Recent Advances in Benzimidazole Chemistry: A Comprehensive Review on Synthetic Approach and Therapeutic Potential

Synthetic approaches of benzimidazole

The synthesis of benzimidazole derivatives typically begins with o-phenylenediamine (OPDA), a benzene-based precursor containing ortho-positioned nitrogen functional groups, enabling efficient cyclization. This methodology is well-documented and serves as a foundational approach in heterocyclic chemistry. In this section, various synthetic strategies are systematically categorized based on the starting materials employed for benzimidazole core formation, providing a comprehensive review of established methodologies in organic synthesis.

From carboxylic acids

The synthesis of benzimidazole (3) proceeds via an initial formylation of o-phenylenediamine (1) using relevant carboxylic acids (2) as a carbonyl donor. The chemical mechanism entails a nucleophilic attack by the amine group of o-phenylenediamine (1) on the electrophilic carbonyl carbon of formic acid (2), resulting in the creation of an intermediate formamide molecule. Under heat circumstances, intramolecular cyclization transpires, aided by proton migration and subsequent dehydration, resulting in the formation of the benzimidazole core structure (3). The final compounds were obtained with an 85% yield^[6,7] [Scheme 1].

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Scheme 1:

Thermal synthesis of benzimidazole.

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When it comes to synthesizing benzimidazole derivatives, the Phillips method is among the most popular choices. The process includes using concentrated hydrochloric acid as a catalyst and solvent in the thermal condensation of o-phenylenediamine (1) with carboxylic acids (2) or their derivatives [Scheme 2]. The reaction mechanism begins with protonation of the carboxyl functional group, enhancing its electrophilicity and facilitating nucleophilic attack by one of the amino groups of o-phenylenediamine (1). The benzimidazole core (3) is produced when an amide intermediate is formed through this reaction. The intermediate then goes through intramolecular cyclization, which involves successive proton transfer and dehydration. The strong acidic medium provided by HCl promotes regioselective cyclization, stabilizing intermediates and ensuring efficient conversion.^[8,6]

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Scheme 2:

Acid-catalyzed benzimidazole synthesis.

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The condensation reaction of o-phenylenediamine (1) with aldehyde or carboxylic acid derivatives is used to synthesize substituted benzimidazoles (4 & 5). Zirconyl nitrate [ZrO(NO₃)₂], a Lewis acid, is used as a catalyst [Scheme 3].^[9] The reaction mechanism involves initial activation of the electrophilic carbonyl carbon by ZrO(NO₃)₂, enhancing its susceptibility to nucleophilic attack from the amine groups of o-phenylenediamine (1). This interaction leads to the formation of an imine intermediate, followed by intramolecular cyclization, proton transfer, and dehydration, ultimately yielding the benzimidazole core structures (4 & 5). The catalytic role of ZrO(NO₃)₂ not only accelerates the reaction but also ensures high regioselectivity and efficiency in the formation of the desired heterocyclic scaffold.^[7,10,11]

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Scheme 3:

Zirconyl nitrate-catalyzed benzimidazole synthesis.

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2-substituted benzimidazole derivatives (7) are synthesized by combining aromatic carboxylic acids (6) with o-phenylenediamine (1) in a one-pot reaction using ammonium chloride as a catalyst. The reaction mechanism involves initial protonation of the carboxyl group by ammonium chloride, enhancing its electrophilicity and facilitating nucleophilic attack by the primary amine of o-phenylenediamine (1). The benzimidazole core is formed through an intramolecular cyclization process that begins with the creation of an amide intermediate and ends with its dehydration. To optimize reaction efficiency at moderate temperatures (80-90°C), ammonium chloride plays a catalytic role that promotes regioselective cyclization. This method is useful since it streamlines the synthetic process and produces 2-substituted benzimidazole derivatives with moderate to good yields. [Scheme 4].^[12,13]

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Scheme 4:

Ammonium chloride-catalyzed benzimidazole synthesis.

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The synthesis of 2-substituted benzimidazole derivatives (9) via microwave irradiation under solvent-free conditions represents an efficient and environmentally friendly approach. This method employs alumina, silica gel, or zeolite HY as heterogeneous catalysts to facilitate the reaction between o-phenylenediamine (1) and aromatic, aliphatic, or heterocyclic carboxylic acids (8). The catalytic process begins with the adsorption of the reactants onto the surface of the solid catalysts, where the active sites enhance electrophilic activation of the carboxyl functional group. The benzimidazole core (9) is produced via intramolecular cyclization and dehydration after an imine intermediate is formed by the interaction of o-phenylenediamine (1) with the activated carboxyl species (8). Microwave irradiation significantly accelerates the reaction by promoting uniform energy distribution, enhancing molecular collisions, and facilitating rapid product formation [Scheme 5].^[14-16]

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Scheme 5:

Microwave-assisted benzimidazole synthesis.

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The synthesis of novel benzimidazole derivatives, as documented by Satija et al^.[17], employs a reflux-based approach using xylene as a solvent and polyphosphoric acid (PPA) as a catalytic medium. The reaction involves the equimolar condensation of o-phenylenediamine (1) with p-aminobenzoic acid (10), leading to the formation of the benzimidazole core structure (11) [Scheme 6]. The process initiates with the activation of p-aminobenzoic acid (10) by polyphosphoric acid, enhancing its electrophilic nature. This activation facilitates nucleophilic attack by o-phenylenediamine (1), forming an amide intermediate. Under reflux conditions, the reaction mixture undergoes cyclization through sequential proton transfers, dehydration, and elimination of water, yielding the benzimidazole framework (11) [Table 1]. The non-polar environment provided by xylene aids in maintaining solubility and optimizing reaction efficiency.^[2,5,17,18]

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Scheme 6:

A reflux-based approach with aromatic carboxylic acids of Benzimidazole synthesis.

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The synthesis of benzimidazole-one derivatives (14) involves the reaction of dimethyl-acetone dicarboxylate (12) with o-phenylenediamine (1). This process proceeds via the formation of a diazepine intermediate (13), which subsequently undergoes structural rearrangement and modification under the action of mercapto-acetic acid [Scheme 7]. The reaction initiates with the nucleophilic attack of o-phenylenediamine (1) on the electrophilic carbonyl sites of dimethyl-acetone dicarboxylate (12), which results in the synthesis of an imine intermediate. Cyclization then occurs, yielding a diazepine derivative (13) through sequential proton transfer and ring closure. The addition of mercaptoacetic acid facilitates further transformation via nucleophilic substitution or thiolation, resulting in the benzimidazolone core (14). This multi-step pathway demonstrates regioselective activation and efficient heterocyclic formation.^[2,5,18,19]

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Scheme 7:

Heterocyclic intermediate rearrangement of the synthetic benzimidazole approach.

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The synthesis of the benzimidazole scaffold (17) with ZnO nanoparticles (NAP-ZnO) as the catalyst is possible with yields ranging from 90 to 98%. The process begins with the condensation of formic acid (16) with substituted o-aryl-diamines (15) at 70°C.^[19,20] This method, studied by Mohammed et al., ^[20]eliminates the need for solvents, reducing environmental impact and cost associated with pricier reagents.^[19,20] It represents a green and efficient strategy for benzimidazole synthesis. NAP-ZnO nanoparticles facilitate the synthesis through Lewis’s acid catalysis, enhancing the electrophilicity of formic acid and promoting nucleophilic attack by o-aryldiamines (15). The reaction proceeds through the protonation of formic acid (16), followed by cyclization and dehydration, leading to the formation of the benzimidazole core (17)^[3,5] [Scheme 8]. The heterogeneous nature of NAP-ZnO allows for easy recovery and reuse, making it a sustainable catalytic system.

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Scheme 8:

NAP-Zno nanocatalyst benzimidazole synthesis.

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A straightforward and effective route for synthesizing benzimidazole-2-thiol derivatives (18) by refluxing o-phenylenediamine (1) with mercaptoacetic acid, leading to the formation of an intermediate of an imine-like structure (18).^[3] The reaction proceeds via nucleophilic substitution and cyclization. The thiol (-SH) group in mercaptoacetic acid enhances nucleophilicity, facilitating interaction with o-phenylenediamine (1).^[1,13] Polynuclear fused benzimidazole derivatives (19 & 20) are formed through intramolecular cyclization, which is enhanced by the presence of aromatic aldehydes and chloroacetic acid [Scheme 9].

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Scheme 9:

Mercaptoacetic acid reflux benzimidazole synthesis.

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From Aldehydes

Patel et al.^[20,21] found that aliphatic or aromatic aldehydes (21), methanol, and molecular oxygen could be used efficiently to synthesize benzimidazole derivatives (22) from o-phenylenediamine (1) at room temperature^[1,5] [Scheme 10]. Instead of relying on hazardous and costly oxidants, this visible-light-driven method enhances efficiency and environmental sustainability by utilizing molecular oxygen as the oxidant, without requiring metal catalysts or toxic reagents. The mechanism involves photoinduced oxidation, where molecular oxygen absorbs energy from visible light, then generates reactive oxygen species that facilitate oxidative activation of aldehydes, promoting condensation and cyclization to yield benzimidazole derivatives (22).^[13,20-22]

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Scheme 10:

Benzimidazole synthesis using molecular oxygen as oxidant.

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Aniket et al.^[23] detailed an iodine-catalyzed 2-aryl-1-arylmethyl-1H-benzimidazole 23 synthesis that uses a one-pot condensation of o-phenylenediamine (1) with aldehydes (21) at 80-90°C for 1.5 h [Scheme 11]. Using this method is simple, fast, and won’t harm the planet. Iodine is a valuable reagent in organic synthesis because it is commercially available, relies on a non-hazardous catalyst, and is affordable.^[20,22,24]. The reaction mechanism follows iodine-mediated electrophilic activation, where iodine enhances the electrophilicity of aldehydes (2), facilitating nucleophilic attack by o-phenylenediamine (1), then leading to imine formation, cyclization, and oxidation, finally yielding the benzimidazole core (23). The advantages of this approach include metal-free catalysis, mild reaction conditions, high efficiency, and sustainability, positioning it as a cost-effective and practical method for synthesizing functionalized benzimidazole derivatives.^[3,5]

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Scheme 11:

Iodine catalyzed benzimidazole synthesis.

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Sodium metabisulfite adsorption on silica gel (SMB-SiO₂) was described by Kumar et al.^[23,25] as a catalyst for an eco-friendly benzimidazole synthesis [Scheme 12]. The mechanism involves the reaction of o-phenylenediamine (1) with benzaldehyde (24) in ethanol, followed by the addition of SMB-SiO₂, which facilitates oxidative cyclization through sulfone-mediated electron transfer.^[1,3,5] The reaction proceeds under mild conditions with continuous stirring for 4 to 8 h, ensuring complete transformation to give substituted benzimidazole derivatives (25) with high purity.^{[20-22,24-26]} This approach underscores the advantages of SMB-SiO₂ as a reusable, non-toxic heterogeneous catalyst, making the protocol more efficient and environmentally friendly.

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Scheme 12:

benzimidazole synthesis using sodium metabisulfite adsorbed on silica gel.

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Lin et al. and Rathod and Biradar described a one-step process for producing benzimidazole derivatives (27). This process involves heating o-phenylenediamine (1) and benzaldehyde (26) to 100°C using atmospheric oxygen as a green oxidant [Scheme 13].^{[22,23,25-29]} The reaction occurs with a nucleophilic assault by o-phenylenediamine (1) on the carbonyl carbon of aldehyde (26), resulting in the formation of an imine intermediate. The subsequent intramolecular cyclization and oxidative dehydrogenation induced by atmospheric oxygen resulted in the creation of the benzimidazole framework (27).^[4]

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Scheme 13:

The use of air as an oxidant in the benzimidazole synthesis.

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Another approach to synthesizing benzimidazole derivatives (29) was presented by Waghmare et al., who used ferric hydrogen sulfate (FSH) as an oxidative catalyst to condense o-phenylenediamine (1) with different aromatic aldehydes (28). An imine intermediate is produced when o-phenylenediamine (1) attacks the carbonyl group of the aldehyde during the initial Schiff base production step of the reaction [Scheme 14].^{[20,22,24,28,30]}. The oxidative nature of FSH facilitates the subsequent cyclization and dehydrogenation, forming the benzimidazole framework (29). The reaction kinetics are influenced by the electronic properties of the aldehydes (28). The electron-withdrawing substituents accelerate the process, enhancing reactivity, whereas electron-donating groups reduce the rate by stabilizing the intermediate. While using water as a solvent is a more environmentally friendly option, it reduces yield since important intermediates may be hydrolyzed.^[25,29,31]

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Scheme 14:

FSH-mediated benzimidazole synthesis.

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Mobinikhaledi et al. developed an efficient and environmentally-friendly synthesis of 2-aryl benzimidazoles (31) by condensing o-phenylenediamine (1) with various aromatic aldehydes (30) in the presence of sodium hexafluoroaluminate (Na₃AlF₆) as a catalyst at 50°C.^{[20,21,23,26,30,32,33]} This reaction follows a nucleophilic addition mechanism, where o-phenylenediamine (1) initially attacks the carbonyl group of the aldehyde (30), forming an imine intermediate. Subsequent cyclization and oxidative dehydrogenation facilitated by Na₃AlF₆ lead to the formation of the benzimidazole scaffold (31a-h) [Scheme 15] [Table 2]. The electronic properties of aldehydes significantly impact the yield, as aromatic aldehydes enhance reactivity through conjugation, whereas aliphatic aldehydes produce only trace amounts due to the absence of resonance stabilization. The resulting 2-aryl benzimidazole derivatives (31) exhibit antibacterial activity.^{[5,27,28,31,33]}

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Scheme 15:

2-Aryl benzimidazole synthesis with Na₃AlF_6.

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Tang et al.[34] developed an efficient and versatile method for the synthesis of 2-substituted-1H-benzo[d]imidazoles (33) via the oxidative cyclization of o-phenylenediamine (1) with a range of aldehydes (32), exploiting dioxane dibromide as a mild and stable catalyst. The reaction proceeds through an initial condensation step, where o-phenylenediamine (1) reacts with the aldehyde (32) to form an imine intermediate, followed by a bromine-mediated oxidation that facilitates cyclization, leading to the benzimidazole framework (33) [Scheme 16] [Table 3]. The protocol offers high selectivity and yield, favoring aromatic aldehydes due to their resonance stabilization, while aliphatic aldehydes exhibit diminished reactivity.^{[20,21,23,28,32,34]}

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Scheme 16:

Dioxane-dibromide-mediated benzimidazole synthesis.

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Sodium dodecyl sulfates (SDS) were used as a catalyst in a surfactant-assisted benzimidazole derivatives (35) synthesis method by Pardeshi et al. which allowed o-phenylenediamine (1) and aryl aldehydes (34) to react in water without the need for an additional oxidizing agent. To begin with, o-phenylenediamine (1), different substituted aromatic aldehydes (34), and water are combined in a round-bottom flask. Then, molecular contacts are enhanced, and the reaction rate is accelerated by adding SDS. Ultrasonic irradiation is then applied. By improving solubility and reaction efficiency, this technique provides greater amounts of benzimidazole derivatives (35) [Scheme 17]. The electronic properties of aldehydes significantly affect the rate of reactions; reaction kinetics are slowed down by electron-donating groups and accelerated by electron-removing groups.^{[20,21,23,29,33,35]} As reported in Table 4, substituted aromatic aldehydes exhibit varying yields, demonstrating the efficiency of SDS as a reaction-promoting surfactant in green chemistry approaches.

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Scheme 17:

SDS-assisted synthesis of benzimidazole derivatives.

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An effective cross-coupling method for the synthesis of benzimidazole derivatives (37) was devised by Kumar et al^.[25] using palladium and copper-based catalysts in the presence of o-phenylenediamine (1) and alkyl or aryl aldehydes, including those containing heteroatoms (36) [Scheme 18].^{[20,21,23,30,34,36]} An intermediate imine is formed by the nucleophilic addition of o-phenylenediamine (1) to aldehyde (36) in the initial reaction. Palladium or copper catalysis facilitates oxidative cyclization, enhancing electron transfer processes that promote the formation of the benzimidazole scaffold (37). By stabilizing reactive intermediates, increasing electron density at critical sites, and facilitating selective bond formation, the catalytic system is essential for maximizing reaction efficiency. This approach demonstrates high yield (95%), broad substrate compatibility, and mild reaction conditions, making it a versatile method for synthesizing benzimidazole derivatives (37) with diverse functionalities, including heteroatom incorporation, for potential pharmaceutical applications.^{[31,32,35-38]}

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Scheme 18:

Cross-coupling strategies for benzimidazole synthesis.

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Benzimidazole derivatives can be synthesized by condensing o-phenylenediamine (1) with an aldehyde (38) in methanol at room temperature with the help of copper (II) hydroxide [Cu(OH)₂], as shown in Scheme 19 [Table 5]. The resulting product has high purity. As a first step in the reaction, o-phenylenediamine (1) forms an imine intermediate by attacking the carbonyl center of aldehyde (38) with its nucleophilic group. The creation of C=N bonds is aided by Cu(OH)₂, which promotes oxidative cyclization and the transfer of electrons. The presence of an open oxygen environment enhances oxidation efficiency, assisting in the dehydrogenation step that finalizes the benzimidazole ring system (39).^{[33,34,37-40]}

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Scheme 19:

Cu(OH)₂-mediated benzimidazole synthesis.

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A more efficient way to synthesize 2-(4-chlorophenyl) benzimidazole (41) is to combine o-phenylenediamine (1) and 4-chlorobenzaldehyde (40) in tetrahydrofuran (THF) at 25°C with tert-butyl nitrite (TBN) as an oxidative agent [Scheme 20]. To initiate the reaction, the carbonyl site of compound 40’s aldehyde is attacked by o-phenylenediamine (1), which forms an imine intermediate through a nucleophilic attack. The benzimidazole framework (41) is more easily formed with the help of radical-mediated electron transfer processes, which the TBN makes easier by facilitating oxidative cyclization. After 30 min of reaction time, 80% of the target product is produced. The reaction can be driven to completion under mild conditions owing to the enhanced reactivity of 4-chlorobenzaldehyde and the presence of THF as a solvent, which guarantees efficient solubility and stability.^{[35-37,39,41-45]}

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Scheme 20:

Tert-butyl nitrite-mediated benzimidazole synthesis.

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An effective and environmentally sustainable technique for the solvent-free synthesis of benzimidazole derivatives (43) can be achieved by directly combining o-phenylenediamine (1) with an aldehyde (42) at 140°C [Scheme 21] [Table 6]. A Schiff base intermediate is formed in the first stages of the reaction by the nucleophilic attack of o-phenylenediamine (1) on the carbonyl carbon of aldehyde (42). Subsequent intramolecular cyclization results in the benzimidazole framework (43), facilitated by the elevated temperature, which enhances molecular collisions and reaction kinetics. The absence of solvent eliminates the need for additional purification steps and improves efficiency and yield. This thermal-activated pathway promotes direct bond formation while preventing undesirable side reactions. This results in a green and cost-effective alternative approach for synthesizing pharmaceutically relevant benzimidazole derivatives.^{[22,27,29,38,44,46]}

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Scheme 21:

Solvent-free benzimidazole synthesis.

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Under mild conditions, benzimidazole derivatives (45) can be successfully produced by condensing o-phenylenediamine (1) with an aldehyde (44) in an aqueous medium at room temperature, with boric acid as a catalyst^[45,47] [Scheme 22]. A nucleophilic attack by o-phenylenediamine (1) on the electrophilic carbonyl site of aldehyde (44) initiates the reaction process, which results in the creation of an imine intermediate. By acting as a Lewis acid catalyst, boric acid speeds up cyclization by stabilizing the transition state and easing proton transfer. The aqueous medium helps in molecular solvation, promoting efficient reaction kinetics and minimizing unwanted side reactions. The intramolecular cyclization leads to the formation of the benzimidazole scaffold (45), offering a sustainable, high-yielding, and environmentally benign synthesis approach for bioactive heterocycles [Table 7].^[5,46,48]

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Scheme 22:

Boric acid-catalyzed benzimidazole synthesis.

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Using aromatic aldehydes (46) and sodium hexafluoroaluminate (Na₃AlF₆) as a catalyst, Mobinikhaledi et al.^[26,31,33] produced 2-aryl benzimidazoles (47) by condensing o-phenylenediamine (1). The reaction was carried out at 50°C [Scheme 23] [Table 8]. Aromatic aldehydes enhance nucleophilicity and stabilize the transition state, leading to high yields, whereas aliphatic aldehydes result in only trace amounts of product due to their weaker electrophilicity and lack of resonance stabilization. Mechanistically, Na₃AlF₆ acts as a Lewis acid, increasing aldehyde electrophilicity, facilitating condensation with (1), and promoting cyclization and aromatization to yield benzimidazole derivatives (47). Preliminary disc diffusion tests demonstrated significant inhibitory zones against both Gram-positive and Gram-negative bacteria, lending credence to the idea that 2-aryl benzimidazoles (47) have antibacterial action.^{[20,22,24,39,40,47-50]}

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Scheme 23:

The synthesis of antibacterial 2-aryl benzimidazoles using Na₃AlF₆.

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A green reaction medium was made possible by Khunt et al. This is an effective and environmentally friendly method of synthesizing a benzimidazole contender (47) by condensing o-phenylenediamine (1) with aldehydes (48) in polyethylene glycol (PEG)-400. By increasing chemical interaction and solubility inside PEG-400, the process was optimized for 80-85°C, which led to excellent yields [Scheme 24].^{[41,42,49-52]} Mechanistically, PEG-400 facilitates the nucleophilic attack of the diamine on the aldehyde, which in turn leads to the creation of an imine intermediate, by functioning as a moderate catalyst and solvent. The benzimidazole core is stabilized by intramolecular cyclization that follows aromatization. Experimental findings indicate that when glycerol/water was employed as an alternative reaction medium, the product formation followed a unique pathway, likely due to altered solvation effects influencing imine formation and cyclization rates.^[43,51,53]

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Scheme 24:

The green synthesis of benzimidazole derivatives using PEG-400.

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O-phenylenediamine (1) and aldehydes (48) undergo cyclic condensation in a bioabsorbable solvent system comprising ethanol and lactic acid, facilitating an environmentally benign reaction under ambient conditions for 4-6 h. Song and Ma reported the efficient one-pot synthesis of disubstituted benzimidazole derivatives (49), demonstrating that lactic acid serves as an optimal medium due to its dual role as a solvent and mild catalytic agent [Scheme 25]. Mechanistically, lactic acid enhances the electrophilicity of the aldehyde (47), promoting nucleophilic attack by o-phenylenediamine (1), leading to imine formation. Subsequent intramolecular cyclization and aromatization stabilize the benzimidazole core, yielding the desired product (48).^{[44,45,52-55]}

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Scheme 25:

Disubstituted benzimidazoles synthesis using lactic acid.

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Benzimidazole synthesis in the presence of a Lewis acid

Using 2-aminobenzyl alcohol (50) and benzonitrile (51), Trivedi et al. and Shah et al. and Mukhopadhyay, conducted research on the microwave-assisted synthesis of 2-substituted benzimidazole derivatives (52) [Scheme 26].^[20,22][24] Under 100 W microwave irradiation for 50 min, the reaction initially results in an inseparable mixture of products due to uncontrolled thermal effects. However, employing Lewis acids such as ZnCl₂ and ZnI₂ significantly enhances selectivity and efficiency. ZnI₂, being more effective, activates the nitrile group, facilitating nucleophilic attack by 2-aminobenzyl alcohol (50), which leads to CN bond formation and subsequent cyclization into the benzimidazole framework (51) [Table 9].^{[46-48,54-60]}

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Scheme 26:

Microwave-assisted benzimidazole synthesis.

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From anhydrides

Zinc acetate acted as a catalyst in a solvent-free green synthesis of polycyclic benzimidazole derivatives (55) by heating carboxylic acid anhydrides (53) and arylene diamines (54) in a solid state [Scheme 27A]. Mechanistically, the benzimidazole core structure is produced by intramolecular cyclization of an intermediate amide, which is formed when zinc acetate aids the nucleophilic attack of the diamine on the anhydride. By shifting the equilibrium toward product production, the lack of solvent improves reaction efficiency while reducing environmental impact.^[49,59,61] The synthesis of benzimidazoles or 1,10-diacyl phenylenediamines can be achieved using acetic anhydride and o-phenylenediamine (1), depending on the reaction conditions [Scheme 27B]. The nucleophilic amino groups of o-phenylenediamine (1) attack the electrophilic carbonyl centers of acetic anhydride, leading to intermediate amide formation. Under prolonged reflux conditions for 5 h, this intermediate undergoes intramolecular cyclization via dehydration, yielding benzimidazole (55) as the final product.^[50,60,62]

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Scheme 27:

Synthesis of benzimidazoles via anhydride condensation and reflux conditions.

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From ketones

Digwal et al_. demonstrated that the reaction of dibenzyl ketones (56) with o-phenylenediamine (1), catalyzed by vanadyl sulfate (VOSO₄), leads to the preferential formation of quinoxaline derivatives, specifically 2,3-diphenylquinoxalines (57), instead of benzimidazoles [Scheme 28]. VOSO₄ functions as a Lewis acid catalyst, facilitating the ketone’s electrophilicity and diamine condensation. The process starts with an o-phenylenediamine (1) nucleophilic attack on the ketone (56), which forms an imine. Then, the quinoxaline core (57) is stabilized through oxidative cyclization. Experimental results indicate that the presence of VOSO₄ facilitates selective quinoxaline synthesis by stabilizing intermediate oxidation states, thereby favoring cyclization over the benzimidazole pathway. This catalytic system underscores the role of transition metal-assisted oxidative strategies in modulating heterocyclic frameworks efficiently.^{[51-54,61-67]}

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Scheme 28:

Synthesis of quinoxaline derivatives using VOSO₄ as a catalyst.

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The feasibility of this strategy for creating benzimidazole frameworks was demonstrated by Alaqeel ^[6], who reported the synthesis of 2-phenyl-5(6)-methyl benzimidazole derivatives (60) by thermal condensation of acetophenone (59) with 3,4-diaminotoluene (58) at 180°C [Scheme 29]. From a mechanistic standpoint, the reaction starts with the nucleophilic attack of diamine (58) on acetophenone (59). This forms a temporary imine intermediate, which then goes through intramolecular cyclization and oxidative aromatization to produce the benzimidazole core (60). Limited experimental results indicate that elevated temperatures facilitate imine formation and promote efficient cyclization, ensuring high regioselectivity in product distribution.^{[55,56,66-69]}

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Scheme 29:

Synthesis of 2-phenyl-5(6)-methylbenzimidazole derivatives via thermal condensation reaction.

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The effective formation of almost quantifiable amounts of 2-(imidazol-4-yl) benzimidazoles (62a-d) is achieved by reacting four imidazole derivatives (61a-d) with ammonium acetate in acetic acid [Scheme 30] [Table 10]. Mechanistically, acetic acid facilitates imine activation, promoting nucleophilic addition of ammonium acetate to the imidazole framework (61). This leads to imidazole ring expansion via condensation, followed by intramolecular cyclization and tautomerization to stabilize the benzimidazole core (62).^{[57,58,68-71]}

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Scheme 30:

Synthetic route to 2-(imidazol-4-yl) benzimidazoles using ammonium acetate.

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From orthoesters

A sustainable and efficient synthesis of benzimidazole derivatives (64) from o-phenylenediamine (1) and orthoesters (63) is achieved using sulfonated rice husk ash as a solid acid catalyst, as described in Scheme 31. The mechanical process involves the creation of an imine intermediate, which is aided by the sulfonated functional groups, which increase electrophilicity and allow o-phenylenediamine (1) to conduct a nucleophilic attack on orthoester (63). The benzimidazole core structure (64) is the end product of intramolecular cyclization and dehydration. Experimental findings demonstrate that the reaction progresses rapidly, yielding high-purity products in a short time frame, with minimal byproduct formation.^{[59-61,70-74]}

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Scheme 31:

Synthesis of benzimidazoles using sulfonated rice husk ash as a catalyst.

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From acid chlorides

The 2,5- (or 2,6-) dimethylbenzimidazole (66) is produced when the reaction of acetyl chloride (65) with 3,4-diaminotoluene (58) takes place in benzene, where high temperatures (200-220°C) encourage intramolecular condensation and dehydration [Scheme 32]. Conversely, cooling the reaction medium stabilizes the intermediate diacetyl-o-phenylenediamine, preventing further cyclization. Pyridine, when heated in a reflux or steam bath environment, acts as a proton scavenger, increasing the effectiveness of the cyclization process. To further control product distribution, N-substituted o-phenylenediamines are preferred; however, experimental results show that benzimidazoles without 1-position substituents can be further acylated using acid chlorides.^[6,20,21,23]

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Scheme 32:

Thermal condensation reaction of acid chlorides for benzimidazoles or acylated derivatives synthesis.

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Heravi and Zadsirjan reported the synthesis of 2-substituted benzimidazoles (68) through the reaction of o-phenylenediamine (1) with acid chloride (65) in dioxane, using zeolite as a catalyst [Scheme 33].^[5] Mechanistically, acid chloride (65) activates the nucleophilic amino groups of o-phenylenediamine (1), leading to initial acylation via electrophilic substitution. Zeolite facilitates cyclization by promoting proton transfer, enabling intramolecular condensation and dehydration to yield the benzimidazole core (68). Experimental results indicate high efficiency and regioselectivity of this one-pot method, eliminating the need for isolating N-acyl phenylenediamine intermediates (67).^{[20,21,23,73,75]}

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Scheme 33:

2-Substituted benzimidazole synthesis catalyzed by zeolite.

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From cyanogen bromide

The synthesis of benzimidazole derivatives (72) via Pellizzari’s method involves the reaction of equimolecular amounts of o-aminophenylurea (69) with cyanogen bromide (70) in an aqueous suspension, ensuring controlled nucleophilic reactivity [Scheme 34]. An intermediate urea derivative (71) is formed through a mechanism involving an the nucleophilic attack of amino group on electrophilic reagent cyanogen bromide (70). This intermediate undergoes intramolecular cyclization, driven by the expulsion of bromide and dehydration, resulting in the formation of the benzimidazole core (72). Experimental observations indicate that aqueous conditions enhance solubility and reaction efficiency, promoting high yields of benzimidazole derivatives with minimal side-product formation.^[6]

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Scheme 34:

Benzimidazole derivatives formation by reacting o-amino-phenyl urea with cyanogen bromide.

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The reaction of cyanogen bromide (70) with o-phenylenediamine (1) produces 2-aminobenzimidazole (73) with great purity [Scheme 35]. Cyanogen bromide (70) functions as an electrophilic reagent, promoting nucleophilic substitution at the cyano group by the amine group of o-phenylenediamine (1). This contact generates a reactive intermediate that undergoes intramolecular cyclization, facilitated by the release of bromide ions, resulting in the creation of the benzimidazole core (73). Experimental studies demonstrate that this transformation occurs swiftly under regulated conditions, with few side reactions, guaranteeing elevated yields. The reaction is further improved by aqueous or organic solvent systems that increase solubility and reaction kinetics, hence maximizing product production.^{[6,62,64,74,76]}

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Scheme 35:

Synthesis of 2-aminobenzimidazoles using cyanogen bromide.

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From orthoformate

Using potassium hydroxide as a catalytic base, benzene-1,2-diamine (74) is refluxed in chloroform with ethyl orthoformate (75) to produce nitrobenzimidazole derivatives (76) [Scheme 36]. Mechanistically, an imine intermediate is formed when benzene-1,2-diamine (74) conducts a nucleophilic attack on ethyl orthoformate (75). Potassium hydroxide facilitates deprotonation and promotes cyclization, enabling intramolecular condensation and dehydration to yield the benzimidazole core structure (76). The presence of chloroform enhances solubility and reaction efficiency by stabilizing reactive intermediates. This approach provides a robust and straightforward pathway for the synthesis of nitro-substituted benzimidazoles with high purity and structural integrity.^[4,6,62,64]

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Scheme 36:

Synthesis of nitrobenzimidazole derivatives using benzene-1,2-diamine and ethyl orthoformate.

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From nitrile

There are a few studies regarding the direct condensation of o-phenylenediamine (1) with nitriles, which showed a 27% yield of 2-methylbenzimidazole (78) from acetonitrile (77) when using anhydrous hydrogen chloride (HCl) at 200°C for 6 h [Scheme 37].^[6]The reaction is initiated by the activation of nitrile via protonation by HCl, generating the highly reactive ammono-acyl chloride (79). This electrophilic intermediate subsequently undergoes intramolecular cyclization with o-phenylenediamine (1), leading to the formation of benzimidazole (78) [Scheme 38].^[63,75,77]

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Scheme 37:

Traditional condensation of benzimidazole synthesis from nitriles.

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Progress in nitrile hydrogenation has recently made it possible to synthesize amines using catalysts based on transition metals at an atom-economical cost. As an example, rhodium phosphide supported on lignin-derived porous carbon (Rh2P/LC) was used in the reductive coupling of nitriles and o-phenylenediamines (1) to produce 2-alkylbenzimidazoles (81) [Scheme 39]. Rh₂P/LC efficiently integrates nitrile hydrogenation, cyclization, and dehydration in a one-pot reaction, achieving >99% yield of 81a at 140°C using either H₂ or hydrazine hydrate (N₂H₄^.H₂O) (80) as a hydrogen source.^[64,76,78]

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Scheme 38:

The reaction mechanism of HCl-induced condensation from nitriles.

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The intermolecular cyclization of 2-iodoanilines (82) with nitriles (83) has been established as an efficient method for benzimidazole synthesis, proceeding under metal-free conditions with potassium tert-butoxide (tBuOK) as the sole base [Scheme 40].^[64,66] Mechanistically, tBuOK facilitates deprotonat ion of the aniline moiety, enhancing nucleophilicity and promoting direct nucleophilic attack on the electrophilic nitrile carbon. This activation triggers subsequent cyclization, leading to benzimidazole formation (84).^[65,77,79]

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Scheme 39:

Present transition-metal-promoted reductive coupling benzimidazole synthesis.

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Scheme 40:

Metal-free and base-promoted cyclization method for benzimidazole synthesis.

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A novel approach for the direct synthesis of N-methylbenzimidazoles (87) from carbonitriles (86) with N-methyl-1,2-phenylenediamine (85) under basic conditions, tolerating acidic environments that are incompatible with acid-labile protective groups such as acetals. Using sodium hydride (NaH) as a base, the reaction proceeds efficiently in toluene at 120-180°C, achieving yields of 50-93% [Scheme 41].^[66,78,80] The NaH deprotonates the amine, generating a nucleophilic species that undergoes cyclization with nitrile, forming the benzimidazole core.^{[67,68,79-82]}

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Scheme 41:

Cross-coupling reaction for benzimidazole synthesis.

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Under basic conditions, 2-aminobenzoxazole and 2-aminobenzimidazole derivatives (90a-c) can be efficiently synthesized using lithium hexamethyldisilazide (LiHMDS) by reacting N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) (88), a nonhazardous electrophilic cyanating agent, with benzene-1,2-diamine (89) and a number of substituted 2-aminophenols (88) [Scheme 42].^[69,81,83] The LiHMDS deprotonates the amino functionality, increasing nucleophilicity and facilitating the direct electrophilic cyanation by NCTS (88). The required heterocyclic compounds are produced by intramolecular cyclization of an N-cyano intermediate that is formed in this procedure.^[70,82,84]

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Scheme 42:

The cyanation mechanism of NCTS benzimidazole synthesis.

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From esters

A more efficient method for producing 2-(trifluoromethyl) benzimidazoles (93) is to combine (2-arylamino) imino phosphoranes (91) with trifluoroacetyl esters or trifluoroacetic anhydride (92) [Scheme 43].^[71,83,85] The reaction initiates with nucleophilic attack by the (2-arylamino) iminophosphorane (91) on the electrophilic trifluoroacetyl ester or anhydride (92), leading to the formation of an amide-like intermediate. Subsequent cyclization via intramolecular condensation results in the benzimidazole core incorporating the trifluoromethyl group (92).^{[72-74,84-88]} The simplicity of this protocol, combined with its mild reaction conditions, enhances its applicability for synthesizing fluorinated benzimidazole derivatives with pharmaceutical relevance.

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Scheme 43:

Synthesis of trifluoromethyl benzimidazoles by condensation reaction.

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The efficient synthesis of benzimidazole derivatives (96) from 3,4-diaminotoluene dihydrochloride (94) and ester compounds (95) has been greatly improved using microwave-assisted techniques in recent investigations, leading to a dramatic increase in reaction speed and yield [Scheme 44]. The condensation of diamine (94) with ester substrates (95) is accelerated by microwave irradiation, which allows for a quick nucleophilic attack on the electrophilic carbonyl site. Then, the benzimidazole core (96) is formed via cyclization. In comparison to more traditional thermal approaches, this one uses targeted dielectric heating to improve energy distribution uniformity and shorten reaction times.^[75,87,89]

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Scheme 44:

Microwave-assisted synthesis of benzimidazole derivatives.

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Green synthesis of benzimidazole

Green chemistry has emerged as a pivotal strategy in the synthesis of benzimidazole derivatives, aiming to reduce environmental impact while maintaining or enhancing synthetic efficiency.^[76,88,90] Traditional methods for benzimidazole synthesis often involve harsh reaction conditions, toxic solvents, and metal-based catalysts, which contribute to environmental pollution and safety concerns. In contrast, green chemistry approaches utilize eco-friendly solvents, such as water, ethanol, or polyethylene glycol (PEG), and employ benign catalysts like ionic liquids, natural acids, or even catalyst-free systems under microwave or ultrasound irradiation.^[77,89,91] As an example, 2-substituted benzimidazoles can be efficiently synthesized with high yields and decreased reaction times by using [BMIM]HSO₄ as an ionic liquid under microwave conditions. Besides that, multicomponent reactions (MCRs) and solvent-free protocols have gained popularity for their atom economy and operational simplicity.^[78,90,92] These innovations not only align with the principles of sustainability but also offer scalable and cost-effective routes for pharmaceutical and industrial applications of benzimidazoles. Nanocatalysts such as Fe₃O₄, ZnO, and TiO₂ have been shown to significantly enhance the efficiency of benzimidazole synthesis by providing high surface area and active sites for the reaction. These catalysts enable solvent-free or aqueous-phase reactions under mild conditions, aligning with green chemistry principles.^[7]

In their study, Enumula et al.^[91,93] detailed a green synthesis method that is both efficient and environmentally friendly for producing benzimidazole derivatives (99). They used solvent-assisted mechanochemical conditions and a catalytic quantity of the ionic liquid 1-ethyl-3-methylimidazolium tetrachloroaluminate ([EMIM]AlCl₄) in ethanol [Scheme 45].^{[39,47,49,79,92,94,]} The reaction proceeds at room temperature through manual grinding in a mortar and pestle, promoting intimate mixing of the reactants and facilitating rapid condensation between o-phenylenediamine (97) and aldehydes (98). By combining the roles of Lewis acid catalyst and reaction medium, the ionic liquid prepares the aldehyde carbonyl group for nucleophilic attack by the amine, which in turn triggers cyclization and dehydration, ultimately producing the benzimidazole scaffold.^{[80,81,93-96]} This protocol aligns with the principles of green chemistry by eliminating the need for hazardous reagents, external heating, and excess solvent, offering a low-energy, high-efficiency method with minimal environmental footprint.

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Scheme 45:

Ionic liquid production of benzimidazole derivatives: an environmentally friendly approach.

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By using phenylsilane (PhSiH₃) with carbon dioxide (CO₂), a greenhouse gas that has been repurposed as a sustainable C1 source, Zhang et al. (102) developed a method for synthesizing benzimidazole derivatives that is both efficient and environmentally aware [Scheme 46].^[39,74,76] The transformation proceeds under mild conditions with tris(pentafluorophenyl)borane, B(C₆F₅)₃, as a Lewis acid catalyst, facilitating high product yields of up to 95%. The mechanism starts by B(C₆F₅)₃ activating PhSiH₃ to generate a reactive hydrosilane species that reduces CO₂ in situ, forming a silanolate intermediate (101) capable of reacting with o-phenylenediamine (100) to induce cyclization and formation of the benzimidazole core (102).^{[82-84,94-99]} This strategy exemplifies the principles of green chemistry by harnessing CO₂ as a feedstock, avoiding harsh reagents or high temperatures, and maximizing atom economy, demonstrating a valuable intersection between synthetic efficiency and environmental responsibility.

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Scheme 46:

CO₂-based benzimidazole green synthesis.

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By generating benzimidazolines (104) in situ without the need for solvents or catalysts, Prajapat et al. demonstrated a metal-free transfer hydrogenation method for the synthesis of benzimidazole derivatives.^[7] The reaction begins with the creation of a benzimidazoline intermediate, which acts as a hydrogen donor and cyclization precursor, by heating o-phenylenediamine (1) and ethyl α-cyanocinnamate (103) in equal proportions at 100°C [Scheme 47]. The benzimidazoline undergoes an intramolecular redox process, transferring hydrogen to the electron-deficient olefin, thereby forming the reduced product alongside the target benzimidazole (104).^[85,98-101] The elimination of volatile organic solvents, toxic metal catalysts, and external hydrogen sources demonstrates a minimalistic, energy-efficient, and atom-economical synthesis approach that aligns strongly with green chemistry concepts.

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Scheme 47:

Metal- and solvent-free transfer hydrogenation synthesis of benzimidazoles.

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The use of arylaldehydes (105) or aryl methylene-malononitriles as starting materials under solvent-free and catalyst-free conditions is a sustainable and efficient way to synthesize benzimidazole derivatives (106). Silica gel is used as an absorbent to facilitate intimate contact between the reagents [Scheme 48].^[7] Both intermittent mechanical grinding and microwave irradiation speed up the condensation of o-phenylenediamine (1) with the carbonyl-containing substrates (105), which in turn speeds up the process. To create the benzimidazole framework (106), the activated carbon center conducts a nucleophilic attack on the amine, and then intramolecular cyclization and dehydration occur. By avoiding the use of harmful catalysts, mechanical force, or microwave energy, and by not using volatile organic solvents, this method demonstrates the principles of green chemistry. The result is a high-yielding, low-waste process that minimizes environmental impact while maintaining synthetic efficiency.

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Scheme 48:

Green synthesis of benzimidazole derivatives by silica support.

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Antibacterial activity

The unique sequence of a novel series of 2-substituted-1-[(5-substituted-phenyl-1,3,4-oxadiazol-2-yl) methyl]-1H-benzimidazoles (107) was described by Salahuddin et al. [Scheme 49] and evaluated their antibacterial efficacy against both Gram-negative and Gram-positive bacteria. The compounds demonstrated significant bactericidal activity, with minimum bactericidal concentrations (MBCs) ranging from 50 to 250 µg mL^-1 against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.^{[87,101–104]}

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Scheme 49:

Benzimidazoles bearing oxazole derivatives as antibacterial compounds.

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The related dimeric metal complexes (109) were effectively produced with an 80% yield by complexing the benzimidazole-based bidentate ligand (108), which was prepared by condensation of 2-(4-aminophenyl) benzimidazole with a 5-bromosalicylaldehyde derivative [Scheme 50]. Both Gram-positive (Micrococcus luteus) and Gram-negative (Escherichia coli and Enterobacter aerogenes) bacteria were effectively inhibited by these complexes. The benzimidazole-based scaffolds showed promise as antibacterial agents, with the metal complexes, especially those of Cu (II) and Ni (II), displaying moderate to exceptional activity.^{[38,39,46-49]}

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Scheme 50:

The production of antimicrobial metallic complexes containing the benzimidazole ligand.

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A novel and efficient synthetic pathway was developed to construct a triaryl benzimidazole core (114), which exhibited potent antibacterial activity against resistant strains VRE and EMRSA [Scheme 51]. The route centered on the formation of an N-pyridyl-benzimidazole scaffold via aromatic nucleophilic substitution, reduction of the nitro group using Raney nickel under hydrogen pressure, and then cyclization in the presence of methyl orthoacetate and p-toluene sulfonic acid. Further elaboration involved Suzuki coupling and amide bond formation, yielding a proof-of-concept compound (115).^[88,103,105]

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Scheme 51:

Synthesis of a potent antibacterial tri-aryl benzimidazole against VRE and EMRSA.

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Through a microwave-assisted condensation of substituted o-phenylenediamines with tailored aldehydes in the presence of Na₂S₂O₅, a series of 2,5-disubstituted benzimidazole derivatives (116a-c) was produced, with excellent yields (∼90%) that are appropriate for biological evaluation [Scheme 52]. The substances that were produced demonstrated potent antimicrobial and antifungal properties when tested against various infectious agents, such as E. coli, Staphylococcus aureus, and Staphylococcus epidermidis.^{[88,89,103-106]}

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Scheme 52:

Synthesis of halogenated benzimidazole derivatives as antimicrobial agents.

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Anticancer activity

Küçükbay et al. recently synthesized a series of novel 1,3-benzimidazole salts and their corresponding metal complexes, demonstrating significant antibacterial and antifungal activity, as well as cytotoxic potential against the A549 lung cancer cell line and the non-cancerous BEAS-2B lung epithelial cell line [Scheme 53].^[90,105-108] Structure-activity relationship (SAR) analysis revealed that substituents at the 5-position, whether electron-donating or electron-withdrawing, enhanced antimicrobial efficacy relative to unsubstituted analogues. Moreover, metal-complexed benzimidazoles (117) without substituents exhibited amplified antimicrobial and cytotoxic effects, highlighting the influence of metal coordination and substitution pattern on biological activity.^[88,103,105]

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Scheme 53:

The development of 1,3-benzimidazole metal complexes and salts with antibacterial properties.

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Indole benzimidazole hybrids are promising anticancer agents due to the well-established bioactivity of both core structures. Phenylindoles have demonstrated efficacy against breast cancer, while various 2-substituted benzimidazoles (118) show cytotoxicity across multiple cancer cell lines. In a ground-breaking study, Karadayi et al. found that adding electron-withdrawing groups at R₂ and p-fluorobenzyl or small alkyl groups at the R₁-position greatly increases anticancer activity. This finding emphasizes the strong SAR within this class of compounds [Scheme 54].^{[88,91,103-107,109]}

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Scheme 54:

Anticancer indole-benzimidazole structure.

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The cytotoxic effects of bis-benzimidazoles against breast (MCF-7) and skin (A431) cancer cells are well-documented, and their ability to inhibit DNA topoisomerase I activity has been investigated extensively. The novel 2-substituted benzimidazoles 119a-c, developed by Hanan M. Refaat^[110], showed encouraging anticancer effects when imbued with either a 5-chloro group or a carboxylic acid at the 5-position [Scheme 55].^{[88,92,103,105,108,111]}

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Scheme 55:

Novel anticancer agents based on 2-substituted benzimidazole derivatives.

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Recent benzimidazole-based metal complexes (120) have shown strong anticancer activity, especially against ovarian cancer cells A-2780, outperforming the standard drug docetaxel with a logIC₅₀ of 0.81 μM (p < 0.05). These results suggest that adding metal ions to benzimidazole structures can significantly boost their anticancer effects across various cancer cell lines, including ovarian cancer cells A-2780 and prostate cancer DU-145 [Scheme 56].^{[88,93,103,105,109,112]}

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Scheme 56:

Synthesis of new benzimidazole metal complexes as anticancer compounds.

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Benzimidazole methyl carbamate drugs (121), originally used to treat parasitic infections, have shown potential as anticancer agents. However, their poor water solubility and limited ability to circulate in the body have restricted their use for treating widespread cancers. To overcome this, Jae Eun Cheong and colleagues ^[111] designed new benzimidazole compounds (122a-c) containing oxetane or amine groups, which improved solubility. These modified compounds effectively inhibited the growth of prostate and lung tumors in preclinical models without causing noticeable toxicity, showing promise for safer, more effective cancer treatment options [Scheme 57].^{[88,94,103,105,110,113]}

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Scheme 57:

New benzimidazole water-soluble carbamates as anticancer drugs.

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A new set of benzimidazole compounds (123), based on ethyl-(1,2-disubstituted)-5-carboxylate structures, was synthesized using 3,4-diamino ethyl benzoates and 4-substituted benzaldehydes in water with sodium bisulfite, yielding 76-90% [Scheme 58]. These compounds showed promising inhibition of sirtuin enzymes SIRT1 and SIRT2, which are involved in cancer progression. Among them, one compound ethyl-2-(4-(dimethylamino) phenyl)-1-phenyl-1H-benzimidazole-5-carboxylate displayed strong SIRT2 inhibitory activity (IC₅₀ = 26.85±1.92 μM) and showed anticancer effects against colon, breast, and leukemia cell lines.^{[39,47,49,95,96,111-115]}

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Scheme 58:

synthesis of 5-ethyl-carboxylate-2-(4-substituted phenyl) benzimidazoles as anticancer agents.

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Alpan et al. developed a series of benzimidazole compounds (124) and tested their ability to block DNA topoisomerase I (Topo-I), an enzyme linked to cancer cell growth. In in-vitro assays, compound (124b) showed stronger inhibitory activity than calprotectin, a well-known Topo-I inhibitor [Scheme 59]. These results suggest that benzimidazole derivatives could be promising candidates for developing next-generation Topo-I targeted anticancer agents.^{[97,98,104,106,110,113,114,116]}

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Scheme 59:

Synthesis of 1H-benzimidazole derivatives as Topo-I targeted anticancer agents.

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LeSann and colleagues^[117] designed and synthesized cis-dichloro platinum (II) complexes using biologically active molecules such as 2-pyridylbenzimidazole, oxazole, and thiazole (125a-c). After characterizing the new compounds, they tested them on both cisplatin-sensitive and cisplatin-resistant cancer cells. One compound in particular, 125a, showed strong anticancer effects, making it a promising option for tackling drug-resistant cancers [Scheme 60].^[98,115,118]

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Scheme 60:

Synthesis of cis-dichloroplatinum anticancer complexes.

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LeSann and colleagues developed a new method to synthesis symmetric bis-benzimidazole compounds with 2-aryl groups, along with related hybrid molecules. These compounds were tested on five different cancer cell lines to assess their anticancer activity. Among them, compound 126b showed the strongest effect, performing better than the standard drug chlorambucil, making it a promising candidate for further cancer research [Scheme 61].^[98,109,111]

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Scheme 61:

Synthesis of bis-(4-[3-chloropropanamide] phenyl)- 5,5-bis-1H-benzimidazole anticancer derivatives.

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A series of benzimidazole derivatives (127-130) was synthesized and biologically evaluated for anticancer activity. These compounds were tested against three human cancer cell lines: Liver HepG2, breast MCF-7, and colon HCT-116. The results indicated that several derivatives exhibited notable cytotoxic effects, with compound-specific activity varying across cell lines. This suggests that structural modifications, particularly involving thiazolidinone and fluorobenzylidene moieties, may enhance the antiproliferative potential of benzimidazole-based scaffolds [Scheme 62].^[99,116,119]

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Scheme 62:

Antiproliferative benzimidazole-based scaffolds.

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Antiviral activity

A series of 2-halogenated-5,6-dichlorobenzimidazole ribonucleosides (compounds 131a-c) featuring chloro, bromo, or iodo substitutions at the 2-position was synthesized in (86-90% yield) [Scheme 63]. These derivatives demonstrated strong antiviral activity against two viral strains, with the 2-bromo derivative (131b) exhibiting a fourfold increase in efficacy compared to the 2-chloro analogue, emphasizing the role of halogen substitution in modulating antiviral potency.^{[39,47,49,100,101,117,118,120,121]}

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Scheme 63:

The synthesis of halogen-5,6-dichlorobenzimidazole ribonucleoside derivatives.

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Chen et al. recently synthesized a new class of benzimidazole flavonoid hybrids, incorporating a 4H-chromen-4-one scaffold, which demonstrated strong antiviral activity against tobacco mosaic virus (TMV) [Scheme 64]. Among these, compound (132), derived from the polyphenolic flavonoid myricetin, exhibited particularly strong efficacy. Myricetin itself is known for diverse biological effects but remains largely confined to preclinical research. By integrating benzimidazole moieties with the chromen-4-one core, the researchers enhanced antiviral potency, showcasing the potential of this scaffold for developing plant-protective agents.^{[88,102,103,105,119,122]}

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Scheme 64:

Synthesis of an antiviral benzimidazole derivative.

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Tonelli et al. developed new benzimidazole-based compounds aimed at treating viruses like coxsackievirus B5, respiratory syncytial virus (RSV), and staphylococcal bacteriophage-1. The most promising compounds were 2-[(benzotriazol-1/2-yl)methyl] benzimidazoles, especially those with di-alkylaminoalkyl (133) or quinolizidin-1-ylalkyl (134) groups at the 1-position, which showed strong antiviral activity against RSV [Scheme 65]. These results highlight how modifying the side chains of benzimidazole structures can boost their effectiveness as antiviral agents.^{[88,103,105,120,123]}

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Scheme 65:

Benzimidazole derivatives as antiviral compounds.

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Tremblay et al. synthesized a series of 5-(5-furan-2-yl-pyrazol-1-yl)-1H-benzimidazole derivatives targeting HIV capsid assembly inhibition, a key step in the virus’s life cycle. SAR studies revealed that specific substitutions significantly enhanced antiviral efficacy. In particular, the addition of a pyridine side chain at N1 (compound 135), a 2-hydroxyphenyl group at C2, and a C16 trifluoromethyl substituent (compound 136) were critical for boosting potency [Scheme 66]. These modifications highlight the importance of these structural features in enhancing anti-HIV activity.^{[88,103-105,121,122,124,125]}

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Scheme 66:

Modified 1H-benzimidazole derivatives at N1, C2, and C16 for HIV-1 inhibition.

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A series of benzimidazole compounds (135) with nitrogen-containing rings was synthesized as a common strategy in the search for new antitubercular drugs. One group of these 5-methyl-carboxylate-substituted benzimidazoles was synthesized in good yields (75-84%) through a reaction involving N-alkyl diaminobenzoate and sodium phenylmethanesulfonate in DMF at 90°C [Scheme 67]. When tested against Mycobacterium species, the derivative that included a trifluoromethyl group showed the strongest antitubercular effect, suggesting this group plays a key role in boosting biological activity.^{[39,47,49,105,123,126]}

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Scheme 67:

Benzimidazole derivatives as antitubercular compounds.

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Anti-inflammatory and analgesic activity

Bugday et al. synthesized a series of N-substituted benzimidazole derivatives with potential analgesic activity by reacting benzimidazole with benzoyl chloride, followed by derivatization with various amines [Scheme 68]. The resulting compounds (136a-d) were tested for their pain-relieving effects and demonstrated notable inhibitory activity, showing comparable or improved efficacy relative to aspirin, a widely used non-steroidal anti-inflammatory drug (NSAID), when administered at equivalent doses. These findings support the promise of N-substituted benzimidazoles as effective candidates for non-opioid analgesic drug development.^{[106,124,127]}

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Scheme 68:

Synthesis of active analgesic N-substituted benzimidazole derivatives.

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Gaba et al. designed and synthesized a series of benzimidazole derivatives (137) as potential gastrointestinal-friendly anti-inflammatory analgesics. Both in vitro and in vivo studies showed moderate anti-inflammatory activity, with inhibition ranging from 52% to 57%, comparable to acetylsalicylic acid (aspirin) [Scheme 69]. SAR analysis indicated that electron-donating groups significantly enhanced analgesic efficacy. Nonetheless, prior research showed that changing parts of the molecule at positions N1, C-2, C-5, and C-6 can further enhance anti-inflammatory activity. These results suggest benzimidazole derivatives could be a safer alternative to traditional NSAIDs.^{[107,125,126,128,129]}

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Scheme 69:

Synthesis of new GI-friendly anti-inflammatory analgesic benzimidazole derivatives.

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A series of imino sugar derivatives of methylbenzimidazole (138) was synthesized and evaluated for anti-inflammatory activity using the cotton pellet granuloma model in rats, with indomethacin serving as the reference drug. The study measured the percentage inhibition of granuloma formation to assess the compounds’ efficacy [Scheme 70].^{[108,127,130]}

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Scheme 70:

Anti-inflammatory methylbenzimidazole-linked imino sugars.

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Antifungal activity

Buğday et al. synthesized a novel series of benzimidazole derivatives (139) conjugated with amino acids and dipeptides, aiming to enhance antimicrobial activity. Biological evaluation revealed that these compounds exhibited moderate to good antifungal activity against Candida albicans and Candida tropicalis, with minimum inhibitory concentrations (MICs) ranging from 100 to 400 μg mL^-1, when compared to the standard antifungal fluconazole. However, the compounds showed limited antibacterial effects, suggesting that their efficacy is more selective toward fungal pathogens [Scheme 71].^{[109,124,127,128,131]}

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Scheme 71:

Amino acid/peptide-benzimidazole conjugates as potent antifungal compounds.

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As part of a continued search for novel antifungal agents, a series of benzimidazole-oxadiazole derivatives (140) was synthesized in (60-80% yield). Compounds bearing meta- and para-hydroxy substituents on the left-hand side of the molecule showed inhibitory effects comparable to standard antifungal agents against Candida species [Scheme 72]. Their mechanism of action is likely associated with inhibition of ergosterol biosynthesis, a key process in fungal membrane integrity.^{[110,113,116]}

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Scheme 72:

A novel antifungal series of benzimidazole-oxadiazole derivatives.

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A comparative study was conducted on benzimidazole-based metal complexes (141), one incorporating Cu (II) and the other Ni (II), to assess their antifungal activity [Scheme 73]. Experimental evaluation revealed that the Cu (II)-benzimidazole complex exhibited superior antifungal efficacy compared to its Ni (II) counterpart.^{[111,129,132]}

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Scheme 73:

Antifungal benzimidazole-based metal complexes.

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A series of novel 5-(nitro/bromo)-styryl-2-benzimidazole derivatives (142) was efficiently synthesized [Scheme 74]. These compounds were evaluated for their in vitro anti-tubercular, antimicrobial, and antifungal activities. Among the tested molecules, those bearing bromo substituents exhibited enhanced antifungal potency compared to their nitro-substituted analogs, indicating that halogen substitution at the 5-position may play a significant role in improving fungal inhibitory effects.^{[112,130,133]}

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Scheme 74:

Halogen functionalized benzimidazoles as promising antifungal agents.

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Antioxidant activity

A new series of 2,4-disubstituted benzimidazole compounds (141) was synthesized [Scheme 75]. Testing showed that both the base and Mannich derivatives had strong antioxidant properties, mainly due to the presence of phenolic groups, making them effective free radical scavengers and potential antioxidant agents.^{[39,49,51,113,131,134]}

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Scheme 75:

Mannich benzimidazole derivatives with antioxidant activity.

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A group of 2-substituted-5-methyl benzimidazole compounds (142) was synthesized and tested for their antioxidant properties. The findings showed that derivatives containing methoxy, nitro substituents had strong free radical scavenging activity, likely due to their electron-donating and -withdrawing effects, respectively, which influence radical stabilization. Halogen-substituted derivatives also showed appreciable activity, suggesting a beneficial role of halogen atoms in enhancing antioxidant efficacy [Scheme 76].^{[114,132,135]}

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Scheme 76:

Antioxidant 2-substituted-5-methyl benzimidazole derivatives (142).

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Several benzimidazole-based compounds were synthesized by combining them with different chemical groups like chalcones, pyrazolines, oxazolines, pyrimidines, and oxiranes. These compounds were tested for their antioxidant activity using the DPPH assay. Among them, compounds (143) and (144) showed strong antioxidant effects at 100 μM concentration, performing better than the standard ascorbic acid. The study found that the epoxide ring in compound (144) and the pyrimidine thione in compound (143) were key to their high activity, while the pyrazoline group in compound (145) had less impact [Scheme 77]. This highlights how specific chemical structures can influence a compound’s ability to neutralize free radicals.^{[115,133,136]}

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Scheme 77:

Antioxidant benzimidazole derivatives evaluated using the DPPH method.

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Antidiabetic activity

Two novel fused heterocyclic benzimidazole derivatives, compound (146) in 58% yield and compound (147) in 67% yield, were synthesized from a benzimidazole precursor [Scheme 78]. These compounds were evaluated for their antidiabetic potential via in vitro inhibition of α-amylase and α-glucosidase enzymes. Compound (146) exhibited potent inhibitory activity against both enzymes, while compound (147) displayed moderate to low activity, suggesting that the expanded fused-ring structure of (146) contributes significantly to its enzyme-binding affinity and biological potency.^{[39,49,51,102,104,116]}

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Scheme 78:

Antidiabetic and enzyme inhibitory effects of some benzimidazole derivatives.

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Nair et al. synthesized a series of benzimidazole derivatives and evaluated their antidiabetic potential using in silico docking and in vitro α-amylase inhibition assays. Based on LibDock scoring, compound (148) was selected for biological testing and demonstrated 49% inhibition of α-amylase activity at 100 μg mL^-1, compared to 68% inhibition by the standard drug acarbose at the same concentration [Scheme 79].^{[117,118,133-138]}

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Scheme 79:

Antidiabetic thiadiazole-substituted benzimidazole.

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Antiprotozoal activity

A series of thieno[2,3-d] pyrimidin-4(3H)-one derivatives (149) and (150) incorporating benzimidazol-2-yl-thioethyl and benzimidazol-2-yl-methanethioethyl groups at the 2-position of the pyrimidine ring was synthesized to evaluate their antiparasitic potential. In in vitro studies against Trichinella spiralis, compound (150), bearing a 5-nitrobenzimidazole moiety, exhibited 95% efficacy at a dose of 5 mg kg^-1, outperforming the reference drug albendazole. A closely related compound achieved 90% activity, indicating that the nitro-substituted benzimidazole core plays a significant role in enhancing antitrichinellosis efficacy [Scheme 80].^{[119-121,136-141]}

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Scheme 80:

Antiparasitic heterocyclic benzimidazole scaffolds.

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A series of novel benzimidazole pentamidine hybrid compounds (151) was synthesized and screened for in vitro antiprotozoal activity against Trichomonas vaginalis, Giardia lamblia, Entamoeba histolytica, Leishmania mexicana, and Plasmodium berghei [Scheme 81]. Several hybrids exhibited potent activity, with significantly lower IC₅₀ values than the reference drugs pentamidine and metronidazole, particularly against T. vaginalis, G. lamblia, and E. histolytica. One standout compound demonstrated a 108-fold increase in efficacy compared to pentamidine against E. histolytica, highlighting the enhanced antiparasitic potential conferred by the benzimidazole-functionalized framework. These results suggest strong promise for these hybrids as broad-spectrum antiparasitic agents.^{[120,122,137,139,140,142]}

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Scheme 81:

Benzimidazole pentamidine hybrids with antiprotozoal activity.

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A series of thioalkylated and thioarylated C-substituted benzimidazole derivatives (152) was synthesized and assessed for antiprotozoal activity against nosocomial strains of Stenotrophomonas maltophilia, using metronidazole as the reference drug. Among the tested compounds, 4,6-dichloro-2-(4-nitrobenzylthio)-benzimidazole exhibited the most pronounced activity, demonstrating superior efficacy compared to the standard [Scheme 82]. These findings suggest that chlorinated and nitro-substituted benzimidazole thioethers may serve as promising scaffolds for the development of antiparasitic agents targeting resistant hospital-acquired pathogens.^{[120,123,137,140,143]}

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Scheme 82:

Chlorinated and nitro-substituted benzimidazole thioethers with antiparasitic activity.

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Antihypertensive activity

Hammad et al. and colleagues designed a series of benzimidazole-based derivatives and evaluated their potential as angiotensin-converting enzyme (ACE) inhibitors through molecular docking and in silico toxicity studies. Among the synthesized compounds, compound (153) demonstrated comparable binding affinity to the reference drug lisinopril [Scheme 83]. This was further supported by in vitro ACE inhibition assays, where compound (153) exhibited an IC₅₀ of 0.81 µM, closely matching lisinopril’s IC₅₀ of 0.86 µM, indicating its equipotent inhibitory activity and potential as a promising lead compound for antihypertensive therapy.^{[118,124,135,138,141,144]}

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Scheme 83:

Benzimidazole-based derivatives as equipotent ACE inhibitors.

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Kankate et al. and colleagues synthesized a series of benzimidazole derivatives to investigate structural features contributing to angiotensin II (AT₁) receptor inhibition. The compounds were evaluated for antihypertensive activity in a dexamethasone-induced hypertensive rat model, using losartan as the reference drug. Among the tested molecules, compound (154) (4′-((6-methyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-1-yl)methyl)-[1,1′-biphenyl]-2-carboxylic acid) exhibited the most pronounced blood pressure-lowering effect, suggesting that the trifluoromethyl-substituted benzimidazole scaffold linked to a biphenyl carboxylic acid moiety enhances AT₁ receptor antagonism and may serve as a promising lead for antihypertensive drug development [Scheme 84].^{[118,125,135,138,139,142,145]}

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Scheme 84:

Trifluoromethyl-substituted benzimidazole scaffold as AT₁ receptor antagonist.

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Anticoagulant activity

Yang et al. synthesized a series of 1,2,5-trisubstituted fluorinated benzimidazole derivatives and evaluated their anticoagulant activity through in vitro thrombin inhibition assays. Compounds (155a-c) exhibited potent anticoagulant effects, with IC₅₀ values of 2.26±0.38, 1.54±0.09, and 3.35±0.87 nmol L^-1, respectively significantly outperforming the reference drug argatroban (IC₅₀ = 9.88 ± 2.26 nmol L^-1) [Scheme 85]. SAR analysis indicated that the presence of a methyl group at the ortho position of the benzene ring enhances thrombin inhibitory potency, highlighting its role in optimizing anticoagulant efficacy.^{[17,118,126,127,135, 138,140,143,144,146,]}

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Scheme 85:

1,2,5-trisubstituted fluorinated benzimidazole derivatives as thrombin inhibitors

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Wang and Ren. and colleagues synthesized a series of substituted 1-ethyl-1H-benzimidazole fluorinated derivatives (156) and evaluated their anti-thrombin activity through in vitro assays. All tested compounds (156a-f) demonstrated superior thrombin inhibition compared to the reference drug argatroban (IC₅₀ = 9.88±2.26nM). Among them, compound (156f) emerged as the most potent, exhibiting an IC₅₀ of 3.21±0.57nM, indicating a significant enhancement in anticoagulant efficacy [Scheme 86]. These findings underscore the potential of fluorinated benzimidazole scaffolds as promising candidates for the development of novel direct thrombin inhibitors.^{[23,118,128,135,138,142,145]}

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Scheme 86:

Fluorinated benzimidazole scaffolds as thrombin inhibitors.

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Antidepressant activity

Tantray et al. and colleagues synthesized a series of benzimidazole-based 1,2,3-triazole 1,3,4-oxadiazole conjugates and evaluated their glycogen synthase kinase-3β (GSK-3β) inhibitory activity. Compound (158) demonstrated potent inhibition, highlighting strong enzyme affinity [Scheme 87]. This compound was further assessed for antidepressant activity using the forced swim test (FST) and tail suspension test (TST) using in vivo models. Interesting, compound (158) exhibited the most pronounced antidepressant effect, surpassing the efficacy of the reference drug fluoxetine, thereby underscoring its potential as a dual GSK-3β inhibitor and antidepressant lead candidate.^{[26,28,118,129,135,143,146]}

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Scheme 87:

Benzimidazole-based 1,2,3-triazole-1,3,4-oxadiazole conjugates as an antidepressant candidate.

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