Glutathione-triggered prodrugs: Design strategies, potential applications, and perspectives.

The burgeoning prodrug strategy offers a promising avenue toward improving the efficacy and specificity of cytotoxic drugs. Elevated intracellular levels of glutathione (GSH) have been regarded as a hallmark of tumor cells and characteristic feature of the tumor microenvironment. Considering the pivotal involvement of elevated GSH in the tumorigenic process, a diverse repertoire of GSH-triggered prodrugs has been developed for cancer therapy, facilitating the attenuation of deleterious side effects associated with conventional chemotherapeutic agents and/or the attainment of more efficacious therapeutic outcomes. These prodrug formulations encompass a spectrum of architectures, spanning from small molecules to polymer-based and organic-inorganic nanomaterial constructs. Although the GSH-triggered prodrugs have been gaining increasing interests, a comprehensive review of the advancements made in the field is still lacking. To fill the existing lacuna, this review undertakes a retrospective analysis of noteworthy research endeavors, based on a categorization of these molecules by their diverse recognition units (i.e., disulfides, diselenides, Michael acceptors, and sulfonamides/sulfonates). This review also focuses on explaining the distinct benefits of employing various chemical architecture strategies in the design of these prodrug agents. Furthermore, we highlight the potential for synergistic functionality by incorporating multiple-targeting conjugates, theranostic entities, and combinational treatment modalities, all of which rely on the GSH-triggering. Overall, an extensive overview of the emerging field is presented in this review, highlighting the obstacles and opportunities that lie ahead. Our overarching goal is to furnish methodological guidance for the development of more efficacious GSH-triggered prodrugs in the future. By assessing the pros and cons of current GSH-triggered prodrugs, we expect that this review will be a handful reference for prodrug design, and would provide a guidance for improving the properties of prodrugs and discovering novel trigger scaffolds for constructing GSH-triggered prodrugs.

Photocatalytic Synthesis and Functionalization of Sulfones, Sulfonamides and Sulfoximines.

Sulfur(VI)-based functional groups are popular scaffolds in a wide variety of research fields including synthetic and medicinal chemistry, as well as chemical biology. The growing interest in sulfur(VI)-containing molecules has motivated the scientific community to explore new methods to synthesize and modify them. Here, photocatalysis plays a key role granting access to new types of reactivity under mild reaction conditions. In this Perspective, we present a selection of works reported in the last six years focused on the photocatalytic assembly and reactivity of sulfones, sulfonamides, and sulfoximines. We addressed the key synthetic intermediates for each transformation, while discussing limitations and strength points of the protocols. Future directions of the field are finally presented.

Dynamics of small molecule-enzyme interactions: Novel benzenesulfonamides as multi-target agents endowed with inhibitory effects against some metabolic enzymes.

In contemporary medicinal chemistry, employing a singular small molecule to concurrently multi-target disparate molecular entities is emerging as a potent strategy in the ongoing battle against metabolic disease. In this study, we present the meticulous design, synthesis, and comprehensive biological evaluation of a novel series of 1,2,3-triazolylmethylthio-1,3,4-oxadiazolylbenzenesulfonamide derivatives (8a-m) as potential multi-target inhibitors against human carbonic anhydrase (EC.4.2.1.1, hCA I/II), α-glycosidase (EC.3.2.1.20, α-GLY), and α-amylase (EC.3.2.1.1, α-AMY). Each synthesized sulfonamide underwent rigorous assessment for inhibitory effects against four distinct enzymes, revealing varying degrees of hCA I/II, a-GLY, and a-AMY inhibition across the tested compounds. hCA I was notably susceptible to inhibition by all compounds, demonstrating remarkably low inhibition constants (KI) ranging from 42.20 ± 3.90 nM to 217.90 ± 11.81 nM compared to the reference standard AAZ (KI of 439.17 ± 9.30 nM). The evaluation against hCA II showed that most of the synthesized compounds exhibited potent inhibition effects with KI values spanning the nanomolar range 16.44 ± 1.53-70.82 ± 4.51 nM, while three specific compounds, namely 8a-b and 8d, showcased lower inhibitory potency than other derivatives that did not exceed that of the reference drug AAZ (with a KI of 98.28 ± 1.69 nM). Moreover, across the spectrum of synthesized compounds, potent inhibition profiles were observed against diabetes mellitus-associated α-GLY (KI values spanning from 0.54 ± 0.06 µM to 5.48 ± 0.50 µM), while significant inhibition effects were noted against α-AMY, with IC50 values ranging between 0.16 ± 0.04 µM and 7.81 ± 0.51 µM) compared to reference standard ACR (KI of 23.53 ± 2.72 µM and IC50 of 48.17 ± 2.34 µM, respectively). Subsequently, these inhibitors were evaluated for their DPPH· and ABTS+· radical scavenging activity. Moreover, molecular docking investigations were meticulously conducted within the active sites of hCA I/II, α-GLY, and α-AMY to provide comprehensive elucidation and rationale for the observed inhibitory outcomes.

Novel inhibitor N-cyclopropyl-4-((4-((4-(trifluoromethyl)phenyl)sulfonyl)piperazin-1-yl)methyl)benzamide attenuates RANKL-mediated osteoclast differentiation in vitro.

Both cyclopropyl amide and piperazine sulfonamide functional groups are known for their various biological properties used for drug development. Herein, we synthesized nine new derivatives with different substituent groups incorporating these moieties and screened them for their anti-osteoclast differentiation activity. After analyzing the structure-activity relationship (SAR), the inhibitory effect against osteoclastogenesis was determined to be dependent on the lipophilicity of the compound. Derivative 5b emerged as the most effective dose-dependent inhibitor after TRAP staining with an IC50 of 0.64 µM against RANKL-induced osteoclast cells. 5b was also able to suppress F-acting ring formation and bone resorption activity of osteoclasts in vitro. Finally, well-acknowledged gene and protein osteoclast-specific marker expression levels were decreased after 5b administration on primary murine osteoclast cells.

Trimethoprim-sulfamethoxazole dosing and outcomes of pulmonary nocardiosis.

BACKGROUND: Nocardia often causes pulmonary infection among those with chronic pulmonary disease or immunocompromising conditions. Trimethoprim-sulfamethoxazole (TMP-SMX) is recommended as first-line treatment, though little data exists regarding outcomes of different dosing regimens. METHODS: We performed a multicenter retrospective cohort study of adult patients with non-disseminated pulmonary nocardiosis initially treated with TMP-SMX monotherapy. Patients' initial TMP-SMX dosing was categorized as high- (> 10 mg/kg/day), intermediate- (5-10 mg/kg/day) or low-dose (< 5 mg/kg/day). Outcomes included one-year mortality, post-treatment recurrence, and dose adjustment or early discontinuation of TMP-SMX. SMX serum concentrations and their effect on management were also assessed. Inverse probability of treatment weighting was applied to Cox regression analyses. RESULTS: Ninety-one patients were included with 24 (26.4%), 37 (40.7%), and 30 (33.0%) treated with high-, intermediate-, and low-dose TMP-SMX, respectively. Patients who initially received low-dose (HR 0.07, 95% CI 0.01-0.68) and intermediate-dose TMP-SMX (HR 0.27, 95% CI 0.07-1.04) had lower risk of one-year mortality than the high-dose group. Risk of recurrence was similar between groups. Nineteen patients had peak SMX serum concentrations measured which resulted in 7 (36.8%) dose changes and was not associated with one-year mortality or recurrence. However, 66.7% of the high-dose group required TMP-SMX dose adjustment/discontinuation compared to 24.3% of the intermediate-dose and 26.7% of the low-dose groups (p = 0.001). CONCLUSIONS: Low- and intermediate-dose TMP-SMX for non-disseminated pulmonary nocardiosis were not associated with poor outcomes compared to high-dose therapy, which had a higher rate of dose adjustment/early discontinuation. Historically used high-dose TMP-SMX may not be necessary for management of isolated pulmonary nocardiosis.

Maize (Zea mays L.) Plants Alter the Fate and Accumulate Nonextractable Residues of Sulfamethoxazole in Farmland Soil.

The fate of sulfonamide antibiotics in farmlands is crucial for food and ecological safety, yet it remains unclear. We used [phenyl-U-14C]-labeled sulfamethoxazole (14C-SMX) to quantitatively investigate the fate of SMX in a soil-maize system for 60 days, based on a six-pool fate model. Formation of nonextractable residues (NERs) was the predominant fate for SMX in unplanted soil, accompanied by minor mineralization. Notably, maize plants significantly increased SMX dissipation (kinetic constant kd = 0.30 day-1 vs 0.17 day-1), while substantially reducing the NER formation (92% vs 58% of initially applied SMX) and accumulating SMX (40%, mostly bound to roots). Significant NERs (maximal 29-42%) were formed via physicochemical entrapment (determined using silylation), which could partially be released and taken up by maize plants. The NERs consisted of a considerable amount of SMX formed via entrapment (1-8%) and alkali-hydrolyzable covalent bonds (2-12%, possibly amide linkage). Six and 10 transformation products were quantified in soil extracts and NERs, respectively, including products of hydroxyl substitution, deamination, and N-acylation, among which N-lactylated SMX was found for the first time. Our findings reveal the composition and instability of SMX-derived NERs in the soil-plant system and underscore the need to study the long-term impacts of reversible NERs.

Emerging Perfluorobutane Sulfonamido Derivatives as a New Trend of Surfactants Used in the Semiconductor Industry.

The semiconductor industry has claimed that perfluorooctanesulfonate (PFOS), a persistent per- and polyfluoroalkyl substance (PFAS), has been eliminated from semiconductor production; however, information about the use of alternative compounds remains limited. This study aimed to develop a nontarget approach to discovering diverse PFAS substitutions used in semiconductor manufacturing. A distinct fragment-based approach has been established to identify the hydrophobic and hydrophilic features of acidic and neutral fluorosurfactants through fragments and neutral losses, including those outside the homologous series. Ten sewage samples from 5 semiconductor plants were analyzed with target and nontarget analysis. Among the 20 identified PFAS spanning 12 subclasses, 15 were reported in semiconductor sewage for the first time. The dominant identified PFAS compounds were C4 sulfonamido derivatives, including perfluorobutane sulfonamido ethanol (FBSE), perfluorobutane sulfonamide (FBSA), and perfluorobutane sulfonamido diethanol (FBSEE diol), with maximum concentrations of 482 µg/L, 141 µg/L, and 83.5 µg/L in sewage, respectively. Subsequently, three ultrashort chain perfluoroalkyl acids (PFAAs) were identified in all samples, ranging from 0.004 to 19.9 µg/L. Three effluent samples from the associated industrial wastewater treatment plants (WWTPs) were further analyzed. This finding, that the C4 sulfonamido acetic acid series constitutes a significant portion (65%-82%) of effluents from WWTP3 and WWTP4, emphasizes the conversion of fluorinated alcohols to fluorinated acids during aerobic treatment. The identification of the intermediate metabolites of FBSEE diol, further supported by our laboratory batch studies, prompts the proposal of a novel metabolic pathway for FBSEE diol. The total amount of perfluorobutane sulfonamido derivatives reached 1934 µg/L (90%), while that of PFAAs, which have typically received attention, was only 205 µg/L (10%). This suggests that perfluorobutane sulfonamido derivatives are emerging as a new trend in fluorosurfactants used in the semiconductor industry, serving as PFAS precursors and contributing to the release of their metabolites into the environment.

Stability and Biotransformation of 6:2 Fluorotelomer Sulfonic Acid, Sulfonamide Amine Oxide, and Sulfonamide Alkylbetaine in Aerobic Sludge.

The 6:2 fluorotelomer sulfonamide (6:2 FTSAm)-based compounds signify a prominent group of per- and polyfluoroalkyl substances (PFAS) widely used in contemporary aqueous film-forming foam (AFFF) formulations. Despite their widespread presence, the biotransformation behavior of these compounds in wastewater treatment plants remains uncertain. This study investigated the biotransformation of 6:2 FTSAm-based amine oxide (6:2 FTNO), alkylbetaine (6:2 FTAB), and 6:2 fluorotelomer sulfonic acid (6:2 FTSA) in aerobic sludge over a 100-day incubation period. The biotransformation of 6:2 fluorotelomer sulfonamide alkylamine (6:2 FTAA), a primary intermediate product of 6:2 FTNO, was indirectly assessed. Their stability was ranked based on the estimated half-lives (t1/2): 6:2 FTAB (no obvious products were detected) ≫ 6:2 FTSA (t1/2 ≈28.8 days) > 6:2 FTAA (t1/2 ≈11.5 days) > 6:2 FTNO (t1/2 ≈1.2 days). Seven transformation products of 6:2 FTSA and 15 products of 6:2 FTNO were identified through nontarget and suspect screening using high-resolution mass spectrometry. The transformation pathways of 6:2 FTNO and 6:2 FTSA in aerobic sludge were proposed. Interestingly, 6:2 FTSAm was hardly hydrolyzed to 6:2 FTSA and further biotransformed to perfluoroalkyl carboxylic acids (PFCAs). Furthermore, the novel pathways for the generation of perfluoroheptanoic acid (PFHpA) from 6:2 FTSA were revealed.

Sulfonamide allergy label and the risk of opportunistic infections in solid organ transplant recipients - A retrospective matched cohort study.

BACKGROUND: While a penicillin allergy label has been linked to various negative clinical outcomes, limited studies have specifically characterized the implication of sulfonamide allergy labels (SAL) on clinical outcomes. We examined the impact of SAL on clinical outcomes of solid organ transplant recipients. METHODS: In this retrospective matched cohort study, we utilized the TriNetX US collaborative Network, a multicenter de-identified US database, and identified solid organ transplant recipients with and without SAL. The 1-year probability of developing Pneumocystis jirovecii pneumonia (PJP), toxoplasmosis, and nocardiosis was estimated and contrasted between the two study groups. The hazard ratio (HR) and the 95% confidence interval (CI) quantified the strength and direction of the association between SAL and these outcomes. RESULTS: When comparing 1571 solid organ transplant recipients with SAL to an equal number of matched controls, patients with SAL had a higher probability of developing nocardiosis (HR 3.85; 95% CI, 1.44-10.30; p = .004; corrected p = .04), and toxoplasmosis (HR, 1.87; 95% CI, 1.10-3.17; p = .019; corrected p = .19), but no difference in the risk of developing PJP (HR, 1.64; 95% CI, 0.68-3.95; p = .27). There was no mortality difference (HR, 1.31; 95% CI, 0.99-1.75; p = .061; corrected p = .6). SAL influenced antibiotic prescription with overutilization of dapsone, atovaquone, and pentamidine and underutilization of trimethoprim and sulfamethoxazole. CONCLUSION: SAL is associated with an increased risk of opportunistic infections following solid organ transplantation. Measures to evaluate and de-label sulfonamide allergy prior to transplantation or desensitizing shortly after transplantation are advisable.

Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors.

A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR, 1H-NMR, 13C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms.

Anticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety.

In the present work, a new series of ethyl pyrazole-containing compounds with side sulphonamide moiety was designed and synthesized. The new derivatives were divided into four groups based on the linker between the sulphonamide and pyridine ring attached to position 4 of the pyrazole ring and the substitution on the phenyl ring at position 3 of the same ring. The linker could be ethyl or propyl linkers. The phenyl ring is substituted with a methoxy group or hydroxyl group at position 3. The aim compounds were tested for their JNK1, JNK2, JNK3, and BRAF(V600E) activities. Compounds 23b, 23c, and 23d showed the highest activity with nanomolar IC50s. The most potent compound over JNK1 was 23d with an IC502 nM. While compound 23c was the most potent over JNK2 with an IC5057 nM. Finally, compound 23b was the most potent over JNK2 and BRAF(V600E) with IC50s of125 nM and 98 nM, respectively. After obtaining kinase inhibitory activity, the compounds were submitted to NCI to test their activity over different cell lines. Compound 23b showed the highest activity over most tested cell lines. In the second part of the present study, the final target compounds were tested for their anti-inflammatory effect. The anti-inflammatory effect of the new final compounds was performed by measuring their ability to inhibit inducible nitric oxide release and prostaglandin E2 production inhibition. Compound 23c showed the highest activity regarding nitric oxide release with IC50 0.63 µM, while compound 21d had the highest activity regarding prostaglandin E2 production with IC50 0.52 µM. The effect of the most potent compounds was tested by western blot against iNOS, COX-1, and COX-2.

Novel quinazoline sulfonamide-based scaffolds modulate methicillin-resistant Staphylococcus aureus (MRSA) pneumonia in immunodeficient irradiated model: Regulatory role of TGF-ß.

A library of new quinazoline pharmacophores bearing benzenesulfonamide moiety was designed and synthesized. Compounds 3a-n were screened for their in vitro antimicrobial activity against eight multidrug-resistant clinical isolates. Compounds 3d and 3n exhibited prominent antibacterial activity, specifically against MRSA. After exhibiting relative in vitro and in vivo safety, compound 3n was selected to assess its anti-inflammatory activity displaying promising COX-2 inhibitory activity compared to Ibuprofen. In vivo experimental MRSA pneumonia model was conducted on immunodeficient (irradiated) mice to reveal the antimicrobial and anti-inflammatory responses of compound 3n compared to azithromycin (AZ). Treatment with compound 3n (10 and 20 mg/kg) as well as AZ resulted in a significant decrease in bacterial counts in lung tissues, suppression of serum C-reactive protein (CRP), lung interleukin-6 (IL-6), myeloperoxidase activity (MPO) and transforming growth factor-ß (TGF-ß). Compound 3n showed a non-significant deviation of lung TGF-ß1 from normal values which in turn controlled the lung inflammatory status and impacted the histopathological results. Molecular docking of 3n showed promising interactions inside the active sites of TGF-ß and COX-2. Our findings present a new dual-target quinazoline benzenesulfonamide derivative 3n, which possesses significant potential for treating MRSA-induced pneumonia in an immunocompromised state.

Design and synthesis of sulfonamide phenothiazine derivatives as novel ferroptosis inhibitors and their therapeutic effects in spinal cord injury.

Ferroptosis is a novel style of cell death, and studies have shown that ferroptosis is strongly associated with spinal cord injury (SCI). A large number of ferroptosis inhibitors have been reported, but so far no ferroptosis inhibitor has been used clinically. Therefore there is an urgent need to discover a better inhibitor of ferroptosis. In this study, 24 novel sulfonamide phenothiazine ferroptosis inhibitors were designed and synthesized, followed by structure-activity relationship studies on these compounds. Among them, compound 23b exhibited the best activity in Erastin-induced PC12 cells (EC50 = 0.001 µM) and demonstrated a low hERG inhibition activity (IC50 > 30 µM). Additionally, compound 23b was identified as a ROS scavenger and showed promising therapeutic effects in an SD rat model of SCI. Importantly, 23b did not display significant toxicity in both in vivo and in vitro experiments and show good pharmacokinetic properties. These findings suggest that compound 23b, a novel ferroptosis inhibitor, holds potential as a therapeutic agent for spinal cord injury and warrants further investigation.

Discovery of 2,4-diarylaminopyrimidine derivatives bearing sulfonamide moiety as novel FAK inhibitors.

Two series of 2,4-diarylaminopyrimidine derivatives containing sulfonamide moiety were designed and synthesized for screening as inhibitors of focal adhesion kinase (FAK). Most compounds significantly inhibited the enzymatic activities of FAK, and the best compound was 7b (IC50 = 0.27 nM). A majority of aminoethyl sulfonamide derivatives could effectively inhibit the proliferation of human cancer cell lines (HCT116, A549, MDA-MB-231 and Hela) expressing high levels of FAK. Particularly, compounds 7b, 7c, and 7o exhibited more significant efficacy against all of four cancer cell lines within concentrations of 1.5 µM. Furthermore, these three compounds displayed higher selectivity of cancer cells over normal cells (SI value > 14), compared to the positive control TAE226 (SI value = 1.63). Interestingly, introduction of dithiocarbamate moiety to the aminoethyl sulfonamide derivatives can indeed improve the antiproliferative activities against A549 cells. Especially, compound 8d demonstrated most significant cytotoxicity activity against A549 cells with an IC50 value of 0.08 µM, which is 20-fold superior to parent compound 7k. Additionally, compound 7b, which display the best anti-FAK potency, can inhibit the clone formation and migration of HCT-116 cells, and cause cell cycle arrest at G2/M phase, inducing apoptosis by promoting ROS production. Overall, these results suggest that 7b is a valuable FAK inhibitor that deserves further optimization to improve its druggability.

Discovery of novel biphenyl-sulfonamide analogues as NLRP3 inflammasome inhibitors.

The aberrant activation of NLRP3 inflammasome has been observed in various human diseases. Targeting the NLRP3 protein with small molecule inhibitors shows immense potential as an effective strategy for disease intervention. Herein, a series of novel biphenyl-sulfonamide NLRP3 inflammasome inhibitors were designed and synthesized. The representative compound H28 was identified as potent and specific NLRP3 inflammasome inhibitor with IC50 values of 0.57 µM. Preliminary mechanistic studies have revealed that compound H28 exhibits direct binding to the NLRP3 protein (KD: 1.15 µM), effectively inhibiting the assembly and activation of the NLRP3 inflammasome. The results in a mouse acute peritonitis model revealed that H28 effectively inhibit the NLRP3 inflammasome pathway, demonstrating their anti-inflammatory properties. Our findings strongly support the further development of H28 as potential lead compound for treating NLRP3-related diseases.

Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies.

In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (Ki) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; Ki: 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50: 53.32 ± 7.74 µM for HT-29; IC50: 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.

Selective degradation of sulfonamide antibiotics by peracetic acid alone: Direct oxidation and radical mechanisms.

In this study, a peracetic acid (PAA) alone process was systematically demonstrated to give a high efficiency in the selective degradation of sulfonamide antibiotics (SAs). The employment of scavengers and probe compounds in this process demonstrates the predominant role of PAA in direct oxidation, and the limited role of carbon-centered radicals (R-O•) in the degradation of representative SA, sulfamethazine (SMT). The process also exhibits high tolerance towards solution pH and competing anions in wastewater, indicating its applicability in enhancing the biodegradation of SAs in wastewater. Furthermore, the relationships between the observed rate constants (kobs) and the molecule descriptors for ten SA compounds are demonstrated through the assessment of structure-activity relationships, calculated from density functional theory (DFT). This study gives new insights into the selectivity, performance and mechanism of PAA direct-oxidation in SA degradation.

Electrochemical detection of sulfanilamide using tannic acid exfoliated MoS2 nanosheets combined with reduced graphene oxide/graphite.

Sulfonamides are a family of synthetic drugs with a broad-spectrum of antimicrobial activity. Like other antimicrobials, they have been found in aquatic environments, making their detection important. Herein, an electrochemical sensor was designed using tannic acid exfoliated few-layered MoS2 sheets, which were combined with a mixture of reduced graphene oxide (rGO) and graphite flakes (G). The rGO/G was formed using electrodeposition, by cycling from -0.5 to -1.5 V in an acidified sulfate solution with well dispersed GO and G. The exfoliated MoS2 sheets were drop cast over the wrinkled rGO/G surface to form the final sensor, GCE/rGO/G/ta-MoS2. The mixture of rGO/G was superior to pure rGO in formulating the sensor. The fabricated sensor exhibited an extended linear range from 0.1 to 566 µM, with a LOD of 86 nM, with good selectivity in the presence of various salts found in water and structurally related drugs from the sulfonamide family. The sensor showed very good reproducibility with the RSD at 0.48 %, repeatability and acceptable long term stability over a 10-day period. Good recovery from both tap and river water was achieved, with recovery ranging from 90.4 to 98.9 % for tap water and from 83.5 to 94.4 % for real river water samples.

Sulfonamide derivatives with benzothiazole scaffold: Synthesis and carbonic anhydrase I-II inhibition properties.

The secondary sulfonamide derivatives containing benzothiazole scaffold (1-10) were synthesized to determine their inhibition properties on two physiologically essential human carbonic anhydrases isoforms (hCAs, EC, 4.2.1.1), hCA I, and hCA II. The inhibitory effects of the compounds on hCA I and hCA II isoenzymes were investigated by comparing their IC50 and Ki values. The Ki values of compounds (1-10) against hCA I and hCA II are in the range of 0.052 ± 0.022-0.971 ± 0.280 and 0.025 ± 0.010-0.682 ± 0.335, respectively. Some of these inhibited the enzyme more effectively than the standard drug, acetazolamide. In particular, compounds 5 and 4 were found to be most effective on hCA I and hCA II.

Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors.

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1H-NMR, 13C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.063-3.368 µM for hCA I and 0.007-4.235 µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50 ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.