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In vitro evidence shows that the acyl- β -D-glucuronide metabolite of candesartan inhibits cytochrome P450 (CYP) 2C8 with an inhibition constant of 7.12 μ M. We investigated the effect of candesartan on the plasma concentrations and glucose-lowering effect of repaglinide, a sensitive clinical CYP2C8 index substrate. In a randomized crossover study, ten healthy volunteers ingested 8 mg of candesartan or placebo daily for three days, and on day 3, they also ingested 0.25 mg of repaglinide one hour after candesartan or placebo. We measured the plasma concentrations of repaglinide, candesartan, and candesartan acyl- β -D-glucuronide, and blood glucose concentrations for up to nine hours after repaglinide intake. Candesartan had no effect on the area under the plasma concentration-time curve and peak plasma concentration of repaglinide compared with placebo, with ratios of geometric means of 1.02 [ P = 0.809; 90% confidence interval (CI) 0.90-1.15] and 1.13 ( P = 0.346; 90% CI 0.90-1.43), respectively. Other pharmacokinetic variables and blood glucose concentrations were neither affected. Candesartan acyl- β -D-glucuronide was detectable in seven subjects, in whom the peak concentration of repaglinide was 1.32-fold higher in the candesartan phase than in the placebo phase ( P = 0.041; 90% CI 1.07-1.62). Systemic concentrations of candesartan acyl- β -D-glucuronide were very low compared with its CYP2C8 inhibition constant (ratio ≪ 0.1). Furthermore, in a cohort of 93 cancer patients, no indication of decreased paclitaxel clearance was found in four patients using candesartan concomitantly. In conclusion, candesartan therapy is unlikely to inhibit CYP2C8-mediated metabolism of other drugs to any clinically significant extent. SIGNIFICANCE STATEMENT: The findings of this study suggest that candesartan is unlikely to cause drug-drug interactions via inhibition of cytochrome P450 (CYP) 2C8. Although candesartan acyl- β -D-glucuronide has been shown to inhibit CYP2C8 in vitro, it shows no clinically relevant CYP2C8 inhibition in humans due to low systemic concentrations., (Copyright © 2024 by The Author(s).)

Hepatocellular carcinoma (HCC) is considered as one of the leading causes of death in liver disease patients. Several signal transduction pathways are involved in HCC pathogenesis. Multikinase inhibitors (MKIs) show beneficial effects for HCC and the FDA approved a few MKIs including sorafenib, lenvatinib for HCC treatments. Here, a novel series of phenylacetamide derivatives were designed, synthesized and evaluated as multikinase inhibitors. Several compounds showed nanomolar IC 50 values against FLT1, FLT3, FLT4, KDR, PDGFRα, PDGFRβ. The compounds were tested against human hepatocellular carcinoma (HCC), human colon adenocarcinoma and human gastric carcinoma cell lines. With favorable pharmacokinetics profiles, compound 12 and compound 14 were selected for in vivo efficacy studies in Hep3B mice models and demonstrated efficacious than sorafenib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Methyl benzimidazole-2-carbamate anthelmintics are a class of oral drugs to treat parasitic worm infections via microtubule disruption for non-systemic indications and currently in use. In order to use for anticancer treatment, the new benzimidazoles needs to improve solubility and pharmacokinetic parameters while maintaining its cellular potency as for systemic drug. Structure-activity-relationship on the benzimidazole is thoroughly examined and a novel benzimidazole-2 propionamide BNZ-111 is identified having good oral exposure and bioavailability in rat. Molecular docking study suggests BNZ-111 have a specific binding mode to the β subunit of curved tubulin. BNZ-111 is potent to cancer cells and possesses good drug-like properties as oral drug. Especially, BNZ-111 is not a P-gp substrate and it demonstrates its efficacy over Paclitaxel-resistance tumor in vivo., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a major role in the development of Rheumatoid Arthritis (RA). In the present study, benzimidazole and benzene sulfonyl scaffold were identified as pharmacophore by analysis of literature reports and novel small molecule IL-6 inhibitors were designed. These were screened via docking with IL-6 (PDB: 1ALU), then and through Lipinski's rule of 5. Based on docking score, 10 best compounds (4a-4e and 7a-7e) were selected for synthesis and evaluated for IL-6 inhibitory activity in vitro. Compounds 4b and 7b showed the maximum inhibition of IL-6 (87.55% and 82.75%, respectively). These compounds were further explored for anti-arthritic activity in vivo using the Incomplete Freund's Adjuvant Model and by morphological and histopathological studies of the inflamed paw. Compound 4b was significantly more active than compound 7b and both were found to be slightly less active than methotrexate. These findings indicate that a benzimidazole nucleus linked to a benzene sulphonyl moiety may prove to be a useful template for the development of new chemical moieties against RA., (© 2024 John Wiley & Sons Ltd.)

Letermovir and maribavir have demonstrated efficacy in the prevention and treatment, respectively, of immunosuppressed patients with cytomegalovirus (CMV) infection and disease. These patients often have polypharmacy making them at risk for drug-drug interactions. Both letermovir and maribavir can be perpetrators and victims of drug-drug interactions. Letermovir is a moderate inhibitor of CYP3A, CYP2C8 and OATP1B1/3, and a moderate inducer of CYP2C19. It is a substrate of UGT1A1/3, BCRP, P-gp and OATP1B1/3. Maribavir is a moderate CYP2C9 inhibitor and a substrate of CYP3A. Drug-drug interactions between these anti-CMV agents and a number of therapeutic classes, such as immunosuppressants, antifungal agents, and hemato-oncological agents, can have clinical consequences and deserve dose modification or close monitoring. In a number of examples, three-way drug interactions need to be assessed. The objective of this review is to provide clinicians with guidance for drug-drug interaction management, based on existing data from drug-drug interaction studies, and extrapolation to other relevant co-medications that have not (yet) been studied but that are frequently used in these patient populations., Competing Interests: Declarations Funding No funding was received for this publication. Conflicts of Interest D.M.B. is co-founder of Global DDI Solutions and received unrestricted research grants from Gilead, ViiV HealthCare, Pfizer and Merck. All payments were invoiced by the Radboudumc and paid to Radboudumc. J.M. has received research support from Pfizer and Gilead and has served as a consultant or speaker for Gilead, Pfizer, MSD, Cidara, Mundipharma, F2G, Amplyx, Basilea, Shionoghi, Synexis and Takeda. L.H. declares no interest with regards to this work. Outside of this work, he has served as consultant to and has received unrestricted research grants from Astellas Pharma, Chiesi, and Sandoz. All payments were invoiced by the Radboudumc and paid to Radboudumc. R.J.M.B. declares no interest with regards to this work. Outside of this work, he has served as consultant to and has received unrestricted research grants from Astellas Pharma Inc., F2G, Gilead sciences, Merck Sharpe and Dohme Corp., Cidara, Mundipharma Inc. and Pfizer Inc. All payments were invoiced by the Radboudumc and paid to Radboudumc. L.N., M.G., N.B., P.L. and M.C.B. have not declared a conflict of interest. Ethics approval Not applicable. Consent to participate Not applicable. Consent for publication Not applicable. Availability of Data and Material Not applicable. Code Availability Not applicable. Author contributions DB performed the initial selection of papers, which were double checked by MG and LN. All authors reviewed draft versions of the paper and the tables, and all authors approved the final version of the paper., (© 2024. The Author(s).)

Cucumber Corynespora leaf spot caused by Corynespora cassiicola is the primary disease responsible for reducing cucumber yield, and prochloraz is the main fungicide used to control C. cassiicola. This study investigated the sensitivity and resistance mechanism of C. cassiicola isolates to prochloraz, and found that C. cassiicola has developed resistance to prochloraz. The prochloraz EC 50 values ranged from 0.02 to 2.33 μg/mL, with a mean of 0.436 ± 0.447 μg/mL. In total, 36 of 146 isolates exhibited prochloraz resistance. The resistant isolates had no fitness cost and could not be completely controlled by 50 μg/mL prochloraz on detached leaves. Prochloraz exhibited positive cross-resistance with propiconazole and tebuconazole but not with difenoconazole, carbendazim, trifloxystrobin and pydiflumetofen. The sensitive isolates had significantly lower ergosterol content than the resistant isolates after prochloraz treatment. Compared to sensitive isolates, prochloraz-resistant isolates had no CcCYP51 gene mutation, but the CcCYP51A and CcCYP51B gene expression levels were significantly higher under the treatment of prochloraz. The overexpression of CcCYP51A and CcCYP51B were associated with prochloraz resistance in C. cassiicola., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

PARP inhibitors (PARPi) benefit only a small subset of patients with DNA homologous recombination (HR) defects. In addition, long-term administration of a PARPi can lead to the development of drug resistance. 2-Hydroxyglutarate (2HG) has long been known as an oncometabolite but is capable of inducing an HR defect, which makes tumor cells exquisitely sensitive to PARPi. To facilitate the translation of this discovery to the treatment of both HR-deficient and HR-proficient tumors, a liposomal formulation was developed for codelivery of 2HG and veliparib, a PARPi. A sequential loading protocol was developed such that the initial loading of 2HG into liposomes greatly facilitated the subsequent, pH gradient-driven remote loading of veliparib. The liposomes co-loaded with veliparib and 2HG exhibited favorable stability, slow kinetics of drug release, and targeted delivery to the tumor. Furthermore, the veliparib/2HG liposomes demonstrated enhanced anti-tumor activity in both PARPi-resistant BRCA mutant cancer and BRCA wildtype cancer by synergistically enhancing the defect in DNA repair. Moreover, combination of veliparib and 2HG via liposomal co-delivery also augmented the function of cytotoxic T cells by activating the STING pathway and downregulating PD-L1 expression via 2HG-induced hypermethylation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes., Competing Interests: Declaration of competing interest The authors declare that no conflict of interest exists, therefore we have nothing to declare., (Copyright © 2024. Published by Elsevier Inc.)

Background: Peach brown rot caused by Monilinia fructicola severely affects the quality and yield of peach, resulting in large economic losses worldwide. Methyl benzimidazole carbamate (MBC) fungicides and sterol demethylation inhibitor (DMI) fungicides are among the most applied chemical classes used to control the disease but resistance in the target pathogen has made them risky choices. Timely monitoring of resistance to these fungicides in orchards could prevent control failure in practice., Results: In the current study, we developed methods based on recombinase polymerase amplification (RPA) and CRISPR/Cas12a systems to detect MBC and DMI resistance based on the E198A mutation in the β-tubulin (MfTub2) gene and the presence of the Mona element in the upstream region of the MfCYP51, respectively. For MBC resistance, RPA primers were designed that artificially incorporated PAM sites to facilitate the CRISPR/Cas12a reaction. Subsequently, specific tcrRNAs were designed based on the E198A mutation site. For the detection of the Mona element, we designed RPA primers M-DMI-F2/M-DMI-R1 that in combination with crRNA1 detected 'Mona' and distinguished resistant from sensitive strains., Conclusion: Both methods exhibited high sensitivity and specificity, requiring only a simple isothermal device to obtain results within 1 h at 37 °C. The FQ-reporter enabled visualization with a handheld UV or white light flashlight. This method was successfully used with purified DNA from lab cultures and crude DNA from symptomatic fruit tissue, highlighting its potential for on-site detection of resistant strains in orchards. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

Complexes [Cu(PI) 2 (H 2 O)](NO 3 ) 2 (1), [Cu(PBI) 2 (NO 3 )]NO 3 (2), [Cu(TBI) 2 (NO 3 )]NO 3 (3), [Cu(BBIP) 2 ](ClO 4 ) 2 (4) and [Cu(BBIP)(CH 3 OH)(ClO 4 ) 2 ] (5) were synthesized from the reactions of Cu(II) salts with 2-(2'-pyridyl)imidazole (PI), (2-(2'-pyridyl)benzimidazole (PBI), 2-(4'-thiazolyl)-benzimidazole (TBI), 2,6-bis(benzimidazol-2-yl)-pyridine (BBIP), respectively. Their compositions and crystal structures were determined. Their in-vitro antitumor activities were screened on four cancer cell lines and one normal cell line (HL-7702) using cisplatin as the positive control. Complexes 2 and 4 show higher cytotoxicity than the other three complexes. The cytotoxicity of complex 2 are comparable to those for cisplatin, and the cytotoxicity for 4 are much higher than those for cisplatin. From a viewpoint of antitumor, 2 might be a nice choice on the tumor cell line of T24 because its IC50 values on T24 and HL-7702 are 15.03 ± 1.10 and 21.34 ± 0.35, respectively. Thus, a mechanistic study for complexes 2 and 4 on T24 cells was conducted. It revealed that they can reduce mitochondrial membrane potential and increase mitochondrial membrane permeability, resulting in increased intracellular ROS levels, Ca 2+ inward flow, dysfunctional mitochondria and the eventual cell apoptosis. In conclusion, they can induce cell apoptosis through mitochondrial dysfunction. These findings could be useful in the development of new antitumor agents., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The implementation of chemoradiation combinations has gained great momentum in clinical practices. However, the full utility of this paradigm is often restricted by the discordant tempos of action of chemotherapy and radiotherapy. Here, a gold nanoparticle-based radiation-responsive nanovesicle system loaded with cisplatin and veliparib, denoted as CV-Au NVs, is developed to augment the concurrent chemoradiation effect in a spatiotemporally controllable manner of drug release. Upon irradiation, the in situ generation of •OH induces the oxidation of polyphenylene sulfide from being hydrophobic to hydrophilic, resulting in the disintegration of the nanovesicles and the rapid release of the entrapped cisplatin and veliparib (the poly ADP-ribose polymerase (PARP) inhibitor). Cisplatin-induced DNA damage and the impairment of the DNA repair mechanism mediated by veliparib synergistically elicit potent pro-apoptotic effects. In vivo studies suggest that one-dose injection of the CV-Au NVs and one-time X-ray irradiation paradigm effectively inhibit tumor growth in the A549 lung cancer model. This study provides new insight into designing nanomedicine platforms in chemoradiation therapy from a vantage point of synergizing both chemotherapy and radiation therapy in a spatiotemporally concurrent manner., (© 2024 Wiley‐VCH GmbH.)

Lung cancer is a complex and heterogeneous disease, which has been associated with various molecular alterations, including the overexpression and mutations of the epidermal growth factor receptor (EGFR). In this study, designed a library of 1843 benzimidazole-1,2,3-triazole hybrids and carried out pharmacophore-based screening to identify potential EGFR inhibitors. The 164 compounds were further evaluated using molecular docking and molecular dynamics simulations to understand the binding interactions between the compounds and the receptor. In-si-lico ADME and toxicity studies were also conducted to assess the drug-likeness and safety of the identified compounds. The results of this study indicate that benzimidazole-1,2,3-triazole hybrids BENZI-0660, BENZI-0125, BENZI-0279, BENZI-0415, BENZI-0437, and BENZI-1110 exhibit dock scores of -9.7, -9.6, -9.6, -9.6, -9.6, -9.6 while referencing molecule -7.9 kcal/mol for EGFR (PDB ID: 4HJO), respectively. The molecular docking and molecular dynamics simulations revealed that the identified compounds formed stable interactions with the active site of EGFR, indicating their potential as inhibitors. The in-silico ADME and toxicity studies showed that the compounds had favorable drug-likeness properties and low toxicity, further supporting their potential as therapeutic agents. Finally, performed DFT studies on the best-selected ligands to gain further insights into their electronic properties. The findings of this study provide important insights into the potential of benzimidazole-1,2,3-triazole hybrids as promising EGFR inhibitors for the treatment of lung cancer. This research opens up a new avenue for the discovery and development of potent and selective EGFR inhibitors for the treatment of lung cancer.Communicated by Ramaswamy H. Sarma.

Background: Anthelmintic resistance (AR) is a global threat to grazing livestock farming. In Italy, anthelmintic efficacy remains high compared to other European countries, but many parts of the country haven't been investigated yet. Local veterinary practitioners from Trentino and Veneto regions reported suspected inefficacy towards anthelmintic drugs in some of their farms, prompting a study on AR in sheep and goat farms of northern Italy. The study aimed to assess anthelmintic effectiveness using genus-specific faecal egg count reduction tests (FECRT), to detect differences in treatment response among nematode genera involved in the infection., Results: Twelve farms (6 sheep and 6 goat farms) were included based on clinical suspicion of AR. Treatments were carried out with either benzimidazoles (BZ) or macrocyclic lactones (ML) Treatment was effective in 3/6 goat trials, with reduced effectiveness to BZ in two farms and to ML the last one. In sheep farms (6/6), effectiveness was consistently and more severely insufficient. Ineffectiveness was particularly high towards Haemonchus contortus, while Oesophagostomum/Chabertia maintained susceptibility in nearly all trials. Trichostrongylus/Teladorsagia exhibited intermediate results., Conclusions: This study reveals diminished efficacy of both BZ and ML in small ruminant farms in north-eastern Italy, an area previously lacking data on the topic, except for goats in South Tyrol. Variability in treatment responses among nematode genera support suspicions of AR, and further concerns are raised by the prevalence of treatment ineffectiveness against the highly pathogenic Haemonchus contortus. This finding underscores the urgent need for comprehensive AR monitoring in the area and improved management practices to prevent further resistance development and protect livestock health., (© 2024. The Author(s).)

Dyslipidemia is the most significant risk factor for cardiovascular diseases (CVDs) Secondary dyslipidemia: its treatments and association with atherosclerosis. Glob Health Med, Efficacy and safety of saroglitazar for the management of dyslipidemia: A systematic review and meta-analysis of interventional studies. The current treatment strategies for managing dyslipidemia focus on reducing low-density lipoprotein cholesterol (LDL-C) to minimize the risks of atherosclerosis and myocardial infarction (MI). Homozygous Familial Hypercholesterolemia (HoFH) is an inherited autosomal dominant disease caused by a mutation in the LDL receptor (LDLr), which can lead to extremely high levels of LDL-C The Beneficial Effect of Lomitapide on the Cardiovascular System in LDLr(-/-) Mice with Obesity, The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity. Although statin therapy has been the primary treatment for dyslipidemia, HoFH patients do not respond well to statins, requiring alternative therapies. Microsomal triglyceride transfer protein (MTP) inhibition has emerged as a potential therapeutic target for treating HoFH. MTP is primarily responsible for transferring triglyceride and other lipids into apolipoprotein B (ApoB) during the assembly of very low-density lipoprotein (VLDL) particles in the liver. Lomitapide, an inhibitor of MTP, has been approved for treatingof HoFH adults. Unlike statins, lomitapide does not act on the LDLr to reduce cholesterol. Instead, lomitapide lowers the levels of ApoB-containing proteins, primarily VLDL, eventually decreasing LDL-C levels. Studies have shown that lomitapide can reduce LDL-C levels by more than 50% in patients with HoFH who have failed to respond adequately to other treatments. Lowering LDL-C levels is important for preventing atherosclerosis, reducing cardiovascular risk, improving endothelial function, and promoting overall cardiovascular health, especially for patients with HoFH Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. This review paper focuses on research findings regarding the therapeutic benefits of lomitapide, highlighting its effectiveness in lowering cholesterol levels and reducing the risk of CVDs The microsomal triglyceride transfer protein inhibitor lomitapide improves vascular function in mice with obesity., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is reliably one of the largest pandemics the world has suffered in recent years. In the search for non-biological antivirals, special emphasis was placed on drug repurposing to accelerate the clinical implementation of effective drugs.The life cycle of the virus has been extensively investigated and many human targets have been identified, such as the molecular chaperone GRP78, representing a host auxiliary factor for SARS-CoV-2 entry. Here we report the inhibitor capacity of TL1228, a small molecule discovered through an in silico screening approach, which could interfere with the interaction of SARS-CoV-2 and its target cells, blocking the recognition of the GRP78 cellular receptor by the viral Spike protein. TL1228 showed in vitro the ability to reduce significantly both pseudoviral and authentic viral activity even through the reduction of GRP78/ACE2 transcript levels. Importantly, TL1228 acts in modulating expression levels of innate immunity and as inflammation markers., (© 2024. The Author(s).)

This study introduces further insights from the hit-to-lead optimization process involving a series of benzimidazole derivatives acting as inhibitors of the cruzain enzyme, which targets Trypanosoma cruzi, the causative parasite of Chagas disease. Here, we present the design, synthesis and biological evaluation of 30 new compounds as a third generation of benzimidazole analogues with trypanocidal activity, aiming to enhance our understanding of their pharmacokinetic profiles and establish a structure-metabolism relationships within the series. The design of these new analogues was guided by the analysis of previous pharmacokinetic results, considering identified metabolic sites and biotransformation studies. This optimization resulted in the discovery of two compounds (42 e and 49 b) exhibiting enhanced metabolic stability, anti-Trypanosoma cruzi activity compared to benznidazole (the reference drug for Chagas disease), as well as being non-cruzain inhibitors, and demonstrating a satisfactory in vitro pharmacokinetic profile. These findings unveil a new subclass of aminobenzimidazole and rigid compounds, which offer potential for further exploration in the quest for discovering novel classes of antichagasic compounds., (© 2024 Wiley-VCH GmbH.)

Glomus tumors (GT) are very rare mesenchymal neoplasms arising from glomus bodies, arteriovenous structures located in the dermis and involved in thermoregulation. Although most are benign, they may occasionally present malignant histological features associated with aggressive clinical behavior, metastatic spread, and poor response to conventional chemotherapy. The BRAF V600E mutation has been identified in a subset of malignant GT, highlighting a promising therapeutic target. Here, we report the impressive clinical and morpho-metabolic response of a metastatic BRAF V600E-mutated glomangiosarcoma after treatment with encorafenib and binimetinib.

The nonproton pumping type II NADH dehydrogenase in Mycobacterium tuberculosis is essential for meeting the energy needs in terms of ATP under normal aerobic and stressful hypoxic environmental states. Type II NADH dehydrogenase conduits electrons into the electron transport chain in Mycobacterium tuberculosis , which results in ATP synthesis. Therefore, the inhibition of NDH-2 ensures the abolishment of the entire ATP synthesis machinery. Also, type II NADH dehydrogenase is absent in the mammalian genome, thus making it a potential target for antituberculosis drug discovery. Herein, we have screened a commercially available library of drug-like molecules and have identified a hit having a benzimidazole core moiety ( 6 , H37Rv mc 2 6230; minimum inhibitory concentration (MIC) = 16 μg/mL and ATP IC 50 = 0.23 μg/mL) interfering with the oxidative phosphorylation pathway. Extensive medicinal chemistry optimization resulted in analogue 8, with MIC = 4 μg/mL and ATP IC 50 = 0.05 μg/mL against the H37Rv mc 2 6230 strain of Mycobacterium tuberculosis . Compounds 6 and 8 were found to be active against mono- and multidrug-resistant mycobacterium strains and demonstrated a bactericidal response. The Peredox-mCherry experiment and identification of single-nucleotide polymorphisms in mutants of CBR-5992 (a known type II NADH dehydrogenase inhibitor) were used to confirm the molecules as inhibitors of the type II NADH dehydrogenase enzyme. The safety index >10 for the test active molecules revealed the safety of test molecules.

Despite the great effort that has gone into developing new molecules as multitarget compounds to treat Alzheimer's disease (AD), none of these have been approved to treat this disease. Therefore, it will be interesting to determine whether benzazoles such as benzimidazole, benzoxazole, and benzothiazole, employed as pharmacophores, could act as multitarget drugs. AD is a multifactorial disease in which several pharmacological targets have been identified-some are involved with amyloid beta (Aβ) production, such as beta secretase (BACE1) and beta amyloid aggregation, while others are involved with the cholinergic system as acetylcholinesterase (AChE) and butirylcholinesterase (BChE) and nicotinic and muscarinic receptors, as well as the hyperphosphorylation of microtubule-associated protein (tau). In this review, we describe the in silico and in vitro evaluation of benzazoles on three important targets in AD: AChE, BACE1, and Aβ. Benzothiazoles and benzimidazoles could be the best benzazoles to act as multitarget drugs for AD because they have been widely evaluated as AChE inhibitors, forming π-π interactions with W286, W86, Y72, and F338, as well as in the AChE gorge and catalytic site. In addition, the sulfur atom from benzothiazol interacts with S286 and the aromatic ring from W84, with these compounds having an IC 50 value in the μM range. Also, benzimidazoles and benzothiazoles can inhibit Aβ aggregation. However, even though benzazoles have not been widely evaluated on BACE1, benzimidazoles evaluated in vitro showed an IC 50 value in the nM range. Therefore, important chemical modifications could be considered to improve multitarget benzazoles' activity, such as substitutions in the aromatic ring with electron withdrawal at position five, or a linker 3 or 4 carbons in length, which would allow for better interaction with targets.

Antimicrobial resistance (AMR) has led to a marked reduction in the effectiveness of many antibiotics, representing a substantial and escalating concern for global health. Particularly alarming is resistance in Gram-negative bacteria due to the scarcity of therapeutic options for treating infections caused by these pathogens. This challenge is further compounded by the rising incidence of resistance to colistin, an antibiotic traditionally considered a last resort for the treatment of multi-drug resistant (MDR) Gram-negative bacterial infections. In this study, we demonstrate that adjuvants restore colistin sensitivity in vivo . We previously reported that the salicylanilide kinase inhibitor IMD-0354, which was originally developed to inhibit the human kinase IKKβ in the NFκB pathway, is a potent colistin adjuvant. Subsequent analog synthesis using an amide isostere approach led to the creation of a series of novel benzimidazole compounds with enhanced colistin adjuvant activity. Herein, we demonstrate that both IMD-0354 and a lead benzimidazole effectively restore colistin susceptibility in mouse models of highly colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii -induced peritonitis. These novel adjuvants show low toxicity in vivo , significantly reduce bacterial load, and prevent dissemination that could otherwise result in systemic infection., Competing Interests: The authors declare no conflict of interest.

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The 3CL protease (3CL pro , M pro ) plays a key role in the replication of the SARS-CoV-2 and was validated as therapeutic target by the development and approval of specific antiviral drugs (nirmatrelvir, ensitrelvir), inhibitors of this protease. Moreover, its high conservation within the coronavirus family renders it an attractive therapeutic target for the development of anti-coronavirus compounds with broad spectrum activity to control COVID-19 and future coronavirus diseases. Here we report on the design, synthesis and structure-activity relationships of a new series of small covalent reversible inhibitors of the SARS-CoV-2 3CL pro . As elucidated thanks to the X-Ray structure of some inhibitors with the 3CL pro , the mode of inhibition involves acylation of the thiol of the catalytic cysteine. The synthesis of 60 analogs led to the identification of compound 56 that inhibits the SARS-CoV-2 3CL pro with high potency (IC 50  = 70 nM) and displays antiviral activity in cells (EC 50  = 3.1 μM). Notably, compound 56 inhibits the 3CL pro of three other human coronaviruses and exhibit a good selectivity against two human cysteine proteases. These results demonstrate the potential of this electrophilic N-acylbenzimidazole series as a basis for further optimization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)

Penicillium expansum is the major fungus that causes blue mold and produces patulin, threatening human health. Due to health and environmental pollution concerns, chitosan (CS) has attracted more and more attention as a safer alternative to synthetic fungicides for the control of blue mold. In the present study, four different benzimidazole groups were introduced onto CS by the acylation reaction to obtain benzimidazole-based chitosan derivatives (R1b-R4b). After being well-characterized with Fourier transform infrared spectroscopy (FTIR), ultraviolet-visible spectroscopy (UV-vis spectra), and nuclear magnetic resonance (NMR), their antifungal activities against P. expansum were screened. Results showed that the inhibitory effects of chitosan derivatives against the pathogen were significantly correlated with chitosan derivatives' concentration and their structures. R4b was shown as optimum with good solubility and antifungal activity with a minimum inhibitory concentration (MIC) value of 0.5 mg/mL and a minimum fungicidal concentration (MFC) value of 2.0 mg/mL. The remarkable antifungal efficiency of R4b against P. expansum was further demonstrated in terms of spore germination, mycelial growth, patulin production, and the preliminary antifungal mechanism. R4b exhibited significant inhibition of patulin production, while its antifungal mechanism was revealed by destroying cell membrane integrity and inducing membrane depolarization. Furthermore, R4b treatment could significantly reduce the incidence of blue mold rot in apple fruit, and the MTT assay showed the nontoxicity of R4b against Raw 264.7, HBZY-1, and Caco-2 cells. Altogether, these results indicate that it is promising to be used as a fruit preservative in the future.

This study examined Haemonchus contortus prevalence and benzimidazole resistance in eight districts of Marathwada, Maharashtra, India. A comprehensive investigation of 264 abomasa of goats collected from abattoirs and goats necropsied at the College of Veterinary Sciences and Animal Husbandry, Parbhani, revealed 21.21 % a prevalence of H. contortus. The incidence of H. contortus did not vary much across seasons and it was highest in summer (23.42 %), followed by monsoon (22.89 %), and lowest in winter (15.71 %). Statistically non-significant (p < 0.05) prevalence was observed in male and female animals. A detailed examination of 168 adult H. contortus worms from eight districts revealed the presence of all conceivable genotypes including homozygous resistant (rr), susceptible (SS), and heterozygous (Sr) BZ susceptible genotypes. The rr was the most frequent at 50 %, followed by SS at 27 % and Sr at 22 %. The presence of the SNP was observed in in all eight randomly selected and sequenced samples., Competing Interests: Declaration of competing interest The authors affirm that they do not possess any identifiable conflicting financial or personal interests that could have potentially influenced the findings presented in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAF V600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients., Methods: In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C)., Results: Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76)., Conclusions: In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).

Direct-acting antivirals ledipasvir (LDV) and daclatasvir (DCV) are widely used as part of combination therapies to treat Hepatitis C infections. Here we show that these compounds inhibit the proliferation, invasion, and colony formation of triple-negative MDA-MB-231 breast cancer cells, SRC-transduced SW620 colon cancer cells and SRC- transduced NIH3T3 fibroblasts. DCV also inhibits the expression of PDL-1, which is responsible for resistance to immunotherapy in breast cancer cells. The demonstrated low toxicity in many Hepatitis C patients suggests LDV and DCV could be used in combination therapies for cancer patients. At the molecular level, these direct-acting antivirals inhibit the phosphorylation of Akt and the ephrin type A receptor 2 (EPHA2) by destabilizing a Src-EPHA2 complex, although they do not affect the general kinase activity of Src. Thus, LDV and DCV could be effective drugs for Src-associated cancers without the inherent toxicity of classical Src inhibitors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

New iridium(III) compounds (C 1 -C 3 ) bearing 2-(1H-benzimidazol-2-yl)quinoline ligands with different side groups (benzyl, 2,3,4,5,6-pentamethylbenzyl and 2,3,4,5,6-pentafluorobenzyl) were synthesized and characterized by using spectroscopic analyses. The effects of different side groups of iridium compounds on the photophysical and electrochemical properties have been investigated. The cytotoxicity and apoptosis of the compounds have been evaluated on breast cancer cell lines using various methods including MTT assay, flow cytometry, qRT-PCR, and colony formation. The cytotoxicity of C 1 , expressed as IC50 values, was found to be 11.76 μM for MDA-MB-231 and 5.35 μM for MCF-7 cells. For C 3 , the IC50 value was 16.22 μM for MDA-MB-231 and 8.85 μM for MCF-7 cells. In both cell lines, increased levels of Bax and caspase 3, along with downregulation of BCL-2 and positive annexin V staining, were observed, confirming apoptosis. Moreover, the colony-forming abilities in both cell lines decreased after C 1 and C 3 complex treatment. All these results suggest that the compounds C 1 and C 3 may have potential in the treatment of breast cancer, though further research is needed to confirm their efficacy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cigdem Sahin reports financial support was provided by Istanbul Medeniyet University. Sevki Arslan reports financial support was provided by Istanbul Medeniyet University. Rafet Kilincarslan reports financial support was provided by Pamukkale University. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

African swine fever virus (ASFV) infection causes a frequently fatal disease in domestic swine that has affected more than 50 countries worldwide since 2021, with a major impact on animal welfare and economy. The development of effective vaccines or antivirals against this disease are urgently required for its effective control. Live detection of viral replication has been used as a tool for the screening and characterization of antiviral compounds in other dsDNA genome containing viruses. Here, we have adapted the ANCHOR fluorescent DNA labelling system to ASFV by constructing and characterizing a novel recombinant virus. We show that this virus is viable and effectively tags viral DNA replication sites, which can be detected and quantified in real time. Further, we have used high content cell microscopy to test the antiviral activity of bisbenzimide compounds and show that Hoechst 33342 has specific anti-ASFV activity. We expect this novel tool to be useful both in the further study of ASFV replication as in the screening of new specific antiviral compounds., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SKG and FG are share-holders of NeoVirTech SAS. SKG is an employee of NeoVirTech SAS. No other conflict of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A new series of benzimidazole-oxindole hybrids 8a-x was discovered as dual cyclin-dependent kinase (CDK2) and glycogen synthase kinase-3-beta (GSK-3β) inhibitors with potent anticancer activity. The synthesized hits displayed potent anticancer activity against national cancer institute cancer cell lines in single-dose and five-dose assays. Moreover, the derivatives 8k, 8l, 8n, 8o, and 8p demonstrated potent cytotoxic activity against PANC-1 cells with IC 50  = 1.88-2.79 µM. In addition, the hybrids 8l, 8n, 8o, and 8p displayed potent antiproliferative activity on the MG-63 cell line (IC 50  = 0.99-1.90 µM). Concurrently, the benzimidazole-oxindole hybrid 8v exhibited potent dual CDK2/GSK-3β inhibitory activity with IC 50 values of 0.04 and 0.021 µM, respectively. In addition, 8v displayed more than 10-fold higher selectivity toward CDK2 and GSK-3 β over CDK1, CDK5, GSK-3α, vascular endothelial growth factor receptor-2, and B-rapidly accelerated fibrosarcoma. Screening of the effect of 8n and 8v on the cell cycle and apoptosis of PANC-1 and MG-63 cells displayed their ability to arrest their cell cycle at the G2-M phase and to potentiate the apoptosis of both cell lines. In silico docking of the benzimidazole-oxindole hybrid 8v into the catalytic pocket of both CDK2 and GSK-3β revealed its perfect fitting through the formation of hydrogen bonding and hydrophobic interactions with the key amino acids in the binding sites. In addition, in silico absorption, distribution, metabolism, excretion studies proved that 8a-x exhibit satisfactory drug-likeness properties for drug development., (© 2024 Deutsche Pharmazeutische Gesellschaft.)

Bis(benzimidazol-2-yl)amine scaffold is not present in dipeptidyl peptidase-4 (DPP-4) inhibitors published so far. Herein, the inhibitory potential of bis(benzimidazol-2-yl)amine derivatives against DPP-4 was evaluated. In non-competitive inhibition mode, three representatives 5, 6, and 7 inhibited DPP-4 in vitro with IC 50 values below 50 μM. The assessed binding pocket of DPP-4 for these benzimidazoles includes the S2 extensive subsite's residues Phe357 and Arg358. None of the lead compounds showed cytotoxicity to human neuroblastoma SH-SY5Y cells at concentrations lower than 10 μM. None showed significant binding affinity at dopamine D 2 , D 3, and histamine H 1 , H 3 receptors, at concentrations lower than 10 μM, leading to preferable outcomes due to mutually opposite effects of these neurotransmitters on each other. The potential beneficial effects on dopamine synthesis and the survival of dopaminergic neurons could be mediated by DPP-4 inhibition. These effective noncompetitive DPP-4 inhibitors, with inhibitory potential better than reference diprotin A (relative inhibitory potency compared to diprotin A is 3.39 and 1.54 for compounds 7 and 5, respectively), with the absence of cytotoxicity to SH-SY5Y cells, are valuable candidates for further evaluation for the treatment of diabetes and associated disruption of neuronal homeostasis., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

In this study, we aimed to enhance the bioavailability of a benzimidazole derivative with potent anticancer potential through a nano-based approach. Benzimidazole-loaded polyethylene glycol-β-cyclodextrin-functionalized curcumin nanocomplex (BMPE-Cur) was prepared and characterized for its physicochemical properties and drug release profiles under different pH conditions. In addition, the biological activities of the nanocomplex including antioxidant potentials and pro-apoptogenic properties, against HepG2, PC3, and the chemo-resistant MCF-7-ADR cell lines relative to the normal Wi-38 cell line were in vitro assessed and compared with those of the free benzimidazole compound. In addition to FTIR, XRD, and NMR spectral studies, a polymeric nanocomplex with an average particle size of 467.7 nm and high stability was successfully developed, as indicated by the negative zeta potential (-28.24 mV). The nanocomplex also showed prolonged pH-sensitive sustained drug release under conditions that replicated the tumor's extra/intracellular pH. The formulated nanocomplex also demonstrated potent radical scavenging capacity owing to the inclusion of curcumin, a known radical quencher. In addition, compared with the free compound, BMPE-Cur induced DNA fragmentation-driven cell cycle arrest in HepG2, PC3, and MCF-7-ADR cells at the G1/S, G1 & S phases; respectively, with remarkable selectivity. In conclusion, the newly formulated BMPE-Cur nanocomplex represents an attractive multitarget anticancer candidate., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the N-benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound 12; the Ames test results of this compound were negative. Notably, compound 12 not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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 1 H NMR, 13 C 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 IC 50  = 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 (IC 50  = 3.20 ± 0.10 μM for AChE and 4.30 ± 0.50 μM for BuChE), analog-4 (IC 50  = 4.30 ± 0.30 μM for AChE and 5.50 ± 0.20 μM for BuChE) and analog-5 (IC 50  = 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., Competing Interests: Declaration of competing interest It is declared that there is no conflict of interest between the authors of the current manuscripts and it is only submitting to Biochemical and Biophysical Research Communication and not submitted elsewhere., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In this study, we synthesized a series of seven benzimidazole derivatives incorporating the structural acidic framework of angiotensin II (Ang II) type 1 receptor (AT 1 R) antagonists (ARA-II) employing a three-step reaction sequence. The chemical structures were confirmed by 1 H NMR, 13 C 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 AT 1 R 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The direct-linked coumarin-benzimidazole hybrids, featuring aryl and n-butyl substituents at the N1-position of benzimidazole were synthesized through a Knoevenagel condensation reaction. This reaction involved the condensation of 1,2-diaminobenzene derivatives with coumarin-3-carboxylic acids in the presence of polyphosphoric acid (PPA) at 154 °C. The in vitro antibacterial potency of the hybrid molecules against different gram-positive and gram-negative bacterial strains led to the identification of the hybrids 6m and 6p with a MIC value of 6.25 μg/mL against a gram-negative bacterium, Klebsiella pneumonia ATCC 27736. Cell viability studies on THP-1 cells demonstrated that the compounds 6m and 6p were non-toxic at a concentration of 50 µM. Furthermore, in vivo efficacy studies using a murine neutropenic thigh infection model revealed that both compounds significantly reduced bacterial (Klebsiella pneumonia ATCC 27736) counts (more than 2 log) compared to the control group. Additionally, both compounds exhibited favorable physicochemical properties and drug-likeness characteristics. Consequently, these compounds hold promise as lead candidates for further development of effective antibacterial drugs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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 IC 50 /120 h of 0.033 μM and a selectivity index (SI) of 7680. This represents a potency 46 times greater than that of benznidazole (IC 50 /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 IC 50 /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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Influenza viruses remain a major threat to human health. Four classes of drugs have been approved for the prevention and treatment of influenza infections. Oseltamivir, a neuraminidase inhibitor, is a first-line anti-influenza drug, and baloxavir is part of the newest generation of anti-influenza drugs that targets the viral polymerase. The emergence of drug resistance has reduced the efficacy of established antiviral drugs. Combination therapy is one of the options for controlling drug resistance and enhancing therapeutical efficacies. Here, we evaluate the antiviral effects of baloxavir combined with neuraminidase inhibitors (NAIs) against wild-type influenza viruses, as well as influenza viruses with drug-resistance mutations. The combination of baloxavir with NAIs led to significant synergistic effects; however, the combination of baloxavir with laninamivir failed to result in a synergistic effect on influenza B viruses. Considering the rapid emergence of drug resistance to baloxavir, we believe that these results will be beneficial for combined drug use against influenza.

The emergence of SARS-CoV-2 and seasonal outbreaks of other respiratory viruses highlight the urgent need for broad-spectrum antivirals to treat respiratory tract infections. Stimulator of interferon genes (STING) is a key component of innate immune signaling and plays a critical role in protection of the host against viral infections. Previously the STING agonist diABZI-4, a diamidobenzimidazole-based compound, demonstrated protection against SARS-CoV-2 both in vitro and in vivo . However, its broad-spectrum antiviral activity against other respiratory viruses in human airway epithelial cells, which are the primary targets of these infections, is not well established. In this study, we demonstrated that diABZI-4 stimulated robust innate immune responses protecting lung cells against a wide range of respiratory viruses, including influenza A virus (IAV), common cold coronaviruses, SARS-CoV-2, human rhinovirus (HRV), and human parainfluenza virus. diABZI-4 was highly active in physiologically relevant human airway epithelial tissues grown at the air-liquid interface, blocking replication of IAV, SARS-CoV-2, and HRV in these tissues. Furthermore, treatment of macrophages with diABZI-4 resulted in the secretion of cytokines that protected the primary airway epithelial cells from IAV infection. Despite the promising in vitro pan-antiviral activity, intranasal administration of diABZI-4 in mice provided early, but not sustained, inhibition of IAV replication in the lungs. These data highlight the complexities of the relationship between timing of STING agonist-driven inflammatory responses and viral replication dynamics, emphasizing the development challenge posed by STING agonists as potential therapeutics against respiratory viruses.

Endometrial cancer (EC) is a common gynecologic malignancy with a rising incidence due to obesity, comorbid conditions, and related lifestyle factors. The standard of care for primary disease consists of surgical resection with/without chemotherapy ± radiotherapy for select patients. Recurrence is common in patients with advanced-stage disease and/or high-risk features, who primarily are treated with systemic therapy. The identification of novel targets in malignant EC has led to the development of wide-range inhibitors. Abemaciclib is an orally active unique cyclin-dependent kinase (CDK) inhibitor, selective for the CDK4 and CDK6 cell cycle pathways. This agent has potential anti-neoplastic activity and is indicated in combination with various therapies such as endocrine therapy, aromatase inhibitors, and hormone therapies, primarily in breast cancer (BC). Herein, we sought to summarize the biochemical/pharmacological properties of abemaciclib and its therapeutic potential in EC. While the therapeutic role(s) of abemaciclib was fairly established in a subset of patients with advanced/metastatic BC through the pivotal MONARCH trials, its attributes and clinical utility in EC are limited. Thus, based on some promising pre-clinical/translational insights and a recent phase II study, we highlight abemaciclib's properties and potential clinical usefulness in patients with EC, particularly in recurrent estrogen-receptor-positive cases.

Ferroptosis is a unique type of cell death, characterized by its reliance on iron dependency and lipid peroxidation (LPO). Consequently, small-molecule ferroptosis modulators have garnered substantial interest as a promising avenue for cancer therapy. Herein, we explored the ferroptosis sensitivity of epigenetic modulators and found that the antiproliferative effects of class I histone deacetylase (HDAC) inhibitors are significantly reliant on ferroptosis. Subsequently, we developed a novel series of HDAC inhibitors, identifying HL-5s with robust inhibitory activity against class I HDACs, particularly HDAC1. Notably, HL-5s induces ferroptosis by augmenting LPO production. Mechanistically, HL-5s increased the YB-1 acetylation and inhibited the Nrf2/HO-1 signaling pathway. Furthermore, HL-5s not only significantly suppresses tumor growth in the PC-9 xenograft model but also remodels the tumor microenvironment in the LLC allograft model. Our study has unveiled that class I HDAC inhibitors can exert antitumor effects by triggering ferroptosis, and HL-5s may serve as a promising candidate for future cancer treatment.

Herein, we described the rational drug design and synthesis of a series of 5-amino-4-fluoro-1 H -benzo[ d ]imidazole-6-carboxamide derivatives that inhibit MEK and RAF kinases. The detailed screening cascades revealed that 16b was a preferred compound, which might act like a "clamp" to stabilize the MEK/RAF complex, thereby effectively inhibiting MEK1, BRAF, and BRAF V600E with IC 50 values of 28, 3, and 3 nM, respectively. 16b possessed an excellent selectivity over other 312 human-related kinases at 1 μM. In vitro, 16b showed potent antiproliferative activities against MIA PaCa-2 (G12C KRAS), HCT116 (G13D KRAS), and C26 (G12D KRAS) cells with IC 50 values of 0.011, 0.079, and 0.096 μM, respectively. CoIP experiments demonstrated that 16b could induce MEK/RAF complex formation. Most importantly, in the C26 syngeneic colorectal and HCT116 mice xenograft tumor models, 16b demonstrated tumor growth inhibition of 70 and 93%, respectively, suggesting that 16b may be a promising MEK/RAF complex inhibitor and worthy of further development.

Cytomegalovirus (CMV) infection is arguably the most important infectious complication that negatively affects the outcome of solid organ transplantation. For decades, CMV management after transplantation has relied on antiviral drugs that inhibit viral DNA polymerase (ganciclovir, foscarnet, and cidofovir). However, their use has been complicated by myelosuppression, nephrotoxicity, and selection of drug-resistant viruses. During the past few years, the therapeutic armamentarium for the management of CMV in solid organ transplant recipients has expanded with the approval of letermovir for CMV prophylaxis in high-risk CMV D+/R- kidney recipients, and maribavir for the treatment of refractory and resistant CMV infection. Both drugs offer significant improvement when compared to standard anti-CMV therapies; letermovir was as efficacious for CMV prevention, whereas maribavir was more effective in treating refractory and resistant CMV infections. Both letermovir and maribavir have favorable safety profiles compared to CMV DNA polymerase inhibitors, without the risk of neutropenia and leukopenia associated with ganciclovir and renal toxicities associated with foscarnet and cidofovir. Moreover, letermovir and maribavir are orally bioavailable, which allows convenient outpatient treatment. However, letermovir and maribavir have a significant drug interaction potential in solid organ transplant recipients, resulting in higher levels of calcineurin inhibitors (cyclosporine and tacrolimus) and mTOR inhibitors (sirolimus and everolimus). Both letermovir and maribavir are CMV-specific and do not have clinical efficacy against other herpes viruses. Thus, there is a need for additional antiviral drugs to prevent herpes simplex and other herpes viruses when clinically indicated. This article provides a comprehensive review of the clinical data supporting the use of letermovir and maribavir in clinical practice. The author provides perspectives on the role of these newly approved drugs in the current management landscape of CMV infection in solid organ transplantation., Competing Interests: Dr Raymund Razonable reports grants from Gilead, grants from Roche, grants from Regeneron, personal fees from Allovir, personal fees from Novartis, outside the submitted work. The author reports no other conflicts of interest in this work., (© 2024 Razonable.)

Background: Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it., Materials and Methods: We conducted a retrospective-prospective, 2-group, observational study to assess the impact of the postbiotic PostbiotiX-Restore, derived by Lactobacillus paracasei CNCM I-5220, on abemaciclib-induced diarrhea in patients with hormone receptor-positive HER2-negative breast cancer. The prospective population (Postbio group) received postbiotic during the first cycle of abemaciclib, while the retrospective one received standard care (Standard group). Diarrhea grading was defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events., Results: During the first cycle, diarrhea occurred in 78.9% of patients in the Standard cohort and 97.1% in the Postbio one, with most cases being G1-G2. Severe (G3) diarrhea was significantly less frequent in the Postbio group (0%) compared to the Standard one (7.9%; P = .029). Over the entire study period, while the grading difference was not statistically significant, G3 events were less frequent in the Postbio population (5.9%) than the Standard one (15.4%). Moreover, Postbio patients required fewer dose reductions due to diarrhea compared to the Standard group (P = .002). Notably, in the Postbio population, G1 and G2 events had short median durations (3 and 1 days, respectively) and, for the 2 patients experiencing G3 events during the second abemaciclib cycle (off postbiotic), diarrhea lasted only 1 day., Conclusions: Our study demonstrates the effect of PostbiotiX-Restore in mitigating abemaciclib-induced diarrhea, resulting in reduced severity, fewer dose reductions, and shorter duration. Further exploration and validation in larger cohorts are needed., (© The Author(s) 2024. Published by Oxford University Press.)

Blockade of Angiotensin type 1 receptor (AT1R) has potential therapeutic utility in the treatment of numerous detrimental consequences of epileptogenesis, including oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction. We have recently shown that many of these pathological processes play a critical role in seizure onset and propagation in the Scn8a-N1768D mouse model. Here we investigate the efficacy and potential mechanism(s) of action of candesartan (CND), an FDA-approved angiotensin receptor blocker (ARB) indicated for hypertension, in improving outcomes in this model of pediatric epilepsy. We compared length of lifespan, seizure frequency, and BBB permeability in juvenile (D/D) and adult (D/+) mice treated with CND at times after seizure onset. We performed RNAseq on hippocampal tissue to quantify differences in genome-wide patterns of transcript abundance and inferred beneficial and detrimental effects of canonical pathways identified by enrichment methods in untreated and treated mice. Our results demonstrate that treatment with CND gives rise to increased survival, longer periods of seizure freedom, and diminished BBB permeability. CND treatment also partially reversed or 'normalized' disease-induced genome-wide gene expression profiles associated with inhibition of NF-κB, TNFα, IL-6, and TGF-β signaling in juvenile and adult mice. Pathway analyses reveal that efficacy of CND is due to its known dual mechanism of action as both an AT1R antagonist and a PPARγ agonist. The robust effectiveness of CND across ages, sexes and mouse strains is a positive indication for its translation to humans and its suitability of use for clinical trials in children with SCN8A epilepsy., (© 2024 The Author(s).)

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To determine the effect of telmisartan on intraocular pressure (IOP), blood pressure (BP), and ocular perfusion pressure (OPP) in normal and glaucomatous cats., Methods: A four-week study was conducted in six normal adult cats, followed by a longer six-month study performed in 37 cats with spontaneous glaucoma and 11 age-matched normal cats. Telmisartan (1 mg/kg/day) or placebo-vehicle were administered orally once daily. IOP was measured by rebound tonometry. BP readings were obtained by oscillometric method. OPP was calculated as mean arterial pressure (MAP) - IOP. IOP and BP were obtained three times a week for the first study and weekly for the second study., Results: Baseline IOP was significantly higher, and OPP was significantly lower in glaucomatous cats than in normal cats (P < 0.0001). These differences between glaucomatous and normal cats persisted throughout the study, regardless of treatment (P < 0.001). No significant differences in IOP, BP, or OPP were detected between any study phases in the first, normal feline cohort or between telmisartan- and placebo-treated glaucomatous cats at any timepoint in the second study., Conclusions: Oral telmisartan was well tolerated and did not have a detrimental effect on BP or OPP in cats but did not lower IOP or improve OPP in cats with glaucoma., Translational Relevance: While showing telmisartan could not be used as a sole therapy for IOP lowering, our data affirmed a lack of detrimental effects of telmisartan on BP and OPP in a translationally-relevant, spontaneous, large animal glaucoma model.

Thyroperoxidase (TPO) is central in thyroid hormone (TH) synthesis and inhibition can lead to TH deficiency. Many chemicals can inhibit TPO activity in vitro, but how this may manifest in the developing thyroid gland at the molecular level is unclear. Here, we characterized the thyroid gland transcriptome of male rats developmentally exposed to the in vitro TPO-inhibitors amitrole, 2-mercaptobenzimidazole (MBI), or cyanamide by use of Bulk-RNA-Barcoding (BRB) and sequencing. Amitrole exposure caused TH deficiency and 149 differentially expressed genes in the thyroid gland. The effects indicated an activated and growing thyroid gland. MBI caused intermittent changes to serum TH concentrations in a previous study and this was accompanied by 60 differentially expressed genes in the present study. More than half of these were also affected by amitrole, indicating that they could be early effect biomarkers of developmental TH system disruption due to TPO inhibition. Further work to validate the signature is needed, including assessment of substance independency and applicability domain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A novel and efficient protocol for the microwave-assisted synthesis of diversely substituted 2,2'-bisbenzimidazol-5,6'-dicarboxylic acid (BIMCA) from the reaction of 3,4-diaminobenzoic acid with oxalic acid has been developed, which proceeds through sequential nucleophilic addition and electrophilic substitution in accordance with the Philips method. The synthetic utility of this strategy was demonstrated by the concise, one-pot synthesis of (BIMCA) and metal complexes. (BIMCA) with a [{Fe(salen)} 2 O] Schiff base ligand complex and new benzimidazole coordination compounds with double oxygen [(BIMCA){Fe(salen)} 2 ] ligand complexes were obtained. The resulting [(BIMCA){Fe(salen)} 2 ] ligand complex was then synthesized from Co(CH 3 COO) 2 .4H 2 O, Ni(CH 3 COO) 2 .4H 2 O and Cu(CH 3 COO) 2 .H 2 O heteronuclear complexes. The condensations proceed with good yield to give products that, in certain instances, are not readily attainable by conventional condensation techniques. The structures of the compounds were identified by Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance ( 1 H NMR), elemental analysis and magnetic susceptibility. The mutagenic potential of the synthesized chemicals was evaluated by the Ames test towards mutant Salmonella typhimurium strains TA98 and TA100. It was recorded that these chemicals had no mutagenic action. Also, antimicrobial activities were screened by broth microdilution test. It was seen that the minimum inhibitory concentration (MIC) against Klebsiella pneumoniae, Staphylococcus aureus and Staphylococcus epidermidis was 0.195 mg/mL, followed by a MIC value of 0.390 mg/mL against Escherichia coli and Salmonella typhimurium. [(BIMCA){Fe(salen)} 2 Co(II)] demonstrated significant antimicrobial activity against Proteus mirabilis and Staphylococcus aureus, with an MIC of 0.195 mg/mL, followed by an MIC of 0.390 mg/mL against Pseudomonas aeruginosa, K. pneumonia and Salmonella typhimurium. The antioxidant properties were examined using various chemical assays, and [(BIMCA){Fe(salen)} 2 O] and (BIMCA) exhibited greater 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability, when compared with other compounds. Enzyme inhibitory effects were tested against acetylcholinesterase (AChE), amylase, butyrylcholinesterase (BChE) and tyrosinase. [(BIMCA){Fe(salen)} 2 Cu(II)] displayed the best AChE (IC 50 0.51 mg/mL), BChE (IC 50 0.51 mg/mL) and tyrosinase (IC 50 1.52 mg/mL) inhibitory effects. Furthermore, molecular docking calculations were performed to gain insights into the interaction between [(BIMCA){Fe(salen)} 2 ] and AChE, and between [(BIMCA){Fe(salen)} 2 Cu(II)] and amylase. Both compounds showed the potential inhibition of the protein targets., (© 2024 John Wiley & Sons Ltd.)

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 β-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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A clinical drug-drug interaction (DDI) study was designed to evaluate the effect of multiple doses of modafinil, a moderate CYP3A4 inducer at a 400 mg QD dose, on the multiple oral dose pharmacokinetics (PK) of encorafenib and its metabolite, LHY746 and binimetinib and its metabolite, AR00426032., Methods: This study was conducted in patients with BRAF V600-mutant advanced solid tumors. Treatment of 400 mg QD modafinil was given on Day 15 through Day 21. Encorafenib 450 mg QD and binimetinib 45 mg BID were administered starting on Day 1. PK sampling was conducted from 0 to 8 h on Day 14 and Day 21. Exposure parameters were calculated for each patient by noncompartmental analysis and geometric least-squares mean ratio. Corresponding 90% confidence intervals were calculated to estimate the magnitude of effects., Results: Among 11 PK evaluable patients, encorafenib C max and AUC last were decreased in presence of steady-state modafinil by 20.2% and 23.8%, respectively. LHY746 exposures were not substantially changed in the presence of steady-state modafinil., Conclusion: The results from this clinical study indicate modafinil 400 mg QD had a weak effect on encorafenib PK. Based on these results, encorafenib can be coadministered with a moderate CYP3A4 inducer without dosing adjustment., Clinical Trial Registration: ClinicalTrials.gov NCT03864042, registered 6 March 2019., (© 2024. The Author(s).)