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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access  Full Text Article                                                                                               Review Article

A Review on the Synthesis, Characterization and Evaluation of Benzimidazole Derivatives for Antimicrobial and Antioxidant Activities

Dharmendra Sahu¹, Rahul Dev ¹, Ruchi Gupta ¹, Niharika Sahu², Rupesh Sahu³, Shiv Kumar Bhardwaj³*

¹ Gracious College of Pharmacy, Village-Belbhata, Abhanpur, Raipur-493661, Chhattisgarh, India

² Columbia College of Pharmacy, Columbia  Professional University, Tekari, Near Vidhansabha Road, Raipur-493111, Chhattisgarh, India

³ Columbia Institute of Pharmacy, Columbia Professional University, Tekari, Near Vidhansabha Road, Raipur-493111, Chhattisgarh, India

Highlights

• Benzimidazole is a privileged nitrogen-containing heterocyclic scaffold with broad medicinal and pharmacological applications.
• Condensation of o-phenylenediamine with aldehydes is a key synthetic route for 2-substituted benzimidazole derivatives.
• Structural modification at the 2-, 5/6- and N-positions enables optimization of antimicrobial and antioxidant activities.
• Benzimidazole derivatives exhibit promising antibacterial, antifungal and free-radical-scavenging activities.
• Green synthesis, nano-catalysis, hybrid pharmacophores, molecular docking and ADME studies offer promising directions for future benzimidazole research.

1. Introduction

Heterocyclic compounds constitute one of the most important classes of molecules in medicinal chemistry because incorporation of heteroatoms into aromatic and partially saturated ring systems can substantially modify molecular recognition, physicochemical properties, metabolic behavior and biological activity.¹ Among nitrogen-containing heterocycles, benzimidazole has emerged as an important privileged scaffold for pharmaceutical research.² It consists of a benzene ring fused to an imidazole ring and contains two nitrogen atoms capable of participating in hydrogen bonding, protonation/deprotonation and other molecular interactions.³ The versatility of the benzimidazole nucleus arises from the possibility of introducing different substituents around the fused heterocyclic system. Modification at the 2-position, 5/6-positions and nitrogen atom can alter lipophilicity, electronic distribution, steric characteristics, solubility and biological target interactions.⁴ Consequently, numerous benzimidazole derivatives have been investigated as antimicrobial, antifungal, antiviral, anticancer, anti-inflammatory, antiulcer, anthelmintic, antitubercular and antioxidant agents.⁵  Several benzimidazole-containing compounds have achieved practical pharmaceutical or agrochemical importance. The scaffold is also present in established antifungal agents such as benomyl, carbendazim, fuberidazole and thiabendazole, demonstrating the relevance of this chemical framework to antimicrobial research.⁶ Figure 1 Structural modification of the benzimidazole scaffold at the C-2, 5/6- and N-positions provides opportunities to modulate biological target interactions, pharmacokinetic/pharmacodynamic (PK/PD) properties and lipophilicity.

Figure 1. Benzimidazole scaffold and major sites of structural modification

(Substitution at the 2-, 5/6- and N-positions modulates target interactions, PK/PD properties, and lipophilicity).

1.1 Medicinal-chemistry significance of benzimidazole

Benzimidazole derivatives have attracted attention because their fused aromatic system provides rigidity while the nitrogen atoms permit diverse intermolecular interactions. The scaffold can participate in hydrogen bonding and π-related interactions and can be incorporated into hybrid molecules containing additional pharmacophores.⁷ The medicinal relevance of benzimidazole is also reflected by the continuous development of new derivatives. Recent reviews emphasize the importance of substitutions at the 2- and 5/6-positions and the incorporation of additional pharmacophores for improving antimicrobial potency and selectivity.⁸

2. Synthesis of benzimidazole derivatives

The synthesis of benzimidazoles has been extensively investigated because the heterocycle can be generated through several convergent synthetic approaches. Classical strategies commonly begin with o-phenylenediamine derivatives and introduce the carbon atom required for formation of the imidazole ring through aldehydes, carboxylic acids, esters, nitriles or related substrates.

2.1 Condensation with aldehydes

The condensation of o-phenylenediamine with aldehydes is among the most frequently employed methods for producing 2-substituted benzimidazoles. Initially, condensation produces an imine or related intermediate, followed by intramolecular cyclization and oxidation to afford the aromatic benzimidazole system.⁹ Various oxidizing agents, catalysts and reaction conditions have been developed to improve yield and selectivity.¹⁰ Figure 2 The synthesis of 2-substituted benzimidazole derivatives commonly involves the condensation of o-phenylenediamine with aldehydes, followed by cyclization to form the benzimidazole ring.

Figure 2. General synthetic route for 2-substituted benzimidazoles

(Condensation and cyclization of o-phenylenediamine with an aldehyde affords 2-substituted benzimidazole derivatives).

2.2 Condensation with carboxylic acids and derivatives

Carboxylic acids and their derivatives can also serve as carbon sources for construction of the benzimidazole ring. Depending on the substrate and reaction conditions, cyclodehydration can generate 2-substituted or more highly functionalized products. Such approaches are useful when incorporation of specific substituents is required.¹¹

2.3 Green synthetic approaches

Recent advances in synthetic chemistry have increasingly focused on minimizing solvent consumption, reaction time, energy requirements, and hazardous waste. Various green strategies have been explored for benzimidazole synthesis, including solvent-free reactions, microwave- and ultrasound-assisted synthesis, recyclable and nano-catalysts, photocatalytic and metal-free catalysis, aqueous reaction media and mechanochemical synthesis. Among these, microwave-assisted, solvent-free, mechanochemical and recyclable catalytic approaches have emerged as particularly promising strategies for achieving more sustainable and efficient benzimidazole synthesis.¹²

Table 1. Major synthetic approaches for benzimidazole derivatives

3. Characterization of benzimidazole derivatives

Reliable structural characterization is essential because biological activity depends directly on molecular identity, substitution pattern, purity and stereochemical/tautomeric state where relevant.

3.1 FTIR spectroscopy

FTIR spectroscopy provides rapid evidence for functional-group transformations. Characteristic absorptions associated with N–H, C=N, aromatic C=C, C–N and substituted functional groups can support formation of the benzimidazole nucleus.²¹

3.2 ^1H NMR spectroscopy

^1H NMR spectroscopy is particularly useful for confirming aromatic proton environments, N–H protons, methyl/methylene substituents, substituent-specific signals and the disappearance of the aldehyde proton. The disappearance of characteristic starting-material signals, together with the emergence of appropriate benzimidazole resonances, provides supporting evidence for cyclization and formation of the benzimidazole ring.²²

3.3 ^13C NMR spectroscopy

^13C NMR provides information regarding the carbon skeleton and is useful for confirming the heteroaromatic C=N-containing environment and substituted aromatic carbons.

3.4 Mass spectrometry

ESI-MS, HRMS or related techniques can establish molecular mass and assist in confirming the proposed molecular formula. Representative studies have used IR, ^1H NMR and ESI-MS for structural elucidation of substituted benzimidazoles.²³

3.5 Elemental analysis

CHN analysis provides an additional method for verifying the elemental composition and purity of synthesized compounds.²⁴

Table 2. Characterization techniques commonly applied to benzimidazole derivatives

4. Antimicrobial activity of benzimidazole derivatives

Antimicrobial resistance has increased the need for new chemical entities with alternative or complementary mechanisms of action. Benzimidazole provides a flexible framework for developing antibacterial and antifungal molecules because modifications around the heterocycle can influence target binding, membrane permeability and cellular accumulation.³³ Recent reviews covering 2018–2024 identify substantial progress in antimicrobial benzimidazole chemistry, including derivatives directed against resistant bacterial and fungal organisms.³⁴

4.1 Antibacterial activity

Benzimidazole derivatives have been extensively investigated against both Gram-positive and Gram-negative bacteria, including Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Streptococcus spp., Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii.³⁵ Notably, N,2,6-trisubstituted benzimidazole derivatives have exhibited MIC values of 4–16 μg/mL against selected MSSA and MRSA strains, highlighting the importance of systematic structural modification for improving antibacterial potency.³⁶ In addition, optimized benzimidazole-based compounds have demonstrated MIC values as low as 0.125 μg/mL against specific E. coli mutant strains, further supporting the potential of the benzimidazole scaffold as a promising framework for the development of novel antibacterial agents.³⁷

4.2 Antifungal activity

Benzimidazole derivatives have demonstrated considerable antifungal potential against clinically important fungal pathogens, particularly Candida, Aspergillus and Fusarium species.³⁸ Their antifungal activity is associated with interference in fungal cellular processes, including ergosterol biosynthesis and membrane integrity. Benzimidazole–1,2,4-triazole derivatives have shown promising activity against Candida species, with selected compounds exhibiting MIC values of approximately 0.97 μg/mL against Candida glabrata.³⁹ Molecular docking studies have suggested favorable interactions with 14α-demethylase (CYP51), a key enzyme involved in fungal ergosterol biosynthesis.⁴⁰ Furthermore, recent benzimidazole-sulfonate derivatives have exhibited pronounced activity against Candida albicans, associated with intracellular ROS accumulation and disruption of ergosterol-associated membrane integrity. These findings highlight benzimidazole as a promising scaffold for the development of novel antifungal agents.⁴¹

5. Evaluation of antimicrobial activity

Antimicrobial evaluation should use standardized methods and appropriate positive and negative controls.

Table 3. Major methods for antimicrobial evaluation

6. Mechanisms Associated with Antimicrobial Activity

The precise mechanism depends on the substitution pattern and molecular target. Potential mechanisms include:

6.1 DNA and topoisomerase-related mechanisms

Bacterial DNA gyrase and topoisomerase IV are validated antibacterial targets. Benzimidazole-containing inhibitors have been developed that interact with these enzymes, demonstrating the potential of the scaffold for targeting bacterial DNA topology.⁵²

6.2 Fungal ergosterol-related mechanisms

Some benzimidazole derivatives interfere with fungal membrane biology. In recent work, benzimidazole derivatives produced ROS accumulation and showed evidence of ergosterol-associated membrane targeting.⁵³

6.3 Membrane disruption

Increasing lipophilicity can improve interaction with microbial membranes, although excessive lipophilicity may adversely affect solubility and selectivity. Recent fluoro-substituted benzimidazoles were associated with morphological changes in S. aureus and K. pneumoniae, supporting membrane-associated effects.⁵⁴

6.4 Enzyme inhibition

The benzimidazole ring can interact with enzymes through hydrogen bonding, π–π interactions and hydrophobic contacts. Hybridization with other pharmacophores may enhance target recognition.⁵⁵ Figure 3 Benzimidazole derivatives may exert antimicrobial effects through multiple mechanisms, including disruption of cell-membrane integrity, inhibition of bacterial DNA enzymes and interference with fungal CYP51-mediated ergosterol biosynthesis, ultimately contributing to ROS imbalance and microbial cell death.

Figure 3. Proposed biological mechanisms of antimicrobial action

7. Structure-Activity Relationship of Benzimidazole Derivatives

The biological performance of benzimidazole derivatives depends strongly on substitution pattern. The 2-position is particularly important because it permits attachment of aromatic, heteroaromatic, alkyl, carbonyl, hydrazone and other pharmacophoric groups. Functionalization at the 5/6 positions can further modify electronic and physicochemical properties.⁵⁶ Recent antimicrobial SAR studies have emphasized the importance of 2- and 5/6-substitution, hybrid pharmacophores and modulation of lipophilicity.⁵⁷

Table 4. Important structural features influencing biological activity

8. Antioxidant activity of benzimidazole derivatives

Oxidative stress results from an imbalance between reactive oxygen/nitrogen species and endogenous antioxidant defenses. Excessive production of reactive species can damage lipids, proteins and nucleic acids. Consequently, compounds capable of scavenging free radicals or inhibiting oxidative damage are of interest in medicinal chemistry. Benzimidazole derivatives containing suitable electron-donating groups can exhibit radical-scavenging activity. The antioxidant behavior is highly dependent on substitution pattern and the ability of the molecule to donate hydrogen/electrons and stabilize the resulting radical.⁶⁸

8.1 DPPH radical-scavenging assay

The 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay is one of the most frequently used methods for preliminary antioxidant screening. A decrease in DPPH absorbance following reaction with the test compound reflects radical-scavenging capacity. A representative study of substituted benzimidazoles reported significant DPPH activity for selected derivatives, with one compound showing an IC₅₀ of 16.73 μg/mL compared with 14.44 μg/mL for BHT under the reported conditions.⁶⁹

8.2 ABTS assay

The ABTS assay evaluates the ability of a compound to reduce the ABTS radical cation. It complements DPPH because differences in radical chemistry and assay environment can reveal antioxidant properties that may not be apparent from a single assay.⁷⁰

8.3 FRAP assay

The ferric-reducing antioxidant power (FRAP) assay measures the reducing ability of a compound. It is useful as a complementary assay because antioxidant activity is not exclusively dependent on direct radical scavenging.⁷¹

8.4 Lipid-peroxidation inhibition

Lipid-peroxidation assays provide additional biological relevance by evaluating whether a compound can inhibit oxidative damage to lipid substrates. Benzimidazole derivatives have been investigated using lipid-peroxidation models, including biological tissue homogenates.⁷²

Table 5. Antioxidant evaluation of benzimidazole derivatives

9. Relationship between antimicrobial and antioxidant properties

The combination of antimicrobial and antioxidant properties makes some benzimidazole derivatives particularly interesting as multifunctional candidates. However, these activities should not automatically be considered mechanistically identical. In some antimicrobial systems, increased ROS generation contributes to microbial killing. Conversely, antioxidant compounds can reduce radical-mediated damage in host tissues. Thus, the desired biological effect may depend on where and how ROS modulation occurs. This distinction is important when designing multifunctional molecules:

Antimicrobial action⁷⁹

Controlled/pro-microbial ROS generation → microbial oxidative damage → microbial death

Antioxidant action

Antimicrobial activity associated with intracellular ROS accumulation may contribute to microbial killing, whereas radical scavenging and reduction of oxidative damage can protect host biomolecules. Recent benzimidazole studies have reported antimicrobial activity associated with intracellular ROS accumulation, while separate derivatives containing phenolic groups have demonstrated significant radical-scavenging antioxidant activity, highlighting the potential of benzimidazole derivatives as multifunctional agents.⁸⁰

10. Recent Trends in benzimidazole-based antimicrobial and antioxidant research

Contemporary benzimidazole research is moving beyond simple synthesis and endpoint biological screening toward integrated medicinal-chemistry optimization. Important trends include:

10.1 Hybrid pharmacophores

Benzimidazole is increasingly combined with diverse pharmacophores, including triazoles, pyrazoles, thiadiazoles, quinolines, sulphonamides, sulfones, hydrazones, amides, and Schiff bases, to generate structurally diverse hybrid molecules. Such molecular hybridization is intended to integrate complementary pharmacophoric features and biological interactions within a single molecular framework, potentially improving target affinity, selectivity, and overall biological activity.⁸¹

10.2 Green chemistry

Solvent-free, microwave, ultrasound, mechanochemical, photocatalytic and recyclable catalytic approaches can reduce environmental burden and improve synthetic efficiency.⁸²

10.3 Computational drug design

Molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT), and ADME prediction are increasingly employed to predict target binding, identify key molecular interactions, elucidate structure–activity relationships (SAR), prioritize promising compounds, estimate physicochemical and pharmacokinetic properties, and reduce unnecessary experimental synthesis. However, molecular docking should be regarded as supportive rather than definitive evidence of biological activity and its predictions should be validated through appropriate experimental studies.⁸³

10.4 Resistance-oriented design

Recent studies increasingly examine benzimidazole derivatives against resistant bacterial strains and investigate combination strategies. This represents an important direction because antimicrobial resistance cannot be adequately addressed by simply increasing the potency of existing mechanisms.⁸⁴

11. Future perspectives

The future development of benzimidazole derivatives should move toward a more integrated and evidence-based drug-discovery strategy.

11.1 Rational SAR optimization

Systematic modification of the 2-, 5/6- and N-positions should be used to establish quantitative relationships between molecular structure and antimicrobial/antioxidant activity.

11.2 Standardized biological evaluation

Future studies should preferably report minimum inhibitory concentration (MIC) values rather than relying solely on inhibition-zone data, together with minimum bactericidal/fungicidal concentrations (MBC/MFC), time-kill kinetics, cytotoxicity and selectivity indices, activity against resistant clinical isolates, appropriate reference drugs and mechanistic assays. Such standardized evaluation would facilitate more reliable comparison of antimicrobial efficacy across different studies.

11.3 Mechanism validation

Molecular docking alone should not be considered sufficient to establish a mechanism. Future work should combine docking with biochemical target assays, genetic studies, resistance mapping, membrane studies, ROS analysis and cellular imaging.

11.4 Antioxidant validation

DPPH or ABTS activity should be complemented by cellular antioxidant models, lipid-peroxidation assays and evaluation of oxidative biomarkers. This is necessary because strong chemical radical-scavenging activity does not necessarily translate into biological antioxidant efficacy.

11.5 Green and scalable synthesis

Future synthetic protocols should prioritize: high yield + low toxicity + low solvent consumption + recyclable catalyst + reduced energy consumption + scalability. Recent literature demonstrates increasing interest in solvent-free, microwave, mechanochemical and catalytic approaches.

11.6 AI/ML-assisted design

Machine-learning approaches could integrate molecular descriptors, substituent characteristics, MIC values, antioxidant IC₅₀ values, ADME properties and toxicity data to prioritize new derivatives before synthesis.

11.7 In vivo translation

A major gap in the current literature is the transition from in vitro activity → cellular efficacy → in vivo efficacy → pharmacokinetics → safety. Future benzimidazole candidates should be evaluated systematically across this translational pathway.

12. Conclusion

Benzimidazole represents a highly versatile and pharmacologically important heterocyclic scaffold for the development of antimicrobial and antioxidant agents. Its fused aromatic–imidazole architecture provides a favorable platform for structural modification, while substitution at the 2-, 5/6- and N-positions enables substantial modulation of physicochemical and biological properties. Conventional condensation of o-phenylenediamine with aldehydes remains an important synthetic strategy, whereas green approaches involving microwave irradiation, solvent-free conditions, aqueous media, nano-catalysts, photocatalysis and recyclable catalysts are expanding the synthetic toolbox.  Reliable characterization using FTIR, ^1H/^13C NMR, mass spectrometry and elemental analysis is fundamental for establishing molecular identity. Biological investigations demonstrate that benzimidazole derivatives can possess meaningful antibacterial and antifungal activities, while selected hydroxylated and appropriately substituted derivatives exhibit antioxidant effects in DPPH, ABTS, FRAP and lipid-peroxidation models. The available evidence further indicates that antimicrobial potency is strongly influenced by substitution pattern, lipophilicity, electronic properties, molecular hybridization and target-specific interactions. Recent research has progressed toward resistant pathogens, hybrid pharmacophores, molecular docking, mechanistic studies and green synthesis.  Nevertheless, important limitations remain, particularly inconsistent biological protocols, limited mechanistic validation, insufficient toxicity and selectivity data, and inadequate translation from in vitro activity to in vivo efficacy. Future research should therefore integrate green synthesis + systematic SAR + standardized antimicrobial testing + mechanistic validation + antioxidant/cellular studies + ADME/toxicity assessment + computational drug design. Such an integrated strategy could facilitate the identification of safer and more effective benzimidazole-based multifunctional leads for antimicrobial and oxidative-stress-related therapeutic applications.

Abbreviations

ABTS: 2,2′-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)
ADME: Absorption, Distribution, Metabolism and Excretion
AI: Artificial Intelligence
DFT: Density Functional Theory
DNA: Deoxyribonucleic Acid
DPPH: 2,2-Diphenyl-1-picrylhydrazyl
ESI-MS: Electrospray Ionization Mass Spectrometry
FIC: Fractional Inhibitory Concentration
FICI: Fractional Inhibitory Concentration Index
FRAP: Ferric-Reducing Antioxidant Power
FTIR: Fourier-Transform Infrared Spectroscopy
HRMS: High-Resolution Mass Spectrometry
IC₅₀: Half-Maximal Inhibitory Concentration
MBC: Minimum Bactericidal Concentration
MFC: Minimum Fungicidal Concentration
MIC: Minimum Inhibitory Concentration
ML: Machine Learning
MRSA: Methicillin-Resistant Staphylococcus aureus
MSSA: Methicillin-Susceptible Staphylococcus aureus
NMR: Nuclear Magnetic Resonance
ORAC: Oxygen Radical Absorbance Capacity
PK/PD: Pharmacokinetics/Pharmacodynamics
ROS: Reactive Oxygen Species
SAR: Structure-Activity Relationship
SEM: Scanning Electron Microscopy
TBARS: Thiobarbituric Acid-Reactive Substances
TEM: Transmission Electron Microscopy
UV-Vis: Ultraviolet-Visible Spectroscopy

Ethics approval and consent to participate: Ethical clearance and informed consent were not required, since this manuscript presents a narrative review based solely on previously published literature and involved no primary research involving humans or animals.

Clinical Trial No: Clinical trial registration was not applicable, as this work is a narrative review of published literature and does not involve clinical trials.

Consent for publication: Clinical trial registration was not applicable, as this manuscript is a narrative review based exclusively on previously published literature and does not involve any clinical trial.

Availability of data and material: Data availability was not applicable, as this manuscript is a narrative review of previously published literature and does not involve any original datasets.

Funding: he authors declare that no specific funding was received from governmental, commercial, or non

profit organizations for the preparation of this review.

Declaration of competing interest: The authors declare that there are no conflicts of interest 

regarding  the publication of this manuscript.

Acknowledgements:  The authors gratefully acknowledge the Principals of Columbia Institute of Pharmacy, Columbia

Professional University, Raipur, Chhattisgarh, India, and Gracious College of Pharmacy, Village  

Belbhata, Abhanpur, Raipur,  Chhattisgarh, India, for their encouragement, institutional support, and

provision of essential infrastructure and library resources for the completion of this review.

Authorship contribution statement:

Dharmendra Sahu: Conceptualization, methodology and critical review of the manuscript.

Rahul Dev: Writing-original draft, review and editing, and critical revision of the manuscript.

Ruchi Gupta: Writing-review and editing.

Niharika Sahu: Visualization, schematic design, graphical abstract development, and figure illustration.

Rupesh Sahu: Literature review, data collection and curation, validation, and manuscript evaluation.

Shiv Kumar Bhardwaj: Writing, methodology, visualization and final manuscript editing.

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