Letters in Drug Design & Discovery - Volume 21, Issue 11, 2024

Background: Cancer has been regarded as the leading cause of death worldwide. Identifying new anti-neoplastics with high potency and low toxicity is urgent. Objective: Podophyllotoxin-based hybrid compounds were synthesized by esterification and characterized using NMR and HR-MS. In vitro cytotoxicity and molecular mechanism studies were performed. Methods: Podophyllotoxin was hybridized with three selected known natural compounds via esterification to develop candidates with increased biological activity or decreased toxicity. The CCK-8 assay, cell cycle analysis, AO/EB staining, immunofluorescent analysis, and molecular modeling were used for investigation. Results: Compound B4 displayed potent anticancer effect on HepG2 and HSC-2 cell lines, with IC50 values of 0.809 ± 0.183 and 0.267 ± 0.038 μM, respectively. Furthermore, B4 exhibited less antiproliferative activity in 293T cells with an IC50 value of 2.303 ± 0.216 μM. In addition, B4 demonstrated strong induction of S phase arrest and apoptosis, as well as demolished the microtubules in HSC-2 cells. Molecular docking study revealed that B4 could bind into the colchicine site of β-tubulin, as well as the interface of the α/β-tubulin dimer. Conclusion: Hybrid B4 exhibited potential anticancer activity, and further investigations can help in identifying novel lead molecules.

Among N-containing heterocycles, pyridine occupies a prominent position due to its presence in nature. Many enzymes in living systems, which are involved in redox reactions, contain pyridine moiety. In addition, its importance in medicinal chemistry and its presence in drugs are well documented. Several pyridine containing compounds are well-known as tubulin polymerization inhibitors and are found to bind with androgen receptors, kinases, carbonic anhydrase and topoisomerase. In recent years, researching have been modifying pyridine containing entities to treat cancer. This review sheds light on recent developments in anticancer studies of pyridine ring-fused heterocyclic compounds.

Drug delivery to the brain is a challenging task as many drugs do not cross the blood-brain barrier (BBB). As a result, designing strategies to target drugs to the brain requires significant effort. However, recent research has focused on the administration of drugs through the nose to the brain, a noninvasive way to bypass the BBB and deliver therapeutic molecules directly to the brain. Nose-to-brain drug delivery is a promising approach that allows for the direct transportation of therapeutic molecules to the brain while increasing drug concentration in the brain. This approach has gained considerable attention due to its non-invasive nature, which makes it feasible, reliable, and efficient. One promising approach for nose-to-brain drug delivery is the use of nanoparticles as a platform for drug and gene delivery. Nanoparticles offer several advantages, including the ability to protect therapeutic drugs from degradation and increase the efficacy of drug delivery due to their unique size, shape, and surface features. Nanoparticles can also be engineered to target specific cells or tissues, enabling more precise drug delivery to the brain. The use of nanoparticles for nose-to-brain drug delivery has been extensively studied, and recent developments have shown promising results. In addition, patents relating to medication targeting via the nasal route have been developed. These patents cover various aspects of drug delivery, including the use of different types of nanoparticles, methods for producing nanoparticles, and methods for delivering nanoparticles to the brain.

In the rapidly expanding chemical realm of heterocyclic compounds with interesting therapeutic properties, the thiophene nucleus has established itself as a prospective entity. The biological activity of comparable substances produced via different pathways is of varying magnitudes. Medicinal chemists use their understanding of multiple synthetic pathways and the various physicochemical properties of such compounds to create a combinatorial library and conduct thorough searches for lead molecules. Due to their vast spectrum of biological actions, heterocyclic compounds play a crucial role in Medicinal chemistry and are extensively researched in the field of drug design and development. Thiophene, a sulfur- containing heterocyclic scaffold, has emerged as a rather well-explored scaffold for the synthesis of a library of molecules with biological functions, including antibacterial, antipsychotic, anticancer, analgesic, anti-inflammatory, anti-arrhythmic, and so on. Depending on the kind and position of substitution, thiophene analogues have been shown to bind to a wide spectrum of cancer-specific protein targets. As a result, thiophene analogues have been found to exert their biological effects by inhibiting various cancerrelated signalling pathways. The study of thiophene in Medicinal chemistry resulted in molecules that combine the thiophene moiety with traditional drug components in a single molecule. This review covers the biological and medical activity of compounds containing a thiophene nucleus, as well as information on thiophene behaviour, synthesis, and agents, with a focus on synthetic techniques, biological profiles, and structure-activity relationship (SAR) research.

Pancreatic lipase is an enzyme that catalyzes the hydrolysis of triglycerides to monoglycerides and free fatty acids which promote and accelerate their absorption by the intestine, thus leading to obesity. Drugs that have numerous side effects explain the beneficial medicinal effect of plants resulting from their Phyto molecules that exhibit strong anti-lipase activity. The present review reveals the medical treatment and consequently the associated side effects. It also represents an update of various medicinal plants and their metabolites that act as lipase inhibitors published between (2020-2022). We have discussed 93 species belonging to 48 different plant families and numerous bioactive molecules exerting this activity. We have compared 29 species for their anti-lipase potential. Fabaceae and Lamiaceae were the most dominant with 7 species, and the highest percentage (95%) for pancreatic lipase inhibitory activity was recorded by “Filipendula kmtaschatia” from Rosaceae family while “Piper betle” from Piperaceae family showed the lowest percentage (15.9%). The medical treatments with low dose effect were liraglutide saxenda (3mg/day), also flavonoids, in particular catechin derivatives, which were the most potent in terms of pancreatic lipase inhibitory activity with the lowest IC50s. This study summarized medical and natural treatments that are used to treat obesity through inhibiting pancreatic lipase and delaying fat assimilation in the intestines. So far, more studies are needed for the use of these as herbal medicine for obesity.

Colorectal cancer is more prevalent in females than males. There are many anticancer drugs accessible for use, but their therapeutic importance is constrained by factors including poor solubility, low absorption, and multi-drug resistance. This review highlights how PLGA may be used to develop polymeric- targeted drug delivery systems that specifically target colorectal cancer. The PLGA polymer, which is disseminated in the colon together with drugs in a regulated and targeted manner, has the distinct characteristics of smart degradation in a biological system. Its degradability is dependent on multiple glycolide units; therefore, a lower glycol concentration improves degradability and vice versa. Also, PLGA facilitates drug delivery in colorectal cancer, enhances the efficacy of the drug, improves the sustained release profile of a drug, improves bioavailability due to prolonged retention time in the colon, enhances solubility, etc. To develop the formulation for improving the cytotoxic impact of various anticancer drugs, the surface modification of PLGA can be carried out by introducing a copolymer. By emphasizing their crucial characterization to demonstrate their therapeutic potential, this literature work has also shed light on recent patents and advancements in PLGA application.

Several studies have shown that high plasma concentrations of asymmetric dimethylarginine (ADMA), a known endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS), correlate with the severity of coronary artery disease (CAD), with worsening of cardiac ischemia/reperfusion (I/R) injury and coronary atherosclerosis. It is believed that it may be an important risk factor for myocardial infarction. ADMA, when in high concentrations, can determine a significant decrease in the synthesis and bioavailability of NO (Nitric oxide) and therefore alter the mechanisms of regulation of coronary vasodilation and vasomotor function of epicardial coronary arteries. Higher serum ADMA concentration is associated with worsening of post-ischemic remodeling since coronary angiogenesis, vasculogenesis, and collateral coronary growth are seriously impaired. In addition, there are reasons to believe that elevated plasma ADMA levels are related to the development of diseases affecting coronary microcirculation, such as ischemic non-obstructive coronary artery disease (INOCA). With the aim of providing the pharmacologist engaged in the design and discovery of new ADMA-lowering drugs with a complete examination of the subject, in this review, we discuss the most important studies related to the correlations between serum ADMA levels and cardiovascular diseases mentioned above. In addition, we critically discuss the main aspects of enzymology, synthesis, and metabolism of ADMA as a prerequisite for understanding the molecular mechanisms through which high concentrations of ADMA could contribute to promoting cardiovascular diseases. ADMA represents a new target for pharmacological modulation of cardiovascular endothelial function and therefore, there is a possibility of using selective pharmacological ADMA lowering drugs in cardiovascular disease with endothelial dysfunction and high plasma ADMA levels.

Background: Inflammation is a complex process. Persistent and uncontrolled inflammation may act as an etiologic factor for many chronic disorders like diabetes. Objective: This review aims to classify the anti-inflammatory and antidiabetic medicinal plants, their traditional uses, and their active compounds that have been tested for their anti-inflammatory and antidiabetic effects. Methods: We checked scientific publications in various electronic databases from 1981 to 2021. All the molecular structures were provided in ADC/ChemSketch. Results: We reviewed 58 species, belonging to 39 families. These species have long been used in traditional medicine to cure a variety of ailments, including, dysentery, typhoid fever, anemia, digestive and cardiac disorders, as well as diabetes and inflammation. Asteraceae represents the dominant family. The most potent anti-inflammatory and antidiabetic active compounds were reviewed including myricetin, quercetin, hesperetin, rutin, luteolin, chlorogenic acid, vanillic acid, gallic acid, ferulic acid, benzoic acid, cinnamic acid, gentisic acid, camphor, 1,8-cineol, p-cymene, limonene, linalool, thymoquinone, carvacrol, aromadendrine, α-pinene, lycopene, phytol, imperatorin, chalepin, hexadecanoic acid, linoleic acid, tellimagrandin I, and trigalloyl glucose. Conclusion: This review indicates that medicinal plants have many therapeutic dynamics against inflammation and diabetes that could be exploited for the discovery of therapeutic preparation or agent for treating the two illnesses at the same time.

Introduction: Osteosarcoma is one of the most prevalent malignant bone tumors with a poor overall prognosis and mainly happens in children and adolescents. Current therapy strategies still possess a lot of limitations, and new and efficient strategies are required. Ezetimibe was previously reported to have its anti-tumor effect in various tumors, but the investigation of Ezetimibe on osteosarcoma is still limited. Aims: This study explores whether ezetimibe could exert an anti-tumor effect on human osteosarcoma cell lines, U2OS, and Saos-2. Methods: The effect of ezetimibe on the proliferation of osteosarcoma was explored by CCK-8 and colony formation assay. The role of ezetimibe on osteosarcoma cell migration and invasion was explored by wound healing assay and transwell assay. The role of ezetimibe on osteosarcoma cell apoptosis was explored by PI/Annexin V analysis. In addition, a western blot was performed to verify the phenotype. Results: The flow cytometry assay indicated that ezetimibe could promote osteosarcoma apoptosis. Western blot assay further demonstrated the effect of ezetimibe on proliferation, migration, invasion and apoptosis- related proteins. Finally, the deep anti-tumor effect of ezetimibe contributed to suppressing the PI3K/AKT signaling pathway. Conclusion: Present data indicated that ezetimibe has an antitumor effect on osteosarcoma and could be considered a future osteosarcoma treatment.

Background: Diabetes mellitus is a chronic metabolic condition marked by persistently elevated blood sugar levels. Key digestive enzymes viz. α-amylase and α-glucosidase, hydrolyze consumed carbohydrates into glucose which raises the postprandial blood glucose level in a diabetic patient. So, the development of α-amylase and α-glucosidase inhibitors procured from medicinal plants to retard starch digestion is an alternative approach for controlling type 2 diabetes mellitus. Objective: The current study aimed to evaluate the inhibitory potentials of the key digestive enzymes viz. α-amylase and α-glucosidase by the extracts of three medicinal plants; red dragon fruit (Hylocereus polyrhizus) pulp and peel, bamboo (Bambusa vulgaris) shoot, turnip (Brassica rapa L.) shoot and leaf by performing α-amylase and α-glucosidase inhibition assays in vitro. Methods: Inhibition of α-amylase activity was conducted using 3,5-dinitrosalicylic acid method, and 4- Nitrophenyl-α-D-glucopyranoside was used as a substrate to perform α-glucosidase inhibition assay in vitro. Results: Among all the selected sample extracts, red dragon fruit pulp expressed the highest percentage of α-amylase inhibition (59.73 ± 4.33%) at the concentration of 1000 μg/mL which is comparable to standard antidiabetic drug Acarbose (70.59 ± 2.64%), whereas the lowest inhibition was observed in turnip shoot extract (42.48 ± 2.10%) at the same concentration. In terms of α-glucosidase inhibition activity, again, red dragon fruit pulp extract demonstrated the maximum inhibition rate (56.42 ± 2.38%) at 1000 μg/mL concentration. This is respectable in comparison to the reference Acarbose (66.45 ± 1.78%). In contrast, turnip shoot extracts displayed the lowest α-glucosidase inhibition activity (38.27 ± 2.21%) at the same concentration. Conclusion: The current study demonstrated that the red dragon fruit pulp extract possesses substantial antihyperglycemic activity (α-amylase inhibition: 59.73 ± 4.33%, α-glucosidase inhibition: 56.42 ± 2.38%) in vitro, which could be a putative nutraceutical to manage postprandial hyperglycemia.

Background: Alzheimer's disease is the most prevalent form of dementia; it affects the brain regions responsible for thought, memory, and language. Dementia cannot currently be cured by any medication. Objective: We aimed to synthesize Pd-NHC type PEPPSI and investigate their biological activity in anticholinesterase enzymes. Methods: In this study, we described preparing a series of Pd-NHC type PEPPSI obtained from their unsymmetrical benzimidazolium salts. These complexes (3a-f) were synthesized from the 2- chloromethyl-1,3-dioxalane benzimidazolium salts, PdCl2, KBr and pyridine. The compounds (3a-f) were tested against two enzymes (AChE and BChE). Results: The results showed that most of the Palladium-NHC complexes effectively inhibited AChE with IC50 values in the range of 4.94 - 40.03 μM, and for BChE are in the range of 4.21 - 21.28 μM. The results showed that the compound (3a) was the most potent inhibitor activity against both AChE and BChE. The inhibition parameter (IC50) was calculated by the spectrophotometric method. The inhibitory effects of the synthesized Pd-NHCs were compared to galantamine as a clinical cholinergic enzyme inhibitor. Additionally, Molecular docking is carried out to estimate the binding pattern between the newly synthesized compounds and both AChE and BChE active sites. Conclusion: The results demonstrated that all synthesized compounds show excellent to moderate inhibition against the examined enzymes (AChE/BChE).

Background: Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer and the fourth leading cause of cancer death in the world. Aims: This study aimed to investigate the efficacy and safety of Lenvatinib + PD-1 inhibitor + TACEHAIC (LePTaHAIC) versus Sorafenib + TACE (SorTACE) for patients with intermediate and advanced HCC. Methods: In this retrospective study, patients diagnosed with BCLC stage B/C HCC were included. All patients were treated with LePTaHAIC (LePTaHAIC group) or SorTACE (SorTACE group) between September 2019 and September 2020. Outcomes, including progression-free survival (PFS), conversion surgical resection rate, objective remission rate (ORR), overall survival (OS), and treatment-related adverse events (AEs) were analyzed and compared between the two treatment modalities. Results: In total, 65 eligible patients were recruited, with 35 assigned to receive LePTaHAIC and 30 assigned to undergo SorTACE. Median PFS (11.4 vs. 5.13 months) and OS (26 vs. 10.08 months) in the LePTaHAIC group were significantly higher compared to the SorTACE group (both P < 0.0001). The ORR (mRECIST standard) of the LePTaHAIC group was markedly higher compared to the SorTACE group (71.4% vs. 40%, P = 0.01). In the LePTaHAIC group, 11 patients underwent surgical resection (BCLC stage B: n = 4, BCLC stage C: n = 7) and 3 patients achieved complete pathological remission (pCR), while one patient in the SorTACE group underwent surgical resection. The conversion surgical resection rate of the LePTaHAIC group was significantly higher compared to the SorTACE group [31.4% (11/35) vs. 3.3% (1/30), P = 0.004]. Patients with LePTaHAIC had more frequent grade 3-4 treatmentrelated AEs, especially thrombocytopenia, compared to the SorTACE group (22.9% vs. 3.3%, P = 0.02). Conclusion: LePTaHAIC exhibited acceptable toxic effects and improved survival compared to SorTACE in intermediate and advanced HCC.

Background: Ginseng is one of the top-selling natural products worldwide and has been shown to have significant effects. Nonetheless, there is limited research on American ginseng when compared to Asian ginseng. A small number of studies have demonstrated the therapeutic benefits of American ginseng, which include antioxidant, anti-inflammatory, and immune-stimulating activities. Objective: The objective of our research is to predict the molecular mechanism by which American ginseng combats Type 2 diabetes mellitus (T2DM) using Network Pharmacology and Molecular Docking techniques. By doing so, we aim to reveal one of the comprehensive mechanisms through which American ginseng exerts its therapeutic effects. Methods: We conducted a search for related compounds in American ginseng using the TCMSP database, which we then utilized to classify potential targets for the major ingredients. We obtained targets associated with T2DM from various databases, including PharmGKB, OMIM, TTD, GeneCards, and DrugBank. Using STRING and Cytoscape software, we constructed PPI networks. We subsequently performed GO and KEGG analysis on the targets using the R programming language. Ligand and target structures were acquired from PubChem and PDB databases, respectively. Chem3D and AutoDock software was used to process the structures, while PyMoL was employed for molecular docking analysis. Results: Several investigations have indicated that PTGS2, NFKBIA, PRKCA, IL1B, NCOA2, and LPL targets are significantly associated with American ginseng's effectiveness in treating T2DM. Molecular docking analysis further validated these findings. We discovered three active components with highaffinity, namely papaverine, ginsenoside-rh2, and beta-sitosterol. Conclusion: The outcomes of our predictions could contribute to the development of American ginseng or its active constituents as an alternative therapy for T2DM.

Background: Pyrazolopyrimidine scaffold is an important pharmacophore in drug discovery. This pharmacophore has been reported to produce numerous biological activities, of which anticancer is an important one. The development of novel pyrazolopyrimidine derivatives is of great importance for antitumor drug research. Objective: Compound 6, a pyrazolopyrimidine derivative reported by our group, showed weak antiproliferative activity with IC50 values of over 30 μM against mantle cell lymphoma (MCL) cell lines. In this study, we will further perform the structural optimization of compound 6 to screen highly active pyrazolopyrimidine derivatives. Methods: A novel series of 1,3,4-trisubstituted pyrazolopyrimidine derivatives were synthesized and their structures were elucidated by ¹H-NMR, ¹³C-NMR, and HRMS. The antiproliferative activities of target compounds against MCL cell lines (Mino, Jeko-1, and Z138) were evaluated by the CellTiter-Glo luminescent cell viability assay. The effect of representative compounds to induce apoptosis was evaluated by Annexin V/Propidium Iodide (PI)-binding assay. Mitochondrial membrane potential and reactive oxygen species (ROS) levels in 15c-treated Z138 cells were tested by JC-1 and DCFH-DA probes, respectively. Results: Most compounds demonstrated improved antiproliferative activity against MCL cell lines compared to the lead compound 6, especially 15c, 15f, 15g, 15j, and 15o, with IC50 values at low micromolar levels. In addition, compound 15c could induce apoptosis in a dose-dependent manner in Z138 cells through reduction of mitochondrial membrane potential and enhancing reactive oxygen species production. Conclusion: The results showed that 1,3,4-trisubstituted pyrazolopyrimidine derivatives could be valuable lead compounds for the further development of anti-lymphoma agents.

Background: Tuberculosis caused by Mycobacterium tuberculosis has been reported to infect about two-third of the global population and to continuously develop multidrug resistance. DNA gyrase, a type II topoisomerase, is a promising target of the quinolone class of drugs in the treatment of tuberculosis. Objective: The present study is focused on the design and synthesis of newer nitrogen heterocyclics containing indole, n-methyl piperazine, piperidine, and pyrrolidine ring structures. Methods: Initially designed compounds were evaluated for their affinity to the DNA gyrase target. The molecular docking performed using FlexX indicated compounds IIb5 (1-(R)-(4-hydroxyphenyl)(4- methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)urea and IIc5 ((1-(R)-(4-hydroxyphenyl)(4-methylpiperazin-1-yl)methyl)-3-((S)-(4-hydroxyphenyl)(4-methylpiperazin- 1-yl)methyl) thiourea to exhibit promising binding affinity (dock score of -15.01 and -13.77) respectively when compared to the reference MFX moxifloxacin (dock score -4.40) with the target 5BS8 (DNA gyrase). Further, the best 10 compounds were synthesized by one-pot synthesis employing the reaction of indole/N-methyl piperazine/piperidine/pyrrolidine with N-substituted benzaldehydes in the presence of acetamide/urea/thiourea to afford the compounds in 54.60% to 85.47% yield. The synthesized compounds were suitably characterized using chromatographic and spectroscopic tools. Results: In the microplate Alamar Blue assay (MABA), compounds IIb1, IIIc2, IIIb1, and IIb5 exhibited good minimum inhibitory concentrations of 1.6 μg/mL, 3.12 μg/mL, and 12.5 μg/mL, respectively, when compared to the standard rifampicin with 0.8 μg/mL inhibitory concentration. The MTB gyrase supercoiling assay performed using Mycobacterium tuberculosis gyrase supercoiling assay kit demonstrated compound IIb5 at a concentration of 300 μg/mL to show gyrase inhibition in comparison to MFX at 60 μg/mL. In the MTT assay performed using the human breast cancer cell line MCF-7, compounds IIc2, IIb5, and IIb1 showed IC50 values of 2.57 μM, 12.54 μM, and 12.75 μM, respectively, compared to doxorubicin (1.10 μM) at 7-48 hrs and 72 hrs of the study. Conclusion: Based on these observations, N-methyl piperazine class of compounds can serve as a lead/pharmacophore for the rational design of potent molecules against MTB gyrase to combat the growing issue of MDR-TB.

Introduction: Identification of the first selective inhibitor, also called “hit molecules, " is crucial for developing drugs against a protein target. However, the crystal structures of protein-ligand complexes are usually not resolved in time due to the process's time-consuming and costly nature. However, it does not prevent scientists from understanding the binding modes' urgent advantages and drawbacks of protein-ligand interaction to guide the optimization of hit molecules. Methods: Here, we have developed a pocket-centric computational strategy to facilitate a comprehensive understanding of the hit molecules against the protein target. Results: The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules. We tested the strategy on the first selective inhibitor, epigallocatechin gallate (EGCG), against human arylacetamide deacetylase (AADAC). Molecular dynamics simulation and MM/PBSA binding energy calculation are used to verify the efficacy of the strategy. Conclusion: The results show that the pocket-centered mapping method not only allows for accurate prediction of the native docking pose and in-depth analysis of the binding mode but also has the potential of rapidly identifying partially unoccupied, unutilized, but targetable pockets to afford optimized hit molecules.

Introduction: The more effective method of preventing many infectious diseases is vaccination. Numerous infectious diseases that affect both humans and animals have significantly decreased as a result of routine immunization. Aim: The present study aimed to compare the efficacy of in-house built chitosan and Polylactide coglycolic acid (PLGA) nanoparticles coupled with Pichia pastoris expressed immunogenic fusion (F) protein of Newcastle disease (ND). Objectives: Synthesis of biodegradable nanoparticles such as PLGA and chitosan offers a promising opportunity as a vaccine delivery system. Methods: Chitosan nanoparticles and PLGA nanoparticles were synthesized by ionic gelation, and double emulsion solvent evaporation, respectively, and the size was 38.6± 0.84 nm and 320 ±1.5nm, respectively. They demonstrated good epitope integrity of recombinant fusion protein and in vitro release kinetics studies have proved consistent release profile of protein. Results: In vivo pathogenicity assay of separately injected nanoparticles has proved no abnormal signs and mortality in chickens. Specific pathogen-free (SPF) chicks were vaccinated with chitosan and PLGA nanoparticles and a recombinant fusion protein of the ND virus. It was demonstrated that PLGA nanoparticles coupled with a fusion protein of Newcastle disease virus conferred a marginally better immune response than chitosan nanoparticles. Comparative study-based results showed that PLGA-based nanoparticles proved a better vaccine delivery vehicle and generated an effective immune response without needing further adjuvants. Conclusion: The present study is a scientific platform for developing the PLGA-based vaccine delivery vehicle to improve immune responses against many infectious diseases.

Background: Diabetes Mellitus (DM) has emerged as one of the major causes behind global all-cause mortality between the age group of 20-79 years. Thioredoxin Interacting Protein (TXNIP) is a naturally occurring protein that primarily acts by binding to TRX protein, thereby inhibiting its ability to maintain the cellular reduced environment and subsequent oxidative stress, which leads to dysfunctional insulin production and pancreatic islet beta cell apoptosis. Objective: By inhibiting the levels of TXNIP, a search for new molecules was carried out by employing an in-silico approach. Methods: Molecular networking study was carried out using Cytoscape, wherein previously FDAapproved drugs were screened to check their ability to interact with TXNIP. This provided 14 drug molecules, which along with 11 previously obtained drug molecules that inhibit TXNIP, were subjected to pharmacophore generation. A pharmacophore was generated using the PharmaGist web server, which when visualised showed two hydrogen bond acceptors and one aromatic ring. Based on the generated pharmacophore model, we carried out virtual screening using ZINCPharmer. A total of 116 HITs were generated based on this pharmacophore model. We then subjected the 116 molecules to Molecular Docking against TXNIP (PDB: 4GEI) by using PyRx and the standard molecules, metformin and rosiglitazone. Results: Compared to the standard, we found 10 molecules that had a better binding affinity towards TXNIP. These 10 molecules were further taken for ADMET studies. From this, all 10 compounds showed good significant ADMET properties. Conclusion: From the preliminary studies, these 10 molecules showed good activity in the reversal of diabetes mellitus by reducing the levels of TXNIP.

Background: Bladder urothelial carcinoma (BUC) is a type of malignant urinary system. Although several strategies have been applied in the treatment of BUC, its survival remains unsatisfactory, especially in the patients with advanced BUC. Vitexin, a natural flavonoid has exhibited the inhibitory effect on various tumors, however, its effect on BUC is still unclear. Objective: This study aimed to explore the effect of vitexin on the progression of BUC. Methods: The toxicity of vitexin on T24 and 5637 cells was detected by cell counting kit-8 (CCK-8). The effects of vitexin on proliferation, apoptosis, invasion, epithelial-mesenchymal transition (EMT) and ferroptosis in BUC cells were determined by CCK-8, flow cytometry, western blot, transwell and immunofluorescence assays. Additionally, the related mechanism was explored by examining the expression of the phosphatidylinositol-3 kinase (PI3K)/protein kinase B (AKT)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway. Besides, in vivo validation was performed in the xenografted mice. Results: Vitexin reduced the BUC cell viability and enhanced the apoptosis rate and the relative protein expression of p53 and cleaved-caspase3. Also, vitexin decreased the invasion number, and increased the relative protein expression of E-cadherin with the decreased N-cadherin protein level in T24 and 5637 cells. Besides, vitexin promoted the levels of ROS and MDA, while reduced the GSH level. Vitexin also increased the level of iron, but decreased the relative protein expression of xCT and GPX4. Erastin further increased the vitexin-induced iron levels, whereas inverse outcomes were observed in the application of ferrostatin-1. Additionally, vitexin decreased the relative protein levels of PI3K, p-AKT/AKT, and nuclear Nrf2, while increased the relative protein level of cytoplasmic Nrf2. Overexpression of PI3K notably inverted the effect of vitexin on cell viability, apoptosis, invasion, level of ROS and iron. Furthermore, vitexin reduced the tumor volume and weight of xenografted mice. Vitexin decreased the protein level of N-cadherin, while increased apoptosis rate of xenografted mice. In addition, vitexin reduced the relative protein levels of PI3K, p-AKT/AKT, and nuclear Nrf2 with the enhanced relative protein expression of cytoplasmic Nrf2 in xenografted mice. Moreover, vitexin decreased the relative protein expression of xCT and GPX4 and the GSH level, whereas increased the MDA level in xenografted mice. Conclusion: Vitexin suppressed malignant proliferation and invasion and induced apoptosis and ferroptosis of BUC involving in PI3K/AKT-Nrf2 pathway.

Background: Chiral azepines are synthesized with remarkable diastereoselectivity, but their biological activity has not been investigated. However, benzazepines have demonstrated notable effects, particularly on the central nervous system (CNS) and infections. This characteristic attracts the interest of bioinformatic investigations in this new family, as their structural similarity can confirm their potential based on their kinship or discovering new options for biological potential. Objective: Possible interaction targets of previously synthesized chiral azepines are investigated. This study involves examining the interaction between these targets, conducting molecular docking analysis, ADME (administration, distribution, metabolism, excretion), and toxicology prediction to assess biological potential. Methods: Modeling 3D-optimized structural, virtual screening, molecular docking, ADME, and toxicological studies were performed. Results: Structural analysis demonstrated potential against neurodegenerative diseases and cancer. In Molecular docking against cancer, pathways dependent on MAP2K1 and COX-2 exhibited energetically superior inhibitors than reference drugs, namely azepines 1, 3, and 6. Additionally, azepines 1 and 8 exhibited selective impacts against GSK3 and HMG-CoA-Reductase, respectively. Azepine 6 demonstrated an effect on CNS vs. GSK3 and HMG-CoA-Reductase, as well as potential against Alzheimer's disease; however, with a lower energy level with subunit 33 GABA-receptor. ADMETx investigations indicated satisfactory results for azepines. However, the opening of the cycle results in adverse effects and increased bioaccumulation, indicating the importance of preserving the integrity of azepine to propose its biological effect. Conclusion: Chiral azepines exhibit significant biological potential, particularly azepine 6 with a methyl substituent, which demonstrates multitarget potential. In addition, p-nitro phenyl substituent makes it highly selective towards CNS diseases. These findings indicate a strong relationship between biological activity and the stability of chiral azepines.