Urease Inhibitors Research Articles

Enhanced efficiency urea fertilizers and timing effects on N2O emissions from spring wheat production in Manitoba

AbstractOpportunities exist to reduce nitrous oxide (N2O) emissions from nitrogen (N) fertilizers using enhanced efficiency fertilizers (EEFs) and managing application timing. This study examined (1) application timing (fall/spring) and (2) fertilizer N source on N2O emissions, yield, and N uptake of Canadian hard red spring wheat (Triticum aestivum L.) in Southern Manitoba. Fertilizer N sources included granular urea and four EEF products: (1) polymer‐coated urea (environmentally smart nitrogen [ESN]); (2) urea plus nitrification inhibitor (eNtrench); (3) urea plus urease inhibitor (Limus); and (4) urea plus nitrification and urease inhibitor (SuperU). Nitrification‐inhibited products most consistently reduced N2O emissions while maintaining productivity. Compared to urea alone, urea + eNtrench was most effective in reducing cumulative N2O emissions by 47%–64% at four of six site‐years. SuperU reduced N2O emissions by 37%–57% at three of six site‐years. ESN and urea + Limus did not affect emissions in most years. Wheat yield, protein, and N uptake were unaffected by N source in five of six site‐years. Compared to spring, fall application gave greater N2O emissions by 33%–67% at three of six site‐years due to spring‐thaw emissions. Fall was inferior to spring application in wetter site years with lower yield, protein, and N uptake. Overall, nitrification‐inhibited products—either alone or with a urease inhibitor—are a promising tool to reduce N2O emissions while maintaining wheat productivity in Manitoba. However, given that there were few consistent increases in yield or protein, the additional cost of the inhibitors will be a barrier to adoption.

Novel Coumarin Derivatives as Potential Urease Inhibitors for Kidney Stone Prevention and Antiulcer Therapy: From Synthesis to In Vivo Evaluation.

The presence of ammonium ions in urine, along with basic pH in the presence of urease-producing bacteria, promotes the production of struvite stones. This causes renal malfunction, which is manifested by symptoms such as fever, nausea, vomiting, and blood in the urine. The involvement of urease in stone formation makes it a good target for finding urease enzyme inhibitors, which have the potential to be developed as lead drugs against kidney stones in the future. The documented ethnopharmacology of coumarin 2-one against bacterial, fungal and viral strains encouraged us to synthesize new derivatives of coumarins by reacting aromatic aldehydes with 4-aminocoumarin. The synthesized compounds (2a to 11a) were evaluated for their antimicrobial, in vitro, and in silico properties against the urease enzyme. The study also covers in vivo determination of the synthesized compounds with respect to different types of induced ulcers. The molecular docking study along with extended MD simulations (100 ns each) and MMPBSA study confirmed the potential inhibitory candidates as evident from computed ∆Gbind (3a = -11.62 and 5a = -12.08 Kcal/mol) against the urease enzyme. The in silico analyses were augmented by an enzymatic assay, which revealed that compounds 3a and 5a had strong inhibitory action, with IC50 of 0.412 µM (64.0% inhibition) and 0.322 µM (77.7% inhibition), respectively, compared to standard (Thiourea) with 82% inhibition at 0.14 µM. Moreover, the most active compound, 5a, was further tested in vivo for antiulcer activity by different types of induced ulcers, including pyloric ligation-, ethanol-, aspirin-, and histamine-induced ulcers. Compound 5a effectively reduced gastric acidity, lipid peroxidation, and ulceration in a rat model while also inhibiting gastric ATPase activity, which makes it a promising candidate for ulcer treatment. As a result of the current research, 3a and 5a may be used as new molecules for developing potent urease inhibitors. Additionally, the compound 3a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 41 ± 0.9 mm and 35 ± 0.9 mm, respectively. Compound 7a showed antibacterial activity against Staphylococcus aureus and Salmonella typhimurium, with zones of inhibition of 30 ± 0.8 mm and 42 ± 0.8 mm, respectively. These results prove that the synthesized compounds also possess good antibacterial potential against Gram-positive and Gram-negative bacterial strains.

Synthesis of Some Benzimidazole-Thiophene Hybrids as Potential Urease and Lipase Inhibitors

Synthesis of Some Benzimidazole-Thiophene Hybrids as Potential Urease and Lipase Inhibitors

Synthesis, Crystal Structures and Urease Inhibition of Zinc(II) Complexes Derived from 1-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)Naphthalen-2-ol

Synthesis, Crystal Structures and Urease Inhibition of Zinc(II) Complexes Derived from 1-(((2-(pyrrolidin-1-yl)ethyl)imino)methyl)Naphthalen-2-ol

Design, molecular docking and synthesis of pyrazino[1,2-a] indole derivatives via tandem Ugi-4CR/intramolecular cyclization as potential urease inhibitor agents

In the present paper, a novel series of pyrazino[1,2-a]indole derivatives 6(a-k) were synthesized by Ugi four-component reaction (U-4CR), followed by an intramolecular cyclization of the Ugi products in the presence of DBU as a catalyst, Subsequently, we assessed their inhibitory activity against Jack bean's urease enzyme in vitro, and some of these derivatives exhibited potent urease inhibition. Notably, compounds 6e (IC50 = 3.55 ± 1.11 µM), 6g (IC50 = 3.18 ± 0.42 µM), and 6j (IC50 = 3.80 ± 0.65 µM) demonstrated urease inhibitory effects comparable to the reference compound, thiourea. Additionally, our docking study corroborated these experimental results, confirming that the pyrazino[1,2-a]indole derivatives (6a-k) effectively interacted with the urease enzyme's active site, exhibiting proper binding energies and modes.

Enhanced-efficiency nitrogen fertilizer provides a reliable option for mitigating global warming potential in agroecosystems worldwide

Enhanced-efficiency nitrogen fertilizer (EENF), developed to improve synchronization between crop nitrogen demand and nitrogen supply, can guarantee global food security and mitigate nitrogen fertilizer-induced environmental consequences. However, comprehensive assessments of how EENF affects CH4 and CO2 emissions from paddies and drylands and the associated benefits are lacking. Here, we present the results of a global meta-analysis conducted to assess the above issues. Our results showed that, on average, applying nitrification inhibitors and coated controlled-release urea to paddy fields significantly decreased CH4 emissions by 24.0 % and 25.3 %, respectively, likely due to the weakened inhibition of NH4+ on CH4 oxidation. A similar effect on CO2 emission was observed when farmers used nitrification inhibitors and coated controlled-release urea in the drylands. The meta-analysis results revealed that all EENF products could help mitigate the global warming potential of paddies and drylands. After incorporating the benefit of global warming potential mitigation into the cost-benefit analysis, coated controlled-release urea application in paddies and drylands produced the largest environmental gains of $ 76.34 ha−1 and $ 79.35 ha−1, respectively. However, the relatively lower purchasing cost and larger yield increase of urease inhibitors resulted in the largest net profits for farmers. Moreover, a greater economic return was generally achieved by applying EENF to paddy fields than by applying EENF to drylands. These findings highlight the role of EENF in mitigating the global warming potential of global paddy and dryland fields, which has facilitated the comprehensive recognition of EENF-induced impacts.

N-acetylcysteine prevents catheter occlusion and inflammation in catheter associated-urinary tract infections by suppressing urease activity.

Proteus mirabilis is a key pathobiont in catheter-associated urinary tract infections (CA-UTIs), which is well known to form crystalline biofilms that occlude catheters. Urease activity alkylates urine through the release of ammonia, consequentially resulting in higher levels of Mg2+ and Ca2+ and formation of crystals. In this study, we showed that N-acetyl cysteine (NAC), a thiol antioxidant, is a potent urease inhibitor that prevents crystalline biofilm formation. To quantify urease activity, Berthelot's method was done on bacterial extracts treated with NAC. We also used an in vitro catheterised glass bladder model to study the effect of NAC treatment on catheter occlusion and biofilm encrustation in P. mirabilis infections. Inductively-coupled plasma mass spectrometry (ICP-MS) was performed on catheter samples to decipher elemental profiles. NAC inhibits urease activity of clinical P. mirabilis isolates at concentrations as low as 1 mM, independent of bacterial killing. The study also showed that NAC is bacteriostatic on P. mirabilis, and inhibited biofilm formation and catheter occlusion in an in vitro. A significant 4-8log10 reduction in viable bacteria was observed in catheters infected in this model. Additionally, biofilms in NAC treated catheters displayed a depletion of calcium, magnesium, or phosphates (>10 fold reduction), thus confirming the absence of any urease activity in the presence of NAC. Interestingly, we also showed that not only is NAC anti-inflammatory in bladder epithelial cells (BECs), but that it mutes its inflammatory response to urease and P. mirabilis infection by reducing the production of IL-6, IL-8 and IL-1b. Using biochemical, microbiological and immunological techniques, this study displays the functionality of NAC in preventing catheter occlusion by inhibiting urease activity. The study also highlights NAC as a strong anti-inflammatory antibiofilm agent that can target both bacterial and host factors in the treatment of CA-UTIs.

Mycobacterium tuberculosis suppresses host DNA repair to boost its intracellular survival

Mycobacterium tuberculosis (Mtb) triggers distinct changes in macrophages, resulting in the formation of lipid droplets that serve as a nutrient source. We discover that Mtb promotes lipid droplets by inhibiting DNA repair responses, resulting in the activation of the type-I IFN pathway and scavenger receptor-A1 (SR-A1)-mediated lipid droplet formation. Bacterial urease C (UreC, Rv1850) inhibits host DNA repair by interacting with RuvB-like protein 2 (RUVBL2) and impeding the formation of the RUVBL1-RUVBL2-RAD51 DNA repair complex. The suppression of this repair pathway increases the abundance of micronuclei that trigger the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway and subsequent interferon-β (IFN-β) production. UreC-mediated activation of the IFN-β pathway upregulates the expression of SR-A1 to form lipid droplets that facilitate Mtb replication. UreC inhibition via a urease inhibitor impaired Mtb growth within macrophages and invivo. Thus, our findings identify mechanisms by which Mtb triggers a cascade of cellular events that establish a nutrient-rich replicative niche.

Design, synthesis, in vitro urease inhibitory potentials and in silico molecular docking study of benzimidazole bearing thiosemicarbazides/sulfonamide Analogues

The nickel-containing urease enzyme is responsible for the pathogenesis of hepatic coma, hepatic encephalopathy, urolithiasis, gastric and peptic ulcer. These enzymes also have a negative effect on the efficacy of soil nitrogen to produce crops. The urease enzyme inhibitors may be thought as a strategy for reducing the negative effects of ureolytic bacteria. The present study involves a novel approach to the synthesis benzimidazole thiosemicarbazides and sulphonamide derivatives as potent urease inhibitor. All the analogues exhibited good inhibition potential. Among the thiosemicarbazides series, the most potent were analogs 1 g and 1 h having an IC50 = 2.40 ± 0.10 and 3.10 ± 0.10 µM respectively. Among the sulphonamide series, the most potent analogs were 2f and 2j having an IC50 = 3.90 ± 0.10 and 1.40 ± 0.001 µM respectively. Structure activity relationship study shows that among the two series, the most potent analogs were those having electron-withdrawing groups. Molecular docking study was carried out to check the interactions between the synthesized compounds and the urease enzyme's active sites. Furthermore, to evaluate the stability of the most active compound in complex with the urease enzyme a total of 200 ns MD simulation was carried out. The MD simulation study revealed that the compound formed a more stable complex with the urease enzyme and remained stable throughout the 200 ns MD simulation. All Compounds were verified for cytotoxicity against 3T3 mouse fibroblast cell line and detected nontoxic.

Glauconitic Siltstone: additive for ammonia retention and reduction of nitrogen volatilization loss

Glauconitic siltstone is sedimentary rock used as raw material to produce a multinutrient fertilizer that can combine with urea to increase their agronomic efficiency. The purpose of this study was to evaluate glauconitic siltstone as additive to reduce nitrogen losses by ammonia volatilization in nitrogen fertilizers. The experiment used randomized block, in a portion subdivided over time, following a 6 x 8 factorial with four replications and treatments comprising glauconitic siltstone mixture at a dose of 100 kg N ha-1 (control, without the application of nitrogen; conventional urea – 45% N; commercial fertilizer registered with the trade name of Super N®; urea with addition of glauconitic siltstone: 9% N; 20 and 31% N) and the remaining portion divided in the collection time at 3, 6, 9, 12, 15, 18, 24 and 30 days after fertilizer application. The collection of the volatilized ammonia was made in a semi-opened free static chamber. The use of glauconitic siltstone associated with urea provided a reduction in loss by volatilization from 10 to 27% in relation to conventional urea. The treatments with application of urea with the urease inhibitor showed the lowest volatilization rate and delay in the volatilization peak, which occurred 17 days after fertilizer application. In addition to providing nutrients to the plants, glauconitic siltstone reduces ammonia losses.

Design, Synthesis, Pharmacological Activities, Structure-Activity Relationship, and In Silico Studies of Novel 5-Substituted-2-(morpholinoimino)-thiazolidin-4-ones.

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones (3-26) and characterized by molecular spectroscopy. The synthesized compounds were subjected to antioxidant activity with anticholinesterase, tyrosinase, and urease inhibition activities and evaluated the structure-activity relationship (SAR) of enzyme inhibition activities. Compound 11 was found to be the most active antioxidant. In anticholinesterase inhibition, compound 12 (IC50: 17.41 ± 0.22 μM) was the most active against AChE, while compounds 3-26 ( except 3, 8, and 17) showed notable activity against BChE. Compounds 17 (IC50: 3.22 ± 0.70 mM), 15 (IC50: 5.19 ± 0.03 mM), 24 (IC50: 7.21 ± 0.27 mM), 23 (IC50: 8.05 ± 0.11 mM), 14 (IC50: 8.10 ± 0.22 mM), 25 (IC50: 8.40 ± 0.64 mM), 26 (IC50: 8.76 ± 0.90 mM), and 22 (IC50: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC50: 16.79 ± 0.19 μM), 19 (IC50: 18.25 ± 0.50 μM), 18 (IC50: 20.24 ± 0.77 μM), 26 (IC50: 21.51 ± 0.44 μM), 25 (IC50: 21.70 ± 0.06 μM), and 24 (IC50: 22.49 ± 0.11 μM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between (1-26) compounds and enzymes at the molecular level. According to the results of this study, the synthesized compounds exhibited a better binding affinity toward these enzymes compared to the positive control. Further, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy and molecular dynamics (MD) simulation analyses were performed for AChE with compound 26, which showed high inhibitory activity in silico and in vitro studies. In conclusion, novel morpholine and thiazolidine-based derivative compounds may be pharmacologically effective agents for AChE, BChE, tyrosinase, and urease enzymes.

Controlled-release urea for use in sugarcane ratoons

Urea is the main solid N fertilizer used worldwide. Among its advantages are the high nutrient content, ease of handling and application, and low cost. Urea is subject to high losses through NH3 volatilization if surface-applied on soils. Therefore, ammonium nitrate is the preferred N source, especially in the ratoon cycles. Urea treated with the urease inhibitor NBPT and controlled-release fertilizers are options to replace ammonium nitrate. Controlled-release urea (CRU) is produced by coating the urea granules with resin or synthetic polymers so that the urea in the nucleus is not in contact with soil moisture. This study aimed to test CRU in sugarcane ratoons compared with ammonium nitrate (AN) and urea treated with urease inhibitor (UR-NBPT) at three rates: 60, 120 and 180 kg ha–1. Efficiency was also compared with two control treatments, the N control and the NPK control. Two field experiments were established and conducted in 2020 and 2021 in Sao Paulo state, Brazil. Sugarcane yield was evaluated in both experiments. N losses as NH3 volatilized were measured in the first experiment. All sources were equally efficient in promoting increases in sugarcane ratoon yield in both experiments. The relative yield obtained with N fertilizers and the control without N showed yield increases in the first experiment of 40, 54 and 68% for 60, 120 and 180 kg N ha–1 as AN, respectively; 29, 61 and 61% for 60, 120 and 180 kg N ha–1 as urea-NBPT, respectively; and 32, 62 and 67% for 60, 120 and 180 kg N ha–1 as CRU, respectively. Yields were higher in the second experiment, but increases in yield were lower compared to the first. Increases of 7, 10 and 16% for AN in three doses, 5, 12, 15% for UR-NBPT and 7, 9 and 14% for CRU were observed, respectively. N losses as NH3 volatilized were relatively low; CRU fertilizer showed good protection against NH3 losses by volatilization, protecting urea for about 30 days. This protection, however, did not affect yield. NH3 losses reached 13% of the N applied in the treatment with urea (about 16 kg N ha–1), 11% for Urea-NBPT (about 13 kg N ha–1) and 9% for CRU (about 11 kg N ha–1). Analyzing the results of both experiments CRU did not show an advantage in efficiency compared to AN and Urea-NBPT.

Synthesis, Crystal Structures and Urease Inhibition of Copper(II) and Cobalt(III) Complexes Derived from (((2-(Pyrrolidin-1-yl)ethyl)imino)methyl)naphthalen-2-ol

Three copper(II) and cobalt(III) complexes, [CuL(dca)]n (1), [CuL(N3)]n (2) and [CoL(N3)2(DMF)] (3), where L is the monoanionic form of the Schiff base (((2-(pyrrolidin-1-yl)ethyl)imino)methyl)naphthalen-2-ol (HL), and dca is dicyanamide, have been prepared and characterized by elemental analyses, IR and UV-Vis spectroscopy, as well as single crystal X-ray diffraction. The Cu atoms in complexes 1 and 2 are in square pyramidal coordination, and the Co atom in complex 3 is in octahedral one. Complexes 1 and 2 inhibit the Jack bean urease with IC50 values of 0.25 ± 0.14 and 0.32 ± 0.15 μmol L–1, respectively. Complex 3 show weak activity on Jack bean urease with percentage inhibition of 37%.

Effects of combined natural synergists and chemical inhibitors on yield, nitrogen utilization and balance in wheat/maize rotation system.

Urease inhibitors and nitrification inhibitors can enhance nitrogen (N) fertilizer utilization efficiency and reducing N losses through regulating urea-N transformation. Common urease or nitrification inhibitors, however, are predominantly chemically synthesized and high-cost. Furthermore, their inhibitory effects are mediated by soil pro-perties, climatic conditions, and crop systems. In this study, we conducted a field experiment using natural synergists humic acid/zeolite, along with chemical nitrification inhibitor dicyandiamide (DCD) and their combination to elucidate the impacts of natural synergists combined with chemical inhibitors on annual yield, nitrogen utilization efficiency, soil nitrate-N accumulation, and nitrogen balance within the wheat/maize rotation system. The treatments included no nitrogen fertilizer application (CK), single application of urea (N), urea +DCD (ND), urea + humic acid (NH), urea + zeolite (NP), urea + urease inhibitor N-butylthiophosphoric triamide + DCD (NUD), urea + humic acid + DCD (NHD), and urea + zeolite + DCD (NPD). The results showed that, compared to the treatments NH and NP, the integration of humic acid or zeolite with DCD (NHD and NPD) significantly increased maize yield (11268 and 11397 kg·hm-2) and total annual yield (20494 and 20582 kg·hm-2), which were comparable to those of combined chemical urease and nitrification inhibitors (NUD). The NHD and NPD treatments had higher nitrogen utilization efficiency and lower soil nitrate-N accumulation in 80-100 cm soil layer across all seasons relative to the N treatment, which had no significant difference compared to the NUD treatment. Furthermore, a decline in soil nitrogen surplus by 10.7% and 13.9% was observed when comparing the NHD and NPD treatments with the NH and NP treatments, respectively. These findings suggested that combined humic acid or zeolite and chemical nitrification inhibitors could effectively enhance crop yield and N utilization efficiency and meet the requirements of the green and environmental preservation of modern agriculture.

Evaluation of synthetic aminoquinoline derivatives as urease inhibitors: in vitro, in silico and kinetic studies.

Background: Quinoline and acyl thiourea scaffolds have major chemical significance in medicinal chemistry. Quinoline-based acyl thiourea derivatives may potentially target the urease enzyme. Materials & methods: Quinoline-based acyl thiourea derivatives 1-26 were synthesized and tested for urease inhibitory activity. Results: 19 derivatives (1-19) showed enhanced urease enzyme inhibitory potential (IC50=1.19-18.92μM) compared with standard thiourea (IC50=19.53±0.032μM), whereas compounds 20-26 were inactive. Compounds with OCH3, OC2H5, Br and CH3 on the aryl ring showed significantly greater inhibitory potential than compounds with hydrocarbon chains of varying length. Molecular docking studies were conducted to investigate ligand interactions with the enzyme's active site. Conclusion: The identified hits can serve as potential leads against the drug target urease in advanced studies.

P46 Evaluation of a Hydroxamate-Based Urease Inhibitor in a Rodent Model of Hepatic Encephalopathy

P46 Evaluation of a Hydroxamate-Based Urease Inhibitor in a Rodent Model of Hepatic Encephalopathy

Ammonia mitigation campaign with smallholder farmers improves air quality while ensuring high cereal production.

Reducing cropland ammonia (NH3) emissions while improving air quality and food supply is a challenge, particularly in China where there are millions of smallholder farmers. We tested the effectiveness of a tailored nitrogen (N) management strategy applied to wheat-maize cropping systems in 'demonstration squares' across Quzhou County in the North China Plain. The N-management techniques included optimal N rates, deep fertilizer placement and application of urease inhibitors, implemented through cooperation between government, researchers, businesses and smallholders. Compared with conventional local smallholder practice, our NH3 mitigation campaign reduced NH3 volatilization from wheat and maize by 49% and 39%, and increased N-use efficiency by 28% and 40% and farmers' profitability by 25% and 19%, respectively, with no detriment to crop yields. County-wide atmospheric NH3 and fine particulate matter (with aerodynamic diameter <2.5 μm) concentrations decreased by 40% and 8%, respectively. County-wide net benefits were estimated at US$7.0 million. Our demonstration-square approach shows that cropland NH3 mitigation and improved air quality and farm profitability can be achieved simultaneously by coordinated actions at the county level.

Exploring the Synthetic Chemistry of Phenyl-3-(5-aryl-2-furyl)- 2-propen-1-ones as Urease Inhibitors: Mechanistic Approach through Urease Inhibition, Molecular Docking and Structure-Activity Relationship.

Furan chalcone scaffolds belong to the most privileged and promising oxygen-containing heterocyclic class of compounds, which have a wide spectrum of therapeutic applications in the field of pharmaceutics, pharmacology, and medicinal chemistry. This research described the synthesis of a series of twelve novel and seven reported furan chalcone (conventional synthetic approach) analogues 4a-s through the application of microwave-assisted synthetic methodology and evaluated for therapeutic inhibition potential against bacterial urease enzyme. In the first step, a series of nineteen substituted 5-aryl-2-furan-2-carbaldehyde derivatives 3a-s were achieved in moderate to good yields (40-70%). These substituted 5-aryl-2-furan-2-carbaldehyde derivatives 3a-s were condensed with acetophenone via Claisen-Schmidt condensation to furnish 19 substituted furan chalcone scaffolds 4a-s in excellent yields (85-92%) in microwave-assisted synthetic approach, while in conventional methodology, these furan chalcone 4a-s were furnished in good yield (65-90%). Furan chalcone structural motifs 4a-s were characterized through elemental analysis and spectroscopic techniques. These nineteen (19)-afforded furan chalcones 4a-s were screened for urease inhibitory chemotherapeutic efficacy and most of the furan chalcones displayed promising urease inhibition activity. The most active urease inhibitors were 1-phenyl-3-[5-(2',5'-dichlorophenyl)-2-furyl]-2-propen-1-one 4h with an IC50 value of 16.13 ± 2.45 μM, and 1-phenyl- 3-[5-(2'-chlorophenyl)-2-furyl] -2-propen-1-one 4s with an IC50 value of 18.75 ± 0.85 μM in comparison with reference drug thiourea (IC50 = 21.25 ± 0.15 μM). These furan chalcone derivatives 4h and 4s are more efficient urease inhibitors than reference drug thiourea. Structure-activity relationship (SAR) revealed that the 2,5-dichloro 4h and 2-chloro 4s moiety containing furan chalcone derivatives may be considered as potential lead reagents for urease inhibition. The in silico molecular docking study results are in agreement with the experimental biological findings. The results of this study may be helpful in the future drug discovery and designing of novel efficient urease inhibitory agents from this biologically active class of furan chalcones.

Reduction of NH3 Emissions from Urea by Long-Term No-Tillage and Stover Mulching with Inhibitors: An Isotopic Field Study in Northeast China

Large nitrogen (N) losses during fertilization in agricultural production may result in energy wastage, soil and water contamination, and potentially influence crop development. Thus, with the help of a 15N-labeled tracer, we carried out a field monitoring analysis of NH3 emissions in a long-term (9-year) conservation tillage agroecosystem of Mollisols in northeast China, in order to determine whether a no-tillage regime and four levels of stover mulching (0%, 33%, 67%, and 100%), combined with urease and nitrification inhibitors, could improve fertilizer utilization efficiency in agricultural systems by reducing ammonia volatilization. Our results showed that in comparison with ridge tillage, no-tillage with stover mulching levels of 33%, 67%, and 100% significantly reduced NH3 emission rates and cumulative volatilization from 159.67 to 130.42 g N ha−1 and 15N-NH3 cumulative volatilization emission by 26% (on average). Furthermore, the application of urease and nitrification inhibitors significantly reduced 15N-NH3 volatilization levels from 1.19 to 0.98 g N ha−1. Our research results demonstrate that a long-term no-tillage regime and straw mulching can significantly reduce NH3 volatilization in fertilizers. Furthermore, when combined with the use of urease and nitrification inhibitors, these practices further enhance the reduction in NH3 volatilization. Although the volatilization of 15N-NH3 is minimally studied in Mollisols, these findings provide a solid foundation for improving fertilizer utilization efficiency, reducing crop production costs and mitigating subsequent environmental pollution.

Acetylsalicylic acid-sulfa drugs conjugates as potential urease inhibitors and anti-inflammatory agents: bio-oriented drug synthesis, molecular docking, and dynamics simulation studies

To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, 1HNMR, 13CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC50 of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin’s performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes. Communicated by Ramaswamy H. Sarma