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).

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.

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvß1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.

Leveraging a rationally designed veliparib-based anilide eliciting anti-leukemic effects for the design of pH-responsive polymer nanoformulation.

Careful recruitment of the components of the HDAC inhibitory template culminated in veliparib-based anilide 8 that elicited remarkable cell growth inhibitory effects against HL-60 cell lines mediated via dual modulation of PARP [(IC50 (PARP1) = 0.02 nM) and IC50 (PARP2) = 1 nM)] and HDACs (IC50 value = 0.05, 0.147 and 0.393 µM (HDAC1, 2 and 3). Compound 8 downregulated the expression levels of signatory biomarkers of PARP and HDAC inhibition. Also, compound 8 arrested the cell cycle at the G0/G1 phase and induced autophagy. Polymer nanoformulation (mPEG-PCl copolymeric micelles loaded with compound 8) was prepared by the nanoprecipitation technique. The mPEG-PCL diblock copolymer was prepared by ring-opening polymerization method using stannous octoate as a catalyst. The morphology of the compound 8@mPEG-PCL was examined using TEM and the substance was determined to be monodispersed, spherical in form, and had an average diameter of 138 nm. The polymer nanoformulation manifested pH-sensitive behaviour as a greater release of compound 8 was observed at 6.2 pH as compared to 7.4 pH mimicking physiological settings. The aforementioned findings indicate that the acidic pH of the tumour microenvironment might stimulate the nanomedicine release which in turn can attenuate the off-target effects precedentially claimed to be associated with HDAC inhibitors.

Design, Synthesis, DFT, docking Studies, and antimicrobial evaluation of novel benzimidazole containing sulphonamide derivatives.

In silico approaches have been employed to design a new series of benzimidazole-containing sulphonamide derivatives and qualified compounds have been synthesized to analyze their potential as antimicrobial agents. Antibacterial screening of all synthesized compounds was done using the broth microdilution method against several human pathogenic bacteria, viz. Gram-positive bacteria [B. cerus (NCIN-2156), B. subtilis (ATCC-6051), S. aureus (NCIM-2079)] and Gram-negative bacteria [P. aeruginosa (NCIM-2036), E. coli (NCIM-2065), and a drug-resistant strain of E. coli (U-621)], and the compounds presented admirable MIC values, ranging between 100-1.56 µg/mL. The combinatorial analysis showed the magnificent inhibitory efficiency of the tested compounds, acquired equipotent to ten-fold more potency compared to original MIC values. An immense synergistic effect was exhibited by the compounds during combination studies with reference drugs chloramphenicol and sulfamethoxazole was presented as fractional inhibitory concentration (∑FIC). Enzyme inhibition studies of all synthesized compounds were done by using peptidyl transferase and dihydropteroate synthase enzymes isolated from E. coli and S. aureus and each of the compound presented the admirable IC50 values, where the lead compound 3 bound to peptidyl transferase (of S. aureus with IC50 363.51 ± 2.54 µM and E. coli IC50 1.04 ± 0.08 µM) & dihydropteroate synthase (of S. aureus IC50 3.51 ± 0.82 µM and E. coli IC50 2.77 ± 0.65 µM), might account for the antimicrobial effect, exhibited excellent inhibition potential. Antifungal screening was also performed employing food poisoning methods against several pathogenic fungal species, viz A. flavus, F. oxysporum, A. niger, and A. brassicae. The obtained result indicated that few compounds can prove to be a potent drug regimen against dreaded MDR strains of microbes. Structural activity relationship (SAR) analysis and docking studies reveal that the presence of electron-withdrawing, polar, and more lipophilic substituents positively favor the antibacterial activity, whereas, electron-withdrawing, more polar, and hydrophilic substituents favor the antifungal activities. A robust coherence has been found in in-silico and in-vitro biological screening results of the compounds.

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson's Disease Mouse Model.

The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer's disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes "anchor" interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson's disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

Repurposing the antihistamine drug bilastine as an anti-cancer metallic drug entity: synthesis and single-crystal X-ray structure analysis of metal-based bilastine and phen [Co(II), Cu(II) and Zn(II)] tailored anticancer chemotherapeutic agents against resistant cancer cells.

Bilastine (BLA), 2-(4-(2-(4-(1-(2-ethoxyethyl)-1H-benzo[d]imidazole-2-yl)-piperidin-1-yl)-ethyl)-phenyl)-2-methylpropanoic acid, is an active antihistamine drug. With the idea of repurposing drugs from the existing pool of 'active' pharmaceutical ingredients, the therapeutic potency of bilastine as an anticancer agent was investigated via the tailored synthesis of a metal-based anticancer drug formulation of the type [BLA(phen)2M(II)]+·X-, where M = Co, Cu, and Zn and X- = NO3 and ClO4. The synthesized metal-based chemotherapeutics derived from the bilastine drug that acts as a ligand were thoroughly characterized using spectroscopic techniques, namely, UV-vis, FT-IR, and EPR (in the case of 1 and 2); 1H-NMR and 13C-NMR (in the case of 3); ESI-MS and single-crystal X-ray diffraction studies. Comprehensive biological studies (DNA binding, cleavage, and cytotoxic activity) using various biophysical and gel electrophoretic methods were carried out to validate their potential as anticancer agents. The cytotoxic activity of 'therapeutically promising' copper(II)-based drug candidate 2 was evaluated against MCF-7, MBA-MD-231, HeLa, HepG2, and Mia-PaCa-2 cancer cells via an SRB assay, and the results demonstrated 2 as a potent anticancer agent at low nanomolar concentrations against all tested cancer cells, preferably with a much superior anticancer efficacy against human pancreatic cancer cells.

Design, Synthesis and Biological Activity of Novel Methoxy- and Hydroxy-Substituted N-Benzimidazole-Derived Carboxamides.

This work presents the design, synthesis and biological activity of novel N-substituted benzimidazole carboxamides bearing either a variable number of methoxy and/or hydroxy groups. The targeted carboxamides were designed to investigate the influence of the number of methoxy and/or hydroxy groups, the type of substituent placed on the N atom of the benzimidazole core and the type of substituent placed on the benzimidazole core on biological activity. The most promising derivatives with pronounced antiproliferative activity proved to be N-methyl-substituted derivatives with hydroxyl and methoxy groups at the phenyl ring and cyano groups on the benzimidazole nuclei with selective activity against the MCF-7 cell line (IC50 = 3.1 µM). In addition, the cyano-substituted derivatives 10 and 11 showed strong antiproliferative activity against the tested cells (IC50 = 1.2-5.3 µM). Several tested compounds showed significantly improved antioxidative activity in all three methods compared to standard BHT. In addition, the antioxidative activity of 9, 10, 32 and 36 in the cells generally confirmed their antioxidant ability demonstrated in vitro. However, their antiproliferative activity was not related to their ability to inhibit oxidative stress nor to their ability to induce it. Compound 8 with two hydroxy and one methoxy group on the phenyl ring showed the strongest antibacterial activity against the Gram-positive strain E. faecalis (MIC = 8 µM).

Biological activity and computational analysis of novel acrylonitrile derived benzazoles as potent antiproliferative agents for pancreatic adenocarcinoma with antioxidative properties.

Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 µM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.

Development of benzimidazole-based compounds as novel capsid assembly modulators for the treatment of HBV infection.

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50 = 2.46 ± 0.33 µM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50 = 0.51 ± 0.20 µM, EC50 = 2.24 ± 0.43 µM, CC50 = 84.29 µM) and high selectivity index. Moreover, treatment with compound 26f for 14 days significantly decreased serum levels of HBV DNA levels in the Hydrodynamic-Injection (HDI) mouse model. Therefore, compound 26f could be considered as a promising candidate drug for further development of novel HBV CAMs with the desired potency and safety.

Design, synthesis, and biological evaluation of novel benzimidazole derivatives as anti-cervical cancer agents through PI3K/Akt/mTOR pathway and tubulin inhibition.

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for cervical cancer treatment. In this study, we designed and synthesized a series of benzimidazole derivatives and evaluated their anti-cervical cancer activity. Compound 4r exhibited strong antiproliferative activity in different cervical cancer cell lines HeLa, SiHa and Ca Ski, and relative lower cytotoxicity to normal hepatic and renal cell lines LO2 and HEK-293t (IC50 values were at 21.08 µM and 23.96 µM respectively). Its IC50 value was at 3.38 µM to the SiHa cells. Further mechanistic studies revealed that 4r induced apoptosis, arrested cell cycle in G2/M phase, suppressed PI3K/Akt/mTOR pathway and inhibit the polymerization of tubulin. Molecular docking study suggested that 4r formed key H-bonds action with PI3Kα (PDB ID:8EXU) and tubulin (PDB ID:1SA0). Zebrafish acute toxicity experiments showed that high concentrations of 4r did not cause death or malformation of zebrafish embryos. All these results demonstrated that 4r would be a promising lead candidate for further development of novel PI3K and tubulin dual inhibitors in cervical cancer treatment.

High affinity and low PARP-trapping benzimidazole derivatives as a potential warhead for PARP1 degraders.

PARPi have been explored and applied in the treatment of various cancers with remarkable efficacy, especially BRCA1/2 mutated ovarian, breast, prostate, and pancreatic cancers. However, PARPi renders inevitable drug resistance and showed high toxicity because of PARP-Trapping with long-term clinic tracking. To overcome the drug resistance and the high toxicity of PARPi, many novel methods have been developed including PROTACs. Being an event-driven technology, PROTACs needs a high affinity, low toxicity warhead with no steric hindrance in binding process. Veliparib shows the lowest PARP-Trapping effect but could hardly to be the warhead of PROTACs because of the strong steric hindrance. Other PARP1 inhibitors showed less steric hindrance but owns high PARP-Trapping effect. Thus, the development of novel warhead with high PARP1 affinity, low PARP1-Trapping, and no steric hindrance would be valuable. In this work, we reserved benzimidazole as the motif to reserve the low PARP1-Trapping effect and substituted the pyrrole by aromatic ring to avoiding the steric hindrance in PARP1 binding cave. Thus, a series of benzimidazole derivates were designed and synthesized, and some biological activities in vitro were evaluated including the inhibition for PARP1 enzyme and the PARP-Trapping effect using MDA-MB-436 cell line. Results showed that the compound 19A10 has higher PARP1 affinity(IC50 = 4.62 nM)) and similar low PARP-Trapping effect compared with Veliparib(IC50 (MDA-MB-436) >100 µM). Docking study showed that the compound 19A10 could avoiding the steric hindrance which was much better than Veliparib. So, the compound 19A10 could potentially be a perfect warhead for PARP1 degraders. Besides, because of the depletion of the PARP1 and the decreasing of the binding capability, we suppose that the PROTACs using 19A10 as the warhead would be no-PARP-Trapping effect. Furthermore, QSAR study showed that to develop novel compounds with high PARP1 binding affinity and low PARP-Trapping, we can choose the skeleton with substituent R1H, R2 = piperiazine, and R3 with large tPSA. And, if we want to develop the compounds with high PARP1 binding affinity and high PARP-Trapping which can possibly improve the lethality against tumor cells, we can choose the skeleton with substituent R1F, R2 = 3-methy-piperiazine, and R3 with large tPSA.

Synthesis, Characterization, and Antifungal Activity of Benzimidazole-Grafted Chitosan against Aspergillus flavus.

Aspergillus flavus contamination in agriculture and food industries poses threats to human health, leading to a requirement of a safe and effective method to control fungal contamination. Chitosan-based nitrogen-containing derivatives have attracted much attention due to their safety and enhanced antimicrobial applications. Herein, a new benzimidazole-grafted chitosan (BAC) was synthesized by linking the chitosan (CS) with a simple benzimidazole compound, 2-benzimidazolepropionic acid (BA). The characterization of BAC was confirmed by Fourier transform infrared (FTIR) spectroscopy and nuclear magnetic resonance spectroscopy (1H and 13C NMR). Then, the efficiency of BAC against A. flavus ACCC 32656 was investigated in terms of spore germination, mycelial growth, and aflatoxin production. BAC showed a much better antifungal effect than CS and BA. The minimum inhibitory concentration (MIC) value was 1.25 mg/mL for BAC, while the highest solubility of CS (16.0 mg/mL) or BA (4.0 mg/mL) could not completely inhibit the growth of A. flavus. Furthermore, results showed that BAC inhibited spore germination and elongation by affecting ergosterol biosynthesis and the cell membrane integrity, leading to the permeabilization of the plasma membrane and leakage of intracellular content. The production of aflatoxin was also inhibited when treated with BAC. These findings indicate that benzimidazole-derived natural CS has the potential to be used as an ideal antifungal agent for food preservation.

Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

Selective Targeting of Regulated Rhabdomyosarcoma Cells by Trinuclear Ruthenium(II)-Arene Complexes.

The use of benzimidazole-based trinuclear ruthenium(II)-arene complexes (1-3) to selectively target the rare cancer rhabdomyosarcoma is reported. Preliminary cytotoxic evaluations of the ruthenium complexes in an eight-cancer cell line panel revealed enhanced, selective cytotoxicity toward rhabdomyosarcoma cells (RMS). The trinuclear complex 1 was noted to show superior short- and long-term cytotoxicity in RMS cell lines and enhanced selectivity relative to cisplatin. Remarkably, 1 inhibits the migration of metastatic RMS cells and maintains superior activity in a 3D multicellular spheroid model in comparison to that of the clinically used cisplatin. Mechanistic insights reveal that 1 effectively induces genomic DNA damage, initiates autophagy, and prompts the intrinsic and extrinsic apoptotic pathways in RMS cells. To the best of our knowledge, 1 is the first trinuclear ruthenium(II) arene complex to selectively kill RMS cells in 2D and 3D cell cultures.

Design and synthesis of novel coumarin-benzimidazole hybrids as human galectin-1 inhibitors.

Aim: To develop novel non-carbohydrate inhibitors of human galectin-1 (GAL-1), we have designed a series of coumarin-benzimidazole hybrids. Methods: We synthesized and characterized the coumarin-benzimidazole hybrids and further evaluated them using an in vitro GAL-1 enzyme-linked immunosorbent assay and in silico methods. Results: Among all, the compounds 6p and 6q were found to be potent, with GAL-1 inhibition of 37.61 and 36.92%, respectively, at 10 µM in GAL-1-expressed cell culture supernatant of MCF-7 cells. These two compounds are feasible for fluorine-18 radiolabeling to develop GAL-1 selective PET radiotracers. Computational studies revealed strong binding interactions of GAL-1 with these novel coumarin-benzimidazole hybrids. Conclusion: Coumarin-benzimidazole hybrids can serve as potential leads to develop selective non-carbohydrate GAL-1 inhibitors for cancer therapy.

[Box: see text].

Benzimidazole and Benzoxazole Derivatives Against Alzheimer's Disease.

Benzimidazole and benzoxazole derivatives are included in the category of medical drugs in a wide range of areas such as anticancer, anticoagulant, antihypertensive, anti- inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, immunomodulators, proton pump inhibitors, hormone modulators, etc. Many researchers have focused on synthesizing more effective benzimidazole and benzoxazole derivatives for screening various biological activities. In addition, there are benzimidazole and benzoxazole rings as bioisosteres of aromatic rings found in drugs used in the treatment of Alzheimer's disease. Because of the diverse activity of the benzimidazole and benzoxazole rings and bioisosteres marketed as drugs for Alzheimer Diseases, designed compounds containing these rings are likely to be effective against Alzheimer's disease. In this study, the effectiveness of compounds containing benzimidazole and benzoxazole rings against Alzheimer's disease will be examined.

Development of Benzimidazole-Substituted Spirocyclopropyl Oxindole Derivatives as Cytotoxic Agents: Tubulin Polymerization Inhibition and Apoptosis Inducing Studies.

A series of spirocyclopropyl oxindoles with benzimidazole substitutions was synthesized and tested for their cytotoxicity against selected human cancer cells. Most of the molecules exhibited significant antiproliferative activity with compound 12 p being the most potent. It exhibited significant cytotoxicity against MCF-7 breast cancer cells (IC50 value 3.14±0.50 µM), evidenced by the decrease in viable cells and increased apoptotic features during phase contrast microscopy, such as AO/EB, DAPI and DCFDA staining studies. Compound 12 p also inhibited cell migration in wound healing assay. Anticancer potential of 12 p was proved by the inhibition of tubulin polymerization with IC50 of 5.64±0.15 µM. These results imply the potential of benzimidazole substituted spirocyclopropyl oxindoles, notably 12 p, as cytotoxic agent for the treatment of breast cancer.

Unlocking the Pharmacological Potential of Benzimidazole Derivatives: A Pathway to Drug Development.

Heterocyclic molecules have fascinated a massive interest in medicinal chemistry. They are heterocyclic compounds that have gained significance due to their diverse variety of pharmacological activities. Benzimidazole is a heterocyclic compound consisting of benzene and imidazole rings. The ease of synthesis and the structural versatility of benzimidazole make it a promising scaffold for drug development. Many biological actions of benzimidazole derivatives have been well documented, including antibacterial, antiviral, anticancer, anti-inflammatory, antitubercular, and anthelmintic properties. The mechanism of action of benzimidazole derivatives varies with their chemical structure and target enzyme. This review has explored numerous methods for producing benzimidazole derivatives as well as a broad range of pharmacological activities. SAR investigations are also discussed in this review as they provide crucial details regarding the essential structural qualities that benzimidazole derivatives must have in order to be biologically active, which could aid in the rational design of new drug candidates. Benzimidazole scaffold is an exclusive structure in drug design and discovery. Many new pharmaceutical drugs containing benzimidazole are anticipated to be available within the next ten years as a result of the extensive therapeutic applications of benzimidazole and its derivatives. This review inspired many researchers to develop more biologically active compounds bearing benzimidazole, expanding the scope of finding a remedy for other diseases. From this study, we concluded that 2-substituted benzimidazole was considered more extensively by researchers.

JHD205, A Novel Abemaciclib Derivative, Exerts Antitumor Effects on Breast Cancer by CDK4/6.

BACKGROUND: Efficient targeted molecular therapeutics are needed for the treatment of triple-negative breast cancer (TNBC), a highly invasive and difficult-to-treat form of breast cancer associated with a poor prognosis. OBJECTIVES: This study aims to evaluate the potential of selective CDK4/6 inhibitors as a therapeutic option for TNBC by impairing the cell cycle G1 phase through the inhibition of retinoblastoma protein (Rb) phosphorylation. METHODS: In this study, we synthesized a compound called JHD205, derived from the chemical structure of Abemaciclib, and examined its inhibitory effects on the malignant characteristics of TNBC cells. RESULTS: Our results demonstrated that JHD205 exhibited superior tumor growth inhibition compared to Abemaciclib in breast cancer xenograft chicken embryo models. Western blot analysis revealed that JHD205 could dosedependently degrade CDK4 and CDK6 while also causing abnormal changes in other proteins associated with CDK4/6, such as p-Rb, Rb, and E2F1. Moreover, JHD205 induced apoptosis and DNA damage and inhibited DNA repair by upregulating Caspase3 and p-H2AX protein levels. CONCLUSION: Collectively, our findings suggest that JHD205 holds promise as a potential treatment for breast carcinoma.