Sulfonamide derivatives targeting urease: Structural diversity and therapeutic potential

Mahmood Ahmed; Asnuzilawati Asari; Muhammad Zaeem Mehdi; Mohammed H. AL Mughram; Ujala Habib; Riaz Hussain; Muhammad Yaseen; Arslan Usman; Mushkbar Fatima; Masooma Irfan; Ali Abbas Aslam

doi:10.25259/AJC_513_2025

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Review Article

ARTICLE IN PRESS

doi:

10.25259/AJC_513_2025

Sulfonamide derivatives targeting urease: Structural diversity and therapeutic potential

Mahmood Ahmed^a,*, Asnuzilawati Asari^b, Muhammad Zaeem Mehdi^a, Mohammed H. AL Mughram^c, Ujala Habib^a, Riaz Hussain^d, Muhammad Yaseen^a, Arslan Usman^a, Mushkbar Fatima^e, Masooma Irfan^f,g, Ali Abbas Aslam^a

aDepartment of Chemistry, Division of Science and Technology, University of Education, College Road, Lahore-54770, Pakistan

bFaculty of Science and Marine Environment, Universiti Malaysia Terengganu, Kuala Nerus, Terengganu, Malaysia

cDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Khalid University, Abha-61421, Saudi Arabia

dDepartment of Chemistry, University of Okara, Okara-56300, Pakistan

ePunjab University College of Pharmacy, University of the Punjab, Lahore-Pakistan

fDepartment of Mathematics, Saveetha School of Engineering (SIMATS), Thandalam 600124, Chennai, Tamil Nadu, India.

gAdvanced Membrane Technology Research Centre (AMTEC), Faculty of Chemical and Energy Engineering, Universiti Teknologi Malaysia, 81310, Johor Bahru, Johor, Malaysia.

* Corresponding author: E-mail address: mahmoodresearchscholar@gmail.com (M. Ahmed)

Received: 2025-05-13, Accepted: 2025-07-05, Epub ahead of print: 2025-10-08,

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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

Abstract

Urease, a nickel-dependent metalloenzyme, plays a pivotal role in microbial survival, nitrogen metabolism, and the pathogenesis of urease-associated diseases, including Helicobacter pylori infections and urolithiasis. The excessive urease activity also contributes to soil alkalization and ammonia volatilization, leading to significant environmental and agricultural concerns. Inhibiting urease has emerged as a promising strategy to combat bacterial resistance and improve agricultural sustainability. Among the diverse classes of urease inhibitors, sulfonamide-containing molecules have gained substantial attention due to their structural versatility, bioavailability, and potent inhibitory activity. Recent advancements in computational approaches, including molecular dynamics simulations and quantum chemical studies, are also addressed to enhance the predictive capabilities of inhibitor design. The key objectives of this review are to comprehensively compile sulfonamide-containing compounds reported as urease inhibitors, analyze their structure-activity relationships (SAR), highlight the most potent derivatives based on IC₅₀ values, and provide insights from molecular docking and mechanistic studies to support future drug design efforts. This comprehensive review emphasized bridging the gap between fundamental urease inhibition studies and translational research, paving the way for developing next-generation urease inhibitors with improved efficacy and selectivity.

Keywords

Bacteria

Helicobacter pylori

Molecular docking

Sulfonamides

Urease

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1. Introduction

Urease, also known as urea amidohydrolase, is a member of the phosphotriesterase and amidohydrolases superfamily. It is a nickel-containing metalloenzyme in organisms ranging from unicellular bacteria to invertebrates and plants [1]. It is a crucial protein involved in virulence and plays a role in the pathogenesis of many diseases. Extracting urease from a plant source is challenging because of the rigid cell wall of agents that interfere with the overall process, such as proteases [2]. Historically, urease derived from Jack bean (Canavalia ensiformis) was the first enzyme to undergo crystallization in 1926, thereby establishing its proteinaceous nature [3,4]. Urease hydrolyzes urea to ammonia and carbon dioxide, speeding up this reaction 1014 times [5]. Phylogenetic studies indicate that ureases derived from various sources exhibit considerable divergence from a shared ancestral protein, as evidenced by a primary sequence identity of approximately 55%, even though they exhibit variations in their quaternary structures [6]. The source of ureases greatly influences their structure, molecular weight, and amino acid sequence. The domain of urease is homotrimeric in bacteria or heterotrimeric in plants [7]. There are three distinct subunits in the heteropolymeric molecules known as bacterial ureases. The Jack bean ureases, on the other hand, are homo hexameric molecules with only six subunits [8]. Regardless, the structures of different proteins are not identical, but their active sites are preserved and mostly identical. The active site comprises two nickel ions in coordination with four histidine residues, a carbamoylated lysine, and an aspartate [4]. H. pylori uses this enzyme to survive in the stomach by developing beneficial conditions by releasing excess ammonia [9]. Many bacteria use this enzyme to get nitrogen for growth. So, it is crucial for the regular nitrogen metabolism of germinating plants. In agriculture, urea fertilizers are often associated with elevated urease activity, precipitating considerable environmental and economic detriments due to the emission of large ammonia into the atmosphere. This phenomenon concurrently inflicts harm upon plants by depriving them of crucial nutrients, inducing secondary ammonia toxicity, and elevating the pH levels of the soil [10]. Since human DNA does not have the code for producing urease, significant urease activity in a pathogenic infection can serve as a biomarker. This makes urease a helpful diagnostic indicator for various infectious diseases. The rapid urease test (RUT) and urea breath test (UBT) are diagnostic methods that leverage urease activity to detect H. pylori infections, aiding clinical diagnosis. RUT measures pH changes in gastric specimens due to urease activity, while UBT involves the detection of labeled carbon dioxide in exhaled air after ingesting labeled urea [4]. The persistent generation of ammonia exacerbates the permeability of the gastric mucosa, consequently precipitating inflammation, ulcers, adenocarcinoma, and lymphoma. Inhibiting urease activity may facilitate the eradication of H. pylori during the initial phases of infection, as the bacterium relies on this enzyme for its survival in the acidic milieu of the stomach. The ureolytic activity of bacteria significantly influences the pathogenesis of human and animal diseases [11].

2. Crystal and Molecular Structure of Urease

The heteromeric molecules that comprise the structure of bacterial ureases comprise three components: α, β, and γ. The triosephosphite isomerase (TIM) barrel structure is the α subunit of the urease structural protein, and the β-β-folding domain is present in the urease structural protein subunit. While the β-fold predominates in the β-subunit, which is situated on the trimer’s exterior side. Additionally, the α-helix and β-folding are both included in the γ-subunit [12]. The H. pylori β-subunit comprises an N-terminal and a C-terminal, and a brief loop situated above and to one side of the subunit connects the two domains. This unique structure connects three subunits. The three subunits are connected end-to-end at their C-termini, making it easier to form trimeric forms [13]. On the other hand, Jack bean ureases are homo hexameric molecules with six subunits. Despite structural variations, the enzyme’s catalytic site generally remains intact. The distinctive characteristic of urease catalytic activity is the constant location of the active site in the subunit with two Ni(II) (Ni₁ and Ni₂) centers. This ligand arrangement yields one pentacoordinated Ni(II) ion (Ni1) with a distorted square-pyramidal geometry and one Ni(II) ion (Ni2) hexacoordinated with a distorted octahedral geometry (Figure 1). A highly preserved amino acid sequence [14] and a metal ion ligand are present in all known ureases. Additionally, metal ions are activators of urease, and the urease structural protein can be activated only when the metal ions enter the active center.

Ni is the most promising activator of urease. On the other hand, other metal ions have minimal impact on the urease activation and have been used as substitutes for Ni ions in various applications [15,16]. Additionally, most of the hydrogen bonds formed by the residues of amino acids, present in the flap area with the substrate, increase the stability of the catalytic transition state and speed up the overall catalytic activity of the reaction. The activation by Ni ions causes the flap of urease to open, allowing substrate urea to enter the active center. Then, the Ni ions react with the carbonyl oxygen of urea to produce the catalytic reaction. This interaction makes the carbon more electrophilic, which makes it more vulnerable to nucleophilic attack. When urea and Ni₁ are mixed, the flap area can be closed [17]. Urea and urease then create a bidentate coordination when Ni₂ reacts with the amino nitrogen atom of urea. This mixture aids the water molecule that connects the two nickel ions in nucleophilically attacking the urea’s carbonyl carbon and rupturing the C-O bond. The nucleophilic assault then aids the production of NH₃ and carbamate. The flap region opens when the catalytic product is finally released, allowing the subsequent urea molecule to enter the active center [18].

3. Chemical and Molecular Biology of Helicobacter Pylori Urease

Gram-negative spiral bacteria called H. pylori, formerly known as Campylobacter pylori, were first identified in the stomach lining of humans in 1982 (Figure 2). In another experiment in 1984, Barry Marshall ate germs from a petri dish and experienced gastritis symptoms within days. H. pylori was conclusively linked to gastritis.

(a) The singular αβ dimeric subunit is depicted with chain β rendered in a silver hue (β); chain α is represented in an ice blue tone (α); the active site covering flap is emphasized in bold ice blue (A); Ni2+ ions are illustrated as purple spheres; the α-helices of the secondary mobile flap are highlighted in a transparent brown color (B); residues associated with the active site are presented in a licorice format (C); regions exhibiting high root mean square fluctuation (RMSF) are denoted in bold yellow (D). Reproduced from the ref. [19], under Creative Commons Attribution (CC BY) license, copyright 2014. (b) Crystal structure of Helicobacter pylori urease. Reproduced from PDB ID. 1E9Z.

This bacterium creates much urease (10–15% of the total protein weight) to survive in the stomach. The 12 active sites in the H. pylori urease contain two Ni²⁺ ions apiece. The two subunits of the enzyme are designated as α and β, respectively. The enzyme exhibits 24 polypeptide chains (12 elongated and 12 abbreviated) within its tetrahedral configuration, consisting of four triangularly arranged units, each classified as a trimeric 3-unit (Figure 3) [20]. Like other ureases, the urease derived from H. pylori features a barrel-shaped active site occluded by a movable flap. The site that coordinates with Ni ion is present in the deepest part of the barrel structure. Penta- and hexacoordinate Ni ions and their coordinating ligands are identified at this Ni²⁺ site. Each Ni²⁺ ion is coordinated by a water molecule, with both entities interconnected by a hydroxide anion in conjunction with the amino acid residues observed within the ions’ coordination sphere. A predominance of hydrophobic amino acids delineates the binding pocket. The conserved residues that constitute the dynamic flap covering the active site are also common among various ureases derived from the crystallographic analyses of the ureases [13]. The inhibition of the urease enzyme presents a rational initial strategy for the eradication of infections associated with H. pylori, thereby mitigating the complications these bacterial colonies engender due to their critical role in the survival of H. pylori within the highly acidic milieu of the stomach [21].

Structure of H. pylori urease. Each color represents a trimeric subunit, and purple spheres represent Nickel ions. Reproduced from the ref. [19], under Creative Commons Attribution (CC BY), license 2014.

The urease is reported to be localized on the cell’s surface, where it is secreted or released. It is generally accepted that urea hydrolysis is completed by urea uptake through a gated channel (Figure 4). In contrast, hydrolysis occurs inside the bacterium, creating a thin layer around the cell’s outer surface [22]. H. pylori can create urease, raising its surroundings’ pH [23].

Urease-catalyzed urea hydrolysis reactions.

4. H. pylori infection and pathogenesis

H. pylori invades the human stomach and produces urease to battle the low pH of the stomach. Then, it uses its flagella to travel to the gastric epithelial cells of the host organism. The bacterial adhesins interact precisely with the host’s cell receptors, resulting in colonization and ultimately leading to permanent infection. H. pylori releases cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA), which cause adverse effects. This leads to the secretion of chemokines by the gastric epithelial layer, which stimulates the neutrophils and initiates innate immunity, ultimately leading to ulcers and gastritis. The pathogenesis of H. pylori is divided into three basic steps. Firstly, it enters the stomach and survives the acidic environment using urease. Then, it uses flagella to swim across the mucus layer of the stomach and finally invades the epithelial layer of the stomach and attaches to the cells by using adhesins, due to which they stay in their place and cause adverse effects in the human body. An overview of this process has been given in Figure 5 [24].

Diagram explaining the infection and pathogenesis of H. pylori. Reproduced from ref. [24], under Creative Commons Attribution (CC BY) license, 2022.

Urease is crucial for H. pylori survival in macrophages because it can control phagosome pH and megasome formation [25]. As antibiotic resistance increases globally, the effectiveness of treating H. pylori infection decreases, indicating the need for a different, more focused strategy to eliminate the illness. Due to the NH₃ loss from fertilizers, ureases have a negative effect not only on human health but also on farmers’ bottom lines. Additionally, urea’s influence on the atmosphere will cause NH₃ to be subsequently deposited on land or in water. Natural ecosystems in the affected region experience eutrophication and acidity as a result. Creating novel, powerful urease inhibitors is essential for controlling the eutrophication and acidity of natural ecosystems and successfully treating human disease [26]. Numerous dangerous clinical situations for human and animal health and agriculture have been proven to occur due to the action of bacterial ureases. According to reports, bacterial ureases play a role in the development of peptic ulcers, infectious stones, and stomach cancer [27]. Finding potential urease inhibitors is, therefore, highly desired [28]. The antibacterial medicines available are ineffective, and only a minute quantity has reached clinical practice. Therefore, developing novel, safe, and potent urease inhibitors is very important, although it has been challenging because urease is involved in various pathological conditions [29].

5. Mechanism of Inhibition of Urease

Biomedical experts have paid close attention to enzyme inhibition in recent decades. Different inhibitors have been found and developed to control a range of illnesses. One of its main characteristics is the enzyme’s selectivity for certain inhibitors, which can range from simple organic molecules to complex molecular structures. The size, structure, and interaction forces that lead to the exact match between the inhibitor and the enzyme determine the inhibitor’s specificity. Under physiological settings, these inhibitions prevent the enzyme from becoming active.

Enzyme inhibition is very important area of pharmaceutical research, as numerous medicines that are effective against various diseases have already been developed. Different compounds coordinate with different types of enzymes to inhibit their catalytic activity. These compounds have acted as therapeutic agents against various diseases, making them important pharmaceutical assets. New antiulcer medications have been considered targets for urease inhibitors [20]. This enzyme catalyzes a reaction in which urea is hydrolyzed to form ammonia and carbamic acid, which, upon further breakdown, yields ammonia and carbon dioxide. High ammonia levels are produced during urea breakdown, which raises pH [30]. Thus, the created ammonia molecules are protonated by water at physiological pH, while carbonic acid dissociates and raises pH. Under physiological circumstances, the carbonic acid proton separates, and the ammonia molecules become protonated to produce ammonium, raising the local pH and potentially interfering with host function, which causes urease activity to have a deleterious impact on human health and agriculture.

To fight environmental pollution and increase the efficiency of plant urea uptake, urease inhibition is the first step in treating diseases associated with urease-producing bacteria. Until now, most urease inhibitor discoveries have come from randomly screening compounds ranging from tens of thousands. However, it is now possible to logically seek these inhibitors thanks to determining high-resolution X-ray structures of native and inhibited ureases from the intricate intricacies of the enzyme’s molecular geometry. These structural investigations disclosed the process underlying urea hydrolysis, paving the path for developing powerful inhibitors using a structure-based approach [31].

6. Modes of Inhibition of Urease

The first step of creating efficient inhibitors is knowing which parts of the protein structure are connected with inhibitors or substrates that satisfy all the structural prerequisites for close contact. The urease active site has been discovered to contain paramagnetic, pseudo-octahedral, and bi-nuclear nickel ions in all of the enzyme-inhibitor complexes studied. We can divide the inhibitors of urease into two groups: firstly, inhibitors that bind in an active-site-directed or substrate-directed manner, and secondly, inhibitors that bind in a directed or non-substrate-like manner.

6.1. Substrate-like or active site-directed inhibitors

The present-day chemotypes and their analogs are active site-directed inhibitors. Each compound connects the two paramagnetic Ni ions in the enzyme’s catalytic site, which is a characteristic that unites them. As a result, the alignment of the octahedral Ni ions and the amino acid residues in the catalytic site is comparable to that of the urease substrate. Two main examples are thiourea and hydroxyurea. Most urease inhibitors found early were strong basic groups, such as amide bond mimics of the molecule that served as the enzyme’s substrate, urea. Substrate-like inhibitors also include phosphazenes and derivatives of hydroxamic acid.

6.2. Non-substrate-like or mechanism-based inhibitors

Mechanism-based inhibitors interfere with the process of enzyme catalysis, leading to enzyme inactivation. These substances are also referred to as non-substrate-like inhibitors. Common inhibitors with a mechanism of action include phosphorodiamidate and imidazoles. The non-substrate-like inhibitors are inert substances having structures distinct from those of the target enzyme’s substrate or product. Before the target is released from the enzyme’s active site, they are converted into a reactive form by the enzyme, which causes it to be inactivated. Recent studies investigated the potential of these mechanism-based inhibitors. Since they are often irreversible, they significantly benefit from competing for reversible inhibitors. The maintenance of steady-state concentrations does not affect inhibitory effects. Despite their enormous promise as medications, no clinically effective enzyme inactivator based on a well-thought-out mechanism has yet been developed for a particular enzyme. One of the reasons is that they are frequently created using fictitious chemistry, which may have several problems, for example, if the theoretical mechanism on which these substances work is unreliable. Secondly, if the substrate’s structural alteration to produce the mechanism-based inactivator results in a distinct chemical composition from that of typical substrate turnover, and finally, if more than one reaction pathway can be followed by the activated product created, only one pathway results in inactivation. In general, only thorough product evaluations allow for the creation of more sophisticated theories about the actual mechanism of action involved. Additionally, mechanism-based inhibitors are unreactive compounds with structures unlike the substrate or the product of the target enzyme. In contrast, reactive substances that form covalent bonds with enzymes may be more selective for the target enzyme and, hence, less hazardous [30].

7. Different Classes of Sulfonamide Derivatives

Sulfonamides are a class of synthetic antibacterial medication with critical pharmacological significance. They treat numerous bacterial illnesses in humans and animals because of their broad antibacterial action spectrum. These are the sulfur-containing organosulfur structures that include SO₂NH₂ and SO₂NH-. They are not naturally biodegradable. These sulfonamides fall into two primary categories: those that include aromatic amines, or “antimicrobials,” and those that do not, or “non-antimicrobials.” While the aromatic amine group is typically lacking in non-antimicrobial sulfonamides, it is present in antimicrobial sulfonamides at the N₄ position [32].

The sulfonamides and their structurally analogous derivatives, including sulfamates and sulfamides, are characterized by the general formula A-SO₂NHR, wherein the functional group is either covalently attached to a heterocyclic, carbohydrate, aromatic, or aliphatic scaffold (designated as type A), or is attached to these scaffolds with the help of a heteroatom, most commonly oxygen or nitrogen, thus resulting in the formation of sulfamates and sulfamides, respectively [33]. The identity of the R substituent may exhibit considerable variability, commencing with hydrogen. Primary sulfonamides/sulfamates/sulfamides are referenced [34], extending to many substituents incorporating heteroatoms such as OH and NH₂. Consequently, this category of compounds can yield an extensive array of derivatives, which are generally readily obtainable through traditional synthetic approaches and embody drug-like characteristics that have been recognized for numerous decades [35,36].

Prominent motifs within medicinal chemistry have encompassed the sulfanilamide or sulfonyl functional groups. Owing to their extensive diversity of biological applications, including antioxidant, antifungal, antibacterial, diuretic, anti-inflammatory, anticancer carbonic anhydrases, antitumor, and GSK inhibitors, as well as in the context of Alzheimer’s disease, anti-tubercular, anti-diabetic, and anti-HIV inhibitors, sulfonamides have recently garnered substantial attention in the fields of biology and medicine (Figure 6). Historically, sulfonamides have been employed against bacterial infections within biological systems [37-40]. To develop potent and safe urease inhibitors, numerous sulfonamide derivatives have been subjected to rigorous investigation over the past few decades. This study has led to the discovery of some compounds, like already available drugs, that can be used as novel, highly effective urease inhibitors. Therefore, this section will present an overview of several sulfonamide derivatives that exhibit potent urease-inhibiting properties.

Representative FDA-approved sulfonamide-containing molecules.

8. Urease Inhibitors

Over the past two decades, the scientific community has focused on designing, synthesizing, characterizing, and studying the wide range of potency of biologically active chemical building blocks. Pathogenic resistance is common, and pharmaceutical research has traditionally placed great importance on finding novel inhibitors with various structural compositions. According to the biological, synthetic, and therapeutic viewpoints, this expanding subject has always been an area of interest. In the past few decades, biomedical experts have paid close attention to enzyme inhibition [41]. An enzyme’s selectivity toward specific inhibitors, which might be either simple organic molecules or complex chemical structures, is one of its fundamental characteristics. The size, structure, and interaction forces that lead to the exact match between the enzyme and inhibitor determine the inhibitor’s specificity. Under physiological circumstances, these inhibitions stop the enzyme from becoming active. Urease inhibitors are essential in preventing the adverse effects caused by urease enzymes and significantly enhance human health. Since urease has various functions and its inhibition has recently gained special attention, many urease inhibitors have been described [42]. Some of the corrosive subordinates in this group are hydroxamic acids, hydroxyurea, phosphorodiamidates, and imidazoles, including rabeprazole, lansoprazole, and omeprazole, as well as thiol derivatives, quinines, Schiff bases, phenols, and thiourea derivatives. Sulfonamides are a very important class of compounds that act as high-ceiling antiglaucoma, antithyroid, anti-inflammatory, diuretic, hypoglycemic, and antibacterial agents [43]. Urease inhibitors can be classified based on their chemical makeup, including metal complexes, sulfonamide, flavone, thiourea, thiazole, coumarin, phosphoramide, hydroxamic acid, indole, chalcone, benzimidazole, barbituric acid, and thiobarbituric acid, as well as quinazolinone, oxadiazole, hydroxamic acids, which were found to be effective against several bacterial ureases, are the most well-known urease inhibitors [1].

9. Classical Urease Inhibitors

The class of urease inhibitors most thoroughly investigated is thought to be hydroxamic acids. The main factor behind the strong inhibitory action against urease is its well-known metal-complexing characteristics, including two nickel ions bound inside the active site. This study investigated several n-aliphatic, m- and p-substituted benzo- and aryl-alkyl hydroxamic acids. The most effective substances had low micromolar IC₅₀ values. The investigation of hydroxamic amino acids and their N-substituted derivatives. By limiting urine alkalization, acetohydroxamic acid was reported to be effective against urinary tract infections [44]. A class of urease inhibitors with the highest activity comprises di- and tri-amides of phosphoric acid (Figure 7). This is a direct result of their high resemblance to the tetrahedral transition state of the enzymatic reaction of urea hydrolysis. Studies on the effect of eradicating microorganisms in vivo demonstrated their effectiveness. Studies on phosphorodiamidate-induced inhibition strongly indicated that phosphorodiamidate was hydrolyzed when bound to the active site, and phosphorodiamidic acid was the true inhibitor.

Phosphorodiamidate as the transition state analogy of urea hydrolysis.

According to another research, the urease complex was discovered after phenyl phosphorodiamidate was added to the enzyme. The major flaw in this family is their poor hydrolytic stability. Amino-phosphinic acids, one type of non-hydrolyzable analog of phosphoramidite, are effective urease inhibitors in bacteria. These substances are the strongest and are used in agriculture as soil urease inhibitors. The tetrahedral intermediate produced by hydroxamic acids and phosphoramide compounds shares structural similarities with the one thought to form after the hydrolysis of urea [13].

Thiourea derivatives have numerous uses in analytical chemistry, agriculture, and medicine. These substances display various biological properties, including antibacterial, antiviral, and fungicidal effects. Due to these key discoveries, thiourea derivatives have drawn more interest in medicinal chemistry and drug development. Importantly, thiourea is a promising inhibitor of urease that might be employed as a lead molecule and positive control in the study of new urease inhibitors [45].

Another group of substances that demonstrated enzyme-inhibiting properties is quinone derivatives. Quinones are a group of physiologically active substances with strong oxidizing potential. Their notable reactivity with the sulfhydryl group, which is manifested in their heightened affinity for the cysteine residues within the enzyme, parallels the mechanism of action observed in structurally analogous α, β-unsaturated ketones, thus underscoring their potential application as urease inhibitors. Investigations on urease isolated from Canavalia ensiformis, Bacillus pasteurii, H. pylori, and Klebsiella oxytoca revealed that halogenated quinones exhibit irreversible and robust inhibitory effects. The halogen type was determined to be of lesser significance; however, substituting it with a hydroxyl (-OH), cyano (-CN), alkoxyl, or alkyl group diminished the affinity of the unsubstituted quinones. Chlorine substitution on benzoquinone yielded compounds that demonstrated the greatest efficacy against H. pylori urease [46].

10. Sulfonamide-Containing Urease Derivatives

10.1. Drug-conjugated sulfonamide derivative

Levofloxacin is an antibiotic in the fluoroquinolone class that is effective against various bacterial infections. Levofloxacin was said to have good urease-inhibiting actions. Recently, a high level of H. pylori resistance to antibiotics has been observed, along with decreased patient compliance, which calls for novel inhibitors with improved efficacy and straightforward therapy [47]. The work reported here aims to synthesize levofloxacin’s Schiff bases using several sulfa medications. Compound 1(a-f) represents the Schiff base created by conjugating the antibiotic levofloxacin with the sulfonamide (Figure 8). A serial dilution was performed within the concentration range of 250-0.49 μM for each compound and for levofloxacin to calculate IC₅₀ values. Their inhibitory values ranged from 0.45 ± 0.21-1.41±0.24 μM. Compound 1f was more effective than levofloxacin (IC₅₀ = 3.21 ± 0.24 μM) as it exhibited the lowest (IC₅₀ = 0.45 ± 0.21 μM) value and showed a competitive mode of inhibition. Its binding interactions have been shown in Figure 9. In contrast, 1a and 1g with IC₅₀ = 0.58 ± 0.11 μM and 0.52 ± 0.11 μM inhibited urease activity in a mixed manner [48].

Competitive inhibitor docking pose: (a) The best-docked position for competitive inhibitor 1f (green sticks) in the urease enzyme catalytic site (b) Surface illustration of a docked 1f compound at a catalytic site. Brown spheres represent Ni ions, and yellow dotted lines depict hydrogen bonding. The surface contour map of the urease enzyme is red in color. Reproduced with permission from the ref. [48], Elsevier, copyright 2021.

Through kinetic analysis, it was determined that compound 1f was a competitive inhibitor with a K_i value of 1.13, and compound 1a was a mixed-type inhibitor with a K_i value of 3.40. The competitive inhibitor 1f molecule was docked at the catalytic site of the urease enzyme following the completion of enzyme kinetic experiments to forecast its likely binding mechanism. The substance has successfully docked in the binding pocket where the piperazine moiety faces the Ni ion and forms an electrostatic contact. The side chain of the ARG439 residue forms an ionic bridge with the three fused rings’ carboxylate groups.

Thus, extending the range of commercial drugs like ciprofloxacin, sulfadiazine, and thiosemicarbazide drugs with sulfonamides for the synthesis of respective compounds 2(a-f), 3(a-f), and 4(a-f). All compounds were screened in a Jack bean urease enzyme inhibition assay. Their inhibitory activity for all compounds was found with their respective IC₅₀ values. For compounds 2a-f, the IC₅₀ values were in the 0.001 ± 0.003-0.110 ± 0.004 μM range. For compounds, 3a-f IC₅₀ values ranged from 0.02 ± 0.000-0.233 ± 0.011 μM, and for compounds 4a-f, the IC₅₀ values ranged from 0.026 ± 0.002-0.2254 ± 0.006 μM [49]. Among the evaluated pharmaceutical derivatives, the ciprofloxacin derivative 2e, the sulfadiazine derivative 3a, and the thiosemicarbazide derivative 4d demonstrated superior efficacy, exhibiting IC₅₀ values of 0.0453 ± 0.0016, 0.00223 ± 0.00021, and 0.0266 ± 0.0021 µM, respectively. In general, ciprofloxacin-modified sulfonamides exhibited enhanced potency in comparison to other derivatives. Docking analysis suggested that the compounds localized in the receptor’s active site most effectively adopted various conformations. The most potent representatives from each category, compounds 2e, 3a, and 4d, were investigated regarding their urease inhibition mechanism. The elucidation of the action mechanism of urease inhibitors 2e, 3a, and 4d indicated that they impede enzyme activity through two distinct pathways: firstly, via competitive inhibition by forming a urease inhibitor complex, and secondly, through non-competitive inhibition by disrupting the urease-substrate (urea)-compound interaction. The docked complexes underwent additional scrutiny based on hydrogen and hydrophobic binding interactions. The structure-activity relationship (SAR) analysis indicated that in the docking of 3a, two hydrogen bonds were identified with HIS593, with bond distances measuring 2.30 Å and 2.60 Å. Furthermore, a singular hydrophobic interaction was noted with ALA636, presenting a bond length of 4.03 Å. The benzene ring’s oxygen group of sulfur, and amino moiety directly interacted with HIS593 through hydrogen bond formation. Analogously, a hydrophobic interaction was formed between the benzyl methyl group and the active site. Three hydrogen bonds were seen in the docking complex of 2e, shown in Figure 10. Hydrogen bonding was confirmed between methoxy and oxygen functional groups of 3e ARG439 and ALA636, with the reported bonding distances of 3.06 Å, 2.92 Å, and 4.40 Å, respectively. Similarly, during the docking of 4d, a single hydrogen bond was detected between ARG439 and an oxygen atom of the ligand, with a bond distance of 1.78 Å shown in Figure 10. It was noted that ARG439 represented the most frequently interacting residue across all docking analyses. All synthesized ligands 2a-f, 3a-f, and 4a-f underwent evaluation in molecular docking assays against urease. The results indicated compound 3a as the most potent inhibitor. Molecular docking has been shown in Figure 10.

The best-synthesized compounds’ binding positions are shown in the center of the binding pocket of urease. The surrounding circles show the individual docking results for the top three compounds. The urease protein is highlighted in grey in every docking complex, whereas the interior is colored olive drab, and the interaction residues are noted in purple. The docking complex’s most active and powerful molecule, 3a, is depicted in the color khaki, while the other compounds, 2e and 4d, are portrayed in salmon and sea green, respectively. The oxygen and amino groups are shown in red and blue, respectively, with the sulfur group in all compounds highlighted in yellow. Reproduced from the ref. [49], under Creative Commons Attribution (CC BY) license, copyright 2017.

In another study, sulfa drugs were conjugated with mefenamic and diclofenac acid and were studied as urease inhibitors. The compounds 5a, 6a, 5g, and 6f were found to be the most potent inhibitors with IC₅₀ values of 3.59 ± 0.07, 5.49 ± 0.34, 7.92 ± 0.27, and 8.35 ± 0.26 µM, respectively. Molecular docking was used further to analyze compound-urease interactions and binding poses, as shown in Figure 11. According to MD simulations, all of the complexes of these conjugates with urease were stable. While keeping the results in view, these compounds can help develop new therapeutic agents for urease-associated diseases [50].

Binding interactions of (a) 5a, (b) 6a, (c) 5g and (d) 6f against urease. Reproduced from the ref. [50], under Creative Commons Attribution (CC BY-NC-ND 4.0) license, copyright 2023.

Another study synthesized innovative compounds by conjugating sulfa drugs with acetylsalicylic acid. The in vitro anti-urease efficacy of the synthesized conjugates was calculated, with thiourea employed as a reference compound for urease inhibition assays, demonstrating an IC₅₀ value of 22.61 µM. All synthesized conjugates exhibited significant inhibitory effects against urease activity. The conjugation of acetylsalicylic acid with sulfanilamide (7a), sulfadiazine (7d), and sulfacetamide (7h) revealed remarkable inhibitory potency, illustrating a competitive inhibition mechanism against urease. The determined IC₅₀ (µM) values for urease inhibition were 2.49 ± 0.35, 6.57 ± 0.44, and 6.21 ± 0.28, respectively. Compound 7a (acetylsalicylic acid-sulfanilamide) demonstrated the highest inhibitory efficacy against urease, with a K_i value of 9.80 µM [51]. The docked conformations of the conjugates were aligned with the co-crystal ligand to evaluate their potential binding modalities, as shown in Figure 12. The molecular docking methodology was utilized to forecast the interaction of compounds under investigation against urease receptors. The ability to inhibit these compounds was calculated by applying molecular docking. The results for mixed and competitive conjugates fell within the range of -7.124 to -4.484 kcal/mol. The molecular interactions of conjugate 7d with urease were analyzed. It revealed the formation of two hydrogen bonds with HIS519 and ARG609, and five hydrophobic interactions.

The possible binding modes of the compounds 7(a-h) were aligned with the reference of the co-crystal ligand. Red sticks represent the co-crystal ligand, while the conjugates are shown in multi-color strips. Reproduced with permission from the ref. [51], Taylor and Francis, copyright 2023.

Conjugate 7h formed two π-alkyl interactions with ALA440 and CYS592, along with three hydrogen bonds involving ARG439, HIS519, and ARG609. Compound 7a formed two hydrogen bonds with ARG439 and HIS519 and four hydrophobic interactions (Figure 13).

Molecular interactions and potential binding mechanisms of inhibitors 7a, 7d, and 7h targeting urease. The spheres indicate different molecular interactions: hydrogen bonds in green, sigma bonds in purple, π-alkyl bonds in magenta, and π-sulfur linkages are shown in orange. Reproduced with permission from the ref. [51], Taylor and Francis, copyright 2023.

Propanamide-conjugated sulfonamides (8a-8h) have been synthesized and evaluated for their inhibitory effects on urease. All synthesized compounds exhibited inhibitory activity within the range of 4.08 ± 0.10-29.64 ± 0.27 μM, in contrast to the standard thiourea, which demonstrated an IC₅₀ value of 22.61 μM. The conjugate comprising naproxen and sulfathiazole displayed the highest potency (8c, IC₅₀ = 5.82 ± 0.28 μM). In contrast, the guanidine (8h, IC₅₀ = 5.06 ± 0.29) and amino (8a, IC₅₀ = 6.69 ± 0.11) groups present on the sulfonamide exhibited superior urease inhibition activities when compared to five- and six-membered heterocyclic substituents. These three compounds inhibited the urease enzyme via a competitive mechanism, achieving inhibition rates of 88.9%, 89.1%, and 89.4%, respectively. In contrast, the remaining conjugates also displayed considerable urease inhibition, ranging from 84.3% to 94.1%; specifically, the naproxen conjugates with sulfadiazine (8d), sulfamerazine (8e), and sulfacetamide (8g) demonstrated a mixed mode of urease inhibition. The competitive mode of inhibition of the conjugates (8a, 8c, and 8h) was substantiated through kinetic studies [52]. The results of docking studies have been shown in Figure 14.

Molecular binding interactions of compounds 8a, 8c, and 8h with urease. Reproduced from the ref. [52], under Creative Commons Attribution (CC BY) license, copyright 2023.

In the domain of docking investigations pertinent to urease, it has been documented that compound 8a established three hydrogen bonds with ASP494, GLY550, and HIS492, in conjunction with hydrophobic and π-πinteractions with LEU523 and HIS492, respectively. Compound 8c exhibited hydrogen bonding with ALA440, ARG439, and GLU493, in addition to four π-Alkyl interactions with PHE605, HIS545, LEU523, and ALA636, two van der Waals interactions with GLY550 and HIS492, alongside one π-sulfur interaction with ASP494. Moreover, compound 8h formed three hydrogen bonds with GLU493, ALA440, and ALA636, supplemented by hydrophobic interactions with LEU523, HIS593, and HIS492.

A study elucidates that the target compounds, ibuprofen and flurbiprofen, were conjugated with various substituted sulfonamides, after which these scaffolds were assessed for their urease inhibitory efficacy. Ibuprofen conjugated with sulfathiazole (9c), flurbiprofen conjugated with sulfadiazine (10d), and sulfamethoxazole (10f) exhibited notable potency and displayed a competitive mode of urease inhibition, with IC₅₀ (µM) values documented at 9.95 ± 0.14, 16.74 ± 0.23, and 13.39 ± 0.11, and corresponding urease inhibition percentages of 90.6%, 84.1%, and 86.1%, respectively. The prominent structural feature of the most effective inhibitor (90.6% inhibition) comprised a thiazole-substituted sulfonamide, wherein 9c demonstrated an IC₅₀ of 9.95 ± 0.14 µM. In contrast, the analogous substituted sulfonamide linked to flurbiprofen 10d (14, IC₅₀ = 16.74 ± 0.23 µM) exhibited a six-fold diminished activity against urease (84.1% inhibition). The acetamide moiety associated with phenyl-alkyl substituents exhibited superior potency to the fluoro-substituted biphenyl group. The conjugates (9a, 9e, 9g, 10e, and 10g) displayed a mixed mode of inhibition, with IC₅₀ (µM) values of 14.26 ± 0.14, 12.43 ± 0.54, 10.27 ± 0.11, 17.48 ± 0.76, and 14.78 ± 0.16, respectively [53]. The mechanisms of binding and the molecular interactions of inhibitors were meticulously studied utilizing molecular docking techniques, as shown in Figure 15. It was observed that compound 9c established three hydrogen bonds with HIS593, ALA440, and ARG609, formed one π-sulfur bond with MET637, and engaged in three hydrophobic interactions. Conjugate 10d participated in hydrogen bonding with ALA440, HIS519, and ARG609; created two π-sulfur bonds with HIS492 and MET637; and experienced van der Waals interactions with LEU595 and PHE605. Finally, conjugate 10f established four hydrogen bonds with ALA440, HIS519, CYS592, and ARG609, formed two π-sulfur bonds, and engaged in four π-alkyl bonds.

The molecular interaction of inhibitors with urease. In this figure, green spheres represent hydrogen bonds, purple spheres indicate σ bonds, orange spheres denote π-sulfur bonds, and magenta spheres signify π-alkyl bonds. Reproduced from the ref. [53] under Creative Commons Attribution (CC BY) license, copyright 2023.

10.2. 4-chlorophenyl sulfonamide derivatives

Derivatives of alkyl phenyl sulfonamide are also effective urease inhibitors. Sulfonamides and phenyl-substituted rings were conjugated to create a wide variety of chemicals. In a study, some chlorinated sulfonamides (7a-i) were produced by mixing 4-chlorobenzenesulfonyl chloride with different substituted anilines while maintaining a basic pH in an aqueous medium and were studied against the urease enzyme (Figure 16). The urease inhibitory activities IC₅₀ (μM) of these compounds 5a-5i have been listed below. These compounds shows 7a (IC₅₀ = 98.09 ± 0.05), 7b (IC₅₀ = 109.01 ± 0.03), 7c (IC₅₀ = 157.7 ± 0.08), 7d (IC₅₀ = 212.91 ± 0.04), 7e (IC₅₀ = 269.21 ± 0.13), 7f (IC₅₀ = 271.08 ± 0.02), 7g (IC₅₀ = 238.33 ± 0.04), 7h (IC₅₀ = 265.08 ± 0.08), and 7i (IC₅₀ = 113.09 ± 0.04) [54].

4-chlorophenyl sulfonamide derivatives 13(a-i).

The screening against the urease enzyme revealed that only compound 13a was reported as the most potent inhibitor for urease, having an IC₅₀ value of 98.09 ± 0.05 µM, with respect to thiourea, a reference standard with an IC₅₀ value of 21.28 ± 0.11 µM. The effective inhibitory activity of this compound was attributed to the presence of alkyl groups at the ortho and meta positions of aniline. Further modifications can improve the ability to inhibit [55].

10.3. Sulfanilamide thiourea derivatives

Thiourea derivatives have numerous uses in analytical chemistry, agriculture, and medicine. These substances have a variety of biological effects, including antibacterial activity. Due to these key thiourea discoveries, thiourea derivatives have drawn more interest in medicinal chemistry and drug discovery [56]. Novel sulfonyl thiourea derivatives (8a-8t) were created in the current study (Figure 17), and their in vitro urease inhibitory activities were tested [57].

Sulfanilamide thiourea derivatives 14 (a-t).

Urease enzyme inhibitory potential of these compounds 14 (a-t) with respective IC₅₀ values ranged from 0.20 ± 0.01-23.0 ± 3.3 μM. A significant proportion of the compounds demonstrated the promising ability to inhibit urease, with IC₅₀ values from 0.20 to 7.50 μM. The most potent compound reported was 14b (IC₅₀ = 0.20 μM), exhibiting a potency 100-fold greater than that of thiourea, the reference inhibitor. Additionally, compound 14l was determined to possess an activity 50-fold superior to that of the standard inhibitor.

Thiourea was subjected to docking analysis against the aligned structures of bacterial urease and Jack bean urease. The predicted binding modes of these compounds have been shown in Figure 18. It was observed that no docking predictions could be produced in the presence of metal pharmacophoric constraints. However, when these constraints were removed, the docking studies showed analogous binding modes of urease structures. Thiourea engages in interactions through hydrogen bonding with the Asp residue (ASP633 in Jack bean urease and ASP363 in bacterial urease), the GLY residue (GLY550 in Jack bean urease and GLY280 in bacterial urease), and the ALA residue (ALA636 in Jack bean urease and ALA170 in bacterial urease). The optimal scoring positions of each compound were scrutinized for binding modes within the active sites of the two enzymes [58].

Predicted docked conformations of all compounds (14a-14t) within the binding pocket of Jack bean urease. The blue spheres indicate the metal pharmacophores surrounding the two nickel (Ni2+). The dotted lines indicate various interactions between compounds and active site residues, including hydrogen bonding and aromatic interactions. The docked poses are depicted in stick representation. Reproduced with permission from the ref. [58], Springer Nature, copyright 2013.

The optimal scoring conformations of all studied compounds were meticulously examined within the binding sites of the two enzymes to elucidate binding modalities, as shown in Figure 19. Consistent binding modalities were observed across all compounds within both urease architectures. The observed docking scores, ranging from −26 to −38 in Jack bean urease and from −34 to −38 in H. pylori urease. It has been consistently noted across all docking analyses derived from both structures that the sulfonamide functional group of the 1-aroyl-3-(4-aminosulfonylphenyl) thiourea derivatives exhibited interactions with the bi-nickel catalytic center of the enzyme. The sulfur atom within the sulfonamide group was positioned nearly identically to the location of the phosphorus atom in PO₄, as observed in the crystal structure. Interactions with both nickel ions were seen in each compound. The remaining R-groups of the compounds exhibited unencumbered conformations directed toward the aperture of the binding site (Figure 20).

(a) Thiourea inside the active site of Jack Bean urease. (b) Thiourea inside the active site of bacterial urease. Reproduced with permission from the ref. [58], Springer Nature, copyright 2013.

The Above figures show the interaction diagram of compounds (14b, 14l), which showed excellent activity against urease. An interaction diagram for inhibitor 14b shows hydrogen bonding by the oxygen of ASP494 and ALA440 residues and a nitro group of HIS593. An interaction diagram for inhibitor 14l (2Cl, 5-NO2) shows hydrogen bonding by the oxygen of ALA636, ARG439, and CME592 residues and the nitro group of HIS593. Reproduced with permission from the ref. [58], Springer Nature, copyright 2013.

10.4. Benzophenone sulfonamide derivative

It is widely known that benzophenones have antibacterial, anti-inflammatory, antioxidant, and urease inhibitory action as chemotherapeutic agents. As one of the fungicides, Fluomorph also features benzophenone as a crucial structural component. The benzophenone sulfonamide hybrids were synthesized and in vitro tested against the urease enzyme. In silico research has also been done to comprehend the active compound’s way of binding to the urease enzyme [59].

The benzophenone sulfonamide 15(a-z) derivatives were synthesized (Figure 21). Among the synthesized derivatives, seventeen compounds with IC₅₀ values ranging from 3.90 to 71.63 μM. The most potent compound, designated as 15l, demonstrated an IC₅₀ value of 3.90 ± 0.81 μM, approximately tenfold more potent than acetohydroxamic acid. A limited examination of the SAR indicates that the hydroxylated benzophenone moiety contributes significantly to the observed inhibitory activity. Additionally, among the hydroxylated benzophenone derivatives, various substituents at the alkyl/aryl sulfonyl moiety correlate with a differential spectrum of biological activity. Within this cohort of synthetic compounds, twelve derivatives possess a hydroxyl group at the 4′-position of the benzophenone moiety, while nineteen derivatives lack a hydroxyl group within the benzophenone framework. In hydroxylated benzophenone molecules, compound 15c (IC₅₀ = 14.51 ± 1.14 μM), having a methoxy group at the 4′′-position of the aryl sulfonyl part, was promising. The compounds 15(a-e) exhibited IC₅₀ values ranging from 3.90 ± 0.81-31.20 ± 0.16.

Benzophenone sulfonamide derivative 15(a-z).

Molecular docking was employed to study the binding modes of these compounds, shown in Figure 22. Compound 15a (docking score = -21.4737), for example, demonstrated an arene-cation interaction with catalytic residue HIS323 and also created connections with both nickel ions of the urease enzyme’s active site. It was the most active chemical in the series because it had a -NO₂ group at the para position

Docking conformation of compound 15a. Reproduced with permission from the ref. [59], Elsevier, copyright 2019.

Molecule 15d, which was the second-most active compound (docking score = -21.3977), displayed comparable interactions, with one phenyl moiety of the ligand in touch with nickel and the other forming an arene-cation connection with HIS323, shown in Figure 23. Although compounds 15a and 15d both demonstrated promising inhibition ability. However, the two differentiated because of chlorine groups in the ortho position and hydroxyl groups in meta positions in compound 15d, making it the second most potent.

Docking conformation of compound 15d. Reproduced with permission from the ref. [59], Elsevier, copyright 2019.

The compound 15b, demonstrating one arene-cation interaction with the enzyme’s catalytic residue HIS323 (docking score = -20.7057), shown in Figure 24.

Docking conformation of compound 15b. Reproduced with permission from the ref. [59], Elsevier, copyright 2019

The substance in question is 15c (docking score = -20.7057), demonstrating one arene-cation interaction with the enzyme’s catalytic residue HIS323, shown in Figure 25 [60].

Docking conformation of compound 15c. Reproduced with permission from the ref. [59], Elsevier, copyright 2019.

10.5. Pyrazolotriazine sulfonamide derivatives

The pyrazolo triazine moiety is reported to be useful in developing inhibitors of enzymes. It helps to satisfy the pharmacophoric requirements during the drug design stage, providing proper structural alterations.

The series of compounds 16(a-j) were synthesized (Figure 26), and their urease inhibition activity ranged from 0.042 ± 0.012-0.080 ± 0.015 μM [61]. The exceptional effectiveness was evidenced by derivatives (16a) and (16i) exhibiting IC₅₀ values of 0.037 and 0.042 μM, respectively. Concerning compound 16a, incorporating the 2-hydroxy-1-methyl ethaneamine moiety with an S configuration at the sulfonamide group is critical for urease inhibitory activity among the evaluated derivatives. This particular moiety in compound 16a is responsible for its enhanced urease inhibitory efficacy. In contrast, the isomeric derivative 16b, distinguished by R-configuration in the sulfonamide portion, demonstrated the lowest activity within the array of synthesized compounds, notwithstanding its display of greater urease inhibitory activity than the reference thiourea.

Pyrazolotriazine Sulfonamide derivatives 16 (a-j).

10.6. Barbituric acid sulfonamide derivatives

It is well known that many thiobarbituric and barbituric acid derivatives have potent antibacterial, sedative, herbicidal, fungicidal, and antiviral effects. Similarly, sulphanilamide’s biological activity has also been extensively studied. The current work was carried out to produce compounds with antibacterial and urease inhibition activity, considering the biological activity of barbituric acids and sulfonamide. Compounds 17(a-j) were synthesized (Figure 27) and screened for urease inhibition.

Barbituric acid sulfonamide derivative 17(a-j).

Compounds showed the inhibitory values (IC₅₀) ranged from 3.76 ± 0.027-96.4 ± 2.33 μM. The compounds 17c, 17d, 17e, 17h, 17i, and 17j were strong inhibitors; compounds 17a and 17g showed average inhibition ability, while compounds 17b showed weak inhibition activity against the urease enzyme [62].

10.7. Curcumin sulfonamide derivatives

Due to the pharmacological safety of curcumin, it has drawn significant interest in biomedical research against various disorders [63]. It demonstrated a variety of biological actions, including antibacterial, antifungal, anti-inflammatory, antioxidant, and cancer-preventive qualities [64,65]. In a work, azomethines (Schiff bases with sulfonamides) are synthesized [66]. The target curcumin-azomethines containing sulfonamide moieties (Figure 28) were prepared by the interaction of curcumin with sulfa drugs such as sulfathiazole, sulfamerazine, sulfafurazole, sulfadiazine, sulfadoxine, and sulfacetamide. The urease inhibitory activity of each produced curcumin derivative was assessed. The most powerful compounds, 18 and 19(a-f), were subjected to kinetic tests at various concentrations to study the inhibition mechanism further.

Curcumin sulfonamide-based derivatives 18, 19 (a-f).

The IC₅₀ values of compounds 18a-f ranged from 11.43 ± 0.21-41.53 ± 0.31 μM, and for the compounds 19a-f ranged from 16.63 ± 0.29-39.97 ± 0.33 μM. The inhibitory mechanism was also examined by conducting kinetic tests on curcumin and thiourea. The most effective compounds, 18d-18e, 19b-19c, and 19e, were tested for the inhibitory mechanism. The molecular docking simulation investigations of the compounds 18c, 18d, and 18e were carried out using the Glide docking software to evaluate the conceivable binding mechanisms of the competitively binding compounds against the urease enzyme, as shown in Figure 29. The optimum docking poses for compounds 18c, 18d, and 18e produced glide scores of -3.709, -3.919, and -3.785 kcal/mol, respectively. The binding site’s electrostatic surface reveals that the enzyme has polar residues near the nickel ions. At the binding pocket’s entry point, as illustrated in Figure 29. Further research demonstrated the creation of a hydrogen bond between the hydroxy hydrogen of compounds 18c, 18d, and 18e and the backbone carbonyl oxygen of the GLY550 residue [67].

(a) Electrostatic surface of the urease enzyme and docked inhibitor shown in cyan, (b) Binding interactions of the docked compound represented in cyan with the urease enzyme in green. Nickel ions are light brown, hydrogen bonding with yellow dotted lines. (c) Binding modes of all competitive inhibitors, 18c in magenta, 18d in white, 18e in yellow. Reproduced with permission from the ref. [67], Copyright 2017, Elsevier.

10.8. Hydrazide-based sulfonamide derivatives

Hydrazides are useful substances that can be employed as ligands in coordination chemistry and for synthesizing heterocyclic systems to prepare metal complexes. The scientific literature frequently mentions hydrazides’ antibacterial characteristics while discussing their bioactivity profiles. This is particularly crucial because the prevalence of strains resistant to antibiotics and other forms of treatment has made it harder and sometimes impossible to cure illnesses. New aliphatic hydrazide-based benzene sulfonamide derivatives 20(a-o) were synthesized (Figure 30). The derivatives 20a-o inhibited the urease activity with IC₅₀ values ranging from 2.10 ± 0.10-25.30 ± 0.30 μM [68].

Hydrazide-based sulfonamide derivatives 20(a-o).

Molecular docking was done to investigate their binding interactions. All compounds had roughly identical properties due to better contacts, although correspondents 20e and 20f were discovered to have strong interactions because of different substituents, as shown in Figure 31. In the current study, the scaffolds (20e and 20f) bearing fluoro and tri-fluoro moieties, respectively, were electron-withdrawing groups; however, properties to form strong hydrogen bonds originated with improved interactions and their layover surface complex structure alongside urease (docking score = 9.80). The presence of attached substituents may have improved these ligands’ interactions. Interactions such as van der Waals, typical hydrogen bonds, alkyl, π-alkyl, salt bridges, halogen, π-sulfur, etc., were seen in the case of correspondents 20e and 20f [68].

Figure 31.

Interaction of the enzyme and ligand of potent compounds against urease. The PLI profile for compound 14e. Reproduced from the ref. [68], under Creative Commons Attribution (CC-BY) license, 2022.

10.9. Oxadiazole sulfonamide derivatives

The five-member heterocyclic molecule oxadiazole comes in four distinct isomeric forms. The 1, 3, and 4-oxadiazole forms are discovered to be the most effective in terms of biological behavior among these forms [69]. Derivatives of sulfonamide and oxadiazole have been established with noteworthy pharmacological properties. The small structural alterations of oxygen- and nitrogen-containing polyfunctional molecules have medicinal potential. This work created derivatives 21a-21p by combining moieties, including 1, 3, 4-oxadiazole, 3-pipecoline, and sulfonamides in a single unit to increase the therapeutic potential for different purposes (Figure 32). The bioactivity of target molecules was assessed as anti-enzymatic potential for the urease enzyme [70].

These oxadiazole sulfonamide derivatives 21(a-p) were tested for their enzyme inhibitory activities against urease. The ability of each produced chemical to inhibit the urease enzyme was assessed. The IC₅₀ values of all the derivatives about thiourea (21.25 ± 0.15 μM) were found to be in the range of 52.45 ± 0.11-398.65 ± 0.48. Only six of the sixteen compounds, 21a, 21b, 21d, 21e, 21f, and 21h, were active. The remaining substances didn’t react with urease in any way and were found to be inactive. These substances were all put to the test against the common inhibitor urea. Only compound 21d, bearing the 3-nitrophenyl group, was the most active one among the six active compounds for anti-urease activity [70].

10.10. Sulfonamide-based Schiff base derivatives

Schiff bases are yet another example of organic molecules from medicinally significant classes. Its derivatives have a wide range of properties. Several investigations have recently described the urease inhibition by Schiff base and sulfonamide derivatives [71]. In search of potent urease inhibitors, some Schiff-based derivatives were synthesized. Sulfonamide derivatives 22(a-i) [72], sulphadiazine derivatives 23(a-i) [73], sulfamethazine and sulfamethoxazole derivatives 24(a-j) [74] by using a wide range of aromatic aldehydes (Figure 33). Inhibitory studies were performed on these compounds. The IC₅₀ values of compounds 22a-r ranged from 2.20 ± 0.45 to 45.56 ± 3.34 μM. Compound 22g, having an IC₅₀ of 2.20 μM, was more potent than the standard Thiourea (IC₅₀ = 20.03 ± 2.06). The compounds, owing to structural similarity with the basic skeleton of the urease substrate, showed good activity. The substituents on the scaffold had a great influence in evaluating the efficacy of urease inhibition; it was observed that halogen groups conjugated with the aromatic ring of aldehydes, specifically chlorine coupled with the hydroxyl moiety on 24g, exhibited significant outcomes that were further substantiated by the SAR analyses. Conversely, compound 22h, characterized by a hydroxyl group at C-2′ and a fluorine atom at C-4′, demonstrated robust anti-urease activity, evidenced by an IC₅₀ value of 5.96 ± 0.052 µM. Kinetic studies performed for these compounds 23a-i show IC₅₀ values in the 2.32 ± 0.54-35.63 ± 1.26.

Sulfonamide-based Schiff bases derivatives 22(a-r), 23(a-u), and 24(a-j).

Molecular docking studies were used to gather data on chemical binding processes. The enzyme’s crystal structure (PDB 4GY7) was employed to examine molecular docking. The most favorable binding conformation of compound 22a has been illustrated in Figure 34. This compound forms hydrogen bonds with key residues within the active site, notably engaging HIS594, which plays a role in coordinating the enzyme’s metallic center. Additionally, it establishes a bidentate interaction with ARG413. Alongside these interactions, the compound also engages in hydrophobic contact with VAL591. For the most potent compound, 22g, its binding mode is characterized by hydrogen bonding, depicted by blue dashed lines, while dotted lines indicate apolar interactions. This compound interacts via hydrogen bonding with the nitrogen of the imidazole ring in HIS594. Furthermore, it demonstrates hydrophobic interactions with nearby amino acids and exhibits a π-cation interaction with ARG439. The binding conformation of compound 22n, shown in Figure 34, reveals its anchoring within the active site through hydrogen bonding with HIS549 and a bidentate interaction with ARG439. The ligand’s aromatic charged center also engages in π-cation interactions with ARG439. Among the derivatives containing hydroxyl and methyl groups, compound 22q, with an IC₅₀ value of 4.64 ± 0.045, emerged as a potent urease inhibitor. Its binding mode, presented in Figure 34, involves a stable hydrogen bonding network with catalytically significant residues. The compound interacts through hydrogen bonding with the charged side chains of HIS492 and ASP494 and also forms a polar interaction with the backbone oxygen atom of HIS594. [72].

The simulated binding mode of compounds 22a, 22g, 22n, and 22q in the binding pocket of Jack bean urease. Reproduced with permission from the ref. [72], Elsevier, copyright 2020.

Studies on the SAR of sulphadiazine derivatives were conducted to screen them in silico to determine their ability to bind to the active site of the urease enzyme and their activity there.

Compound 23a, one of the most active derivatives of sulphadiazine, was identified as a possible inhibitor by in vitro and in silico studies and by strong hydrogen bonding, hydrophobic, and cation interactions (Figure 35). With the nitrogen of the A440, the oxygen from the sulfonamide moiety created a hydrogen bond. In addition, the imidazole ring of H593 interacts with the nitrogen of the Schiff base by hydrogen bonding, and the nitrogen of the pyridazine interacts with the imidazole ring of H594 through hydrogen bonding [73]. Strong hydrogen bonds were seen among the oxygen of the amino acid E493 and the hydroxyl group of the connected aryl ring in compound 23b, which possesses a hydroxyl at the ortho position of the aryl ring. The substance also demonstrated a hydrogen bonding connection between the nitrogen of the imine and the side chain of the imidazole ring of H593. More information revealed that the substance also interacts hydrophobically with the amino acids in urease to form a bond (Figure 36).

Binding interaction of 23a in the active site of Jack bean urease. Reproduced from the ref. [73], under Creative Commons Attribution (CC-BY) license, 2021.

23b in the active site of Jack Bean urease. Reproduced from the ref. [73], under Creative Commons Attribution (CC-BY) license, 2021.

Compound 23g, which has an aryl ring with fluorine at the para position, demonstrated a-polar interactions and hydrogen bonds (Figure 37). In this molecule, the pyridazine ring’s nitrogen is connected to R439 via a hydrogen link while connecting to H94’s imidazole ring via another hydrogen bond. Through hydrogen bonding, the nitrogen of the imine bond also communicates with the amino acid H593’s imidazole ring. Based on its strong in vitro and in silico activities, this substance may be effective against the urease enzyme [73].

23g in the active site of Jack Bean Urease. Reproduced from the ref. [73], under Creative Commons Attribution (CC-BY) license, 2021.

Compound 23j, featuring a hydroxyl group at the ortho position and a fluorine substituent at the para position of the aromatic ring, demonstrated both apolar and hydrogen bonding interactions. The nitrogen atom within the sulfonamide group formed an interaction with amino acid D494, while the nitrogen in the pyridazine ring engaged with the side chain of H593. Additionally, compound 23j exhibited hydrophobic interactions with amino acids D521 and E525 (Figure 38). Based on molecular docking analysis, these interactions suggest that this compound has the potential to act as a strong urease inhibitor.

Binding interaction of 23j in the active site of Jack bean urease. Reproduced from the ref. [73] under Creative Commons Attribution (CC-BY) license, 2021.

Molecular docking studies were done to learn more about potential compound binding processes. The enzyme’s crystal structure (PDB 4GY7) was employed to examine molecular docking. The recently created derivatives 24(a-j) were docked utilizing the previously described docking methodology. The best drug-docking conformations were seen inside the binding pocket with the right orientation. The hydrophobic and hydrophilic amino acids coexist at the active site. A good in-silico and in-vitro inhibitory potential was shown by the halogen-substituted sulfamethazine derivative 24a, which has fluorine at the para position of the aryl ring. According to the examination of compound 24a’s top-ranked docking pose, the molecule mediates hydrogen bonding with residues in the binding site. Hydrophobic interactions were also present in the molecule. Compound 24e, which featured chlorine at the para position and fluorine at the ortho position, showed a favorable interaction pattern consistent with its biological activity. Investigations of its main interactions showed that the imidazole side chain of H593 formed a hydrogen bond with the nitrogen of the pyrimidine ring in the sulfamethazine and showed a bond distance of 3.13 Å. This conjugate also exhibited hydrophobic interactions. Furthermore, a halogen bond is also present between the oxygen of D521 and the fluorine of the aryl ring. In silico results revealed that compound 24i, which has chlorine at para and hydroxyl at ortho positions, was identified as a potent inhibitor. The nitrogen of the imidazole ring in H594 forms a hydrogen bond with the hydroxyl of the connected aldehyde. In addition to hydrogen bonding, 24i demonstrated cation interaction with amino acid H594 (Figure 39). Only the aryl portion of the compound is directly involved in bonding, as shown in the figure. The other components are not directly involved in bonding, but they may still impact the compound’s overall electronic environment, which would explain the good in vitro inhibition [74].

Binding modes of compounds 24a, 24e, 24i in the binding pocket of Jack Bean Urease. Reproduced with permission from the ref. [74], Elsevier, copyright 2020.

10.11. Acetamide sulfonamide derivatives

A study synthesized novel sulfonamide compounds 25(a-f) (Figure 40) with an eye towards their possible use as jack bean urease enzyme inhibitors. The data obtained demonstrated outstanding activity of these synthetic compounds compared to the reference, with IC₅₀ values in the micromolar range. The IC₅₀ values of these compounds ranged from 0.0171 ± 0.0070-0.0698 ± 0.0014 μM [5]. Benzenesulfonohydrazide compounds 26(a-e) were used to study their urease inhibition. These compounds showed an inhibitory effect against urease, and their IC₅₀ values ranged from 1.11 ± 0.29-4.89 ± 0.09 μM [1].

Acetamide sulfonamide derivatives 25(a-f), 26(a-e), and 27(a-j).

Compound 25f was docked against jack bean urease to identify its most stable conformational orientation. The oxygen atom in 25f established significant interactions with VAL640, while additional residues in proximity to the ligand structure included GLU642, GLY641, ARG639, GLN635, and HIS585 (Figure 41). Previous studies have also highlighted the crucial role of these residues in binding with other urease inhibitors, further supporting the reliability of our docking results. The docking position of compound 25f has been illustrated in Figure 39 [5].

Docking complex of 25f. Reproduced with permission from the ref. [5], Thieme, Copyright 2018.

The competitive inhibitor 26b was docked in the urease enzyme’s active region, as shown in Figure 42. An electrostatic interaction occurs between the zinc metal ion and the pyridine ring. The Molecular electrostatic potential (MEP) analysis also reveals that the pyridine’s N atom has a considerable propensity for nucleophilic attack, which may have contributed to the 26b compound’s observed posture. The molecule is pushed closer to the active site by the tail part’s exposure of the toluene moiety towards the solvent side. It also formed t-type π-π interactions with HIS519 and HIS492 residues, which may be what made the drug a competitive inhibitor. The compound has fit well in the binding site [1].

Binding mode of competitive inhibitor (26b) in the urease enzyme. (a) Best docked pose of 26b compounds (green sticks) in the urease active site (cyan sticks), nickel ions are mentioned with the brown sphere. (b) 2D view of 26b docking pose in the active site. Reproduced with permission from the ref. [1], Elsevier, copyright 2020.

In another study, 2-iminothiazoline heterocycles with sulfanilamide nuclei were synthesized 27(a-j) and tested for their ability to suppress Jack bean urease. The compounds showed inhibitory activity (IC₅₀) in the range of 0.072 ± 0.015 to 0.35 ± 0.017μM [75]. Molecular docking of (27a-j) into the crystal structure of jack bean urease was carried out to clarify the inhibitory mechanism identified by the kinetics investigation, as shown in Figure 43. The compounds’ best docking conformations were neatly arranged inside the active site. Amino acids that were both hydrophilic and hydrophobic were used to build the active site. Each ligand interacted with the nickel ions in some way. Theoretical findings supported the experimental findings, which showed that all compounds had significantly higher activity levels than standard medications. This can be attributed to the multiple interactions between ligands and the numerous interactions with the Jack bean urease’s key residues compared to thiourea, the standard medication.

Docked poses of the ligands (27b) and (27f) inside the active site in 2D space. Reproduced with permission from the ref. [75], John Wiley and Sons, copyright 2016.

10.12. Thiophene sulfonamide derivatives

Thiophene derivatives are highly significant heterocycles in medicinal chemistry and have exceptional applicability across various fields [76]. 5-arylthiophene-2-sulfonylacetamide derivatives 28(a-g) were synthesized (Figure 44). The urease activity of compounds was measured at varying concentrations, and urease inhibition activity was investigated to get insights into their interaction with the active site. The inhibitory effect for these compounds was in the range of 23.3 ± 0.21-218±1.98 μM. Among all the compounds, 28b was most potent at concentrations of 40 µg/mL and 80 µg/mL and percentage inhibition values of 92.12 ± 0.21 and 94.66 ± 0.11, respectively, with an IC₅₀ value of ∼17.1 ± 0.15 µg/mL. Also, some other compounds exhibited significant activity against the urease enzyme. This study showed that 5-aryl thiophenes bearing sulphonylacetamide moieties are potent compounds with immense potential in the pharmaceutical industry [77].

Thiophene sulfonamide derivatives 28(a-g).

10.13. Bis-indole sulfonamide derivatives

Several bis-indole sulfonamide derivatives 29(a-l) were synthesized (Figure 45) and screened for urease inhibition [78].

Kinetic studies were performed for these compounds 29a-l, showing the inhibitory effect for urease; their IC₅₀ values ranged from 3.30 ± 0.20-19.60 ± 0.40 μM. Molecular docking research was conducted to understand how bis-indole-containing sulfonamide analogs decrease the activity of the urease enzyme, as shown in Figure 46. According to the docking results we obtained, these synthetic variants fit perfectly in the urease substrate binding site. A thorough examination of protein-ligand interaction (PLI) revealed that most of these effective chemicals against urease bind effectively to the target protein’s polar, basic, and acidic residues. With a docking score of -8.9067 and four non-covalent interactions with ASP494, ALA436, GLN635, and ALA440, analog 29e was discovered to be the most effective. Analogue 29a came in second with a docking score of -8.5766 and one hydrogen bond donor, which shows that both compounds have promising binding affinities [78].

Docking poses of the compounds (29a), (29b), (29d), and (29e). Reproduced with permission from the ref. [78], Elsevier, 2023.

11. Conclusion and Future Prospects

Urease is a crucial metalloenzyme implicated in various medical, environmental, and agricultural challenges. Its excessive activity plays a central role in the pathogenesis of Helicobacter pylori infections, urinary stone formation, and soil alkalization. Thus, urease inhibition has emerged as a promising strategy for developing novel therapeutics and enhancing agricultural sustainability. Among the diverse classes of urease inhibitors, sulfonamide-based compounds have demonstrated significant potential due to their structural adaptability, diverse biological activities, and strong enzyme-binding capabilities. This review highlights the inhibition mechanism, structural diversity, and biological activities of numerous inhibitors containing the sulfonamide moiety. Numerous classes of sulfonamide moiety, including chlorinated sulfonamides, drug-conjugated sulfonamides, benzophenone sulfonamides, sulfanilamide thiourea derivatives, and many others, have been investigated for their inhibition ability against urease. According to the results, these compounds showed potent results with IC₅₀ values in the nanomolar range. Overall, developing sulfonamide-based urease inhibitors is a promising advancement in medicinal chemistry and opens many doors for developing compounds with improved selectivity and efficiency. The quest for sulfonamide-based urease inhibitors is still in its early stages, and this topic holds immense potential for future research. They can be further investigated to improve their efficiency and selectivity, ultimately increasing their inhibition potential. Future research should focus on further modifying these compounds to improve their inhibition abilities. SAR studies can be employed to study the main features that contribute to the efficiency of these inhibitors and then use that information to develop more efficient inhibitors.

Despite these advancements, several challenges remain. The bioavailability, selectivity, and toxicity profiles of sulfonamide-based inhibitors require further optimization for clinical translation. Moreover, bacterial resistance to urease inhibitors necessitates exploring novel structural modifications to enhance their therapeutic efficacy. Future research should focus on integrating artificial intelligence (AI)-driven drug discovery, high-throughput screening, and in vivo validation studies to accelerate the development of next-generation urease inhibitors. Additionally, investigating the role of multi-targeted inhibitors that modulate other virulence factors alongside urease may open new avenues in antimicrobial therapy. In the agricultural sector, urease inhibitors hold immense potential in mitigating nitrogen loss from fertilizers and improving soil health. Sustainable and eco-friendly sulfonamide-based inhibitors should be explored to minimize environmental impact while maintaining high efficacy. The intersection of biotechnology and nanotechnology also presents exciting opportunities for developing nanoformulations of urease inhibitors for controlled release and targeted action.

In conclusion, sulfonamide-based urease inhibitors represent a promising medicinal and agricultural chemistry frontier. The continued exploration of novel derivatives, guided by computational and experimental approaches, will be instrumental in overcoming existing challenges and unlocking new therapeutic and industrial applications. A multidisciplinary approach integrating synthetic chemistry, biochemistry, computational modeling, and translational research will be the key to advancing urease inhibition strategies and their real-world applications.

Acknowledgment

The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through Large Research Project under grant number RGP2/329/46.

CRediT authorship contribution statement

Mahmood Ahmed: Conceptualization, Writing - original draft, Writing - Review & editing, Asnuzilawati Asari: Supervision, Writing - Review & editing, Muhammad Zaeem Mehdi: Writing - original draft, Mohammed H. AL Mughram: Data curation, Visualization, Ujala Habib: Data curation, Visualization, Riaz Hussain: Validation, Riaz Hussain: Muhammad Yaseen: Data curation, Visualization, Arslan Usman: Validation, Masooma Irfan: Data curation, Mushkbar Fatima: Data curation, Visualization, Ali Abbas Aslam: Writing - original draft, Validation.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Declaration of Generative AI and AI-assisted technologies in the writing process

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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1. Introduction

2. Crystal and Molecular Structure of Urease

3. Chemical and Molecular Biology of Helicobacter Pylori Urease

4. H. pylori infection and pathogenesis

5. Mechanism of Inhibition of Urease

6. Modes of Inhibition of Urease

6.1. Substrate-like or active site-directed inhibitors
6.2. Non-substrate-like or mechanism-based inhibitors

7. Different Classes of Sulfonamide Derivatives

8. Urease Inhibitors

9. Classical Urease Inhibitors

10. Sulfonamide-Containing Urease Derivatives

10.1. Drug-conjugated sulfonamide derivative
10.2. 4-chlorophenyl sulfonamide derivatives
10.3. Sulfanilamide thiourea derivatives
10.4. Benzophenone sulfonamide derivative
10.5. Pyrazolotriazine sulfonamide derivatives
10.6. Barbituric acid sulfonamide derivatives
10.7. Curcumin sulfonamide derivatives
10.8. Hydrazide-based sulfonamide derivatives
10.9. Oxadiazole sulfonamide derivatives
10.10. Sulfonamide-based Schiff base derivatives
10.11. Acetamide sulfonamide derivatives
10.12. Thiophene sulfonamide derivatives
10.13. Bis-indole sulfonamide derivatives

11. Conclusion and Future Prospects

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Sulfonamide derivatives targeting urease: Structural diversity and therapeutic potential

Abstract

Keywords

Bacteria

Helicobacter pylori

Molecular docking

Sulfonamides

Urease

1. Introduction

2. Crystal and Molecular Structure of Urease

3. Chemical and Molecular Biology of Helicobacter Pylori Urease

4. H. pylori infection and pathogenesis

5. Mechanism of Inhibition of Urease

6. Modes of Inhibition of Urease

6.1. Substrate-like or active site-directed inhibitors

6.2. Non-substrate-like or mechanism-based inhibitors

7. Different Classes of Sulfonamide Derivatives

8. Urease Inhibitors

9. Classical Urease Inhibitors

10. Sulfonamide-Containing Urease Derivatives

10.1. Drug-conjugated sulfonamide derivative

10.2. 4-chlorophenyl sulfonamide derivatives

10.3. Sulfanilamide thiourea derivatives

10.4. Benzophenone sulfonamide derivative

10.5. Pyrazolotriazine sulfonamide derivatives

10.6. Barbituric acid sulfonamide derivatives

10.7. Curcumin sulfonamide derivatives

10.8. Hydrazide-based sulfonamide derivatives

10.9. Oxadiazole sulfonamide derivatives

10.10. Sulfonamide-based Schiff base derivatives

10.11. Acetamide sulfonamide derivatives

10.12. Thiophene sulfonamide derivatives

10.13. Bis-indole sulfonamide derivatives

11. Conclusion and Future Prospects

Acknowledgment

CRediT authorship contribution statement

Declaration of competing interest

Declaration of Generative AI and AI-assisted technologies in the writing process

References

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