A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis

Background Glioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA. Methods Synthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model. Results We discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT). Conclusion Our study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.

Phytochemicals as Potential Curative Agents against Viral Infection: A Review

The present pandemic erupted due to highly contagious coronavirus SARS-CoV- 2, and lack of any efficient therapy to restrain its infection and treatment, led the scientific community to re-evaluate the efficacy of commonly available phytochemicals as potential therapeutic agents. The vast pharmacological activities and medicinal significance of the plant-derived natural products against a diverse range of physiological disorders and diseases are well documented. Under the current health emergency across the world, there is an urgent requirement of repurposing of the available FDA approved drugs and natural products which could help in controlling the infections and alleviating the severity of the diseases as discovering entirely new chemical entity as a novel drug would be a protracted and costly journey. Some of the phytochemicals have already displayed potential anti-viral activity against different targets of SARS-CoV-2 virus. The present review would provide an account of the prevalent phytochemicals with antiviral activities, which would help in the development of promising drug therapy for the treatment of COVID-19 and similar such highly infectious viruses.

Phytochemicals as Potential Curative Agents against Viral Infection: A Review

The present pandemic erupted due to highly contagious coronavirus SARS-CoV- 2, and lack of any efficient therapy to restrain its infection and treatment, led the scientific community to re-evaluate the efficacy of commonly available phytochemicals as potential therapeutic agents. The vast pharmacological activities and medicinal significance of the plant-derived natural products against a diverse range of physiological disorders and diseases are well documented. Under the current health emergency across the world, there is an urgent requirement of repurposing of the available FDA approved drugs and natural products which could help in controlling the infections and alleviating the severity of the diseases as discovering entirely new chemical entity as a novel drug would be a protracted and costly journey. Some of the phytochemicals have already displayed potential anti-viral activity against different targets of SARS-CoV-2 virus. The present review would provide an account of the prevalent phytochemicals with antiviral activities, which would help in the development of promising drug therapy for the treatment of COVID-19 and similar such highly infectious viruses.

In vitro antidiabetic evaluation of nanoparticles encompass dual bioflavonoid

The flavonoids which are widely spread in plants. It can be categorized as flavonols, flavonols, flavanones, flavones, anthocyanidin and isoflavones. Apigenin and Hesperidin account these three flavonoids used a significant proportion of flavonol intake in the diet as a functional food. Among all other flavonoids, Apigenin has many health cares and disease-prevention benefits. Polymer-based formulations, such as nanoemulsions and solid lipid nanoparticles, have been developed to increase the therapeutic efficacy of flavonoids. New drug delivery systems such as Dual Loaded Flavono Nanoparticulate System (DLFNPs) have not yet been studied with Apigenin and Hesperidin. In the present study, dual loaded flavonol nanoparticulate systems have been developed for oral delivery of Apigenin to enhance its antioxidant and antidiabetic activities. The fabrication of Dual Loaded Flavono Nanoparticles by Nano precipitation technique. Prepared Dual Loaded Flavono polymeric nanoparticles were subjected to characterization and various pharmacological activities. In vitro results revealed that the Alfa amylase percentage of inhibition 33.5% for Nanoparticles Encompass Dual Bioflavonoid by the indication pet ether extracts have lesser activity. This work will be useful for diabetic research workers to be found in the new chemical entity for the treatment of DM and its associated diseases.

Characterizations and Assays of α-Glucosidase Inhibition Activity on Gallic Acid Cocrystals: Can the Cocrystals be Defined as a New Chemical Entity During Binding with the α-Glucosidase?

Cocrystallization with co-former (CCF) has proved to be a powerful approach to improve the solubility and even bioavailability of poorly water-soluble active pharmaceutical ingredients (APIs). However, it is still uncertain whether a cocrystal would exert the pharmacological activity in the form of a new chemical entity, an API-CCF supramolecule. In the present study, gallic acid (GA)-glutaric acid and GA-succinimide cocrystals were screened. The solubility, dissolution rate and oral bioavailability of the two cocrystals were evaluated. As expected, AUCs of GA-glutaric acid and GA-succinimide cocrystals were 1.86-fold and 2.60-fold higher than that of single GA, respectively. Moreover, experimental evaluations on α-glucosidase inhibition activity in vitro and theoretical simulations were used to detect whether the two cocrystals would be recognized as a new chemical entity during binding with α-glucosidase, a target protein in hypoglycemic mechanisms. The enzyme activity evaluation results showed that both GA and glutaric acid displayed α-glucosidase inhibition activity, and GA-glutaric acid cocrystals showed strengthened α-glucosidase inhibition activity at a moderate concentration, which is attributed to synergism of the two components. Molecular docking displayed that the GA-glutaric acid complex deeply entered the active cavity of the α-glucosidase in the form of a supramolecule, which made the guest-enzyme binding configuration more stable. For the GA and succinimide system, succinimide showed no enzyme inhibition activity, however, the GA-succinimide complex presented slightly higher α-glucosidase inhibition activity than that of GA. Molecular docking simulation indicated that the guest molecules entering the active cavity of the α-glucosidase were free GA and succinimide, not the GA-succinimide supramolecule.

Synthesis of Substituted imidazo [1, 5-a] pyrimidine-2-(1H)-one Core Structure

Background and Objective: The objective of our work was to establish a facile and scalable synthesis of imidazopyridone for further use in medicinal chemistry applications. An easy synthesis of a core scaffold will enable the medicinal chemistry community to use imidazopyridone as a privileged scaffold in new chemical entity (NCE) synthesis. Materials and Methods: The synthesis was achieved from commercially available and cheap raw materials like amino acetonitrile hydrochloride or commercially available guanidine. Results: Simple transformation starting from amino acetonitrile hydrochloride leads to the synthesis of a versatile imidazo [1, 5-a] pyrimidine-2-(1H)-one core structure. Using suitable functionalized starting materials, a set of NCEs were synthesized to demonstrate the application of the developed synthetic scheme. Similarly, guanidine was also used to synthesize a regioisomer of imidazopyridone in moderate to good yields. Conclusion: We demonstrate the synthesis of two different regio-isomers of imidazopyrimidinone using simple chemical transformations. Its application in synthesizing NCEs has also been exhibited in the present work.

A KNIME Workflow for Automated Structure Verification

Adequate characterization of chemical entities made for biological screening in the drug discovery context is critical. Incorrectly characterized structures lead to mistakes in the interpretation of structure–activity relationships and confuse an already multidimensional optimization problem. Mistakes in the later use of these compounds waste money and valuable resources in a discovery process already under cost pressure. Left unidentified, these errors lead to problems in project data packages during quality review. At worst, they put intellectual property and patent integrity at risk. We describe a KNIME workflow for the early and automated identification of these errors during registration of a new chemical entity into the corporate screening catalog. This Automated Structure Verification workflow provides early identification (within 24 hours) of missing or inconsistent analytical data and therefore reduces any mistakes that inevitably get made. Automated identification removes the burden of work from the chemist submitting the compound into the registration system. No additional work is required unless a problem is identified and the submitter alerted. Before implementation, 14% of samples within the existing sample catalog were missing data on initial pass. A year after implementation, only 0.2% were missing data.

Evaluation of metabolic stability of antimalarial and antiretroviral drugs

The concomitant administration of drugs and antimalarial drugs is recommended for the treatment of HIV (Human Immunodeficiency Virus) patients with malaria resulting in drug-drug interactions (DDI) causing either lack of efficacy or toxicities. Drug metabolism is often the first step in understanding the DDI potential of either a new chemical entity or a combination of drugs. inhibitor (PI) such as is a potent CYP 3A4 inhibitor and may interact with these antimalarial drugs that are metabolized by CYP3A4 to cause metabolism-related DDI's. the present study is an attempt to evaluate the potential for a drug-drug interaction between and through metabolic stability studies. Metabolic stability of antimalarial and drugs alone and in combination with and without and was evaluated using human liver (HLM). The antimalarial drugs , and were metabolically unstable alone (% metabolism ≥ 80%) and in combination with other antimalarial drugs in HLM. , and were metabolically stable (% metabolism ≤ 30%). drug was metabolically unstable while was moderately stable. intrinsic clearance of antimalarial drugs , and decreased from 106.4, 290.6 and 230 ml/min/kg to 32, 44.8 and 49.5 ml/min/kg in the presence of . However, there was no change in the intrinsic clearance of , and in the presence of . did not alter the clearance of antimalarial drugs. This study suggests that affected the clearance of a few antimalarial drugs in HLM probably by the inhibition of CYP3A4 and findings may need to be further evaluated in clinical studies.