Introduction

Cancer is a non-communicable disease that poses a significant global health burden. The disease is characterized by the loss of control over cell cycle regulation and cell homeostatic function in multicellular organisms, resulting in abnormal and uncontrolled cell proliferation.1 As a result, cells will continue to proliferate, leading to the development of abnormal tissue growth and tumor growth. The process of cancer progression, or carcinogenesis, involves a series of microevolutionary changes in cancer growth that can occur over several months or years, progressing through various stages and ultimately leading to a malignant state.2 Curing cancer remains highly challenging due to the complexity of its underlying molecular mechanisms. Current treatment strategies primarily aim to alleviate symptoms, improve the patient’s quality of life, and minimize the risk of recurrence. Therapeutic approaches for cancer patients differ significantly from those for non-cancer patients. Cancer therapies encompass a broad range of interventions such as radiotherapy, chemotherapy, and hormone therapy, as well as surgery.3,4

Cancer treatment with chemotherapy is probably the most recognized cancer treatment by the general public. Chemotherapy involves the administration of specialized drugs to patients, which aim to prevent the spread of cancer cells, slow their growth, and ultimately kill cancer cells. Various anticancer drugs have been developed, including drugs that stimulate the differentiation of cancer cells into benign cells, drugs that enhance the effectiveness of radiation, and drugs that modulate the immune response against cancer cells.5,6 Additionally, numerous drugs have been developed based on the molecular characteristics of cancer cells. However, these therapies often face challenges such as drug resistance, reduced tolerance, limited selectivity, and a range of adverse side effects. A variety of drugs have been used in cancer treatment, including epirubicin, doxorubicin, vinorelbine, docetaxel, sorafenib, cisplatin, and busulfan.

Pyrazolines are an intriguing class of heterocyclic compounds that have attracted significant attention in drug design and development. Their importance lies in their ability to serve as isosteres of other heterocyclic rings, such as imidazole, thiazole, tetrazole, isoxazole, and oxazole.7 This property enables pyrazolines to modulate the physicochemical properties and biological activities of these compounds, resulting in a diverse range of lead compounds with potential therapeutic applications. Structurally, pyrazoline comprises a five-membered ring containing two adjacent nitrogen atoms and one endocyclic double bond. Pyrazoline can exist in three different isomeric forms, 1-pyrazoline, 2-pyrazoline, and 3-pyrazoline, depending on the position of the double bond in the ring, as shown in Figure 1. Among these, 2-pyrazoline has been studied most extensively due to its greater stability compared to the other two forms.8 Pyrazoline derivatives have garnered significant attention in medicinal chemistry due to their diverse range of biological activities. These compounds exhibit a broad spectrum of pharmacological properties, making them attractive targets for drug discovery and development. A wide range of biological activities of pyrazoline derivatives have been reported, including anticancer,9–11 anti-Alzheimer,12,13 antitubercular,14,15 anticonvulsant,16,17 anti-inflammatory,18–20 antidepressant,21 antimicrobial,14,22–24 anti-HIV,25–27 antimalarial,28 anti-Parkinson,29,30 antioxidant,20,31,32 antiviral,33 anti-amoebic,34,35 anti-diabetic36 (Figure 2).

Figure 1 Chemical structures of 1-pyrazoline, 2-pyrazoline, and 3-pyrazoline isomers.

Figure 2 Overview of the biological activities of pyrazoline derivatives.

Sulfonamides, particularly benzenesulfonamide derivatives, are another important class of pharmacophores in medicinal chemistry.37 Characterized by a sulfonamide group attached to a benzene ring, benzenesulfonamide compounds are well known for their ability to form strong hydrogen bonds with biological targets, resulting in high binding affinity and improved pharmacokinetic profiles. These properties have made sulfonamide derivatives potent inhibitors of enzymes, such as carbonic anhydrases, which are often upregulated in tumor environments and play key roles in processes including cell proliferation, survival, and metastasis.38,39 Various sulfonamide derivatives have been developed for biological purposes, including antibacterial,40 antifungal,41 antioxidant,42 anti-inflammatory,43 antidiabetic,44 anticancer,45–47 antihypertensive,48 antimicrobial,49 antimycobacterial,50,51 antimalarial,52 antiprotozoal53 activities. Moreover, some benzenesulfonamide derivatives exhibit a broad spectrum of biological activities, such as carbonic anhydrase inhibitors,54,55 herbicides and plant growth regulators,56–58 elastase inhibitors,59 and Clostridium histolyticum collagenase inhibitors.60

The objective of this review is to comprehensively examine recent developments in the discovery and synthesis of pyrazoline benzenesulfonamide derivatives as potent anticancer agents against various types of cancer to date. This information will assist chemists and biologists in identifying promising structural frameworks, thereby guiding chemical synthesis efforts toward the discovery and development of more effective anticancer agents.

Clinically Available Drugs and Under Developments Containing Pyrazoline

The pyrazoline ring system represents a prominent structural motif widely found in clinically approved pharmaceuticals targeting a broad spectrum of diseases. Numerous marketed drugs, as shown in Figure 3, including antipyrine, phenylbutazone, edavarone, axitinib, and others, feature the pyrazoline moiety, underscoring its significance as a privileged scaffold in medicinal chemistry. The versatility of the pyrazoline core is attributed to its broad spectrum of biological activities, which encompass anti-inflammatory, anticancer, analgesic, and cardiovascular effects, among others. This remarkable pharmacological profile has sparked sustained scientific interest and extensive research efforts aimed at developing novel pyrazoline derivatives with enhanced efficacy and safety. Consequently, beyond approved therapeutics, a diverse array of new pyrazoline-based compounds is in various stages of preclinical and clinical evaluation, highlighting the ongoing expansion of this class for therapeutic innovation.

Figure 3 Representative clinically used and investigational drugs with a pyrazoline scaffold.

Phenazone, also known as antipyrine, is a non-steroidal anti-inflammatory drug (NSAID) with analgesic and antipyretic properties. Its effects are believed to be mediated through the inhibition of cyclooxygenase isoforms, specifically COX-1, COX-2, and COX-3, which are involved in prostaglandin (PG) synthesis.61,62 Phenylbutazone is another NSAID that exhibits analgesic and antipyretic activities and is used in some instances related to acute pain and musculoskeletal disorders, such as ankylosing spondylitis and rheumatoid arthritis.63,64 Ramifenazone is a pyrazole derivative that acts as a non-steroidal anti-inflammatory drug, exhibiting analgesic, antipyretic, anti-inflammatory, and antimicrobial properties.65 Famprofazone is an NSAID with analgesic, anti-inflammatory, and antipyretic effects and is notable for being metabolized to methamphetamine and/or amphetamine.66,67

Morazone is an NSAID used as an analgesic and is metabolized into phenmetrazine.68 Oxyphenbutazone is a metabolite of phenylbutazone possesses anti-inflammatory effects. It is an orally active, non-selective COX inhibitor that has been shown to kill non-replicating Mycobacterium tuberculosis selectively.69,70 Aminophenazone is another NSAID used as analgesics, antipyretics, and anti-inflammatories.71 Its mechanism of action involves inhibiting COX-1 and COX-2 enzymes.72 Metamizole is an analgesic, antipyretic, and spasmolytic drug used to treat both acute and chronic pain and fever. The most important side effect of metamizole is the development of agranulocytosis.73 Edaravone is a free radical scavenger used as a neuroprotective agent in patients with acute ischemic stroke and amyotrophic lateral sclerosis.74,75

Sulfinpyrazone is an oral uricosuric agent used to treat chronic or intermittent gouty arthritis. It competitively inhibits the reabsorption of uric acid at the proximal convoluted tubule, thereby facilitating urinary excretion of uric acid and reducing plasma urate concentrations.76,77 Muzolimine is a diuretic that has been proposed for the treatment of hypertension, known for its high ceiling effect similar to loop diuretics.78 It can also be used in cardiovascular disease research.79 Ibrutinib is a Bruton’s tyrosine kinase inhibitor used in the treatment of lymphoid cancers, including chronic lymphocytic leukemia, Waldenström macroglobulinemia, and mantle cell lymphoma.80 Ibipinabant is a potent, selective, and orally active antagonist of the cannabinoid CB1 receptor with potential applications in obesity and diabetes research.81,82 Axitinib is a potent and selective antagonist inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. It can suppress tumor growth and metastasis by inhibiting both angiogenesis and lymphangiogenesis. Additionally, it exerts antitumor effects through mechanisms involving the induction of apoptosis in tumor cells.83

Enflicoxib (E-6087) is a new pyrazoline derivative and an NSAID used for the treatment of pain and osteoarthritis. It functions as a selective COX-2 inhibitor with potent anti-inflammatory and analgesic activity.84,85 SLV-330 is a drug candidate for the treatment of central nervous system (CNS) disorders and acts as a cannabinoid CB1 receptor antagonist.86 Lificiguat (YC-1) was initially identified as an activator of NO-independent soluble guanylyl cyclase. It inhibits platelet aggregation and prevents vascular contraction. Additionally, it exhibits potent anticancer activity through various mechanisms in multiple cancer cell lines.87,88 Pictilisib (GDC-0941) is a specific PI3K inhibitor with good clinical tolerability and promising anti-neoplastic activity in adult cancers; it also demonstrates anti-proliferative and pro-apoptotic effects in pediatric human medulloblastoma cell lines.89 Pyrazoloacridine (NSC 366140) is a pyrazoline-fused acridine analogue currently under investigation in Phase II clinical trials as an anticancer agent.90

Synthetic Approaches for the Preparation of Pyrazoline Benzenesulfonamide Derivatives

Pyrazoline derivatives can be synthesized using either one-pot or two-pot techniques, as illustrated in Figure 4. The one-pot technique entails a multicomponent reaction in a single vessel, wherein an aromatic ketone, an aromatic aldehyde, and hydrazine are combined directly to afford the corresponding pyrazoline scaffold.91–93 In contrast, the two-pot technique involves of multiple reaction steps and is more commonly reported for the synthesis of pyrazoline derivatives than the one-pot technique.94 The two-pot technique consists of two synthetic steps. It first involves the preparation of chalcones, followed by cyclization with hydrazine under suitable reaction conditions.95,96 This is supported by other studies, which report that pyrazoline derivatives are generally obtained by first synthesizing chalcones, followed by the formation of pyrazolines in acidic or basic medium or alcoholic solvents.97 A widely accepted mechanism for chalcone synthesis is the Claisen-Schmidt condensation, which involves a base-catalyzed cross-aldol reaction between aromatic aldehydes and ketones. Under basic conditions, the enolate ion derived from the ketone attacks the carbonyl carbon of the aldehyde, leading to the formation of a β-hydroxyketone intermediate, which subsequently undergoes dehydration to yield the corresponding chalcone,98 as illustrated in Figure 5.

Figure 4 Schematic representation of one-pot and two-pot synthetic strategies for pyrazoline derivatives.

Figure 5 General reaction and mechanism of chalcone synthesis by base-catalyzed Claisen-Schmidt condensation.

Multiple synthetic strategies have been established for the construction of pyrazoline derivatives, with the Knoevenagel and Fisher methods being among the most extensively utilized. These approaches enable efficient synthesis of structurally diverse pyrazolines, commonly achieved through the reaction of α,β-unsaturated carbonyl compounds with hydrazine or phenylhydrazine in the presence of acetic acid.99,100 As illustrated in Figure 6, two mechanistic pathways have been proposed for the cyclization of α,β-enones with hydrazine derivatives, contingent on variables such as reaction conditions, catalyst, and substrate structure. The first route proceeds via formation of a hydrazone intermediate, followed by intramolecular cyclization to yield the desired 2-pyrazoline scaffold. Alternatively, the reaction may proceed through an aza-Michael addition, forming an aza-Michael intermediate that subsequently undergoes cyclization and water elimination to afford the 2-pyrazoline core. Both mechanisms reflect the strategic versatility available for the tailored synthesis of pyrazoline compounds.97,101,102

Figure 6 Reaction scheme and mechanistic pathways for the synthesis of 2-pyrazoline derivatives from chalcone and hydrazine. Top: Reaction overview showing the condensation of a chalcone and hydrazine to yield either a hydrazone or aza-Michael intermediate, leading to 2-pyrazoline. Bottom: Mechanism reaction pathways for 2-pyrazoline, (A1) the chalcone and hydrazine condense to form a hydrazone intermediate, which subsequently undergoes nucleophilic cyclization and proton transfers to yield 2-pyrazoline via intramolecular attack at the enone carbon, (A2) starting with the same hydrazone intermediate, ring closure occurs through a different cyclization route, with nucleophilic attack at the β-carbon, leading to the formation of 2-pyrazoline, (B) hydrazine directly adds to the α,β-unsaturated carbonyl of the chalcone via an aza-Michael reaction, forming an intermediate that cyclizes and then eliminates water to provide the 2-pyrazoline product.

Figure 7 Synthesis of 4-hydrazinylbenzenesulfonamide. Sulfanilamide (1) was converted through a diazotization reaction to form a diazonium salt intermediate (2), followed by reduction to yield 4-hydrazinylbenzenesulfonamide (3).

The synthesis of pyrazoline derivatives can be carried out using various heating methods, including microwave irradiation, ultrasonic irradiation, grinding techniques, ionic liquids, and conventional methods.103–105 These methods offer several improvements over traditional protocols, notably faster reaction rates, higher yields, and greater environmental compatibility. Additionally, a wide range of solvents can be used, such as methanol, ethanol, toluene, pyridine, polyethylene glycol (PEG), dimethylformamide (DMF), tetrahydrofuran (THF), and dimethyl sulfoxide (DMSO).106–108 These solvents are selected based on their specific properties, such as polarity and their ability to dissolve reactants, which can significantly influence the reaction’s efficiency and outcome. Various catalysts have also been reported for the synthesis of pyrazoline derivatives. These include acids such as formic acid, acetic acid, glacial acetic acid, hydrochloric acid, chloroacetic acid, propionic acid, acetic anhydride, butyric acid, gallic acid, sulfuric acid,109–112 as well as bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, and triethylamine (TEA).113–115 The choice of catalyst depends on the specific reaction conditions and the desired outcome. Hydrazines are the most frequently used reactants, as they provide both nitrogen atoms in the 2-pyrazoline ring.

Pyrazoline benzenesulfonamide derivatives can be synthesized via one-step, two-step, or multi-step reactions. A one-step approach, such as a one-pot reaction, can directly yield pyrazoline compounds using suitable reactants like acetophenone, benzaldehyde, and 4-hydrazinylbenzenesulfonamide. The two-step reaction typically involves a Claisen-Schmidt condensation reaction followed by cyclization with 4-hydrazinylbenzenesulfonamide. Multi-step reactions involve multiple reactions to obtain the final pyrazoline derivative. For example, hydrazine or 4-hydrazinylbenzenesulfonamide (3) can be prepared from sulfanilamide (1) through a diazotization reaction with sodium nitrite (NaNO2) in hydrochloric acid (HCl) to form a diazonium salt intermediate (2), followed by reduction using stannous chloride (SnCl2) in hydrochloric acid (HCl), as depicted in Figure 7.15,116,117

Pyrazoline benzenesulfonamide derivatives can be synthesized via a one-pot, one-step reaction using a base catalyst, as depicted in Figure 8. The synthesis involves a direct reaction between aromatic ketones (1), aromatic aldehydes (2), and 4-hydrazinylbenzenesulfonamide (3) in the presence of sodium hydroxide (NaOH) as a base catalyst in absolute ethanol. The reaction is carried out in a sealed-vessel reactor (Monowave 50) equipped with a stir bar and pressure tube at 80°C for 2 hours, yielding 3,5-diphenylpyrazoline benzenesulfonamide derivatives (4), with yields ranging from 25% to 87%.118 Another study reported that pyrazoline benzenesulfonamide derivatives can also be synthesized under catalyst-free conditions using microwave irradiation. In this case, the pyrazoline compounds were obtained through a two-step reaction, as depicted in Figure 9. In the first step, chalcones were prepared via the Claisen–Schmidt condensation reaction using a base catalyst in ethanol, or through an aldol condensation reaction catalyzed by thionyl chloride (SOCl2) in absolute ethanol, involving the appropriate acetophenone (1) and appropriate benzaldehyde (2) at room temperature. In the second step, the suitable chalcone derivatives (3) were reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (4) in methanol or ethanol under microwave irradiation for 7 to 60 minutes, affording pyrazoline benzenesulfonamide derivatives bearing substituted-diphenyl (5), substituted-phenyl and styryl (6), and thiophene and substituted-phenyl (7), with yields ranging from 4 to 98%.119–121

Figure 8 One-pot synthesis of 3,5-diphenyl pyrazoline benzenesulfonamide derivatives. Aromatic ketones (1), aromatic aldehydes (2), and 4-hydrazinylbenzenesulfonamide (3) were reacted under a sealed-vessel reactor (Monowave 50) to yield 3,5-diphenylpyrazoline benzenesulfonamide derivatives (4).

Figure 9 Microwave-assisted synthesis of various pyrazoline benzenesulfonamide derivatives. Appropriate acetophenone (1) condensed with appropriate benzaldehyde (2) to prepare chalcone derivatives (3), then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (4) under microwave irradiation to afford pyrazoline benzenesulfonamide derivatives bearing substituted-diphenyl (5), substituted-phenyl and styryl (6), and thiophene and substituted-phenyl (7).

Pyrazoline benzenesulfonamide derivatives have also been synthesized under acidic conditions using ultrasound irradiation, through a stepwise process, as depicted in Figure 10. Initially, 2,4-dimethoxybenzaldehyde (1) reacts with methylmagnesium iodide (CH3-MgI) to produce 1-(2,4-dimethoxyphenyl)ethanol (2). This intermediate is then oxidized in the presence of magnesium oxide (MgO) under reflux for 2 hours at 80°C, affording 2,4-dimethoxyacetophenone (3). Subsequent Claisen–Schmidt condensation of 2,4-dimethoxyacetophenone (3) with a substituted aromatic aldehyde (4) in ethanol at room temperature afforded chalcone derivatives (5). In parallel, 4-hydrazinylbenzenesulfonamide hydrochloride (6) is obtained from sulfanilamide via a diazotization-reduction sequence. In the final stage, the chalcones (5) are cyclized with 4-hydrazinylbenzenesulfonamide hydrochloride (6) using acetic acid as a catalyst under ultrasound irradiation at 65°C for 50–90 minutes in open vessels, affording pyrazoline benzenesulfonamide derivatives bearing 2,4-dimethoxyphenyl and thiophene (7), 2,4-dimethoxyphenyl and furan (8), and 2,4-dimethoxyphenyl and substituted-phenyl (9), with yields ranging from 72% to 85%.116 This ultrasound-assisted method provides an efficient and environmentally benign pathway for generating structurally diverse pyrazoline benzenesulfonamide analogues.

Figure 10 Ultrasound-assisted synthesis of pyrazoline benzenesulfonamide derivatives. 2,4-dimethoxybenzaldehyde (1) was converted to 1-(2,4-dimethoxyphenyl)ethanol (2), then oxidized to yield 2,4-dimethoxyacetophenone (3), then condensed with substituted aromatic aldehyde (4) to afford chalcone derivatives (5), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (6) under ultrasound irradiation to produce pyrazoline benzenesulfonamide derivatives bearing 2,4-dimethoxyphenyl and thiophene (7), 2,4-dimethoxyphenyl and furan (8), and 2,4-dimethoxyphenyl and substituted-phenyl (9).

A widely used conventional method for synthesizing pyrazoline benzenesulfonamide involves a two-step reaction. The first step involves a Claisen–Schmidt condensation reaction between an appropriate aromatic aldehyde and an aromatic ketone in the presence of a base or acid catalyst, yielding α,β-unsaturated carbonyl compounds known as chalcones. In the second step, the chalcone is then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride in an acidic or basic medium, or simply in alcoholic solvents such as ethanol or methanol. The reaction mixture is typically heated under reflux for several hours or longer, depending on the substrate, to promote intramolecular cyclization and form the pyrazoline ring. After completion, the reaction mixture is cooled, and the crude product is isolated by filtration and purified by recrystallization. This conventional synthetic approach is widely employed owing to its straightforward procedure and adaptability, allowing for diverse substitution patterns at the 3- and 5-positions of the pyrazoline core. This method facilitates the incorporation of a broad array of aromatic and heteroaromatic groups, including 1,5,6,7-tetrahydro-4H-indol-4-one,122 naphthalene,123 thiazole,124 pyridine,125,126 benzo[d][1,3]dioxole,127,128 2H-chromen-2-one,129 pyrazole,130,131 as well as phenoxybenzene and (benzyloxy)benzene.132 In addition, substituents such as furan, thiophene, styrene, anthracene, and diphenyl133–140 have also been introduced through this strategy. As illustrated in Figure 11, this versatile protocol provides access to structurally diverse pyrazoline benzenesulfonamide derivatives (1–18) with variable yields, highlighting its utility in generating novel analogues with potential pharmacological relevance.

Figure 11 Synthesis of substituted pyrazoline benzenesulfonamide derivatives containing various heterocyclic and aromatic substituents using the conventional method. Appropriate acetophenone and appropriate benzaldehyde were condensed to prepare chalcone derivatives, which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride under reflux conditions to yield structurally diverse pyrazoline benzenesulfonamide derivatives. Structures 1–18 represent products bearing: furan/thiophene and pyrazole (1), substituted-phenyl and styryl (2), substituted-phenyl and naphthalene (3), substituted-phenyl and anthracene (4), substituted-phenyl and benzo[d]dioxole (5), pyridine and substituted-phenyl (6), phenoxybenzene or (benzyloxy)benzene and substituted-phenyl (7), thiophene and benzo[d]dioxole (8), furan/thiophene and substituted-phenyl (9), furan and/or thiophene (10), substituted-phenyl and furan/thiophene (11), substituted-phenyl and 1,5,6,7-tetrahydro-4H-indol-4-one (12), 2H-chromen-2-one and substituted-phenyl (13), substituted diphenyl (14), p-tolyl and pyrazole (15), pyrazole and substituted-phenyl (16), thiazole and substituted-phenyl (17), and 2-vinylfuran or 2-vinylthiophene and furan/thiophene (18).

The synthesis of pyrazoline benzenesulfonamide derivatives incorporating a ferrocene organometallic moiety is accomplished via a stepwise protocol, as depicted in Figure 12. Initially, a Claisen-Schmidt condensation is employed, wherein acetylferrocene (1) reacts with various substituted benzaldehydes (2) in the presence of potassium hydroxide (KOH) in ethanol at room temperature, affording the corresponding ferrocenyl chalcone intermediates (3). In the subsequent step, these intermediates undergo cyclization with 4-hydrazynylbenzenesulfonamide hydrochloride (4) in an ethanol–acetic acid mixture (1:2) at 100°C for 21–22 hours, yielding pyrazoline benzenesulfonamide derivatives bearing ferrocene and aryl groups (5) in moderate to good yields ranging from 49% to 74%.141

Figure 12 Synthesis of ferrocene-substituted pyrazoline benzenesulfonamide derivatives. Acetylferrocene (1) condensed with substituted benzaldehydes (2) to prepare ferrocenyl chalcones (3), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (4) to produce pyrazoline benzenesulfonamide derivatives bearing ferrocene and aryl moieties (5).

Pyrazoline benzenesulfonamide derivatives bearing benzodioxole and benzodioxane moieties can be efficiently synthesized through a sequential three-step process, as depicted in Figure 13. As reported by Yan et al,142 the first step involves alkylation of protocatechuic aldehyde (1) with dibromomethane (2a) or 1,2-dibromoethane (2b) using anhydrous potassium carbonate (K2CO3) in dimethylformamide (DMF) at 70°C to afford benzo oxygen heterocyclic intermediates (3). The resulting intermediates undergo a Claisen–Schmidt condensation with various substituted acetophenones (4) in ethanol, catalyzed by potassium hydroxide (KOH), yielding the corresponding chalcone derivatives (5). In the final step, a cyclization reaction was performed on the resulting chalcone with 4-hydrazinylbenzenesulfonamide hydrochloride (6) in ethanol, using glacial acetic acid as a catalyst, under reflux overnight. This process affords pyrazoline benzenesulfonamide derivatives bearing benzodioxole (7) and benzodioxane (8) moieties, with yields of 59–78% and 60–76%, respectively.

Figure 13 Synthesis of pyrazoline benzenesulfonamide derivatives bearing benzodioxole and benzodioxane moieties. Protocatechuic aldehyde (1) was alkylated with dibromomethane (2a) or 1,2-dibromoethane (2b) to yield benzo oxygen heterocyclic (3), then condensed with substituted acetophenones (4) to afford chalcone derivatives (5), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (6) to produce pyrazoline benzenesulfonamide derivatives bearing benzodioxole (7) and benzodioxane (8) moieties.

The synthesis of tetrazole-bearing pyrazoline benzenesulfonamide derivatives was conducted using a systematic three-step process, as depicted in Figure 14. In the first step, 4-aminoacetophenone (1) was converted into a tetrazole-substituted acetophenone (2) through a cyclization reaction with sodium azide (NaN3) and triethyl orthoformate (TEOF) in glacial acetic acid under reflux conditions for 12 hours. In the second step, acetophenone was condensed with substituted benzaldehydes (3), specifically 3,4-dimethoxybenzaldehyde and 3,4,5-trimethoxybenzaldehyde in the presence of potassium hydroxide (KOH) in absolute ethanol at room temperature for 10–12 hours. This reaction proceeds via an aldol condensation mechanism, yielding tetrazole-substituted chalcones (4). In the final step, cyclization was achieved by reacting the chalcone with 4-hydrazinylbenzenesulfonamide hydrochloride (5) in absolute ethanol under reflux conditions for 18 hours. This reaction affords pyrazoline benzenesulfonamide derivatives bearing a tetrazole moiety (6), with yields of 51% and 46%.143

Figure 14 Synthesis of tetrazole–beraing pyrazoline benzenesulfonamide derivatives. 4-aminoacetophenone (1) was converted to a tetrazole–substituted acetophenone (2), then condensed with substituted benzaldehydes (3) to afford tetrazole–substituted chalcones (4), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (5) to produce pyrazoline benzenesulfonamide derivatives bearing a tetrazole moiety (6).

The synthesis of morpholine-bearing pyrazoline benzenesulfonamide derivatives is accomplished through a sequential three-step process, as depicted in Figure 15. In the first step, morpholine (1) was reacted with 4-fluorobenzaldehyde (2) in dimethyl sulfoxide (DMSO) at 120°C for 4 hours to afford 4-morpholinobenzaldehyde (3). In the second step, the resulting aldehyde undergoes Claisen–Schmidt condensation with substituted acetophenone (4) in ethanol at 0°C, affording morpholine- substituted chalcone intermediates (5). In the final step, cyclization reaction of the resulting chalcone with 4-hydrazinylbenzenesulfonamide (6) in ethanol, using glacial acetic acid as a catalyst, under reflux conditions at 80°C for 8 hours. This reaction affords pyrazoline benzenesulfonamide derivatives bearing a morpholine moiety (7).144

Figure 15 Synthesis of morpholine-bearing pyrazoline benzenesulfonamide derivatives. Morpholine (1) was reacted with 4-fluorobenzaldehyde (2) to yield 4-morpholinobenzaldehyde (3), then condensed with substituted acetophenone (4) to afford morpholine–substituted chalcone derivatives (5), which then reacted with 4-hydrazinylbenzenesulfonamide (6) to produce pyrazoline benzenesulfonamide derivatives bearing a morpholine moiety (7).

The synthesis of pyrazoline benzenesulfonamide derivatives featuring a methanesulfonamide moiety involves a concise three-step process, as depicted in Figure 16. In the first step, N-(4-acetylphenyl)-N-(methylsulfonyl)methanesulfonamide (3) was synthesized by reacting 4-aminoacetophenone (1) with methanesulfonyl chloride (2) in dichloromethane (CH2Cl2) using triethylamine (TEA) as a base. This intermediate is subsequently subjected to Claisen–Schmidt condensation with various substituted benzaldehydes (4) in absolute ethanol, catalyzed by sodium ethoxide at room temperature, yielding methanesulfonamide-bearing chalcone derivatives (5) in good yields. The final step, the cyclization of these chalcones with 4-hydrazinylbenzenesulfonamide hydrochloride (6) in absolute ethanol under reflux conditions for 6–24 hours, affords pyrazoline benzenesulfonamide derivatives featuring a methanesulfonamide moiety (7), with yields ranging from 41% to 42%.145

Figure 16 Synthesis of pyrazoline benzenesulfonamide derivatives featuring a methanesulfonamide moiety. 4-Aminoacetophenone (1) was reacted with methanesulfonyl chloride (2) to afford N-(4-acetylphenyl)-N-(methylsulfonyl)methanesulfonamide (3), then condensed with substituted benzaldehydes (4) to prepare methanesulfonamide–bearing chalcone derivatives (5), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (6) to produce pyrazoline benzenesulfonamide derivatives featuring a methanesulfonamide moiety (7).

The synthesis of pyrazole-linked pyrazoline benzenesulfonamide derivatives proceeds through a multi-step sequence, as depicted in Figure 17. In the first step, substituted acetophenones (1) undergo condensation with phenylhydrazine (2) in ethanol using acetic acid as a catalyst at room temperature, forming hydrazone intermediates (3).146 These intermediates are then subjected to the Vilsmeier–Haack reaction with phosphoryl chloride (POCl3) and dimethylformamide (DMF) under reflux conditions in the presence of sodium bicarbonate (NaHCO3), affording pyrazole carbaldehydes (4). Subsequent Claisen–Schmidt condensation of the pyrazole carbaldehydes with various substituted acetophenones (5) in methanol and sodium hydroxide (NaOH) yields chalcone intermediates (6) in good yields (56–79%). The final step involves the cyclization reaction of the resulting chalcone intermediates with 4-hydrazinylbenzenesulfonamide (7) in methanol, catalyzed by hydrochloric acid (HCl) under reflux conditions. This reaction affords pyrazole-linked pyrazoline benzenesulfonamide derivatives (8), with yields ranging from 54% to 76%.145

Figure 17 Synthesis of pyrazole-linked pyrazoline benzenesulfonamide derivatives. Substituted acetophenone (1) was condensed with phenylhydrazine (2) to form hydrazone intermediates (3), then subjected to the Vilsmeier–Haack reaction to afford pyrazole carbaldehydes (4), which then condensed with substituted acetophenones (5) to afford pyrazole–linked chalcone intermediates (6), which then reacted with 4-hydrazinylbenzenesulfonamide (7) to produce pyrazole–linked pyrazoline benzenesulfonamide derivatives (8).

The synthesis of coumarin-linked pyrazoline benzenesulfonamide derivatives proceeds through a well-defined a multi-step process, as depicted in Figure 18. Initially, 7-hydroxycoumarin (1) was acetylated with acetic anhydride (2) under reflux for 5 hours, producing 7-acetoxycoumarin (3). Subsequent Friedel–Crafts acylation with aluminium chloride (AlCl3) at 145°C for 1 hour affords 8-acetyl-7-hydroxycoumarin (4). This intermediate then undergoes methylation using methyl iodide (CH3I) in dry acetone under reflux for 24 hours, yielding 8-acetyl-7-methoxycoumarin (5). In the next stage, the Claisen–Schmidt condensation of 8-acetyl-7-methoxycoumarin (5) with various aromatic aldehydes (6) in 10% sodium hydroxide (NaOH) solution in ethanol at room temperature for 24 hours generates coumarin–chalcone derivatives (7). Finally, the cyclization of these chalcones with 4-hydrazinylbenzenesulfonamide (8) in absolute ethanol under reflux for 16 hours afforded coumarin–pyrazoline benzenesulfonamide hybrids (9), which were obtained in yields ranging from 65% to 70%.147

Figure 18 Synthesis of coumarin-linked pyrazoline benzenesulfonamide hybrids. 7-hydroxycoumarin (1) was acetylated with acetic anhydride (2) to yield 7-acetoxycoumarin (3), then acylated with aluminium chloride (AlCl3) to afford 8-acetyl-7-hydroxycoumarin (4), then methylated using methyl iodide (CH3I) to yield 8-acetyl-7-methoxycoumarin (5), then condensated with various aromatic aldehydes (6) generates coumarin–linked chalcone derivatives (7), which then reacted with 4-hydrazinylbenzenesulfonamide (8) to produce coumarin–linked pyrazoline benzenesulfonamide derivatives (9).

The synthesis of oxazoline-based pyrazoline benzenesulfonamide derivatives was achieved through a structured multi-step synthetic strategy, as depicted in Figure 19. The synthesis begins with the O-alkylation of p-hydroxyacetophenone (1) using ethyl bromoacetate (2) as the alkylating agent in dry acetone, with potassium carbonate as base, under reflux conditions to afford ethyl 2-(4-acetylphenoxy)acetate (3). Subsequent hydrolysis of the ester group yields 2-(4-acetylphenoxy)acetic acid (4), followed by cyclization with ethanolamine in methanol under reflux conditions to afford the oxazoline intermediate (5). This intermediate is subjected to a Claisen–Schmidt condensation with various aromatic aldehydes (6) in methanol in the presence of sodium hydroxide (NaOH) to afford a series of oxazoline–based chalcone derivatives (7). The resulting chalcones undergo cyclization with 4-hydrazinylbenzenesulfonamide (8) in methanol under reflux, followed by the addition of hydrochloric acid (HCl), yielding oxazoline–based pyrazoline benzenesulfonamide derivatives bearing a phenyl group (9) and benzodioxane (10), with yields of 62–72% and 62%, respectively.148

Figure 19 Synthesis of oxazoline-based pyrazoline benzenesulfonamide derivatives. p-Hydroxyacetophenone (1) was alkylated with ethyl bromoacetate (2) to afford ethyl 2-(4-acetylphenoxy)acetate (3), then hydrolysis of the ester group yields 2-(4-acetylphenoxy)acetic acid (4), followed by cyclization with ethanolamine to yield oxazoline–based acetophenone (5), then condensated with various aromatic aldehydes (6) to afford oxazoline–based chalcone derivatives (7), which then reacted 4-hydrazinylbenzenesulfonamide (8) to produce oxazoline–based pyrazoline benzenesulfonamide derivatives bearing a phenyl group (9) and benzodioxane (10).

The synthesis of chloropyrazole benzenesulfonamide–linked pyrazoline benzenesulfonamide derivatives, as reported by Gul et al149 and Khloya et al,150 was accomplished through a well-defined multi-step process, as depicted in Figure 20. The synthesis commences with the condensation of ethyl acetoacetate (2) with 4-hydrazinylbenzenesulfonamide hydrochloride (1) in ethanol under reflux, resulting in the formation of the pyrazolone intermediate (3). This intermediate then undergoes a Vilsmeier–Haack reaction using dimethylformamide (DMF) and phosphoryl chloride (POCl3), which introduces a formyl substituent at the 4-position and a chloro substituent at the 5-position of the pyrazole ring, affording N-(5-chloro-4-formyl-3-methyl pyrazole)-4-phenylsulfonyl-N,N-dimethylformimidamide (4). During this process, the sulfonamide group is temporarily protected through conversion to an N-[(dimethylamino)methylidine]sulfonamide group. Subsequent acidic treatment removes the dimethylaminomethyl protecting group, regenerating the free sulfonamide moiety and yielding 5-chloro-3-methyl-4-formylpyrazole benzenesulfonamide (5). In the next step, this intermediate undergoes a Claisen–Schmidt condensation with substituted acetophenones (6) in ethanol, catalyzed by potassium hydroxide (KOH) to yield chalcone derivatives (7). In the final step, these chalcones undergo cyclization with 4-hydrazinylbenzenesulfonamide hydrochloride in ethanol, in the presence of glacial acetic acid under reflux conditions, yielding chloropyrazole benzenesulfonamide–linked pyrazoline benzenesulfonamide derivatives (8).

Figure 20 Synthesis of chloropyrazole benzenesulfonamide-linked pyrazoline benzenesulfonamide derivatives. 4-hydrazinylbenzenesulfonamide hydrochloride (1) reacted with ethyl acetoacetate (2) to form the pyrazolone intermediate (3), then undergoes a Vilsmeier–Haack reaction to afford N-(5-chloro-4-formyl-3-methyl pyrazole)-4-phenylsulfonyl-N, N-dimethylformimidamide (4), then removes the dimethylaminomethyl protecting group, regenerating the free sulfonamide moiety to yield 5-chloro-3-methyl-4-formylpyrazole benzenesulfonamide (5), then condensated with substituted acetophenones (6) to prepare chalcone derivatives (7), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride to produce chloropyrazole benzenesulfonamide-linked pyrazoline benzenesulfonamide derivatives (8).

The synthesis of pyrazoline benzenesulfonamide derivatives containing pyrazole benzenesulfonamide, as reported by Kumar et al,151 was achieved through a systematic multi-step process, as depicted in Figure 21. The first step involves the preparation of intermediate 4-formylpyrazole bearing a benzenesulfonamide substituent at the N-1 position (1), according to established procedures. This intermediates was then subjected to Claisen–Schmidt condensation with appropriate acetophenones (2) in a mixed solvent system of methanol and tetrahydrofuran (THF), with sodium hydroxide (NaOH) as base, yielding in the formation of chalcone derivatives (3) in moderate to good yields. Subsequently, cyclization of the chalcone intermediates is carried out using 4-hydrazinylbenzenesulfonamide hydrochloride (4) under reflux in an ethanol/THF mixture, using a catalytic amount of acetic acid. This step affords pyrazoline benzenesulfonamide containing pyrazole benzenesulfonamide derivatives (5), with yields ranging from 65% to 84%.

Figure 21 Synthesis of pyrazoline benzenesulfonamide derivatives containing pyrazole benzenesulfonamide. Preparation of intermediate 4-formylpyrazole bearing a benzenesulfonamide substituent at the N-1 position (1), then condensed with substituted acetophenones (2) to prepare chalcone derivatives (3), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (4) to produce pyrazoline benzenesulfonamide derivatives containing pyrazole benzenesulfonamide (5).

The synthesis of pyrazoline benzenesulfonamide derivatives bearing benzofuran and pyrazole moieties, as reported by Ragab et al,152 was achieved through a structured multi-step synthetic strategy, as depicted in Figure 22. For Scheme A, the synthesis commences with the alkaline hydrolysis of the natural furochromone precursor (1) in aqueous KOH (5%), affording 1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethanone (2). This benzofuran–based ketone was then subjected to Claisen–Schmidt condensation with a pyrazole-4-carbaldehyde (3) in a sodium hydroxide–ethanol system at room temperature, resulting hydroxybenzofuranyl–pyrazolyl chalcone intermediates (4). Subsequently, cyclization of these chalcone intermediates with 4-hydrazinylbenzenesulfonamide hydrochloride (5) in ethanol under reflux for 16–48 hours, yielding pyrazoline benzenesulfonamide derivatives bearing pyrazole and benzofuran moieties (6), with yields ranging from 40% to 60%. Scheme B details a parallel pathway beginning with the Claisen–Schmidt condensation between appropriately substituted acetophenone (1) and pyrazole-4-carbaldehyde derivatives (2) in ethanol with sodium hydroxide (NaOH), generating pyrazolyl chalcone intermediates (3). Cyclization of these chalcone intermediates with 4-hydrazinylbenzenesulfonamide hydrochloride (4) under reflux in ethanol for 16–48 h, yielding pyrazoline benzenesulfonamide derivatives bearing a pyrazole moiety (5), with yields ranging from 30% to 55%. This synthetic pathway thus provides efficient access to novel benzofuran–pyrazole–pyrazoline benzenesulfonamide derivatives, supporting the exploration of new molecular scaffolds in drug discovery.

Figure 22 Synthesis of pyrazoline benzenesulfonamide derivatives bearing benzofuran and pyrazole moieties. (A) Natural furochromone (1) was converted to 1-(6-hydroxy-4,7-dimethoxybenzofuran-5-yl)ethanone (2), then condensed with pyrazole-4-carbaldehyde derivatives (3) to prepare hydroxybenzofuranyl–pyrazolyl chalcone intermediates (4), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (5) to produce pyrazoline benzenesulfonamide derivatives bearing pyrazole and benzofuran moieties (6). (B) Substituted acetophenone (1) was condensed with pyrazole-4-carbaldehyde derivatives (2) to prepare pyrazolyl chalcone intermediates (3), which then reacted with 4-hydrazinylbenzenesulfonamide hydrochloride (4) to produce pyrazoline benzenesulfonamide derivatives bearing a pyrazole moiety (5).

The synthesis of pyrazoline benzenesulfonamide derivatives bearing pyrazole–quinoline scaffold substituted with either a furan or thiophene side chain, as reported by Zala et al,15 proceeds via a convergent multi-step process, as depicted in Figure 23. The route initiates with the preparation of 7-chloro-4-hydrazinylquinoline (3), achieved by refluxing 4,7-dichloroquinoline (1) with hydrazine hydrate (2) in ethanol for 8 hours. In parallel, 4-hydrazinylbenzenesulfonamide (8) is synthesized through diazotization of sulfanilamide using sodium nitrite and hydrochloric acid at low temperature, followed by reduction with stannous chloride, as per established literature methods (not explicitly depicted in this scheme). The Vilsmeier–Haack formylation was then performed by reacting the quinoline hydrazine intermediate (3) with a suitable furan or thiophene acetyl (4) in the presence of dimethylformamide (DMF) and phosphoryl chloride (POCl3) at 75–80°C for 6 hours, affording the corresponding pyrazole-4-carbaldehyde intermediates (5). These intermediates are subsequently subjected to Claisen–Schmidt condensation with various substituted acetophenones (6) in methanol, in the presence of sodium hydroxide (NaOH) at room temperature for 10–12 hours, generating chalcone intermediates (7). The final step involves cyclization, where the resulting chalcones are reacted with 4-hydrazinylbenzenesulfonamide (8) in ethanol using a catalytic amount of concentrated hydrochloric acid (HCl), under reflux at 75°C for 6–8 hours, yielding pyrazoline benzenesulfonamide derivatives bearing the central pyrazole–quinoline scaffold substituted with either a furan or thiophene side chain (9), with yields ranging from 78% to 86%.

Figure 23 Synthesis of pyrazoline benzenesulfonamide derivatives bearing pyrazole–quinoline scaffold substituted with either a furan or thiophene side chain. 4,7-Dichloroquinoline (1) was reacted with hydrazine hydrate (2) to form 7-chloro-4-hydrazinylquinoline (3), then underwent the Vilsmeier–Haack reaction with a suitable furan or thiophene acetyl (4) to afford pyrazole-4-carbaldehyde intermediates (5), then condensed with substituted acetophenones (6) to prepare chalcone intermediates (7), which then reacted with 4-hydrazinylbenzenesulfonamide (8) to produce pyrazoline benzenesulfonamide derivatives bearing pyrazole–quinoline scaffold substituted with either a furan or thiophene side chain (9).

Dekhane et al153 reported an efficient and versatile synthetic protocol for the construction of pyrazoline benzenesulfonamide derivatives bearing 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,2,4-oxadiazole, and tetrazole rings, as depicted in Figure 24. The synthesis begins with the esterification of the potassium salt of 4-(4-chlorophenyl)-2-oxobut-3-enoic acid in ethanol using thionyl chloride to obtain the corresponding 4-(4-chlorophenyl)-2-oxo-but-3-enoic acid ethyl ester (1). This ester was then reacted with 4-hydrazinylbenzenesulfonamide in ethanol and acetic acid under reflux, yielding the 5-(4-chlorophenyl)-1-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester (2). These esters were converted to carbohydrazides (3) by treating with hydrazine hydrate in ethanol under reflux conditions. Reaction of esters (2) with aqueous ammonia in tetrahydrofuran (THF) at 50–55°C to give amide derivatives (4), then upon dehydration with oxalyl chloride in dimethylformamide (DMF) at 0°C, provides the corresponding nitrile derivatives (5). These nitriles reacted with hydroxylamine hydrochloride in the presence of sodium carbonate (Na2CO3) in methanol at 25–30°C, yielding carboxamidines (6). Carbohydrazides (3) reacted with carbonyldiimidazole (CDI) in(THF) using triethylamine (Et3N) to form 2-hydroxy-1,3,4-oxadiazoles (7), or with carbon disulfide (CS2) in the presence of potassium hydroxide in methanol to yield 2-thiol-1,3,4-oxadiazoles (8). Reacting the carbohydrazides with cyanogen bromide (CNBr) and sodium bicarbonate (NaHCO3) in a dioxane–water mixture affords 2-amino-1,3,4-oxadiazoles (9). For thiadiazole synthesis, carbohydrazides were reacted sequentially with CS2/KOH, methyl iodide (MeI), then cyclized with p-toluenesulfonic acid in toluene, affording 2-thiomethyl-1,3,4-thiadiazoles (10). Carboxamidines (6) reacted with ethyl chloroformate in pyridine, then refluxed in xylene to yield 5-hydroxy-1,2,4-oxadiazole (11), or acylated with acetic anhydride in the p