Novel pentafluorosulfanyl-containing triclocarban analogs selectively kill Gram-positive bacteria.

Novel antimicrobial agents are needed to combat antimicrobial resistance. This study tested novel pentafluorosulfanyl-containing triclocarban analogs for their potential antibacterial efficacy. Standard procedures were used to produce pentafluorosulfanyl-containing triclocarban analogs. Twenty new compounds were tested against seven Gram-positive and Gram-negative indicator strains as well as 10 clinical isolates for their antibacterial and antibiofilm activity. Mechanistic investigations focused on damage to cell membrane, oxidizing reduced thiols, iron-sulfur clusters, and oxidative stress to explain the compounds' activity. Safety profiles were assessed using cytotoxicity experiments in eukaryotic cell lines. Following screening, selected components had significantly better antibacterial and antibiofilm activity against Gram-positive bacteria in lower concentrations in comparison to ciprofloxacin and gentamycin. For instance, one compound had a minimum inhibitory concentration of <0.0003 mM, but ciprofloxacin had 0.08 mM. Mechanistic studies show that these novel compounds do not affect reduced thiol content, iron-sulfur clusters, or hydrogen peroxide pathways. Their impact comes from Gram-positive bacterial cell membrane damage. Tests on cell culture toxicity and host component safety showed promise. Novel diarylurea compounds show promise as Gram-positive antimicrobials. These compounds offer prospects for study and optimization. IMPORTANCE: The rise of antibiotic resistance among bacterial pathogens poses a significant threat to global health, underscoring the urgent need for novel antimicrobial agents. This study presents research on a promising class of novel compounds with potent antibacterial properties against Gram-positive bacteria, notably Staphylococcus aureus and MRSA. What sets these novel analogs apart is their superior efficacy at substantially lower concentrations compared with commonly used antibiotics like ciprofloxacin and gentamycin. Importantly, these compounds act by disrupting the bacterial cell membrane, offering a unique mechanism that could potentially circumvent existing resistance mechanisms. Preliminary safety assessments also highlight their potential for therapeutic use. This study not only opens new avenues for combating antibiotic-resistant infections but also underscores the importance of innovative chemical approaches in addressing the global antimicrobial resistance crisis.

Triclosan and triclocarban weaken the olfactory capacity of goldfish by constraining odorant recognition, disrupting olfactory signal transduction, and disturbing olfactory information processing.

Recently, increased production and consumption of disinfectants such as triclosan (TCS) and triclocarban (TCC) have led to massive pollution of the environment, which draws global concern over the potential risk to aquatic organisms. However, the olfactory toxicity of disinfectants in fish remains elusive to date. In the present study, the impact of TCS and TCC on the olfactory capacity of goldfish was assessed by neurophysiological and behavioral approaches. As shown by the reduced distribution shifts toward amino acid stimuli and hampered electro-olfactogram responses, our results demonstrated that TCS/TCC treatment would cause deterioration of the olfactory ability of goldfish. Our further analysis found that TCS/TCC exposure suppressed the expression of olfactory G protein-coupled receptors in the olfactory epithelium, restricted the transformation of odorant stimulation into electrical responses by disturbing the cAMP signaling pathway and ion transportation, and induced apoptosis and inflammation in the olfactory bulb. In conclusion, our results demonstrated that an environmentally realistic level of TCS/TCC would weaken the olfactory capacity of goldfish by constraining odorant recognition efficiency, disrupting olfactory signal generation and transduction, and disturbing olfactory information processing.

The Different Facets of Triclocarban: A Review.

In the late 1930s and early 1940s, it was discovered that the substitution on aromatic rings of hydrogen atoms with chlorine yielded a novel chemistry of antimicrobials. However, within a few years, many of these compounds and formulations showed adverse effects, including human toxicity, ecotoxicity, and unwanted environmental persistence and bioaccumulation, quickly leading to regulatory bans and phase-outs. Among these, the triclocarban, a polychlorinated aromatic antimicrobial agent, was employed as a major ingredient of toys, clothing, food packaging materials, food industry floors, medical supplies, and especially of personal care products, such as soaps, toothpaste, and shampoo. Triclocarban has been widely used for over 50 years, but only recently some concerns were raised about its endocrine disruptive properties. In September 2016, the U.S. Food and Drug Administration banned its use in over-the-counter hand and body washes because of its toxicity. The withdrawal of triclocarban has prompted the efforts to search for new antimicrobial compounds and several analogues of triclocarban have also been studied. In this review, an examination of different facets of triclocarban and its analogues will be analyzed.

A Review on the Fate of Legacy and Alternative Antimicrobials and Their Metabolites during Wastewater and Sludge Treatment.

Antimicrobial compounds are used in a broad range of personal care, consumer and healthcare products and are frequently encountered in modern life. The use of these compounds is being reexamined as their safety, effectiveness and necessity are increasingly being questioned by regulators and consumers alike. Wastewater often contains significant amounts of these chemicals, much of which ends up being released into the environment as existing wastewater and sludge treatment processes are simply not designed to treat many of these contaminants. Furthermore, many biotic and abiotic processes during wastewater treatment can generate significant quantities of potentially toxic and persistent antimicrobial metabolites and byproducts, many of which may be even more concerning than their parent antimicrobials. This review article explores the occurrence and fate of two of the most common legacy antimicrobials, triclosan and triclocarban, their metabolites/byproducts during wastewater and sludge treatment and their potential impacts on the environment. This article also explores the fate and transformation of emerging alternative antimicrobials and addresses some of the growing concerns regarding these compounds. This is becoming increasingly important as consumers and regulators alike shift away from legacy antimicrobials to alternative chemicals which may have similar environmental and human health concerns.

Fate, risk and removal of triclocarban: A critical review.

The halogenated antimicrobial triclocarban (TCC) has large production and consumption over last decades. Its extensive utilization in personal care products and insufficient treatment in conventional wastewater treatment plants (WWTPs) has led to its listing as one of emerging organic contaminants (EOCs). Due to the hydrophobicity and chemical stability of TCC, it has been omnipresent detected in terrestrial and aquatic environments, and its prolonged exposure has thrown potential pernicious threat to ecosystem and human health. Considering its recalcitrance, especially under anoxic conditions, both biological and non-biological methods have been exploited for its removal. The efficiency of advanced oxidation processes was optimistic, but complete removal can rarely be realized through a single method. The biodegradation of TCC either with microbial community or pure culture is feasible but efficient bacterial degraders and the molecular mechanism of degradation need to be further explored. This review provides comprehensive information of the occurrence, potential ecological and health effects, and biological and non-biological removal of TCC, and outlines future prospects for the risk evaluation and enhanced bioremediation of TCC in various environments.

Genotoxicity assessment of triclocarban by comet and micronucleus assays and Ames test.

The widespread usage and ubiquitous distribution of triclocarban (3,4,4'-trichlorocarbanilide, TCC) have raised public concerns about its health effects. At present, there is little information about the genotoxicity of TCC. In this study, we used a battery of genotoxicity testing methods including salmonella reverse mutation test (Ames test), comet assay and micronucleus assay to detect the effects of TCC on gene mutation, DNA breakage, and chromosome damage. The results of Ames test showed that TCC at 0.1-1000 µg/plate did not significantly increase the number of revertant colonies in the four standard Salmonella typhimurium strains, i.e., TA97, TA98, TA100, and TA102, when compared to the vehicle control. The results from comet assay demonstrated that exposure to 5, 10, or 15 µM TCC for 24 h did not significantly increase the percentage of comet cells, tail length (TL), DNA in tail (T DNA%), or olive tail moment (OTM) in keratinocyte HaCaT and hepatic L02 cells. Moreover, TCC did not markedly enhance the frequency of micronucleated cells or micronuclei in HaCaT and L02 cells in the micronucleus assay. Taken together, the results indicated that TCC did not exhibit any genotoxic effects. Our study provides additional information for the safety profile of TCC.

The Effect of Substitution Pattern on Binding Ability in Regioisomeric Ion Pair Receptors Based on an Aminobenzoic Platform.

A series of ditopic ion pair receptors equipped with 4-nitrophenylurea and 1-aza-18-crown-6-ether linked by ortho-(1), meta-(2), and para-(3) substituted benzoic acid were readily synthesized in three steps from commercially available materials. The binding properties of these regioisomeric receptors were determined using UV-vis and 1H NMR spectroscopy in MeCN and in the solid state by single-crystal X-ray diffraction crystallography. The solution studies revealed that, apart from carboxylates, all the anions tested formed stronger complexes in the presence of sodium cations. Receptors 2 and 3 were found to interact with ion pairs with remarkably higher affinity than ortho-substituted 1. 1H NMR titration experiments showed that both urea NH protons interacted with anions with comparable strength in the case of receptors 2 and 3, but only one of the NHs was effective in anion binding in the case of receptor 1. X-ray analysis of the crystal structure of receptor 1 and 1·NaPF6 complex showed that binding was hampered due to the formation of an intramolecular hydrogen bond. Analysis of the crystal structures of 2·NaBr and 3·NaBr complexes revealed that proper mutual orientation of binding domains was responsible for the improved binding of the sodium salts.

Detection of p-Nitroaniline Released from Degradation of 4,4'-Dinitrocarbanilide in Chicken Breast during Thermal Processing.

The diphenylurea 4,4'-dinitrocarbanilide (DNC) is the residue of concern left in edible tissues of broilers fed diets containing the anticoccidial nicarbazin. When chicken meat is submitted to thermal processing, p-nitroaniline (p-NA) is expected from DNC degradation. This work aimed at evaluating whether thermal processing of DNC-containing chicken meat induces p-NA appearance. First, a hydrolysis assay was performed in aqueous solutions at 100 °C in different pH, confirming that DNC cleavage yields p-NA. Then a novel LC-MS/MS method was used to detect traces of this aromatic amine in DNC-containing chicken breast fillets subjected to cooking methods. Our evidence showed p-NA occurrence in such chicken meat samples, which corroborated results from hydrolysis assay. The p-NA appearance in fillets was rather discrete during boiling treatment, but its concentration became pronounced over time for grilling, frying, and roasting, achieving respectively 326.3, 640.0, and 456.9 µg/kg. As far as we are concerned, no other research identified degradation products from DNC residue in heat-processed chicken fillets. Therefore, this study leads to additional approaches to assess impacts on food safety.

Investigation of the molecular interactions of triclocarban with human serum albumin using multispectroscopies and molecular modeling.

Triclocarban (TCC), as a broad spectrum antibacterial agent widely used in personal care products, has recently been recognized as environmental pollutant with the potential of adversely affecting wildlife and human health. However, the behavior of TCC in blood circulatory system and the potential toxicity of TCC at the molecular level have been poorly investigated. In this study, the effect of TCC on human serum albumin (HSA) and the binding mechanism of TCC to HSA were examined using spectroscopic techniques and molecular modeling methods. The fluorescence results suggested that the fluorescence of HSA was quenched by TCC through a static quenching mechanism and nonradiation energy transfer, and TCC was bound to HSA with moderately strong binding affinity via hydrophobic interaction based on the analysis of the thermodynamic parameters. The site marker competitive experiments revealed that TCC bound into subdomain IIA (site I) of HSA. In addition, the results obtained from the circular dichroism, Fourier transform infrared (FT-IR), 8-anilino-1-naphthalenesulfonic acid fluorescence, synchronous fluorescence, three-dimensional fluorescence spectra and dynamic light scattering suggested the change in the microenvironment and conformation of HSA during the binding reaction. Finally, the best binding mode of TCC and specific interaction of TCC with amino acid residues were determined using molecular docking and molecular dynamics simulations. In a word, the present studies can provide a way to help us well understand the transport, distribution and toxicity effect of TCC when it diffused in the human body. Communicated by Ramaswamy H. Sarma.

Structure and specificity of several triclocarban-binding single domain camelid antibody fragments.

The variable VHH domains of camelid single chain antibodies have been useful in numerous biotechnology applications due to their simplicity, biophysical properties, and abilities to bind to their cognate antigens with high affinities and specificity. Their interactions with proteins have been well-studied, but considerably less work has been done to characterize their ability to bind haptens. A high-resolution structural study of three nanobodies (T4, T9, and T10) which have been shown to bind triclocarban (TCC, 3-(4-chlorophenyl)-1-(3,4-dichlorophenyl)urea) with near-nanomolar affinity shows that binding occurs in a tunnel largely formed by CDR1 rather than a surface or lateral binding mode seen in other nanobody-hapten interactions. Additional significant interactions are formed with a non-hypervariable loop, sometimes dubbed "CDR4". A comparison of apo and holo forms of T9 and T10 shows that the binding site undergoes little conformational change upon binding of TCC. Structures of three nanobody-TCC complexes demonstrated there was not a standard binding mode. T4 and T9 have a high degree of sequence identity and bind the hapten in a nearly identical manner, while the more divergent T10 binds TCC in a slightly displaced orientation with the urea moiety rotated approximately 180° along the long axis of the molecule. In addition to methotrexate, this is the second report of haptens binding in a tunnel formed by CDR1, suggesting that compounds with similar hydrophobicity and shape could be recognized by nanobodies in analogous fashion. Structure-guided mutations failed to improve binding affinity for T4 and T9 underscoring the high degree of natural optimization.

Impact of a Single Hydrogen Substitution by Fluorine on the Molecular Interaction and Miscibility between Sorafenib and Polymers.

We aim to understand the potential impact of a modest chemical modification of a drug molecule on the downstream design of its amorphous solid dispersion (ASD) formulation. To this end, we used sorafenib (SOR) and its fluorinated form, regorafenib (REG), as model drugs, to assess the impact of a single hydrogen substitution by fluorine on the molecular interaction and miscibility between drug and PVP or PVP-VA, two commonly used polymers for ASDs. In this study, we observed that the Tg values of PVP or PVP-VA based ASDs of SOR deviated positively from the Gordon-Taylor prediction, which assumes ideal mixing, yet the Tg of REG ASDs deviated negatively from or matched well with the ideal mixing model, suggesting much stronger drug-polymer interactions in SOR ASDs compared with the REG ASDs. Using solution NMR and computational methods, we proved that a six-member-ring formed between the carbonyl groups on the polymers and the uramido hydrogen of SOR or REG, through intermolecular hydrogen bonding. However, steric hindrance resulting from fluorination in REG caused weaker interaction between REG-polymer than SOR-polymer. To further confirm this mechanism, we investigated the molecular interactions of other two uramido-containing model compounds, triclocarban (TCC) and gliclazide (GCZ), with PVP. We found that TCC but not GCZ formed a hexatomic ring with PVP. We concluded that PVP based polymers can easily interact with N, N'-disubstituted urea compounds with a trans-trans structure in the form of hexatomic rings, and the interaction strength of the hexatomic ring largely depended on the chemistry of drug molecules. This study illustrated that even a slight chemical modification on drug molecules could result in substantial difference in drug-polymer interactions, thus significantly impacting polymer selection and pharmaceutical performance of their ASD formulations.

Pentafluorosulfanyl-containing Triclocarban Analogs with Potent Antimicrobial Activity.

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N'-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.

Degradation of 4,4'-Dinitrocarbanilide in Chicken Breast by Thermal Processing.

Nicarbazin is one of the major anticoccidials used in broiler feeds. The compound 4,4'-dinitrocarbanilide (DNC) is the marker residue of concern left from nicarbazin in chicken meat. The effect of thermal processing on DNC content accumulated in chicken breast was assessed, and samples were analyzed by liquid chromatography-tandem mass spectrometry. Five conventional cooking methods were evaluated: boiling, grilling, microwaving, frying, and roasting. To ensure DNC in meat, broilers were fed nicarbazin without withdrawal period. All heating methods surpassed the 70 °C end point core temperature in chicken breast. Maximum DNC degradation was reached at 10 min for boiling, at 30 min for grilling, and at 2 min for microwaving, and no further reduction was observed for longer thermal processing time. Boiling was more efficient in reducing DNC (69%). Grilling, microwaving, and frying achieved on average 55% of degradation. The outcomes reported herein may be considered in decision-making regarding further review of maximum residue limits.

Environmental risk assessment of triclosan and triclocarban from personal care products in South Africa.

Trends in the widespread use of personal care products (PCPs) containing triclosan (TCS) and triclocarban (TCC) have led to continuous emissions of these chemicals into the environment. Consequently, both chemicals are ubiquitously present at high concentrations in the aquatic systems based on widely reported measured environmental concentration (MECs) data in different environmental systems (e.g. freshwater) worldwide, especially in developed countries. In developing countries, however, lack of MECs data is a major issue, and therefore, inhibits effective risk assessment of these chemicals. Herein, TCS and TCC releases from personal care products (PCPs) were quantified, using a modelling approach to determine predicted environmental concentrations (PECs) in wastewater, freshwater, and soils, and likely risk(s) were estimated by calculating risk quotient (RQs). TCS and TCC in freshwater had RQs >1 based on estimated PECs with wide variations (≈2-232) as performed across the three dilutions factors (1, 3, and 10) considered in this study; an indicator of their likely adverse effect on freshwater organisms. In untreated and treated wastewater, TCS RQs values for bacteria were >1, but <1 for TCC, implying the former may adversely affect the functioning of wastewater treatment plants (WWTPs), and with no plausible impacts from the latter. In terrestrial systems, RQ results for individual chemicals revealed no or limited risks; therefore, additional investigations are required on their toxicity, as effects data was very limited and characterised by wide variations. Future national monitoring programs in developing countries should consider including TCS and TCC as the results suggest both chemicals are of concern to freshwater, and TCS in WWTPs. Potential risks of their metabolites remain unquantified to date.

Benzo[d]thiazole-2-carbanilides as new anti-TB chemotypes: Design, synthesis, biological evaluation, and structure-activity relationship.

Tuberculosis is the second leading cause of deaths worldwide. The inadequacy of existing drugs to treat TB due to developed resistance and TB-HIV synergism urges for new anti-TB drugs. Seventy-two benzo[d]thiazole-2-carbanilides have been synthesized through CDI-mediated direct coupling of benzo[d]thiazole-2-carboxylic acids with aromatic amines using a three step methodology which includes a green protocol for synthesis of ethyl benzo[d]thiazole-2-carboxylates, precursor of the desired carboxylic acids. The compounds were evaluated in vitro for anti-tubercular activity against M. tuberculosis H37Rv (ATCC27294 strain). Thirty-two compounds exhibiting MIC values in the range of 0.78-6.25 µg/mL (1.9-23 µM) were subjected to cell viability test against RAW 264.7 cell lines and thirty compounds were found to be non-toxic (<50% inhibition). The most active compounds with MIC of 0.78 µg/mL (e.g., 4i, 4n, 4s, 4w, 6f, 6h, 6u, 7e, 7h, 7p, 7r and 7w) exhibit therapeutic index of 64. The structure activity relationship of the N-arylbenzo[d]thiazole-2-carboxamides has been established for anti-mycobacterial activity. Molecular docking suggests that the compounds 7w, 4i and 4n bind to the catalytic site of the enzyme ATP Phosphoribosyltransferase (HisG) and might be attributed to their anti-TB potential. These can serve as a new starting point for the development of anti-TB agents with therapeutic potential.

Binding studies of triclocarban with bovine serum albumin: Insights from multi-spectroscopy and molecular modeling methods.

The antimicrobial triclocarban (TCC) is frequently found in various personal care products (PCPs), and recent studies have demonstrated that it shows a high unintended biological activity on humans and wildlife. To evaluate the toxicity of TCC at the protein level, the effect of TCC on bovine serum albumin (BSA) has been investigated using various spectroscopic methods in combination with molecular modeling. Analysis of fluorescence quenching data of BSA revealed the formation of a ground state BSA-TCC complex with a binding constant of 2.58 × 104 M-1 at 298 K. The values of the thermodynamic parameters suggested that the binding of TCC to BSA was driven mainly by hydrophobic interaction and hydrogen bond. Site marker competitive experiments coupled with molecular docking studies confirmed that site I was the main binding site for TCC on BSA. Furthermore, TCC binding to BSA led to conformational and structural alterations of BSA as revealed by multi-spectroscopic studies. In addition, the stability of BSA and BSA-TCC complex were well analyzed by the molecular dynamics studies. In short, this work indicated that TCC could interact with BSA and impact the conformation of BSA, which could provide valuable information to understand the toxicity mechanism of TCC.

Using mass struvite precipitation to remove recalcitrant nutrients and micropollutants from anaerobic digestion dewatering centrate.

The primary objective of this research was to remove recalcitrant nutrients from anaerobically digested sludge dewatering centrate. A struvite precipitation methodology is proposed where salt crystals are encouraged to ballast colloidal particles through heterogeneous nucleation and subsequent crystal growth. The secondary objective was to assess presence of micropollutants in precipitates. Four biologically unique dewatering centrates were used to test the precipitation methodology on the variety of anaerobic digester configurations that can be expected from municipal wastewater treatment plant. The effect of digestion sludge retention time (2 day, 20 day) and digestion temperature (35 °C, 55 °C) on the removal of dissolved unreactive phosphorus (P) and nitrogen (N) was monitored. Averaged across all four centrates, the precipitation methodology resulted in dissolved unreactive P and N removal of 82.4% and 66.6%, respectively. Antimicrobial contaminants (triclosan, triclocarban) were observed in the precipitates at minute concentrations (<18 ng/g-dry solids). Therefore, mass struvite precipitation can provide a means of recalcitrant nutrient treatment and reactive nutrient recovery without the micropollutant burden of biosolids land application.

Degradation of triclosan and triclocarban and formation of transformation products in activated sludge using benchtop bioreactors.

Benchtop bioreactors were run aerobically with activated sludge samples collected from a large municipal wastewater treatment plant (WWTP) to understand how increased hydraulic retention time (HRT), sludge retention time (SRT), and varying treatment temperatures (21°C and 30°C) impact concentrations of the endocrine disrupting antimicrobials triclosan (TCS), triclocarban (TCC), and their transformation products. Samples from the reactors were collected periodically over a 122-196h period and the solid and liquid fraction were separately quantitated for TCS, TCC, and methyltriclosan (MeTCS) and scanned qualitatively for six other transformation products. Results indicated that TCS, TCC and MeTCS were predominately associated with the solids fraction of the activated sludge with only nominal concentrations in the liquids fraction. TCS was degraded in the solids fraction, with increased rates at 30°C (-0.0224 ± 0.007h-1) when compared to reactors run at 21°C (- 0.0170 ± 0.003h-1). Conversely, TCC concentrations did not significantly change in solids samples from reactors run at 21°C, while an increase in reactor temperature to 30°C resulted in TCC degradation at an average rate of - 0.0158 ± 0.012h-1. Additionally, MeTCS formation in the solids fraction was observed in three out of four reactors run - indicating a notable transformation of TCS. Qualitative appearance of 2,4-dichlorophenol and 4-chloroanaline was observed in the liquids fraction of all reactor samples. The remaining four qualitatively scanned compounds were not detected. These experiments demonstrate that increased HRT, SRT, and temperature result in enhanced removal of TCS and TCC from wastewater during the activated sludge process. Furthermore, a substantial formation of TCS into MeTCS was observed.

Triclocarban: UV photolysis, wastewater disinfection, and ecotoxicity assessment using molecular biomarkers.

Triclocarban (TCC) is an antibacterial agent found in pharmaceuticals and personal care products (PPCP). It is potentially bioaccumulative and an endocrine disruptor, being classified as a contaminant of emerging concern (CEC). In normal uses, approximately 96% of the used TCC can be washed down the drain going into the sewer system and eventually enter in the aquatic environment. UV photolysis can be used to photodegrade TCC and ecotoxicity assays could indicate the photodegradation efficiency, since the enormous structural diversity of photoproducts and their low concentrations do not always allow to identify and quantify them. In this work, the TCC was efficiently degraded by UVC direct photolysis and the ecotoxicity of the UV-treated mixtures was investigated. Bioassays indicates that Daphnia similis (48 h EC50 = 0.044 µM) was more sensitive to TCC than Pseudokirchneriella subcapitata (72 h IC50 = 1.01 µM). TCC and its photoproducts caused significant effects on Eisenia andrei biochemical responses (catalase and glutathione-S-transferase); 48 h was a critical exposure time, since GST reached the highest activity values. UVC reduced the TCC toxic effect after 120 min. Furthermore, TCC was photodegraded in domestic wastewater which was simultaneously disinfected for total coliform bacterial (TCB) (360 min) and Escherichia coli (60 min). Graphical abstract TCC degradation and ecotoxicological assessment.

Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus.

A new class of diphenylurea was identified as a novel antibacterial scaffold with an antibacterial spectrum that includes highly resistant staphylococcal isolates, namely methicillin- and vancomycin-resistant Staphylococcus aureus (MRSA & VRSA). Starting with a lead compound 3 that carries an aminoguanidine functionality from one side and a n-butyl moiety on the other ring, several analogues were prepared. Considering the pharmacokinetic parameters as a key factor in structural optimization, the structure-activity-relationships (SARs) at the lipophilic side chain were rigorously examined leading to the discovery of the cycloheptyloxyl analogue 21n as a potential drug-candidate. This compound has several notable advantages over vancomycin and linezolid including rapid killing kinetics against MRSA and the ability to target and reduce the burden of MRSA harboring inside immune cells (macrophages). Furthermore, the potent anti-MRSA activity of 21n was confirmed in vivo using a Caenorhabditis elegans animal model. The present study provides a foundation for further development of diphenylurea compounds as potential therapeutic agents to address the burgeoning challenge of bacterial resistance to antibiotics.