of which have not been previously reported and a majority of the corresponding ligands (N-arylsulfonyl-DPEN) have not been described in imine ATH. The study demonstrates that the structure of the sulfonamide fragment strongly affects the catalytic activity. By monitoring the reaction kinetics, it was found that the reactivity of certain complexes was moderately enhanced and the enantioselectivity was affected as well, albeit to a lesser extent. No simple structure–activity pattern was found, suggesting that extensive screening experiments are necessary in order to obtain the optimal catalyst for a particular substrate. The study complements other previously reported works on structure–activity relationships concerning Ru(II)-catalyzed ATH by adding a new dimension of investigation.

Sulfonamides incorporating heteropolycyclic scaffolds show potent inhibitory action against carbonic anhydrase isoforms I, II, IX and XII

Three series of polycyclic compounds possessing either primary sulfonamide or carboxylic acid moieties as zinc-binding groups were investigated as inhibitors of four physiologically relevant CA isoforms, the cytosolic hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides reported here showed excellent inhibitory effects against isoforms hCA II, IX and XII, but no highly isoform-selective inhibition profiles. On the other hand, the carboxylates selectively inhibited hCA IX (KIs ranging between 40.8 and 92.7nM) without inhibiting significantly the other isoforms. Sulfonamides/carboxylates incorporating polycyclic ring systems such as benzothiopyranopyrimidine, pyridothiopyranopyrimidine or dihydrobenzothiopyrano[4,3-c]pyrazole may be considered as interesting candidates for exploring the design of isoform-selective CAIs with various pharmacologic applications.

Metal complexes of benzimidazole derived sulfonamide: Synthesis, molecular structures and antimicrobial activity

Benzimidazole and sulfonamide moieties are found in a number of pharmaceutically active molecules. By incorporating the sulfonamide pharmacophore into the benzimidazole scaffold, we prepared 2-(o-sulfamoylphenyl)benzimidazole 1 from saccharin as a precursor. Ligand 1 was coordinated to the divalent transition metals Mn(II) 2, Co(II) 3, Ni(II) 4, Cu(II) 5 and Zn(II) 6 to yield complexes of the general formula [ML2(H2O)n] (n=2 for 2 and n=0 for 3–6). All the compounds were characterized by elemental analysis, conductivity measurements, magnetic susceptibility, FT-IR and NMR spectroscopy. The molecular structures of 1, 3 and 6 were determined by X-ray diffraction analysis. In all metal complexes, 1 behaved as a bidentate chelating ligand through the sulfonamidate nitrogen and the endocyclic nitrogen of benzimidazole. The molecular structures of 3 and 6 showed tetrahedral geometry around the Co(II) and Zn(II) centers, respectively. The molar conductivity data revealed the metal complexes to be non-electrolytes. The benzenesulfonamide derivative and its metal complexes were evaluated for their potential antimicrobial activity against a range of bacterial and fungal strains. [Co(2-(o-sulfamoylphenyl)benzimidazolate)2] 3 was identified as the most active antibacterial compound, while none of the compounds exhibited antifungal activity.

Synthesis and Biological Activities Evaluation of New Spiro Heterocycles Containing 1,2,4-Triazole, Piperidine and Sulfonamide Moieties

Synthesis and Biological Activities Evaluation of New Spiro Heterocycles Containing 1,2,4-Triazole, Piperidine and Sulfonamide Moieties

Detection and quantification of ATP in human blood serum.

Two fluorometric sensors based on the tri-serine tri-lactone scaffold and thiourea or sulfonamide moieties serving as hydrogen bond donors allowing for anion binding are described. The sensor utilizing thiourea as a recognition moiety shows fluorescence enhancement while the sensor with sulfonamide shows quenching upon addition of phosphates. Sensor arrays composed of two sensors are able to discriminate structurally similar organic phosphates in the presence of interferents in human blood serum. The quantitative analysis of ATP in human blood serum shows high accuracy (the root mean square error of prediction, 1.65%) without requiring any sample pretreatment.

Novel 3-Pyridinecarbonitrile Incorporating Sulfonamide Moieties as Anti-Breast Cancer Agents

Novel 3-Pyridinecarbonitrile Incorporating Sulfonamide Moieties as Anti-Breast Cancer Agents

Synthesis and Antioxidant Evaluation of Some Novel Thiophene, Pyrazole, Chromene, Pyrazolotriazine Derivatives Bearing Sulfonamide Moiety

As a part of ongoing studies in developing new potent antioxidant agents, N‐[4‐(aminosulfonyl)phenyl]‐2‐cyanoacetamide (3) was utilized as key intermediate for the synthesis of some new thiophene, chromene, and pyrazolotriazine pyridine derivatives. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, 1H‐NMR, and mass spectral data. Representative compounds of the synthesized products were tested and evaluated as antioxidant. Compounds 7 and 30 are promising compounds.

Photoswitchable Arene Ruthenium Complexes Containing o-Sulfonamide Azobenzene Ligands

A series of arene ruthenium complexes containing o-sulfonamide azobenzene ligands were synthesized and found to exhibit uncommon coordination pattern with an exocyclic N═N bond. Upon irradiation, these complexes cleanly undergo E → Z photoisomerization followed by thermal Z → E isomerization (upon resting in the dark) whose rate is dependent on the solvent, the nature of the arene group, the sulfonamide moiety, and azobenzene substitution, as revealed by structure–property studies.

Molecular Modeling, Synthesis, and Anti-HIV Activity ofNovel Isoindolinedione Analogues as Potent Non-nucleoside Reverse Transcriptase Inhibitors.

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti-HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti-HIV activity and the molecules having sulfonamide linkages were the most potent HIV-RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood-brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti-HIV drugs. In vitro screening was performed using HIV-1 strain IIIB in MT-4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV-1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under invitro conditions. Some of these molecules have shown good anti-HIV activity at 3-4nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV-1. Novel isoindolinedione derivatives as probable NNRTIs have been synthesized and characterized. Some of these molecules have shown good anti-HIV activity at 3-4nm concentrations.

N-Alkylated arylsulfonamides of (aryloxy)ethyl piperidines: 5-HT7 receptor selectivity versus multireceptor profile

The N-alkylation of the sulfonamide moiety, in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines, may be considered as a strategy for the design of selective 5-HT7 receptor ligands or multifunctional agents to extend a polypharmacological approach to the treatment of complex diseases. The study allowed for the identification of 31 (1-methyl-N-{1-[2-(2-(t-butyl)phenoxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), a potent and selective 5-HT7 receptor antagonist and 33 (1-methyl-N-{1-[2-(biphenyl-2-yloxy)ethyl]piperidin-4-yl}-N-cyclopropylmethyl-1H-pyrazole-4-sulfonamide), as multimodal 5-HT/dopamine receptor ligand, as 5-HT2A/5-HT7/D2 receptor antagonists. Both selected compounds were evaluated in vivo in a forced swim test (FST) in mice and in a novel object recognition (NOR) task in rats, demonstrating distinct antidepressant-like and pro-cognitive properties (MED=1.25mg/kg and 1mg/kg, ip, respectively). These findings warrant further studies to explore the therapeutic potential of N-alkylated arylsulfonamides for the treatment of CNS disorders.

ChemInform Abstract: Gadolinium‐Catalyzed Regio‐ and Enantioselective Aminolysis of Aromatic trans‐2,3‐Epoxy Sulfonamides.

AbstractAn unprecedented aminolysis of epoxy sulfonamides with the sulfonamide moiety as directing group is developed.

N-Substituted N' -(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines – Antibacterial, Cytotoxic Activities and Some Structure-Activity Relationships

A series of N-substituted N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidine derivatives bearing sulfonamide moiety have been screened in vitro for antibacterial activity against isolates from patients with infections of oral cavity, respiratory tract and intestinal tract. The majority of compounds exhibited good antibacterial potency. 1-[4-Chloro-5-methyl-2-(4-trifluoromethylbenzylthio)benzenesulfonyl]-3-(3-sulfamoylphenyl)guanidine (13) showed very strong activity, with MIC ≤ 6.2 μg/ml against eleven bacteria strains belonged to Gram-positive anaerobes and aerobes. Furthermore, compound 13 exhibited promising activity toward highly resistant microorganisms such as methicillin-resistant Staphylococcus aureus and Enterococcusfaecalis. It was found that Parvimonas micra, Finegoldia magna, Peptostreptococcus anaerobius, Propionibacterium acnes showed the highest susceptibility toward the investigated guanidines.

Novel 1,4-naphthoquinone-based sulfonamides: Synthesis, QSAR, anticancer and antimalarial studies

A novel series of 1,4-naphthoquinones (33–44) tethered by open and closed chain sulfonamide moieties were designed, synthesized and evaluated for their cytotoxic and antimalarial activities. All quinone-sulfonamide derivatives displayed a broad spectrum of cytotoxic activities against all of the tested cancer cell lines including HuCCA-1, HepG2, A549 and MOLT-3. Most quinones (33–36 and 38–43) exerted higher anticancer activity against HepG2 cell than that of the etoposide. The open chain analogs 36 and 42 were shown to be the most potent compounds. Notably, the restricted sulfonamide analog 38 with 6,7-dimethoxy groups exhibited the most potent antimalarial activity (IC50 = 2.8 μM). Quantitative structure–activity relationships (QSAR) study was performed to reveal important chemical features governing the biological activities. Five constructed QSAR models provided acceptable predictive performance (Rcv 0.5647–0.9317 and RMSEcv 0.1231–0.2825). Four additional sets of structurally modified compounds were generated in silico (34a–34d, 36a–36k, 40a–40d and 42a–42k) in which their activities were predicted using the constructed QSAR models. A comprehensive discussion of the structure–activity relationships was made and a set of promising compounds (i.e., 33, 36, 38, 42, 36d, 36f, 42e, 42g and 42f) was suggested for further development as anticancer and antimalarial agents.

Diazonium salt-mediated synthesis of new amino, hydroxy, propargyl, and maleinimido-containing superparamagnetic Fe@C nanoparticles as platforms for linking bio-entities or organocatalytic moieties

New magnetic Fe@C nanoparticles in the size range of about 20–50 nm functionalized with amino, hydroxy, propargyl, or maleinimido groups were synthesized by reaction with aryl diazonium salts. Aryl diazonium salts wherein the functional groups are linked via a sulfonamide moiety turned out to be advantageous over those with direct linkage. The obtained Fe@C nanoparticles represent magnetic nanoplatforms for linking bio-entities and organocatalysts using amide formation, CuAAC, or thiol-ene click chemistry as exemplified by selected examples. The Fe@C nanoparticles obtained exhibit supramolecular behavior with high value of saturation magnetization rendering them attractive for practical applications in biomedicine and organocatalysis.

Identification and Characterization of an Irreversible Inhibitor of CDK2

SummaryIrreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.