Innovative approaches to Alzheimer's therapy: Harnessing the power of heterocycles, oxidative stress management, and nanomaterial drug delivery system.

Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aß). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.

Targeted Cancer Stem Cell Therapeutics: An Update.

Cancer stem cells (CSCs) have become a key player in the growth of tumors, the spread of cancer, and the resistance to therapeutic interventions. Targeting these elusive cell populations has the potential to fundamentally alter cancer treatment plans. CSCs, also known as tumor-initiating cells (TICs), are thought to play a role in both medication resistance and cancer recurrence. This is explained by their capacity to regenerate themselves and change into different kinds of cancer cells. Due to their higher expression of ATP-binding cassette (ABC) membrane transporters, enhanced epithelial to mesenchymal (EMT) characteristics, improved immune evasion, activation of survival signaling pathways, and improved DNA repair mechanisms, CSCs exhibit extraordinary resistance to therapies. This comprehensive analysis delves into advancements in the domain of Targeted Cancer Stem Cell Therapeutics, concentrating on unraveling the distinctive traits of CSCs and the therapeutic methods devised to eliminate them.

Effectiveness of estrogen and its derivatives over dexamethasone in the treatment of COVID-19.

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein Mpro, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess in vitro anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through in vitro and in vivo studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.

Targeting Various Pathogenic Pathways for the Development of Antialzheimer's Drugs: An Update.

Alzheimer's disease (AD) has been recognized as the most important cause of dementia, which is estimated to contribute more than 2 trillion USD in medical costs. AD patients encounter progressive neurodegenerative dementia associated with behavioural, linguistic, and visuospatial deficits. Although studies on the discovery of amyloid ß (Aß) and tau (the essential elements of plaques and tangles in AD) have shed light on the molecular pathological processes of AD, the exact cause of the condition is still largely unknown. The involvement of various proteins, such as amyloid-ß, prion protein, tau, and α-synuclein has been linked to AD pathogenesis. The current AD treatments are mainly based on symptomatic management and restoration of neurotransmitters' balance. There is a significant need to develop medications that can alter the underlying disease process and prevent its progression. The present manuscript provides a review of various hypotheses that have been proposed for AD pathogenesis. The manuscript has also explored the development of novel anti-AD drugs based on various pathogenic pathways, which are recently under various clinical trial phases.

Immunology of osteoporosis: relevance of inflammatory targets for the development of novel interventions.

Osteoporosis is recognized as low bone mass and deteriorated bone microarchitecture. It is the leading cause of fractures and consequent morbidity globally. The established pathophysiological evidence favors the endocrine factors for osteoporosis and the role of the immune system on the skeletal system has been recently identified. Due to the common developmental niche bone and immune system interactions have led to the emergence of osteoimmunology. Immune dysregulation can initiate inflammatory conditions that adversely affect bone integrity. The role of immune cells, such as T-lymphocytes subsets (Th17), cannot be neglected in the pathogenesis of osteoporosis. Local inflammation within the bone from any cause attracts immune cells that participate in the activation of osteoclasts. This work summarizes the present knowledge of osteoimmunology in reference to osteoporosis and identifies novel targets for immunotherapy of osteoporosis.

Application of In silico Methods in the Design of Drugs for Neurodegenerative Diseases.

Neurodegenerative diseases are complex disorders that cause neuron loss, brain aging and ultimately lead to death. These diseases are difficult to treat because of the complex nature of the nervous system, and the available medicines are unable to heal them effectively. This fact implies the need for novel therapeutics to be designed that are ready to stop or a minimum of retard the neurodegeneration process. These days, Computer-Assisted Drug Design (CADD) approaches are a passage to extend the drug development efficiency and to reduce time and cost because traditional drug discovery is both time-consuming as well as costly. Computational or in silico methods came up with powerful tools in drug design against neurodegenerative diseases. This review presents the approaches and theoretical basis of CADD. Also, the successful applications of various in silico studies, including homology modeling, molecular docking, Quantitative Structure-Activity Relationship (QSAR), Molecular Dynamic (MD), De novo drug design, Pharmacophore-based drug design, Virtual Screening (VS), LIGPLOT Analysis, In silico ADMET and drug safety prediction, for treating neurodegenerative diseases have also been included in this review. Major emphasis is given to Alzheimer's disease and Parkinson's disease because these two are the most familiar neurodegenerative diseases.

Nutraceuticals for Sleep Disorders.

Sleep is considered as one of the most important aspects for maintaining a healthy life. For a person to function normally, at least 6-8 hours of sleep daily is necessary. Sleep not only affects our mood, but also regulates the efficiency of work done. Many complications arise due to inadequacy of sleep. The unhealthy food and lifestyle choices have made us more prone to sleep disorders. The medications used for the treatment of sleep disorders are mainly habit forming and have tendencies of withdrawal symptoms. This inadequacy in medication has lead to search for newer, better options. The field of nutraceuticals fits apt for treating such disorders. The quality of being non-toxic, non-habit forming, and being practically more efficient has had made it an excellent option. Nutraceuticals make use of food or part of food for the treatment or to prevent any disease. Remarkable positive effects of nutraceuticals like Caffeine, Chamomile, Kava kava, Cherries and Cherry juice, L tryptophan, Valerian, Vitamin D, Marijuana, melatonin, Lemon balm had been mentioned in the treatment of sleep disorders. The present review gives a general overview of nutraceuticals and discusses their use in sleep disorders.

Decoding Novel Mechanisms and Emerging Therapeutic Strategies in Breast Cancer Resistance.

Breast cancer (BC), an intricate and highly heterogeneous disorder, has presently afflicted 2.09 million females globally. Chemoresistance remains a paramount challenge in the treatment of BC. Owing to its assorted nature, the chemoresistant mechanisms of BC still need intensive research. Accumulating evidence suggests that abnormalities related to the biogenesis of cancer stem cells (CSCs) and microRNAs (miRNAs) are associated with BC progression and chemoresistance. The presently available interventions are inadequate to target chemoresistance, therefore more efficient alternatives are urgently needed to improvise existing therapeutic regimens. A myriad of strategies is being explored, such as immunotherapy, gene therapy, and combination treatment to surmount chemoresistance. Additionally, nanoparticles as chemotherapeutic carriers put forward the options to encapsulate numerous drugs, alone as well as in combination for cancer theranostics. This review summarizes the chemoresistance mechanisms of miRNAs and CSCs as well as the most recently documented therapeutic approaches for the treatment of chemoresistance in BC. By unraveling the underpinning mechanism of BC chemoresistance, researchers could possibly develop more efficient treatment strategies towards BC.

Anticonvulsant evaluation of 2-pyrazolines carrying naphthyl moiety: An insight into synthesis and molecular docking study

A series of N-substituted-3-(napthalen-2-yl)-5-substituted phenyl-4,5-dihydropyrazole-1-carbothioamide derivatives (4a-n) were synthesized with the view of structural requirements of pharmacophore for potential anticonvulsant agents. The synthesized compounds were assayed intraperitoneally (i.p.) and subcutaneously (s.c.) in mice against seizures induced by MES and scPTZ methods, respectively.Neurologic deficit was evaluated by rotarod method. Among the tested compounds, 4g, 4i, 4j and 4n emerged as the most active molecule in the MES model at a dose of 30 mg/kg at 0.5h comparable to standardscarbamazepine and phenytoin. In the scPTZ test,4e and 4l were found to be most active compounds at the lowest dose of 30 mg/kg at 0.5h, in the management of the convulsive disorder. Molecular docking studies of the titled compounds were also donewith 3D crystal structure of human cytosolic branched chain amino transferase (hBCATc) enzyme and compound 4e was found to have five hydrogen bond interactions with the most important active site residues.In neurotoxicity studies, except compounds 4b, 4c, 4h and 4k, rest of the compounds showed no sign of toxicity.

Pharmacological evidences for cytotoxic and antitumor properties of Boswellic acids from Boswellia serrata.

ETHNOPHARMACOLOGICAL RELEVANCE: Increasing research on traditional herbal medicines and their phytoconstituents has recognized their usefulness in complementary as adjuvant to chemotherapy in various types of cancers. The oleo-gum resin of Boswellia serrata tree is one such folk medicine, which has been traditionally used for religious, cosmetic as well as medical purposes since ages. The oleo-gum resin of the plant has been used in traditional medicine to treat variety of conditions including inflammatory diseases like arthritis, asthma, chronic pain, bowel conditions and many other diseases. This review presents an overview of scientific studies on cytotoxic and antitumor properties of B. serrata and its constituents. MATERIALS AND METHODS: Literature search was carried out for activities of B. serrata and various isolated boswellic acids such as ß-boswellic acid, 11-keto-ß-boswellic acid and acetyl-11-keto-ß-boswellic acid reported in various cancer types in vitro as well as in vivo. RESULTS: The triterpenoidal fraction of B. serrata (containing boswellic acids) is responsible for the cytotoxic and antitumor properties. Among the screened compounds, 3-O-acetyl-11-keto-ß-boswellic acid has been found to be most promising cytotoxic molecule. The cytotoxic and antitumor effects are mainly due to induction of apoptosis through caspase activation, increased Bax expression, NF-κB down regulation and induction of poly (ADP)-ribose polymerase (PARP) cleavage. CONCLUSIONS: Boswellic acids appear to be promising candidates for anticancer drug development in future. However, further in vivo studies are needed. Studies in combination with clinically used anticancer drugs and QSAR studies on individual boswellic acid also need to be carried out.

Past, Present and Future of Antiepileptic Drug Therapy - Finding a Place for Heterocyclics.

Epilepsy is a serious brain condition characterized by recurring seizures. It affects millions of people across the globe. Much advancement in the past has improved the understanding of the underlying pathophysiology and risk factors for epilepsy. These advances have led to the development of both new terminologies and classification as well as treatment strategies for the disease. Despite the fact that various antiepileptic drugs have been developed in past decades, major part of affected population remains either resistant or refractory to the currently available therapy. Also, none of these anticonvulsant agents are devoid of serious side effect. Therefore, constant efforts are being made to develop antiepileptic drugs with improved efficacy and better pharmacokinetic and safety profile. The new structural classes which are being developed broadly amides, amino acids and a number of heterocyclic agents like oxadiazoles, benzimidazoles, benzothazoles, pyrazoles, indoles and benzothaizoles etc. These new compounds have potential for identification of novel targets and drug development. This review makes a note of these issues and describes recent developments in antiepileptic drug discovery.

New benzo[d]thiazol-2-yl-aminoacetamides as potential anticonvulsants: synthesis, activity and prediction of molecular properties.

A series of N-(substituted-2-oxo-4-phenylazetidin-1-yl)-2-((6-substitutedbenzo[d]thiazol-2-yl)amino)acetamide derivatives were synthesized using pharmacophoric features with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain, the nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). The synthesized molecules were initially screened for anticonvulsant activity using the maximal electroshock seizure (MES) test and the subcutaneous pentylenetetrazole test in albino mice. An acute neurotoxicity study on the synthesized molecules was also carried out using the rotarod test. The results of these tests revealed that two compounds, 5b and 5q, showed promising activity with ED50 values of 15.4 and 18.6 mg/kg and protective indices of 20.7 and 34.9 in the MES test, respectively, which are found to be approximately fourfold higher than those of the standard drugs phenytoin (6.9) and carbamazepine (8.1). These molecules may act as lead of the designed scheme. The pharmacokinetic profiles of all the synthesized compounds were estimated using Molinspiration software. None of the compounds violated Lipinski's "rule of five". The possible structure-activity relationship was discussed. In conclusion, this manuscript shows that the developed model has a highly prognostic power for the further investigation of better benzothiazole derivatives for future discovery and development.

Preliminary anticonvulsant and toxicity screening of substituted benzylidenehydrazinyl-N-(6-substituted benzo[d]thiazol-2-yl)propanamides.

Keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity, a new series of 3-(2-(substitutedbenzylidene)hydrazinyl)-N-(substituted benzo[d]thiazol-2-yl)-propanamides were synthesized with aromatic hydrophobic aryl ring (A), NH-C=O as hydrogen bonding domain (HBD), nitrogen atom as electron donor (D), and phenyl as distal aryl ring (C). Synthesized compounds were characterized by FTIR, (1)H NMR, (13)C NMR, mass spectroscopy, and elemental analysis. Preliminary in vivo anticonvulsant screening (phase I) was performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Based on anticonvulsant screening results, two compounds, 5h and 5p, were found to be most active; they exhibited activity comparable to standard drugs phenytoin (PHY) and carbamazepine (CBZ). These active compounds were subjected to phase II and phase III screening, where they displayed much higher protective index (PI) in comparison to the standard drugs. In phase IV screening, the bioavailability of active compounds was assessed on oral administration. Further, preliminary safety profiles of 5h and 5p were evaluated by the neurotoxicity testing and liver enzyme estimation.

Anticonvulsant evaluation of some newer benzimidazole derivatives: design and synthesis.

A series of new 2-[(1-substituted phenylethylidine) hydrazine]-N-phenyl-1H-benzo[d]imidazole-1-carbothioamides (4a-n) were designed and synthesized to have the pharmacophoric elements essential for anticonvulsant activity. The key step in the synthesis of the title compounds involves the reaction of 2-mercaptobenzimidazole with hydrazine hydrate, substituted acetophenones and phenylisothiocyanate to get the compounds in good yields. All the newly synthesized compounds were screened by two most adopted models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Interestingly, compounds 4e, 4f, 4g, 4h and 4j exhibited potent anticonvulsant results and in the neurotoxicity screening, most of the compounds were devoid of toxicity at the dose of 60 and 100 mg/kg.

Genomic analysis of DNA binding and gene regulation by homologous nucleoid-associated proteins IHF and HU in Escherichia coli K12.

IHF and HU are two heterodimeric nucleoid-associated proteins (NAP) that belong to the same protein family but interact differently with the DNA. IHF is a sequence-specific DNA-binding protein that bends the DNA by over 160°. HU is the most conserved NAP, which binds non-specifically to duplex DNA with a particular preference for targeting nicked and bent DNA. Despite their importance, the in vivo interactions of the two proteins to the DNA remain to be described at a high resolution and on a genome-wide scale. Further, the effects of these proteins on gene expression on a global scale remain contentious. Finally, the contrast between the functions of the homo- and heterodimeric forms of proteins deserves the attention of further study. Here we present a genome-scale study of HU- and IHF binding to the Escherichia coli K12 chromosome using ChIP-seq. We also perform microarray analysis of gene expression in single- and double-deletion mutants of each protein to identify their regulons. The sequence-specific binding profile of IHF encompasses ∼30% of all operons, though the expression of <10% of these is affected by its deletion suggesting combinatorial control or a molecular backup. The binding profile for HU is reflective of relatively non-specific binding to the chromosome, however, with a preference for A/T-rich DNA. The HU regulon comprises highly conserved genes including those that are essential and possibly supercoiling sensitive. Finally, by performing ChIP-seq experiments, where possible, of each subunit of IHF and HU in the absence of the other subunit, we define genome-wide maps of DNA binding of the proteins in their hetero- and homodimeric forms.

Design, synthesis and evaluation of anticonvulsant activity of pyridinyl-pyrrolidones: a pharmacophore hybrid approach.

Various 1-[6-(4-substituted phenyl)-3-cyano-4-(substituted phenyl)-pyridin-2-yl]-5-oxopyrrolidine-3-carboxylic acids (3a-t) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED(50) values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED(50) = 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.

Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review.

Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression), obsessive-compulsive disorder (in both adult and paediatric populations), bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression.

anticonvulsant and toxicity evaluation of newer 4H-benzo[1,4]oxazin-3-ones: The effect of two hydrogen bonding domains.

A series of (Z)-2-(substituted aryl)-N-(3-oxo-4-(substituted carbamothioyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yl) hydrazine carboxamides (6a-r) was synthesized using 2-amino-5-nitrophenol as a starting material. All the synthesized compounds possessed two hydrogen-bonding domains and their effect on the activity was studied thereof. The anticonvulsant activity was assessed by the maximal electroshock test (MES), subcutaneous pentylenetetrazole test (scPTZ) and intraperitoneal thiosemicarbazide test (ipTSC). Compounds (6b, 6h, 6i, and 6p) were found to be the most potent of the series as they showed 83-100% protection in the MES test. They also displayed considerable activity in the chemically induced seizure tests. Most of the tested compounds were devoid of the neurotoxic and hepatotoxic effects.