A review on phytochemicals as combating weapon for multidrug resistance in cancer.

One can recognize multidrug resistance (MDR) and residue as a biggest difficulty in cancer specialist. Chemotherapy-resistant cancer may be successfully treated by combining MDR-reversing phytochemicals with anticancer drugs. Though, clinical application of phytochemicals either alone or in conjunction with chemotherapy is still in its early stages or requires more research to determine their safety and efficacy. In this review we highlighted topics related to MDR in cancer, including an introduction to subject, mechanism of action of efflux pump, specific proteins involved in drug resistance, altered drug targets, increased drug metabolism, and potential role of phytochemicals in overcoming drug resistance.

Targeting Diabetes with Azole-derived Medicinal Agents.

Azoles have long been regarded as an ideal scaffold for the development of numerous innovative therapeutic agents as well as other incredibly adaptable and beneficial chemicals with prospective uses in a variety of fields, including materials, energetics (explosophores), and catalysis (azole organocatalytic arbitration). Azoles exhibit promising pharmacological activities, including antimicrobial, antidiabetic, antiviral, antidepressant, antihistaminic, antitumor, antioxidant, antiallergic, antihelmintic, and antihypertensive activity. According to a database analysis of U.S. FDAapproved medications, 59% of specific medications are connected to small molecules that have heterocycles having nitrogen atoms. The azole moiety has impressive electron abundance. Azoles promptly attach to various receptors as well as enzymes in the physiological environment via distinct specialized interactions, contributing to their anti-diabetic potential. This review encompasses the recent research progress on potent azole-derived antidiabetic agents that can be used as an alternative for the management of type-2 diabetes.

A Promising Paradigm Shift in Cancer Treatment with FGFR Inhibitors.

FGFR have been demonstrated to perform a crucial role in biological processes but their overexpression has been perceived as the operator component in the occurrence and progression of different types of carcinoma. Out of all the interest around cancer, FGFR inhibitors have assembled pace over the past few years. Therefore, FGFR inhibitors are one of the main fundamental tools to reverse drug resistance, tumor growth, and angiogenesis. Currently, many FGFR inhibitors are under the development stage or have been developed. Due to great demand and hotspots, different pharmacophores were approached to access structurally diverse FGFR inhibitors. Here, we have selected to present several representative examples such as Naphthyl, Pyrimidine, Pyridazine, Indole, and Quinoline derivatives that illustrate the diversity and advances of FGFR inhibitors in medicinal chemistry. This review focuses on the SAR study of FGFR inhibitors last five years which will be a great future scope that influences the medicinal chemist to work towards more achievements in this area.

Molecular Docking, Pharmacophore Modeling, and ADMET Prediction of Novel Heterocyclic Leads as Glucokinase Activators.

BACKGROUND: A pivotal impetus has driven the development of numerous small molecules aiming to improve therapeutic strategies for type 2 diabetes. Glucokinase (GK) activation has been offered a new realm of therapeutic antidiabetic activity with novel heter-ocyclic derivatives. In the context of antidiabetic drug design, GK is an interesting and newly validated target. A key enzyme needed for blood glucose homeostasis is Glucokinase, which is dysfunctional in individuals with type 2 diabetes. Heterocyclic derivatives are utilized in this innovative approach to activate GK enzymes as medicinal agents that will significantly improve type 2 diabetes management. OBJECTIVE: To address type 2 diabetes, as well as minimize unwanted side effects, this research endeavor aimed to develop activators of glucokinase. METHODS: A rigorous scrutiny was conducted of the Maybridge online repository, which houses a formidable collection of 53,000 lead compounds. A collection of 125 compounds that contain the thiazolidinedione core was selected from this extensive collection. The struc-tures were generated using ChemDraw 2D, stabilized conformation with ChemBioDraw Ul-tra, and docked using Auto Dock Vina 1.5.6 in this methodology. In addition, log P was pre-dicted online using the Swiss ADME algorithm. The PKCSM software was used to predict the toxicity of the leading compounds. RESULTS: The highest binding affinity was found for AS72 and AS108 to GK receptors. GI absorption and excretion of these compounds were efficient due to Lipinski's Rule of Five compliance. When compared with the standard drugs Dorzagliatin (GKA) and MRK (co-crys-tallized ligand), these substances demonstrated a notable lack of AMES toxicity, skin sensiti-zation, and hepatotoxicity. CONCLUSION: In recent studies, lead molecules that possess enhanced pharmacokinetic profiles, increased binding affinity, and lower toxicity were developed to act as glucokinase activators.

Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment.

BACKGROUND: Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function, an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic derivatives. OBJECTIVE: The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed in the treatment of type 2 diabetes. METHODS: Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium, Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore, these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis was conducted using PKCSM software on the primary compounds to assess potential toxicity. RESULTS: Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK) binding was significantly enhanced by most of these compounds. Based on superior binding characteristics compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin sensitization, AMES toxicity, and hepatotoxicity. CONCLUSION: Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000 compounds that contain the coumarin nucleus. APV12, with its high binding affinity, favorable ADMET (adjusted drug metabolic equivalents), minimal toxicity, and favorable pharmacokinetic profile warrants consideration for progress to in vitro testing. Nevertheless, to uncover potential therapeutic implications, particularly in the context of type 2 diabetes, thorough investigations and in-vivo evaluations are necessary for benchmarking before therapeutic use, especially experiments involving the STZ diabetic rat model.

Insights to the emerging potential of glucokinase activators as antidiabetic agent.

The glucokinase enzyme (belongs to the hexokinase family) is present in liver cells and ß-cells of the pancreas. Glucokinase acts as a catalyst in the conversion of glucose-6-phosphate from glucose which is rate-limiting step in glucose metabolism. Glucokinase becomes malfunctional or remains inactivated in diabetes. Glucokinase activators are compounds that bind at the allosteric site of the glucokinase enzyme and activate it. This article highlights the patent and recent research papers history with possible SAR from year 2014-2023. The data comprises the discussion of novel chemotypes (GKAs) that are being targeted for drug development and entered into clinical trials. GK activators have attracted massive interest since successful results have been reported from clinical trials data.

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Therapeutic charisma of imidazo [2,1-b] [1,3,4]-thiadiazole analogues: a patent review.

Imidazothiadiazole was discovered around the 1950s era, containing an imidazole ring fused to a thiadiazole ring. Imidazothiadiazole exhibit versatile pharmacological properties including anticonvulsant, cardiotonic, anti-inflammatory, diuretic, antifungal, antibacterial and anticancer. Despite of the being discovered in 1950s, the imidazothiadiazole derivatives are unable to being processed to clinical trials because of lack of bioavailability, efficacy and cytotoxicity. The recent patent literature focused on structural modification of imidazothiadiazole core to overcome these problems. This review limelight a disease-centric perspective on patented imidazothiadiazole from 2015-2023 and to understand their mechanism of action in related diseases. The relevant granted patent applications were located using patent databases, Google Patents, USPTO, EPO, WIPO, Espacenet and Lens.

Oral insulin delivery: a patent review.

Insulin, on oral administration, is very troublesome because of its limited bioavailability. The evolution of oral insulin delivery formulations is greatly desired for non-invasive therapy by overcoming its low bioavailability, GIT enzymatic deactivation, poor lipophilicity and low stability. Different approaches have been proposed to boost oral insulin bioavailability in insulin-delivery systems and emerging effective therapies by using nanoparticle formulation, nanocapsid, modified chitosan particles, polydopamine microcapsules and nanoliposomes. The present review includes patents and patent applications that were published between 2017 and January 2022.

DNA intercalators as anticancer agents.

Cancer is one of the most prevailing disease conditions, which occurs due to uncontrolled cell division either due to natural mutation to the genes or due to changes induced by physical, chemical, or biological carcinogens. According to WHO, it is the second leading cause of death worldwide and has reported 10 million deaths in 2020. Hence, there arises the need for better chemotherapies and DNA intercalators are one such emerging therapy for cancer. DNA intercalating agents reversibly intercalate with the double-helical structure of DNA by interacting with adjacent base pairs and disrupting the structure of DNA and thereby causing cell death. Here, we discuss the different classes of organo-intercalators used in cancer therapy describing their anticancer and intercalation ability by different methods along with their structure-activity relationship and mechanism of action.