Breaking barriers with tofersen: Enhancing therapeutic opportunities in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease. METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary. RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS. CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.

Unlocking InhA: Novel approaches to inhibit Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis continues to pose a health security risk and remains a public health emergency. Antimicrobial resistance result from treatment regimens that are both insufficient and incomplete leading to the emergence of multidrug-resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug-resistant tuberculosis. The impact of tuberculosis on the people suffering from HIV (Human immunodeficiency virus infection) have resulted in the increased research efforts in designing and discovery of novel antitubercular drugs that may result in decreasing treatment duration, minimising the need for multiple drug intake, minimising cytotoxicity and enhancing the mechanism of action of drug. While many drugs are available to treat tuberculosis, a precise and timely cure is still absent. Consequently, further investigation is needed to identify more recent molecular equivalents that have the potential to swiftly remove this disease. Isoniazid (INH), a treatment for tuberculosis (TB), targets the enzyme InhA (mycobacterium enoyl acyl carrier protein reductase), the Mycobacterium tuberculosis enoyl-acyl carrier protein (ACP) reductase, most common INH resistance is circumvented by InhA inhibitors that do not require KatG (catalase-peroxidase) activation, as a result, researchers are trying to work in the area of development of InhA inhibitors which could help in eradicating the era of tuberculosis from the world.

Exploration of oxadiazole clubbed benzhydrylpiperazine pharmacophoric features as structural feature for antidepressant activity: In vitro, in vivo and in silico analysis.

Arylpiperazine clubbed various heterocyclic molecules present potential pharmacophoric structural features for the development of psychoactive drugs. There are various CNS active molecules possessing arylpiperazine moiety in their pharmacophore approved by USFDA. In the current study, we have explored the benzhydrylpiperazine moiety clubbed with various substituted oxadiazole moieties (AP1-12) for their monoamine oxidase (MAO) inhibition and antidepressant potential. Compounds AP3 and AP12 exhibited highly potent and selective MAO-A inhibition with IC50 values of 1.34 ± 0.93 µM and 1.13 ± 0.54 µM, respectively, and a selectivity index of 10- and 13-folds, respectively. Both the compounds displayed reversible binding character at the active site of MAO-A. In further in vivo evaluation, both the compounds AP3 and AP12 displayed potential antidepressant-like character in FST and TST studies via significantly reduced immobility time in comparison to non-treated animals. These compounds displayed no cytotoxicity in SH-SY5Y cell lines, which indicates that these compounds are safe for further evaluation. In silico studies reveal that synthesized compounds possess drug-likeness with minimal to no toxicity. In silico studies were conducted to understand the binding interactions and stability of compounds at the binding pocket of enzyme and observed that both the best compounds fit well at the active site of MAO-A lined by amino acid residues Tyr69, Asn181, Phe208, Ile335, Leu337, Phe352, and Tyr444 similar to standard MAO-A inhibitor clorgiline. The molecular dynamic studies demonstrated that AP3 and AP12 formed quite a stable complex at the active site of MAO-A and did not break under small abruption forces. The favourable binding interactions and appropriate ADMET properties present the benzhydrylpiperazine clubbed oxadiazole pharmacophoric features as a potential structural skeleton for further clinical evaluation and development of a new antidepressant drug molecule.

An insight into recent updates on analytical techniques for bioactive alkaloids.

INTRODUCTION: Alkaloids represent a wide class of naturally existing nitrogen-containing organic compounds having diverse biological activities. They are primary bioactive substances extracted from diverse plant parts. Due to their diverse biological activities, they are frequently used as medicines. The alkaloids have diverse pharmacological impacts on the human body; alkaloids are used for prevention, treatment, and reduction of discomfort associated with chronic illnesses. As most alkaloids exist in plants in complex form, combined with numerous other natural plant components, it is essential to recognize and characterize these molecules using different analytical techniques. OBJECTIVES: We aimed to review the literature on the methods and protocols for the analysis of naturally occurring alkaloids. METHODS: We carried out a literature survey using the PubMed, Scopus, and Google Scholar databases and other relevant published materials. The keywords used in the searches were "alkaloids," "analytical methods," "HPLC method," "GC method," "electrochemical methods," and "bioanalytical methods," in various combinations. RESULTS: In this article, several classes of alkaloids are presented, along with their biological activities. Moreover, it includes a thorough explanation of chromatographic techniques, hyphenated techniques, electrochemical techniques, and current trending analytical methods utilized for the isolation, identification, and comprehensive characterization of alkaloids. CONCLUSIONS: The various analytical techniques play an important role in the identification as well as the characterization of various alkaloids from plants, plasma samples, and urine samples. The hyphenation of various chromatographic techniques with mass spectrometry and NMR spectroscopy plays a crucial role in the characterization of unknown compounds.

Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders.

The sodium dependent SLC13 family transporters comprise of five genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5 (NaCT). Among them, NaDC1, NaDC3 and NaCT are sodium dependent transporters belonging to family of dicarboxylates (succinate, malate, α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human NaCT structures have still not been crystallized, therefore structural information is taken from the related bacterial transporter of VcINDY. Citrate in the cytosol works as a precursor for the fatty acid synthesis, cholesterol, and low-density lipoproteins. The excess citrate from the matrix is translocated to the cytosol for fatty acid synthesis through these transporters and thus controls the energy balance by downregulating the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown. These transporters play an important role in regulating various metabolic diseases including cancer, diabetes, obesity, fatty liver diseases and CNS disorders. These di and tricarboxylate transporters are emerging as new targets for metabolic disorders such as obesity and diabetes. The mutation in the function of the NaCT causes several neurological diseases including neonatal epilepsy and impaired brain development whereas mutation of genes coding for citrate transport present in the liver may provide positive effect. Therefore, continued efforts from the earlier work on citrate transporters are required for the development of citrate inhibitors. This review discusses the structure, function, and regulation of the NaCT transporter. The review also highlights citrate role in diagnosing diseases such as cancer, diabetes, fatty liver, and diabetes. The therapeutic perspective of synthetic inhibitors against NaCT transporters is succinctly summarized.

Recent advances in nitrogen-containing heterocyclic compounds as receptor tyrosine kinase inhibitors for the treatment of cancer: Biological activity and structural activity relationship.

Erratic cell proliferation is the initial symptom of cancer, which can eventually metastasize to other organs. Before cancer becomes metastatic, its spread is triggered by pro-angiogenic factors including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), Platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and Platelet Factor (PF4), all of which are part of receptor tyrosine kinase (RTK) family. Receptor tyrosine kinases (RTKs) are cell-surface proteins and aresignaling enzymes that transfer ATP-phosphate to tyrosine residue substrates. Important biological processes like proliferation, differentiation, motility, and cell-cycle regulation are all possessedby these proteins. Unusual RTK expression is typically associated with cell growth abnormalities, which is linked to tumor acquisition, angiogenesis, and cancer progression. In addition to the already available medications, numerous other heterocyclic are being studied for their potential action against a variety of cancers. In the fight against cancer, in particular, these heterocycles have been used for their dynamic core scaffold and their inherent adaptability. In this review article, we have compiled last five years research work including nitrogen containing heterocycles that have targeted RTK. Herein, the SAR and activity of various compounds containing diverse heterocyclic (pyrimidine, indole, pyridine, pyrazole, benzimidazole, and pyrrole) scaffolds are discussed, and they may prove useful in the future for designing new leads against RTKs. Our focus in this manuscript is to comprehensively review the latest research on the biological activity and structural activity relationship of nitrogen compounds as RTK inhibitors. We believe that this may be an important contribution to the field, as it can help guide future research efforts and facilitate the development of more effective cancer therapies.

Design, synthesis of 1,2,4-triazine derivatives as antidepressant and antioxidant agents: In vitro, in vivo and in silico studies.

The novel series of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides (R: 1-12) were designed, synthesized and evaluated for in-vitro and in-vivo antidepressant-like activity. In MAO-A inhibition assay, compound R: 5 and R: 9 displayed most potent activity with IC50 = 0.12 and 0.30 µM. R: 5 and R: 9 were also evaluated for in-vivo antidepressant using FST and TST. In both models, the test samples R: 5 and R: 9 showed noteworthy antidepressant effect. R: 5 showed 46.48 % and 45.96 % reduction in immobility in FST and TST respectively at dosage of 30 mg/kg (p.o). Whereas compound R: 9 reduced the immobility time by 52.76 % and 47.14 % as compared to control in FST and TST, respectively at same dosage. Both the compounds were also tested for behavioural study using actophotometer and grip tests. None of compounds exhibited decrease in locomotor activity. Further, these compounds were subjected to in silico studies to determine their ADME properties along with binding energies and binding orientions. In ADME studies none of the compounds violated the Lipinski rule and all other parameters were also within the acceptable ranges. In docking study R: 5 (-10.7) and R: 9 (-10.4) were also displayed highest docking score. These encouraging results present the pharmacophoric features of substituted-N-(5,6-diphenyl-1,2,4-triazin-3-yl) benzamides as interesting lead for further development of new antidepressant drug molecules.

Recent Update on Bacteria as a Delivery Carrier in Cancer Therapy: From Evil to Allies.

Cancer is associated with a comprehensive burden that significantly affects patient's quality of life. Even though patients' disease condition is improving following conventional therapies, researchers are studying alternative tools that can penetrate solid tumours to deliver the therapeutics due to issues of developing resistance by the cancer cells. Treating cancer is not the only the goal in cancer therapy; it also includes protecting non-cancerous cells from the toxic effects of anti-cancer agents. Thus, various advanced techniques, such as cell-based drug delivery, bacteria-mediated therapy, and nanoparticles, are devised for site-specific delivery of drugs. One of the novel methods that can be targeted to deliver anti-cancer agents is by utilising genetically modified non-pathogenic bacterial species. This is due to the ability of bacterial species to multiply selectively or non-selectively on tumour cells, resulting in biofilms that leads to disruption of metastasis process. In preclinical studies, this technology has shown significant results in terms of efficacy, and some are currently under investigation. Therefore, researchers have conducted studies on bacteria transporting the anti-cancer drug to targeted tumours. Alternatively, bacterial ghosts and bacterial spores are utilised to deliver anti-cancer drugs. Although in vivo studies of bacteria-mediated cancer therapy have shown successful outcome, further research on bacteria, specifically their targeting mechanism, is required to establish a complete clinical approach in cancer treatment. This review has focused on the up-to-date understanding of bacteria as a therapeutic carrier in the treatment of cancer as an emerging field.

Recent developments in mitogen activated protein kinase inhibitors as potential anticancer agents.

The mitogen activated protein kinase (MAPK) belongs to group of kinase that links the extracellular stimuli to intracellular response. The MAPK signalling pathway (RAS-RAF-MEK-ERK) involved in different pathological conditions like cancer, caused due to genetic or any other factor such as physical or environmental. Many studies have been conducted on the pathological view of MAPK cascade and its associated element like RAS, RAF, MEK, ERK or its isoforms, and still the research is going on particularly with respect to its activation, regulation and inhibition. The MAPK signalling pathway has become the area of research to identify new target for the management of cancer. A number of heterocyclics are key to fight with the cancer associated with these enzymes thus give some hope in the management of cancer by inhibiting MAPK cascade. In the present article, we have focussed on MAPK signalling pathway and role of different heterocyclic scaffolds bearing nitrogen, sulphur and oxygen and about their potential to block MAPK signalling pathway. The heterocyclics are gaining importance due to high potency and selectivity with less off-target effects against different targets involved in the MAPK signalling pathway. We have tried to cover recent advancements in the MAPK signalling pathway inhibitors with an aim to get better understanding of the mechanism of action of the compounds. Several compounds in the preclinical and clinical studies have been thoroughly dealt with. In addition to the synthetic compounds, a significant number of natural products containing heterocyclic moieties as MAPK signalling pathway inhibitors have been put together. The structure activity relationship along with docking studies have been discussed to apprehend the mechanistic studies of various compounds that will ultimately help to design and develop more MAPK signalling pathway inhibitors.

Epidermal growth factor receptor inhibitors as potential anticancer agents: An update of recent progress.

Epidermal growth factor receptor (EGFR) is a vital intermediate in cell signaling pathway including cell proliferation, angiogenesis, apoptosis, and metastatic spread and also having four divergent members with similar structural features, such as EGFR (HER1/ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4). Despite this, clinically exploited inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific thus provoking unenviable adverse effects. Some of the paramount obstacles to generate and develop new lead molecules of EGFR inhibitors are drug resistance, mutation, and also selectivity which inspire medicinal chemists to generate novel chemotypes. The discovery of therapeutic agents that inhibit the precise stage in tumorous cells such as EGFR is one of the chief successful targets in many cancer therapies, including lung and breast cancers. This review aims to compile the various recent progressions (2016-2021) in the discovery and development of diverse epidermal growth factor receptor (EGFR) inhibitors belonging to distinct structural classes like pyrazoline, pyrazole, imidazole, pyrimidine, coumarin, benzothiazole, etc. We have summarized preclinical and clinical data, structure-activity relationships (SAR) containing mechanistic and in silico studies to provide proposals for the design and invention of new EGFR inhibitors with therapeutic significance. The detailed progress of the work in the field will provide inexorable scope for the development of novel drug candidates with greater selectivity and efficacy.

Voltage gated sodium channel inhibitors as anticonvulsant drugs: A systematic review on recent developments and structure activity relationship studies.

Voltage-gated sodium channel blockers are one of the vital targets for the management of several central nervous system diseases, including epilepsy, chronic pain, psychiatric disorders, and spasticity. The voltage-gated sodium channels play a key role in controlling cellular excitability. This reduction in excitotoxicity is also applied to improve the symptoms of epileptic conditions. The effectiveness of antiepileptic drugs as sodium channel depends upon the reversible blocking of the spontaneous discharge without blocking its propagation. There are number of antiepileptic drug(s) which are in pipeline to flour the market to conquer abnormal neuronal excitability. They inhibit the seizures through the inhibition of complex voltage- and frequency-dependent ionic currents through sodium channels. Over the past decade, the sodium channel is one of the most explored targets to control or treat the seizure, but there has not been any game-changing discovery yet. Although there are large numbers of drugs approved for the treatment of epilepsy, however they are associated with several acute to chronic side effects. Many research groups have tirelessly worked for better therapeutic medication on this popular target to treat epileptic seizures. The review quotes briefly the developments of the approved examples of sodium channel blockers as anticonvulsant drugs. Medicinal chemists have tried the design and development of some more potent anticonvulsant drugs to minimize the toxicity that are discussed here, and an emphasis is given for their possible mechanism and the structure-activity relationship (SAR).

Thiophene-based derivatives as anticancer agents: An overview on decade's work.

Heterocyclic compounds hold a pivotal place in medicinal chemistry due to their wide range of biological activities and thus, are exhaustively explored in the field of drug design and development. Continuous efforts are being carried out for the development of medicinal agents especially, for dreadful diseases like cancer. Thiophene, a sulfur containing heterocyclic scaffold, has emerged as one of the relatively well-explored scaffold for the development of library of molecules having potential anticancer profile. Thiophene analogs have been reported to bind with a wide range of cancer-specific protein targets, depending on the nature and position of substitutions. Accordingly, thiophene analogs have been reported to cause their biological action through inhibition of different signaling pathways involved in cancer. Functionally, different anticancer targets require different structural features, so researchers have tried to synthesize new thiophene derivatives with varied substitutions. In the present review, authors have presented the information available on thiophene-based molecules as anticancer agents with special focus on synthetic methodologies, biological profile and structure activity relationship (SAR) studies. Various patents granted for thiophene containing molecules as anticancer have also been included.

Role of heterocyclic compounds in SARS and SARS CoV-2 pandemic.

Coronaviruses have led to severe emergencies in the world since the outbreak of SARS CoV in 2002, followed by MERS CoV in 2012. SARS CoV-2, the novel pandemic caused by coronaviruses that began in December 2019 in China has led to a total of 24,066,076 confirmed cases and a death toll of 823,572 as reported by World Health Organisation on 26 August 2020, spreading to 213 countries and territories. However, there are still no vaccines or medications available till date against SARS coronaviruses which is an urgent requirement to control the current pandemic like situations. Since many decades, heterocyclic scaffolds have been explored exhaustively for their anticancer, antimalarial, anti-inflammatory, antitubercular, antimicrobial, antidiabetic, antiviral and many more treatment capabilities. Therefore, through this review, we have tried to emphasize on the anticipated role of heterocyclic scaffolds in the design and discovery of the much-awaited anti-SARS CoV-2 therapy, by exploring the research articles depicting different heterocyclic moieties as targeting SARS, MERS and SARS CoV-2 coronaviruses. The heterocyclic motifs mentioned in the review can serve as crucial resources for the development of SARS coronaviruses treatment strategies.

Synthesis, biological evaluation and molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones derivatives.

A series of thirteen novel 2,4-thiazolidinedione derivatives were synthesized through three step reaction procedure. The title compounds were synthesized by Knoevenagel condensation at the 5th position of the 2,4-thiazolidinedione ring. Various physicochemical and spectral studies were conducted to characterize the synthesized derivatives including- IR, Mass, 1H NMR, 13C NMR and elemental analysis. The derivatives were screened for in vivo anti diabetic, in vivo anti-inflammatory and in vitro free radical scavenging activities by carrageenan induced rat paw edema method, alloxan induced diabetes in wistar rats method and FRAP (ferric reducing antioxidant power) method respectively. Some of the derivatives emerged out as potent antidiabetic, anti inflammatory and free radical scavenging agents. Molecular docking was carried out to investigate some possible structural insights into the potential binding patterns of the most potent anti-diabetic molecules NB7,NB12 and NB13 with the active sites of target PPARγ (PDB ID: 2PRG) using MOE software. Dichloro derivative compound NB-7 has shown great potential in the present study as it not only has maximum antidiabetic activity but also possess excellent anti-inflammatory and antioxidant potential.

Synthesis and biological evaluation of thiazolidine-2,4-dione-pyrazole conjugates as antidiabetic, anti-inflammatory and antioxidant agents.

A series of fourteen novel thiazolidine-2,4-dione derivatives clubbed with pyrazole moiety were synthesized via four step reaction procedure. Reactions were monitored by thin layer chromatography and were characterized by physicochemical and spectrophotometric (IR, Mass, 1HNMR and 13CNMR) analysis. The spectral data were in good agreement with their structures. The title compounds were docked against peroxisome proliferated activated receptors (PPAR-γ) and alpha-amylase and further evaluated for in vivo and in vitro antidiabetic, in vitro anti-inflammatory and antioxidant activities. Compound GB14 exhibited significant blood glucose lowering activity and was also found to be active inhibitor of alpha-amylase. Compound GB7 was found to be potent anti-inflammatory agent in terms of reducing inflammatory markers (TNF-α, IL-ß, MDA) and also showed antioxidant activity to good extent. Therefore, these compounds may be considered as promising candidates for the development of new antidiabetic agents.

Journey of Teplizumab: A Promising Drug in the Treatment of Type 1 Diabetes Mellitus.

Type 1 diabetes (T1D) is a chronic autoimmune disease caused by CD4+ and CD8+ that are activated via CD3+ cells and finally lead to the macrophages destroying the beta cells in the pancreas thereby causing diabetes. The anti-CD3 humanized monoclonal antibody was approved on 17th November 2022 by the United States Food Drug Administration (USFDA) with the name teplizumab and the brand name TZIELD. This is the only approved drug that treats type 1 diabetes (T1D) by delaying the onset of stage 3 in type 1 diabetes (T1D). This review outlines essential features of teplizumab including its brief introduction to its mechanism and other therapies for the treatment and various risks as well as the pharmacokinetics and pharmacodynamics of this disease and the clinical trial reports for the completed and ongoing therapies.

Heterocyclic compounds as xanthine oxidase inhibitors for the management of hyperuricemia: synthetic strategies, structure-activity relationship and molecular docking studies (2018-2024).

Hyperuricemia is characterized by higher-than-normal levels of uric acid in the bloodstream. This condition can increase the likelihood of developing gout, a form of arthritis triggered by the deposition of urate crystals in the joints, leading to inflammation and pain. An essential part of purine metabolism is played by the enzyme xanthine oxidase (XO), which transforms xanthine and hypoxanthine into uric acid. Despite its vital role, diseases such as gout have been associated with elevated uric acid levels, which are linked to increased XO activity. To manage hyperuricemia, this study focuses on potential nitrogen based heterocyclic compounds that may serve as XO inhibitors which may lower uric acid levels and prevent hyperuricemia. Xanthine oxidase inhibitors are a class of medications used to treat conditions like gout by reducing the production of uric acid. The present study demonstrates numerous compounds, particularly nitrogen containing heterocyclic compounds including their synthesis, structure-activity relationship, and molecular docking studies. This paper also contains drugs undergoing clinical studies and the xanthine oxidase inhibitors that have been approved by the FDA.

Resilience Against Resistance: Exploring Cutting-edge Therapies for Methicillin-resistant Staphylococcus aureus (MRSA).

Methicillin-resistant Staphylococcus aureus [MRSA] stands as an enduring threat within healthcare landscapes, characterized by its ability to rapidly evolve and develop resistance to conventional antibiotics. This comprehensive review embarks on a journey through the historical landscape of MRSA, elucidating its initial emergence and subsequent evolution of resistance mechanisms over time. The narrative unfolds to underscore the profound impact of MRSA on patient outcomes and healthcare systems globally. Current trends in MRSA therapies come under meticulous scrutiny, spotlighting the limitations and challenges associated with existing treatment modalities. This analysis underscores the critical need for transformative and innovative therapeutic strategies to effectively combat the ever-growing spectre of drug resistance in MRSA from the exploration of novel antibiotics designed to overcome resistance mechanisms to the promising potential of phage therapy and immunotherapies. Amidst the exploration of innovative therapies, the review identifies and discusses emerging issues and challenges in MRSA management. Insights are provided into the intricate web of obstacles hindering the adoption and implementation of new therapeutic strategies. Furthermore, the socio-economic implications of MRSA and drug resistance are brought to the forefront, emphasizing the broader impact on public health and healthcare systems. In parallel, historical perspectives on MRSA research illuminate key milestones in scientific understanding and technological advancements. The evolution of research strategies and their impact on our ability to comprehend and combat MRSA is examined, providing context for the current state of the field. In conclusion, this review summarizes major findings and drawing implications for the future of MRSA treatment. Recommendations for further research and clinical practice are outlined, encapsulating a holistic overview of the resilient efforts against resistance in the ongoing battle against MRSA.

BBBper: A Machine Learning-based Online Tool for Blood-Brain Barrier (BBB) Permeability Prediction.

AIMS: Neuronal disorders have affected more than 15% of the world's population, signifying the importance of continued design and development of drugs that can cross the Blood-Brain Barrier (BBB). BACKGROUND: BBB limits the permeability of external compounds by 98% to maintain and regulate brain homeostasis. Hence, BBB permeability prediction is vital to predict the activity of a drug-like substance. OBJECTIVE: Here, we report about developing BBBper (Blood-Brain Barrier permeability prediction) using machine learning tool. METHOD: A supervised machine learning-based online tool, based on physicochemical parameters to predict the BBB permeability of given chemical compounds was developed. The user-end webpage was developed in HTML and linked with back-end server by a python script to run user queries and results. RESULT: BBBper uses a random forest algorithm at the back end, showing 97% accuracy on the external dataset, compared to 70-92% accuracy of currently available web-based BBB permeability prediction tools. CONCLUSION: The BBBper web tool is freely available at http://bbbper.mdu.ac.in.

An Insight into Medicinal Chemistry and SAR Studies of Cholinesterase and BACE-1 Inhibitors for Alzheimer's Disease.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.