Pharmacological Characterization Research Articles

A sleepy cannabis constituent: cannabinol and its active metabolite influence sleep architecture in rats

AbstractMedicinal cannabis is being used worldwide and there is increasing use of novel cannabis products in the community. Cannabis contains the major cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), but also an array of minor cannabinoids that have undergone much less pharmacological characterization. Cannabinol (CBN) is a minor cannabinoid used in the community in “isolate’ products and is claimed to have pro-sleep effects comparable to conventional sleep medications. However, no study has yet examined whether it impacts sleep architecture using objective sleep measures. The effects of CBN on sleep in rats using polysomnography were therefore examined. CBN increased total sleep time, although there was evidence of biphasic effects with initial sleep suppression before a dramatic increase in sleep. CBN increased both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. The magnitude of the effect of CBN on NREM was comparable to the sleep aid zolpidem, although, unlike CBN, zolpidem did not influence REM sleep. Following CBN dosing, 11-hydroxy-CBN, a primary metabolite of CBN surprisingly attained equivalently high brain concentrations to CBN. 11-hydroxy-CBN was active at cannabinoid CB1 receptors with comparable potency and efficacy to Δ9-THC, however, CBN had much lower activity. We then discovered that the metabolite 11-hydroxy-CBN also influenced sleep architecture, albeit with some subtle differences from CBN itself. This study shows CBN affects sleep using objective sleep measures and suggests an active metabolite may contribute to its hypnotic action.

Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists

Synthesis and Pharmacological Characterization of Fluorescent Ligands Targeting the Angiotensin II Receptors Derived from Agonists, β-Arrestin-Biased Agonists, and Antagonists

The use of azithromycin in the treatment of inflammatory diseases of the upper respiratory tract and ear

Despite the extensive accumulated clinical experience, inflammatory diseases of the upper respiratory tract and ear still remain an important problem in the field of otorhinolaryngology, especially pediatric practice, since these diseases are associated with the risk of complications. One of the reasons for the ineffectiveness of conservative treatment is the incorrect initial antibacterial therapy. Errors in antimicrobial therapy are associated with both insufficient knowledge of clinical pharmacology by doctors and incorrect interpretation of anamnestic and clinical data, which leads to incorrect treatment of CCA. The aim of the work is to analyze the use of azithromycin in the treatment of upper respiratory tract and ear infections in children, based on pharmacological characteristics, as well as to consider current methods of antibiotic therapy in pediatric practice. An analysis of the literature and our own observations allows us to conclude that azithromycin is an effective antibacterial drug. Taking into account the low toxicity and good bioavailability, azithromycin continues to be one of the main drugs in the arsenal of doctors for the treatment of various infections, including respiratory diseases and infectious processes of ENT organs in children caused by both typical and atypical bacterial pathogens. The convenient dosage form and simple dosage regimen make this drug a popular choice in outpatient pediatric practice, which confirms the widespread use and trust in this antibacterial drug among both doctors and parents.

The possible protective effect of luteolin on cardiovascular and hepatic changes in metabolic syndrome rat model.

The metabolic syndrome, or MetS, is currently a global health concern. The anti-inflammatory, anti-proliferative, and antioxidant properties of luteolin are some of its advantageous pharmacological characteristics. This research was designed to establish a MetS rat model and investigate the possible protective effect of luteolin on cardiovascular, hepatic, and metabolic changes in diet-induced metabolic syndrome in rats. Forty adult male albino rats were split into four groups: a negative control group, a group treated with luteolin, a group induced MetS (fed 20% fructose), and a group treated with luteolin (fed 20% fructose and given luteolin). Following the experiment after 8weeks, biochemical, histological (light and electron), and immunohistochemistry analyses were performed on liver and heart tissues. Serum levels of cTnI, CK-MB, and LDH were significantly elevated in response to the cardiovascular effect of MetS. Furthermore, compared to the negative control group, the MetS group showed a marked increase in lipid peroxidation in the cardiac and hepatic tissues, as evidenced by elevated levels of MDA and a decline in the antioxidant defense system, as demonstrated by lower activities of GSH and SOD. The fatty liver-induced group exhibited histological alterations, including disrupted hepatic architecture, dilated and congested central veins, blood sinusoids, and portal veins. In addition to nuclear structural alterations, most hepatocytes displayed varying degrees of cytoplasmic vacuolation, mitochondrial alterations, and endoplasmic reticulum dilatation. These alterations were linked to inflammatory cellular infiltrations, collagen fiber deposition, active hepatic stellate cells, and scattered hypertrophied Kupffer cells, as demonstrated by electron microscopy and validated by immunohistochemical analysis. It is interesting to note that eosinophils were seen between the liver cells and in dilated blood sinusoids. Moreover, the biochemical (hepatic and cardiac) and histological (liver) changes were significantly less severe in luteolin-treated raton a high-fructose diet.These results suggested that luteolin protects against a type of metabolic syndrome that is produced experimentally.

Therapeutic Potential of Quercetin Analogous: Prospective and Advances.

The purpose of the article is to investigate the therapeutic potential of quer-cetin and related compounds by elucidating their pharmacological characteristics and molecular mechanisms of action. The potential benefits of quercetin and its analogs for cardiovascular health, disorders of the brain, metabolic disorders, and more are discussed in the discussion part of this page. Concerns about their clinical efficacy due to issues with bioavailability and distribution are also discussed. This region of the paper emphasizes the importance of researchers and clinicians working together to maximize the incorporation of these chemicals into real-world therapeutic approaches. In conclusion, quercetin, along with related substances, shows great potential in a wide range of therapeutic settings. Potentially useful for the management of a wide variety of illnesses, their multiple methods of action include the regulation of pathways for cell signaling and interaction with different enzymes. However, additional clinical tri-als are needed to verify their efficacy and safety.

Antiproliferative and Morphological Effects of Fenretinide Lipid Nanosystems in Colon Adenocarcinoma Cells

Objective: Colon adenocarcinoma is characterized by the downregulation of the retinoic acid receptor, making natural retinoids such as all-trans retinoic acid, 9-cis retinoic acid and 13-cis retinoic acid effective in treatment and chemoprevention due to their ability to increase RARβ expression. However, major limitations to their use include tolerability and acquired resistance. In this study, we evaluated fenretinide, a semisynthetic derivative of all-trans retinoic acid, in an HT-29 cell line. Fenretinide was evaluated both as a free drug and encapsulated in self-assembling phosphatidylcholine nanosystems with the aim of increasing the aqueous solubility and cell availability of the drug. Methods: Fenretinide was encapsulated in lipid nanosystems obtained in water by the dispersion of an amphiphilic mixture of phospholipids, glyceryl tributyrate and polysorbate 80. The physico-chemical characterization of the nanosystems was carried out by dynamic light scattering and spectrophotometry. The biological activity was evaluated by quantitative phase imaging microscopy, MTT assay, flow cytometry and confocal laser-scanning fluorescence microscopy. Results: Fenretinide in phosphatidylcholine nanosystems was more active than free fenretinide in inhibiting HT-29 cells’ proliferation, as indicated by quantitative phase imaging data. Indeed, encapsulated fenretinide increased duplication time, decreased dry mass and decreased the rate of cell growth more efficiently than fenretinide. Moreover, encapsulated fenretinide effectively decreased the motility of the cells that survived the treatment. Conclusions: The results indicate that the proposed nanosystems can be considered a valuable alternative to natural retinoids in the chemoprevention and treatment of colorectal cancer. This is due to the favorable pharmacologic characteristics of fenretinide in colorectal cancer and the improved drug activity provided by nanoencapsulation.

Pharmacological characterization of prostaglandin E2 EP2 and EP4 receptors in male rat locus coeruleus neurons ex vivo

The inflammatory mediator prostaglandin E2 (PGE2) binds to Gs-coupled EP2 and EP4 receptors. These receptors are located in the locus coeruleus (LC), the principal noradrenergic nucleus in the brain, but their functional role remains unknown. In this study, the PGE2 EP2 and EP4 receptors in LC cells from male rat brain slices were pharmacologically characterized by single-unit extracellular electrophysiology. The EP2 receptor agonists butaprost (0.01–10 μM) and treprostinil (0.03–10 µM) and the EP4 receptor agonists rivenprost (0.01 nM–1 µM) and TCS2510 (0.20 nM–2 µM) increased the firing rate of LC neurons in a concentration-dependent manner. The EP2 receptor antagonist PF-04418948 (10 nM) hindered the excitatory effect of butaprost and treprostinil while the EP4 receptor antagonist L-161,982 (30 and 300 nM) blocked the excitatory effect caused by rivenprost and TCS2510. The effects of butaprost and rivenprost were prevented by extracellular sodium replacement but were not modified by the protein kinase A (PKA) activator 8-Br-cAMP (1 mM) or the inhibitor H-89 (10 μM). However, the Gβγ subunit blocker gallein (20 μM) hindered the stimulatory effect of butaprost while the Gαs subunit inhibitor NF449 (10 µM) prevented that of rivenprost. Finally, rivenprost-induced stimulation (30 nM) was not occluded by butaprost (1 µM).In conclusion, activation of EP2 and EP4 receptors excites LC noradrenergic neurons through sodium-dependent currents via different G protein subunits in male rat brain slices. EP2 and EP4 in the LC may constitute pharmacological targets for the treatment of pain, fever, drug addiction, anxiety and neuroinflammatory diseases.

Chemical Probes Review: Choosing the Right Path Towards Pharmacological Targets in Drug Discovery, Challenges and Future Perspectives.

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and α-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries.

Characterization of novel nitazene recreational drugs: Insights into their risk potential from in vitro µ-opioid receptor assays and in vivo behavioral studies in mice

2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand (3[H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. In vivo, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl N-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α’-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.

Synthesis and Pharmacological Characterization of Adrenocorticotropic Hormone (ACTH 1–24) and C-Terminal Truncated Analogues Identifies the Minimal ACTH N-Terminal Fragment Required for Melanocorton-2 Receptor Activation

Synthesis and Pharmacological Characterization of Adrenocorticotropic Hormone (ACTH 1–24) and C-Terminal Truncated Analogues Identifies the Minimal ACTH N-Terminal Fragment Required for Melanocorton-2 Receptor Activation

Evaluation of the Activity of Olibanum Oil as an Immune Booster in Rats

The applications of herbal medicine have recently acquired growing interest in range of the prophylaxis and treatment of diseases. Olibanum has been used since ancient eras and several reports studied the pharmacological characteristics of boswellic acid, particularly their effect on the inflammatory response, analgesic properties, and anti-arthritic activity mostly in cell lines, but new approaches include animal models to assess these natural derivatives effects taking into consideration of being safer than synthetic preparations. The impact of olibanum oil on several parameters was studied in rats during this study. These included white blood cell (WBC) count, lactate dehydrogenase (LDH), and C reactive protein (CRP), as well as other pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the cytokine interleukin -10 (IL-10) that is anti-inflammatory. Total WBCs in addition to IL-10 levels significantly increased in the oil-treated group in comparison with the control one, while the rats treated with olibanum oil revealed a significant reduced level of LDH, CRP, IL-6 and TNF- α compared with the controls (p < 0.05). These outcomes indicate that olibanum oil treatment are manifested by cytokine changes, it can improve the anti-inflammatory response and down-regulate the pro-inflammatory cytokines. So, the promising impact of olibanum oils as an immunomodulator could be used in alternative therapies.

Research Progress on the Treatment of Vascular Vertigo with Active Ingredients of Pueraria Lobata

Vascular vertigo is a common disease among middle-aged and elderly patients with vertigo, caused by cerebrovascular diseases, which seriously affects the quality of life of patients. Its pathogenesis is diverse, and there is still a lack of clear and effective therapeutic drugs in clinical practice. Pueraria lobata, as a commonly used traditional Chinese medicine for treating brain diseases, is widely used in clinical practice and has great development prospects. By summarizing the network pharmacology and clinical medication rules of vascular vertigo, it was found that Pueraria lobata is a high-frequency single traditional Chinese medicine for treating this disease. Modern pharmacological research has found that the main components of Pueraria lobata, such as isoflavones, triterpenes, coumarins, and alkaline compounds, can all play a preventive and therapeutic role in vascular dizziness. This article summarizes the published domestic and foreign papers and experiments, and takes the pathogenesis of vascular vertigo and the pharmacological characteristics of Pueraria lobata as a breakthrough point. Through sorting, it was found that Pueraria lobata exerts pharmacological effects in improving vascular endothelial function, regulating lipid metabolism, anticoagulation and antithrombotic effects, inhibiting oxidative stress, and regulating inflammatory reactions, and has significant effects on the clinical treatment of vascular vertigo.

A synthetic method to assay polycystin channel biophysics.

Ion channels are biological transistors that control ionic flux across cell membranes to regulate electrical transmission and signal transduction. They are found in all biological membranes and their conductive state kinetics are frequently disrupted in human diseases. Organelle ion channels are among the most resistant to functional and pharmacological interrogation. Traditional channel protein reconstitution methods rely upon exogenous expression and/or purification from endogenous cellular sources which are frequently contaminated by resident ionophores. Here, we describe a fully synthetic method to assay functional properties of polycystin channels that natively traffic to primary cilia and endoplasmic reticulum organelles. Using this method, we characterize their oligomeric assembly, membrane integration, orientation, and conductance while comparing these results to their endogenous channel properties. Outcomes define a novel synthetic approach that can be applied broadly to investigate channels resistant to biophysical analysis and pharmacological characterization.

A synthetic method to assay polycystin channel biophysics

Ion channels are biological transistors that control ionic flux across cell membranes to regulate electrical transmission and signal transduction. They are found in all biological membranes and their conductive state kinetics are frequently disrupted in human diseases. Organelle ion channels are among the most resistant to functional and pharmacological interrogation. Traditional channel protein reconstitution methods rely upon exogenous expression and/or purification from endogenous cellular sources which are frequently contaminated by resident ionophores. Here, we describe a fully synthetic method to assay functional properties of polycystin channels that natively traffic to primary cilia and endoplasmic reticulum organelles. Using this method, we characterize their oligomeric assembly, membrane integration, orientation, and conductance while comparing these results to their endogenous channel properties. Outcomes define a novel synthetic approach that can be applied broadly to investigate channels resistant to biophysical analysis and pharmacological characterization.

Bempedoic Acid, the First-in-Class Oral ATP Citrate Lyase Inhibitor with Hypocholesterolemic Activity: Clinical Pharmacology and Drug–Drug Interactions

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug–drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid–CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid–CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein–cholesterol (LDL-C) (20–25%), non-high-density lipoprotein–cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid–glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications.

Genome-wide computational analysis of the dirigent gene family in Solanum lycopersicum

BackgroundDirigent (DIR) genes play a key role in the development of organic products in plants. They confer conformational influence on processes that lack stereoselectivity and regioselectivity through processes that are mostly understood. They are required to produce lignans, which are a unique and widely distributed family of plant secondary metabolites with intriguing pharmacological characteristics and potential role in plant development. DIR genes are implicated in the process of lignification and protect plants from environmental stresses, including biotic and abiotic stresses. Nevertheless, no research has been performed on the DIR gene family in Solanum lycopersicum. This study provides detailed information on the DIR gene family in S. lycopersicum.Methods and resultsThe conserved domain analysis, phylogenetic analysis, evolutionary adaptation, cis-acting elements, proteomic analysis, signal peptide detection, transmembrane potential analysis, sequence identity and similarity analysis, gene assembly, genomic localization, duplication of gene analysis, and evolutionary linkage of 31 potential DIR genes were studied. All these analyses provide a deep understanding of DIR genes in the S. lycopersicum genome that will provide a useful reference for further functional analysis of the DIR genes in S. lycopersicum.ConclusionThis research provides an in-depth and comprehensive explanation of the detailed process and structural characterization of DIR genes in the genome of S. lycopersicum, laying the groundwork for future plant genetic engineering and crop development exploration. This work will provide valuable information for identifying DIR genes in higher plants and support future research on the DIR gene family.

Ganoderma lucidum triterpenoids investigating their role in medicinal applications and genomic protection.

Ganoderma lucidum (GL) is a white rot fungus widely used for its pharmacological properties and health benefits. GL consists of several biological components, including polysaccharides, sterols, and triterpenoids. Triterpenoids are often found in GL in the form of lanostane-type triterpenoids with quadrilateral carbon structures. The study revealed that triterpenoids have diverse biological properties and can be categorized based on their functional groups. Triterpenoids derived from GL have shown potential medicinal applications. They can disrupt the cell cycle by inhibiting β-catenin or protein kinase C activity, leading to anti-cancer, anti-inflammatory, and anti-diabetic effects. They can also reduce the production of inflammatory cytokines, thus mitigating inflammation. Additionally, triterpenoids have been found to enhance the immune system's defenses against various health conditions. They possess antioxidant, antiparasitic, anti-hyperlipidemic, and antimicrobial activities, making them suitable for pharmaceutical applications. Furthermore, triterpenoids are believed to afford radioprotection to DNA, protecting it from radiation damage. This review focuses on the types of triterpenoids isolated from GL, their synthesis pathways, and their chemical structures. Additionally, it highlights the pharmacological characteristics of triterpenoids derived from GL, emphasizing their significant role in various therapeutic applications and health benefits for both humans and animals.

In Silico and ADMET Studies of Spiro-Quinazoline Compounds as Acetylcholine Esterase Inhibitors Against Alzheimer's Disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative condition characterized by progressive cognitive decline and memory impairment resulting from the degeneration and death of brain neurons. Acetylcholinesterase (AChE) inhibitors are used in primary pharmacotherapy for numerous neurodegenerative conditions, providing their capacity to modulate acetylcholine levels crucial for cognitive function. Recently, quinazoline derivatives have emerged as a compelling model for neurodegenerative disease treatment, showcasing promising pharmacological features. Their unique structural features and pharmacokinetic profiles have sparked interest in their potential efficacy and safety across diverse neurodegenerative disorders. The exposure of quinazoline derivatives as a potential therapeutic way underscores the imperative for continued research exploration. Their multifaceted mechanisms of action and ability to target various pathways implicated in neurodegeneration offer exciting prospects for developing novel, effective, and well-tolerated treatments. Further investigations into their pharmacological activities and precise therapeutic roles are essential to advance our understanding of neurodegenerative disease pathophysiology and promote the development of modern therapeutic strategies to address this critical medical challenge. Quinazoline derivatives have gained eminent acetylcholinesterase (AChE) inhibitory activity. Their ability to effectively modulate AChE activity makes them promising candidates for treating neurological disorders, particularly Alzheimer's disease (AD). Their intricate molecular structures confer selectivity and affinity for AChE, offering potential for the development of novel therapeutic agents targeting cholinergic pathways. Hence, in this study, we designed, synthesized, and characterized a series of spiro[cycloalakane-1,2'-quinazoline derivatives (1-6) to assess their possible AChE inhibiting ability using docking into the active sites. The AChE inhibitory potential of spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) was explored via docking studies of the AChE active site. The findings revealed significant inhibitory activity and highlighted the promising nature of these derivatives. The synthesized spiro[cycloalkane-1,2'-quinazoline derivatives (1-6) exhibited their notable potential as AChE inhibitors. The observed significant inhibitory activity suggested that these derivatives warrant further exploration as candidates for developing therapeutic agents in AChE inhibitory pathways. This study emphasizes the relevance of quinazoline derivatives in searching for novel treatments for neurological disorders, particularly associated with cholinergic dysfunction, and they could be a useful alternative therapeutic agent.

Mavorixafor: A spotlight on the clinical aspects and prospects of the first USFDA-approved treatment for the primary immunodeficiency WHIM syndrome

WHIM syndrome (WHIMS) is an extremely rare, severe, and potentially fatal genetic condition that affects the immune system, leading to warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM). Effective therapy for WHIMS requires regular monitoring, medical intervention, and a collaborative approach to treatment. Due to the limited therapeutic options, addressing WHIMS is an unmet medical need. The United States Food and Drug Administration (USFDA) recently granted approval for mavorixafor as the first treatment for WHIMS. This review focuses on the pharmacological characteristics, clinical investigations, associated inventions, and prospects of mavorixafor. The literature for this article was searched on PubMed, reputable websites (USFDA and X4 Pharmaceuticals) and free patent databases like Espacenet. WHIMS is distinguished by severe neutropenia and hypogammaglobulinemia, which increases the risk of developing cancer. Mavorixafor enhances the movement of neutrophils and lymphocytes from the bone marrow (BM) to the bloodstream. Hence, it could be beneficial for managing medical illnesses characterized by a decrease in the quantity of neutrophils and lymphocytes in the bloodstream. X4 Pharmaceuticals has submitted patent applications for the utilization of mavorixafor in the treatment of diverse cancer types, inflammatory ailments, B-cell dysfunction, Waldenstrom's macroglobulinemia, and primary immunodeficiency disorders. This suggests that mavorixafor can effectively treat various disorders either alone or when used in conjunction with other medications. It will be intriguing to observe the future approvals of mavorixafor for various disorders.Keywords: Mavorixafor; WHIM syndrome; Cancer; Immunodeficiency; Patent; Prospect

In vitro and In Silico Molecular Modeling Studies of Newly Synthesized Pyrrole Derivatives for their Antimicrobial and Anticancer Properties

Background: Pyrroles are biologically active scaffolds that can have a number of different effects. They also have unique pharmacophores inside their ring system that make it easier to make molecules that are more active. Significantly, in the past ten years, research has been conducted on the anti-bacterial properties, with a particular emphasis on drug-resistant Gram-positive and Gram-negative pathogens such as mycobacteria. Additionally, scaffolds based on pyrroles were utilized in the production of anti-tumor medicines that function by modulating or suppressing genes. Objective: This research aimed to create new pyrrole derivatives by chemical means and evaluate their antimicrobial and anticancer properties. Methods: By reacting diverse 1H-pyrrole-2-carbohydrazide derivatives with benzaldehyde under normal conditions, a number of pyrrole variations were created. IR, mass spectroscopy, NMR, and elemental analysis were used to characterize the synthesized compounds. The serial dilution method was used to assess antimicrobial activity, along with a molecular docking study against the enzyme α-topoisomerase II (α-Topo II), which effectively controls the topology of DNA. This enzyme is strongly expressed in rapidly dividing cells and is crucial for transcription, replication, and chromosome structure. Pyrrole and its synthetic derivatives are known to exhibit strong anticancer activity by specifically targeting α-Topo II, which has led multiple researchers to investigate α-Topo II inhibitors as potential anticancer medicines. Consequently, designing pyrroline derivatives is interesting since the succinimide portion of the joined heteroaromatic molecule can selectively engage with the ATP binding pocket via the hydrogen bond network. Newer synthesized compounds were also docked via Schrodinger 2022-4 into the active pocket of the three-dimensional crystallographic structure of the ATP site of human topoisomerase IIα (htopo IIα) (PDB ID: 1zxm). Results: Among the newly synthesized pyrrole derivatives, compounds demonstrated significant anti- microbial activity. In addition, the AutoDock Vina application was used to perform in-silico docking computations. Compounds 1a and 1h were found to have a stronger antiproliferative effect than compounds against MCF-07 breast cancer cell linen our study, ligands 1a and 1b exhibited better binding energies of -5.049 and -5.035 kcal/mol, respectively. Most of the synthesized pyrrole derivatives showed promising antiproliferative effects; however, further in vivo investigations are needed to confirm or refute these results. Conclusion: The results of this investigation show that pyrrole derivatives have the potential to be effective antimicrobial and anticancer agents. While resolving safety issues, the structural alterations carried out in this study enhanced the compounds' medicinal capabilities. To clarify the underlying mechanisms of action and enhance the pharmacological characteristics of these new pyrrole derivatives, further research is necessary.