Quantitative tests of albendazole resistance in Caenorhabditis elegans beta-tubulin mutants.

Benzimidazole (BZ) anthelmintics are among the most important treatments for parasitic nematode infections in the developing world. Widespread BZ resistance in veterinary parasites and emerging resistance in human parasites raise major concerns for the continued use of BZs. Knowledge of the mechanisms of resistance is necessary to make informed treatment decisions and circumvent resistance. Benzimidazole resistance has traditionally been associated with mutations and natural variants in the C. elegans beta-tubulin gene ben-1 and orthologs in parasitic species. However, variants in ben-1 alone do not explain the differences in BZ responses across parasite populations. Here, we examined the roles of five C. elegans beta-tubulin genes (tbb-1, mec-7, tbb-4, ben-1, and tbb-6) in the BZ response as well as to determine if another beta-tubulin acts redundantly with ben-1. We generated C. elegans strains with a loss of each beta-tubulin gene, as well as strains with a loss of tbb-1, mec-7, tbb-4, or tbb-6 in a genetic background that also lacks ben-1. We found that the loss of ben-1 conferred the maximum level of resistance following exposure to a single concentration of albendazole, and the loss of a second beta-tubulin gene did not alter the level of resistance. However, additional traits other than larval development could be affected by the loss of additional beta-tubulins, and the roles of other beta-tubulin genes might be revealed at different albendazole concentrations. Therefore, further work is needed to fully define the possible roles of other beta-tubulin genes in the BZ response.

Synthesis and activity of benzimidazole N-Acylhydrazones against Trypanosoma cruzi, Leishmania amazonensis and Leishmania infantum.

In this study, we present the design, synthesis, and cytotoxic evaluation of a series of benzimidazole N-acylhydrazones against strains of T. cruzi (Y and Tulahuen) and Leishmania species (L. amazonensis and L. infantum). Compound (E)-N'-((5-Nitrofuran-2-yl)methylene)-1H-benzo[d]imidazole-2-carbohydrazide demonstrated significant activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 0.033 µM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC50/120 h = 1.520 µM, SI = 1390). Another compound (E)-N'-(2-Hydroxybenzylidene)-1H-benzo[d]imidazole-2-carbohydrazide showed promising activity against both trypomastigote and amastigote forms (Tulahuen strain), with an IC50/120 h of 3.600 µM and an SI of 14.70. However, its efficacy against L. infantum and L. amazonensis was comparatively lower. These findings provide valuable insights for the development of more effective treatments against Trypanosoma cruzi.

Synthesis and crystal structure of bis-(2-aminobenzimidazolium) catena-[metavanadate(V)].

The structure of polymeric catena-poly[2-amino-benzimidazolium [[dioxidovanadium(V)]-µ-oxido]], {(C7H8N3)2[V2O6]} n , has monoclinic symmetry. The title compound is of inter-est with respect to anti-cancer activity. In the crystal structure, infinite linear zigzag vanadate (V2O6)2- chains, constructed from corner-sharing VO4 tetra-hedra and that run parallel to the a axis, are present. Two different protonated 2-amino-benzimidazole mol-ecules are located between the (V2O6)2- chains and form classical N-H⋯O hydrogen bonds with the vanadate oxygen atoms, which contribute to the cohesion of the structure.

Synthesis, biosimulation and pharmacological evaluation of benzimidazole derivatives with antihypertensive multitarget effect.

In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT1R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1H NMR, 13C NMR and mass spectral data. Through biosimulation, compounds 1-7 were identified as computational safe hits, thus, best candidates underwent ex vivo testing against two distinct mechanisms implicated in hypertension: antagonism of the Ang II type 1 receptor and the blockade of calcium channel. Molecular docking studies helped to understand at the molecular level the dual vasorelaxant effects with the recognition sites of the AT1R and the L-type calcium channel. In an in vivo spontaneously hypertensive rat model (SHR), intraperitoneally administration of compound 1 at 20 mg/kg resulted in a 25 % reduction in systolic blood pressure, demonstrating both ex vivo vasorelaxant action and in vivo antihypertensive multitarget efficacy. ©2024 Elsevier.

Benzimidazole-based structure optimization to discover novel anti-gastric cancer agents targeting ROS/MAPK pathway.

Given the malignancy of gastric cancer, developing highly effective and low-toxic targeted drugs is essential to prolong patient survival and improve patient outcomes. In this study, we conducted structural optimizations based on the benzimidazole scaffold. Notably, compound 8 f presented the most potent antiproliferative activity in MGC803 cells and induced cell cycle arrest at the G0/G1 phase. Further mechanistic studies demonstrated that compound 8 f caused the apoptosis of MGC803 cells by elevating intracellular reactive oxygen species (ROS) levels and activating the mitogen-activated protein kinase (MAPK) signaling pathway, accompanied by corresponding markers change. In vivo investigations additionally validated the inhibitory effect of compound 8 f on tumor growth in xenograft models bearing MGC803 cells without obvious toxicity. Our studies suggest that compound 8 f holds promise as a potential and safe lead compound for developing anti-gastric cancer agents.

Expanding the Structural Diversity of Tubulin-Targeting Agents: Development of Highly Potent Benzimidazoles for Treating Fungal Diseases.

Benzimidazoles, the representative pharmacophore of fungicides, have excellent antifungal potency, but their simple structure and single site of action have hindered their wider application in agriculture. In order to extend the structural diversity of tubulin-targeted benzimidazoles, novel benzimidazole derivatives were prepared by introducing the attractive pyrimidine pharmacophore. 2-((6-(4-(trifluoromethyl)phenoxy)pyrimidin-4-yl)thio)-1H-benzo[d]imidazole (A25) exhibited optimal antifungal activity against Sclerotinia sclerotiorum (S. s.), affording an excellent half-maximal effective concentration (EC50) of 0.158 µg/mL, which was higher than that of the reference agent carbendazim (EC50 = 0.594 µg/mL). Pot experiments revealed that compound A25 (200 µg/mL) had acceptable protective activity (84.7%) and curative activity (78.1%), which were comparable with that of carbendazim (protective activity: 90.8%; curative activity: 69.9%). Molecular docking displayed that multiple hydrogen bonds and π-π interactions could be formed between A25 and ß-tubulin, resulting in a stronger bonding effect than carbendazim. Fluorescence imaging revealed that the structure of intracellular microtubules can be changed significantly after A25 treatment. Overall, these remarkable antifungal profiles of constructed novel benzimidazole derivatives could facilitate the application of novel microtubule-targeting agents.

Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer.

OBJECTIVE: Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. METHODS: The human EOC cell lines A2780, HeyA8, SKOV3ip1, A2780-CP20, HeyA8-MDR, and SKOV3-TR were treated with BNZ-111, and cell proliferation, apoptosis, and cell cycle were assessed. RESULTS: It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating ß-3 tubulin expression to suppress microtubule dynamics. CONCLUSION: BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology.

Recent development and strategies towards target interactions: Synthesis, characterization and in silico analysis of benzimidazole based thiadiazole as potential anti-Alzheimer agents.

In the current research study, we aim to design and synthesize highly potent hybrid analogs of benzimidazole derived thiadiazole based Schiff base derivatives which can combat the cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase) accountable for developing Alzheimer's disease. In this context, we have synthesized 15 analogs of benzimidazole based thiadiazole derivatives, which were subsequently confirmed through spectroscopic techniques including 1H NMR, 13C NMR and HREI-MS. Biological investigation of all the analogs revealed their varied acetylcholinesterase inhibitory potency covering a range between 3.20 ± 0.10 µM to 20.50 ± 0.20 µM as well as butyrylcholinesterase inhibitory potential with a range of 4.30 ± 0.50 µM to 20.70 ± 0.50 µM when compared with the standard drug Donepezil having IC50 = 6.70 ± 0.20 µM for AChE and 7.90 ± 0.10 µM for BuChE. The promising inhibition by the analogs was evaluated in SAR analysis, where analog-1 (IC50 = 3.20 ± 0.10 µM for AChE and 4.30 ± 0.50 µM for BuChE), analog-4 (IC50 = 4.30 ± 0.30 µM for AChE and 5.50 ± 0.20 µM for BuChE) and analog-5 (IC50 = 4.10 ± 0.30 µM for AChE and 4.60 ± 0.40 µM for BuChE) were found as the lead candidates. Moreover, molecular docking and ADME analysis were conducted to explore the better binding interactions and drugs likeness respectively.

Dynamic and structural response of a multispecies biofilm to environmental perturbations induced by the continuous increase of benzimidazole fungicides in a permeable reactive biobarrier.

Purpose: This work explores the dynamics of spatiotemporal changes in the taxonomic structure of biofilms and the degradation kinetics of three imidazole group compounds: carbendazim (CBZ), methyl thiophanate (MT), and benomyl (BN) by a multispecies microbial community attached to a fixed bed horizontal tubular reactor (HTR). This bioreactor mimics a permeable reactive biobarrier, which helps prevent the contamination of water bodies by pesticides in agricultural wastewater. Methods: To rapidly quantify the microbial response to crescent loading rates of benzimidazole compounds, a gradient system was used to transiently raise the fungicide volumetric loading rates, measuring the structural and functional dynamics response of a microbial community in terms of the volumetric removal rates of the HTR entering pollutants. Results: The loading rate gradient of benzimidazole compounds severely impacts the spatiotemporal taxonomic structure of the HTR biofilm-forming microbial community. Notable differences with the original structure in HTR stable conditions can be noted after three historical contingencies (CBZ, MT, and BN gradient loading rates). It was evidenced that the microbial community did not return to the composition prior to environmental disturbances; however, the functional similarity of microbial communities after steady state reestablishment was observed. Conclusions: The usefulness of the method of gradual delivery of potentially toxic agents for a microbial community immobilized in a tubular biofilm reactor was shown since its functional and structural dynamics were quickly evaluated in response to fungicide composition and concentration changes. The rapid adjustment of the contaminants' removal rates indicates that even with changes in the taxonomic structure of a microbial community, its functional redundancy favors its adjustment to gradual environmental disturbances.

In Vitro Lethality of Fenbendazole to the Eyeworm Oxyspirura petrowi.

Oxyspirura petrowi is a heteroxenous nematode that infects the harderian gland and other ocular tissues in birds. High-intensity infections often cause damage to the infected tissues. Due to the nature of the infection sites, treatment of O. petrowi in these hosts can be difficult. Fenbendazole (FBZ) is a common anthelmintic used to treat birds for helminth infections; however, little information exists as to the efficacy of the drug on O. petrowi infections. The present study aims to estimate lethal concentrations of FBZ to O. petrowi. Adult O. petrowi were maintained in vitro and exposed to doses of 5, 50, 100, and 200 µM concentrations of FBZ and included both negative and vehicle controls. Exposure lasted 7.5 days and lethality was determined for each treatment. Negative and vehicle controls did not differ, and both had 75% survival at the end of the treatment period. The percentage survivorship in ascending order of concentration, corrected for the controls, was 66.67%, 44.44%, 33.33%, and 0%. LC10, LC50, and LC90 estimates were 7.5 ± 0.26, 49.1 ± 1.69, and 163.2 ± 5.63 µM, respectively. In the context of known pharmacokinetics of FBZ in birds, a single oral dose of FBZ can achieve exposure levels that are lethal to O. petrowi, but the drug does not stay in the system long enough. Thus, treatment of O. petrowi infections will require multiple oral doses over several days.

Discovery of novel benzimidazole derivatives as selective and reversible monoamine oxidase B inhibitors for Parkinson's disease treatment.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. The development of novel scaffolds for human monoamine oxidase B (hMAO-B) inhibitors with reversible properties represents an important strategy to improve the efficacy and safety for PD treatment. In the current work, we have devised and assessed two innovative derivative series serving as hMAO-B inhibitors. These series have utilized benzimidazole as a scaffold and strategically incorporated a primary amide group, which is recognized as a pivotal pharmacophore in subsequent activity screening and reversible mode of action. Among these compounds, 16d has emerged as the most potent hMAO-B inhibitor with an IC50 value of 67.3 nM, comparable to safinamide (IC50 = 42.6 nM) in vitro. Besides, 16d demonstrated good selectivity towards hMAO-B isoenzyme with a selectivity index over 387. Importantly, in line with the design purpose, 16d inhibited hMAO-B in a competitive and reversible manner (Ki = 82.50 nM). Moreover, 16d exhibited a good safety profile in both cellular and acute toxicity assays in mice. It also displayed ideal pharmacokinetic properties and blood-brain barrier permeability in vivo, essential prerequisites for central nervous system medicines. In the MPTP-induced PD mouse model, 16d significantly alleviated the motor impairment, especially muscle relaxation and motor coordination. Therefore, 16d, serving as a lead compound, holds instructive significance for subsequent investigations regarding its application in the treatment of PD.

New benzimidazole-oxadiazole derivatives as potent VEGFR-2 inhibitors: Synthesis, anticancer evaluation, and docking study.

We report herein, the design and synthesis of benzimidazole-oxadiazole derivatives as new inhibitors for vascular endothelial growth factor receptor-2 (VEGFR-2). The designed members were assessed for their in vitro anticancer activity against three cancer cell lines and two normal cell lines; A549, MCF-7, PANC-1, hTERT-HPNE and CCD-19Lu. Compounds 4c and 4d were found to be the most effective compounds against three cancer cell lines. Compounds 4c and 4d were then tested for their in vitro VEGFR-2 inhibitory activity, safety profiles, and selectivity indices using the normal hTERT-HPNE and CCD-19Lu cell lines. It was determined that compound 4c was the most effective and safe member of the produced chemical family. Vascular endothelial growth factor A (VEGFA) immunolocalizations of compounds 4c and 4d were evaluated relative to control by VEGFA immunofluorescence staining. Compounds 4c and 4d inhibited VEGFR-2 enzyme with half-maximal inhibitory concentration values of 0.475 ± 0.021 and 0.618 ± 0.028 µM, respectively. Molecular docking of the target compounds was carried out in the active site of VEGFR-2 (Protein Data Bank: 4ASD).

Design and synthesis of large Stokes shift DNA dyes with reduced genotoxicity.

Despite intensive search over the past decades, only a few small-molecule DNA fluorescent dyes were found with large Stokes shifts. These molecules, however, are often too toxic for widespread usage. Here, we designed DNA-specific fluorescent dyes rooted in benzimidazole architectures with a hitherto unexplored molecular framework based on thiazole-benzimidazole scaffolding. We further incorporated a pyrazole ring with an extended sidechain to prevent cell penetration. These novel benzimidazole derivatives were predicted by quantum calculations and subsequently validated to have large Stokes shifts ranging from 135 to 143 nm, with their emission colors changed from capri blue for the Hoechst reference compound to iguana green. These readily-synthesized compounds, which displayed improved DNA staining intensity and detection limits along with a complete loss of capability for cellular membrane permeation and negligible mutagenic effects as designed, offer a safer alternative to the existing high-performance small-molecule DNA fluorescent dyes.

In Silico Study, Protein Kinase Inhibition and Molecular Docking Study of Benzimidazole Derivatives.

Kinase enzymes play an important role in cellular proliferation, and inhibition of their activity is a major goal of cancer therapy. Protein kinase inhibitors as benzimidazole derivatives can be applied for prevention or treatment of cancers through inhibition of cell proliferation. To evaluate their protein kinase inhibitory effects, as well as the in silico study for active benzimidazole derivatives. Benzimidazole derivatives has presented significant therapeutic potential against several disorders and known to have numerous biological activities (such as antibacterial, antiviral and anti-inflammatory). Benzimidazole derivatives have shown significant potential in the reduction of viral load as well as in enhancing immunity. To forecast absorption, distribution, metabolism, excretion and toxicity, simply known as ADMET and the Lipinski rule of five parameters of the examined substances, the admetSAR and Swiss ADME were used. The ADMET predictions revealed that the compounds had good and safe pharmacokinetic features, making them acceptable for further development as therapeutic candidates in clinical trials. This study primarily focused on blocking 2 key targets of kinase proteins (CDK4/CycD1 and Aurora B). 2-Phenylbenzimidazole has shown the greatest inhibitory potential (with a binding energy of -8.2 kcal/mol) against protein kinase inhibitors. This study results would pave the potential lead medication for anticancer therapeutic strategies.

Exploring the versatility of sulfur-containing heterocyclic metal complexes: Application in medical and prospects of visible-light-driven photocatalysis.

Numerous heterocyclic moieties serve as the foundational structure for clinically employed drugs, underscoring the significance of heterocycles in the innovation of pharmacologically active compounds. In the present investigation, a heterocyclic skeleton of thiophene-clubbed benzimidazole (tmb) was developed and utilized to synthesize seven novel series of metal (M(II) = Co, Ni, Cu, and Zn) complexes to explore diverse applications including pharmacological and photocatalytic performance. A sharp singlet peak appeared at 5.72 ppm (tmb) and 5.94 ppm for the Zn(II)-tmb complex corresponding to -CH2 protons, as evidenced by 1H NMR results, confirming the formation of targeted compounds. Antimicrobial assay and docking studies confirmed that the mixed metal complex; [Cu(tmb)2(1,10-phen)Cl2] possesses the highest activity and displayed significant biofilm inhibition, achieving 86.35 and 89.8% at concentrations of 1 and 0.020 mg/mL, respectively against E. coli. Furthermore, the photocatalytic activity was monitored by the degradation of methylene blue dye under direct sunlight and [Cu(tmb)2Cl2] exhibited a maximum degradation efficiency of 96.15% in 45 min. These findings could serve as inspiration for the development of benzimidazole-based metal complexes as effective anti-biofilm and photocatalytic agents.

Synthesis, Characterization, and Cytotoxicity Evaluation of Novel Water-Soluble Cationic Platinum(II) Organometallic Complexes with Phenanthroline and Imidazolic Ligands.

Platinum-based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water-soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η1-C2H4OEt)(phen)] (1, phen=1,10-phenanthroline) precursor, specifically [Pt(NH3)(η1-C2H4OEt)(phen)]Cl (2), [Pt(1-hexyl-1H-imidazole)(η1-C2H4OEt)(phen)]Cl (3), and [Pt(1-hexyl-1H-benzo[d]imidazole)(η1-C2H4OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki-1), and normal human renal cells (HK-2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki-1) among the tested complexes, compared to healthy cells (HK-2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum-based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties.

Reticular Chemistry Directed "One-Pot" Strategy to in situ Construct Organic Linkers and Zirconium-Organic Frameworks.

Zirconium-based metal-organic frameworks (Zr-MOFs) have emerged as one of the most studied MOFs due to the unlimited numbers of organic linkers and the varying Zr-oxo clusters. However, the synthesis of carboxylic acids, especially multitopic carboxylic acids, is always a great challenge for the discovery of new Zr-MOFs. As an alternative approach, the in situ "one-pot" strategy can address this limitation, where the generation of organic linkers from the corresponding precursors and the sequential construction of MOFs are integrated into one solvothermal condition. Herein, inspired by benzimidazole-contained compounds synthesized via reaction of aldehyde and o-phenylenediamine, tri-, tetra-, penta- and hexa-topic carboxylic acids and a series of corresponding Zr-MOFs can be prepared via the in situ "one-pot" method under the same solvothermal conditions. This strategy can be utilized not only to prepare reported Zr-MOFs constructed using benzimidazole-contained linkers, but also to rationally design, construct and realize functionalities of zirconium-pentacarboxylate frameworks guided by reticular chemistry. More importantly, in situ "one-pot" method can facilitate the discovery of new Zr-MOFs, such as zirconium-hexacarboxylate frameworks. The present study demonstrates the promising potential of benzimidazole-inspired in situ "one-pot" approach in the crystal engineering of structure- and property-specific Zr-MOFs, especially with the guidance of reticular chemistry.

Benzimidazole as a Privileged Scaffold in Drug Design and Discovery.

Benzimidazole is a privileged drug design and discovery scaffold with various phar-macological activities, including antimicrobial, anticancer, antitubercular, anti-inflammatory, an-tidiabetic, antihypertensive, antimalarial, and many more. This scaffold can be observed in the structure of numerous FDA-approved drugs and employed in medicinal chemistry to develop novel bioactive compounds through rational drug design. Its broad pharmacological significance is due to physicochemical attributes, including H-bond donor-acceptor efficiency, π-π stacking interactions, and hydrophobic interactions; these characteristics enable benzimidazole derivatives to bind with macromolecules efficiently. This article emphasizes mechanisms, SAR, and docking studies to unveil benzimidazole's various active hybrids accountable for diversified activities. It will assist researchers in strategically designing various novel benzimidazole-endowed hybrids to develop clinically active therapeutic candidates.

Multiple UDP glycosyltransferases modulate benzimidazole drug sensitivity in the nematode Caenorhabditis elegans in an additive manner.

Xenobiotic biotransformation is an important modulator of anthelmintic drug potency and a potential mechanism of anthelmintic resistance. Both the free-living nematode Caenorhabditis elegans and the ruminant parasite Haemonchus contortus biotransform benzimidazole drugs by glucose conjugation, likely catalysed by UDP-glycosyltransferase (UGT) enzymes. To identify C. elegans genes involved in benzimidazole drug detoxification, we first used a comparative phylogenetic analysis of UGTs from humans, C. elegans and H. contortus, combined with available RNAseq datasets to identify which of the 63 C. elegans ugt genes are most likely to be involved in benzimidazole drug biotransformation. RNA interference knockdown of 15 prioritized C. elegans genes identified those that sensitized animals to the benzimidazole derivative albendazole (ABZ). Genetic mutations subsequently revealed that loss of ugt-9 and ugt-11 had the strongest effects. The "ugt-9 cluster" includes these genes, together with six other closely related ugts. A CRISPR-Cas-9 deletion that removed seven of the eight ugt-9 cluster genes had greater ABZ sensitivity than the single largest-effect mutation. Furthermore, a double mutant of ugt-22 (which is not a member of the ugt-9 cluster) with the ugt-9 cluster deletion further increased ABZ sensitivity. This additivity of mutant phenotypes suggest that ugt genes act in parallel, which could have several, not mutually exclusive, explanations. ugt mutations have different effects with different benzimidazole derivatives, suggesting that enzymes with different specificities could together more efficiently detoxify drugs. Expression patterns of ugt-9, ugt-11 and ugt-22 gfp reporters differ and so likely act in different tissues which may, at least in part, explain their additive effects on drug potency. Overexpression of ugt-9 alone was sufficient to confer partial ABZ resistance, indicating increasing total UGT activity protects animals. In summary, our results suggest that the multiple UGT enzymes have overlapping but not completely redundant functions in benzimidazole drug detoxification and may represent "druggable" targets to improve benzimidazole drug potency.

Synthesis and anti-inflammatory activity of benzimidazole derivatives; an in vitro, in vivo and in silico approach.

Many non-steroidal anti-inflammatory drugs (NSAIDs) concurrently inhibit both COX-1 and COX-2, with a preference for specifically targeting COX-2 due to its significant involvement in various pathologies. In addition to COX enzymes, several other targets, including Aldose reductase, Aldo-ketoreductase family 1-member C2, and Phospholipase A2, have been identified as contributors to inflammation and a myriad of other diseases. In this context, a series of 2-substituted benzimidazole derivatives was synthesized and assessed for their anti-inflammatory potential through both in vitro and in vivo assays. Molecular docking studies were conducted to elucidate the mechanism of action of these compounds against COX enzymes and other therapeutic targets associated with NSAIDs, such as Aldose reductase, AIKRC, and Phospholipase A2. Among the synthesized compounds, B2, B4, B7, and B8 demonstrated IC50 values lower than the standard ibuprofen, as determined by the Luminol-enhanced chemiluminescence assay. Validation of these findings was achieved through an in vivo carrageenan-induced mice paw edema model, confirming a comparable anti-inflammatory effect to diclofenac sodium observed in vitro. Notably, these compounds exhibited significant binding affinity with all therapeutic targets investigated in this study. These results suggest that the newly synthesized derivatives possess noteworthy anti-inflammatory potential, warranting further exploration for the development of novel multi-targeting inhibitors.