<![CDATA[Letters in Drug Design & Discovery (Volume 21 - Issue 8)]]> https://www.benthamscience.com/journal/57 RSS Feed for Journals | BenthamScience EurekaSelect (+https://www.benthamscience.com) 2024-03-26 <![CDATA[Letters in Drug Design & Discovery (Volume 21 - Issue 8)]]> https://www.benthamscience.com/journal/57 <![CDATA[Anti-colorectal Cancer Activity of Quinazoline Derivatives: A Comprehensive Review]]>https://www.benthamscience.com/article/1301042024-03-26 Introduction and Objective: The identification of a bioactive template (or lead) is one of the important features of modern drug discovery. Natural products, synthetic and biotechnological sources, serve as important templates for the development of novel bioactive molecules. Quinazoline is one of the heterocyclic templates present in many natural and synthetic drugs and exhibits various biological activities, including anticancer, by blocking the pharmacological pathway of different targets.

Methodology: In this study, the data was collected from the literature and patents to examine the anticolorectal cancer efficacy of quinazoline compounds and their mechanism of actions. According to the published literature and patents, the benzene and/or pyrimidine rings of the quinazoline have been substituted with amino groups or substituted amino groups to develop novel analogues endowed with anticancer properties. The anti-colorectal cancer activity of quinazolines was due to the flexible chain containing terminal phenyl and/or heterocyclic rings (thiazole, pyrazole, piperidine, piperazine, etc.).

Results: These quinazoline derivatives were found to inhibit the growth of colorectal cancer cells by modulating the expression of specific genes and proteins involved in cancer progression, such as receptor tyrosine kinases, epidermal growth factor receptors, dihydrofolate reductase, topoisomerases, histone deacetylase, and apoptotic proteins.

Conclusion: These findings suggest that the quinazoline nucleus may be exploited to identify new anticolorectal cancer agents with suitable pharmacokinetic profiles.

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<![CDATA[Recent Advances in the Development of RET Inhibitors]]>https://www.benthamscience.com/article/1300122024-03-26 Background: Rearranged during transfection (RET) is a receptor tyrosine kinase and a bona fide oncogene that drives various cancers. Oncogenic RET induces abnormal activation of RET kinase, causing tumorigenesis. RET can be abnormally activated through RET point mutations and RET fusions. Although RET kinase has been discovered in tumors more than 30 years ago, patients with RET-altered tumors gain limited benefits from multikinase inhibitors (MKIs). In 2020, pralsetinib and selpercatinib were approved by FDA for the treatment of RET-altered tumors.

Objective: Recently reported RET inhibitors were reviewed to provide an overview of the development of novel RET inhibitors.

Methods: Literatures, patents, and conference proceedings published in the past five years were collected. Only RET inhibitors with novel scaffolds or in vivo efficacy were discussed in this review. The enzymebased and cell-based activities, PK profiles, antitumor activities in vivo, and clinical efficacy of the selected RET inhibitors were described.

Results: Great efforts have been spent on the development of RET inhibitors, leading to increased RETtargeted therapies. Due to high potency and specificity, pralsetinib and selpercatinib resulted in a >8- month improvement in overall survival, compared to MKIs. However, solvent-front mutants emerged and contributed to the acquired resistance to pralsetinib and selpercatinib. To overcome solvent front mutants, TPX-0046, TAS0953, and LOX-260 are investigated in early clinical studies.

Conclusion: Zeteletinib, SYHA1815, TPX-0046, TAS0953, and LOX-260 are potential therapies for RET-altered cancers. In addition, macrocyclic inhibitors, allosteric inhibitors, and PROTACs are three promising strategies to address the potential drug resistance of RET.

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<![CDATA[Overview of the Current Advancements and Trends in the Transungual Drug Delivery System]]>https://www.benthamscience.com/article/1300202024-03-26 Background: Drug delivery across human nails is termed a transungual drug delivery system. It is recommended for the amelioration of nail disorders and infectious nail diseases like onychomycosis. Thereby, vivid anti-fungal regimens have been prescribed in the form of different types of formulations, including nail lacquers, nail film, nail paint, and other types for treating onychomycosis.

Methods: All the formulations currently marketed or being marketed for the transungal drug delivery system were thoroughly studied, compared, and evaluated for their advantages and disadvantages so that a new vision can be sustained along the path of creating newer anti-fungal transunguals, keeping in mind the anatomy of the nail and various parameters that govern bioavailability of active pharmaceutical ingredients across the nail bed. Accordingly, different techniques are devised to enhance permeation across the nail. The various parameters used to evaluate these formulations depend upon their physical, chemical, and mechanical properties.

Conclusion: The recent approaches in transungual novel drug delivery systems have been reported while exemplifying a few patented and marketed formulations, along with the clinical trial status of these formulations. There is a need for the development of new techniques to overcome all the loopholes present in the ongoing treatment techniques and the formulations used nowadays for the treatments of diseases that occur in nails. After thoroughly detailing transungal novel drug delivery systems, we envisage great opportunities for the researchers to carry out novel work in chemotherapy through nails.

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<![CDATA[Application of Nanotechnology for Herbal Medicine Development: A Review]]>https://www.benthamscience.com/article/1300502024-03-26 Background: Herbal medicines have been extensively used to treat diseases since the prehistoric era, but written records date back more than 5,000 years only. All civilizations developed their knowledge of herbal medicines in a well-ordered system, such as Ayurveda, Unani, Traditional Chinese Medicine, etc. The interest in traditional medicine declined after the discovery of modern medicine. However, in the 21st century, herbal medicines are staging a comeback as the dangers and limitations of modern medicine have become more apparent and herbal medicines are viewed as a balanced and moderate approach to healing

Methods: This review includes the nanoformulations of phytoconstituents and extract. Advancements in analysis and clinical research prove the efficacy of nano-herbal medicines in preventing and treating diseases. This review is mostly about how nanotechnology can be used to help herbal medicines work better.

Results: The major problems with herbal medicines are their poor solubility and stability. New technological advancements are capable of removing the problems associated with herbal medicine. Novel drug delivery systems such as microemulsion, liposome, niosome, and nano-drug delivery systems are used to enhance the safety and efficacy of herbal medicines.

Conclusion: Nanotechnology has significant merit for herbal medicines, such as improving solubility, bioavailability, pharmacological activity enhancement, and stability enhancement.

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<![CDATA[Description and <i>In silico</i> ADME Studies of US-FDA Approved Drugs or Drugs under Clinical Trial which Violate the Lipinski’s Rule of 5]]>https://www.benthamscience.com/article/1297932024-03-26 Background & Objective: Christopher A. Lipinski, in 1997, formulated Lipinski’s rule of five for drug-likeness prediction of potent molecules. It states that molecular weight (less than 500 Daltons), octanol/water partition coefficient (not exceeding more than 5), hydrogen bond acceptor (no more than 10), and hydrogen bond donor (no more than 5) are important for good oral bioavailability. Many drugs among various important classes such as antibiotics, anti-cancer, HIV and HCV protease inhibitors, immunosuppressants, cardiovascular, antifungal, and other miscellaneous classes are approved by FDA or other drug regulatory authorities as clinical use lie beyond the rule of five. In this review, beyond the rule of 5 drugs belonging to these classes (which are either currently approved or under clinical study) are explored and their ADME properties are analyzed.

Methods: Data of 73 beyond the rule of 5 drugs, belonging to various classes, were collected and their ADME properties were calculated using the Qikprop prediction program of maestro 12.9 module of Schrodinger software.

Results: Out of 73 drugs, 4 had at least 1 Rule of 5 (Ro5) violation, 16 had at least 2, 31 had at least 3 out of which 22 drugs had 4, Ro5 violations.

Conclusion: Drugs not obeying the rule of five may also serve as good clinical candidates and potential candidates should not be discarded only on the basis of this rule.

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<![CDATA[Review on Paclitaxel Derivatization: Enhanced Anticancer Action]]>https://www.benthamscience.com/article/1299862024-03-26 Background: The United States Food and Drug Administration (FDA) has authorized paclitaxel for the treatment of numerous types of cancer, including breast, lung, ovarian, and Kaposi's sarcoma. It possesses all the characteristics of BCS class IV medications, including low bioavailability, low water solubility, poor permeability, unpredictable and poor absorption, and inter- and intrasubject variability.

Objective: The purpose of this research was to evaluate previous efforts done to derivatize paclitaxel for greater effectiveness.

Methods: A systematic literature review was conducted from a variety of sources, including published research, review articles, and patents, that mainly focus on the derivatization of paclitaxel that has been done in the last 10 years to enhance its solubility, permeability, and bioavailability. Different forms of derivatization were done in order to improve the drug's ability to be absorbed by the body, as well as its solubility and bioavailability.

Results: This article explores the current and future strategies for increasing the anti-cancer efficacy of paclitaxel by enhancing its bioavailability, solubility, and penetration efficacy. Some examples are lipidbased delivery systems, polymer-based nanocarriers, crystal engineering (nanocrystals and co-crystals), liquidsolid technologies, and self-emulsifying solid dispersions. Other strategies are also discussed in this article.

Conclusion: It is quite likely that this review article will contain perfect fragments of evidence for building a new model for the application of paclitaxel in the treatment of cancer.

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<![CDATA[Assessment of Wine Quality, Traceability and Detection of Grapes Wine, Detection of Harmful Substances in Alcohol and Liquor Composition Analysis]]>https://www.benthamscience.com/article/1298792024-03-26Aureobasidium, Cladosporium, Candida, Filobasidium, Hanseniaspora, Hannaella, Saccharomyces, Wickerhamomyce, Alternaria, Starmerella, Acetobacter, Papiliotrema, Bradyrhizobium, Leuconostoclia, Gluconobacter, Comamonas, and Massilia, are significantly correlated with changes of physiological properties and volatile compounds. Phenolic compounds, shortened as phenolics, are a vital parameter to the quality of wine, and wine phenolics include two main families: non-flavonoids, which consist of hydroxybenzoic acids (HBAs), hydroxycinnamic acids (HCAs), and stilbenes, and flavonoids, comprising flavonols, flavan-3-ols, and anthocyanins. Wine quality is determined by either sensory tests or physicochemical tests, and the latter analyse the wine’s chemical parameters such as sugar, pH, and alcohol level. The most important constituents found in wine are Terpenes; Aldehydes, Pyrazines, Esters, Ketones and diketones, Mercaptans, and Lactones. In wine quality analysis, the most chief variables are volatile acidity, alcohol, sulphates, citric acid, density, total sulfur dioxide, chlorides, pH, fixed acidity, free sulfur dioxide, and residual sugar. Some classifiers utilized for wine quality prediction in machine learning are: k-Nearest Neighbor (KNN), Random Forest, Decision Tree, Support Vector Machines, Linear Regression, Stochastic Gradient Descent, Artificial Neural Networks (ANN), and Naive Bayes. This article is aimed to review wine quality parameters, detection and traceability of wine, and detection of harmful substances in alcohol and liquor composition analysis.]]> <![CDATA[The Effects of <i>Trigonella Foenum-graecum</i> L. on Post-surgical Adhesion Band Formation]]>https://www.benthamscience.com/article/1310012024-03-26Trigonella Foenum-graecum L. (Fenugreek) have been reported in various studies. In this experiment, a murine model was used to evaluate the potential anti-adhesive activity of Fenugreek in vivo.

Objective: This experiment aimed to examine the anti-adhesive activity of Fenugreek in the prevention of postsurgical Intra-abdominal adhesions.

Methods: We have adhered to the ARRIVE guidelines during these experimental studies. After abdominal surgery, for nine days, Fenugreek (400 mg/kg) was given by gavage to male Wistar rats (n = 6). Following that, all animals were sacrificed to assess the anti-inflammatory and anti-fibrotic effects of Fenugreek using Hematoxylin & eosin staining and Masson’s trichrome staining.

Results: Our results showed that Fenugreek hydro-alcoholic extract could significantly reduce the adhesion band formation based on Nair and Leach Scoring system (P < 0.01). The histological assessment also represented less inflammatory cell infiltration and less collagen deposition in the treatment group than in the positive control group (P < 0.01).

Conclusion: This study showed that Fenugreek extract could attenuate post-surgical adhesion band formation by inhibiting pathological responses (Inflammation and fibrosis) following surgery.]]> <![CDATA[Formulation and Characterisation of Fluconazole Loaded MCM-41 Powder for Topical Drug Delivery]]>https://www.benthamscience.com/article/1299312024-03-26 Purpose: The use of common carriers like talc for topical drug delivery leads to diminished efficacy as a result of poor aqueous solubility and low dissolution rate. The objective of this study was to improve the efficiency of fluconazole topical dosage form using MCM-41 as a carrier material. The aim was to load fluconazole in carriers like MCM-41 as well as ß-Cyclodextrin and to compare the prepared powder formulation with the marketed formulations.

Methods: Fluconazole complex was formulated with the use of MCM-41 and ß-CD as carriers in different proportions by melt, solvent evaporation and kneading method. The complex was developed into a powder formulation. These formulations were subjected to in vitro anti-fungal activity tests on candida albicans.

Results: The inclusion compound was characterised by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and FTIR. The optimised method of preparation determined by in vitro dissolution was the melt method. The optimised formulation was then subjected to anti-fungal activity test. Formulation B containing MCM-41 as the bulk excipient had better performance than the marketed formulation; it showed 92.95 ± 0.33% CDR compared to 74.96 ± 0.47% CDR at the end of 1 hour and increased moisture adsorption.

Conclusion: Thus, a fluconazole topical formulation with improved drug dissolution and moisture adsorption was designed. From in vitro tests, it was seen that the prepared formulation had better performance compared to the commercial formulation against skin mycotic infections and could be used for its treatment.

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<![CDATA[Exploration and Validation of Lead Molecules against Yellow Fever through High Throughput Virtual Screening and Molecular Dynamics Simulation]]>https://www.benthamscience.com/article/1297402024-03-26Background: Yellow fever (YF) is a mosquito-borne flaviviral hemorrhagic fever (VHF) that causes severe hepatitis, renal failure, bleeding, and quick terminal events such as shock and multi-organ failure. There are currently no particular anti-viral medications for the management of the YF virus (YFV). Despite the availability of a commercial YFV vaccination, there are roughly 30,000 fatalities globally each year, with instances rising over the previous 20 years. After being translocated into the endoplasmic reticulum lumen, glycosylated NS1 resides as a membrane-associated dimer, where it is required for viral genome replication. The secreted hexamer NS1 has a role in immune evasion and pathogenesis and has been discovered as a possible diagnostic marker for the early identification of viral infections.

Objective: The main aim of this study is to analyze the small molecule as a potent drug candidate against the target NS1 protein.

Methods: In this study, Computational approaches, including high throughput virtual screening, molecular docking, and dynamics simulation, were carried out against the target NS1 protein using three different chemical libraries Enamine, Asinex, and NCI. The selected lead compounds were validated through HOMO-LUMO analysis, ADME prediction, and Toxicity parameters to analyze the biological and pharmacological properties of the lead small molecules.

Results: From the result, it was concluded that the leads possessed the highest docking scores, interacting with the binding residues, and were stable in the simulation period.

Conclusion: Overall findings revealed that the lead three small molecules could act as the potential drug candidate for the target NS1 protein to inhibit the diseasing efficacy of Yellow fever.

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<![CDATA[Pyridazinone-substituted Benzenesulfonamides Demonstrate Inhibition of Monoamine Oxidase]]>https://www.benthamscience.com/article/1302792024-03-26 Background: The monoamine oxidase (MAO) enzymes are important drug targets. Inhibitors of MAO-A and MAO-B have been used to treat the symptoms of depression and Parkinson’s disease.

Methods: A series of seventeen pyridazinone-substituted benzenesulfonamides was synthesized and evaluated as potential inhibitors of human MAO-A and MAO-B. This study is a continuation of our interest in the pharmacological activities of sulfonamide compounds.

Results: Among the compounds evaluated, only 10 and 18 demonstrated appreciable inhibition of MAOB with IC50 values of 2.90 and 4.36 μM, respectively. None of the benzenesulfonamides inhibited the MAO-A isoform. Potential binding orientations and interactions of 10 and 18 with the active site of MAO-B were investigated by computational approaches.

Conclusion: Although these potencies are modest, this study is the first report on MAO inhibition by this class of compounds. Active MAO-B inhibitors may serve as leads for the future discovery of therapeutic agents for neurodegenerative disorders, such as Parkinson’s disease.

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