Pyrazole Scaffold: Potential PTP1B Inhibitors for Diabetes Treatment.

The overexpression of the Protein Tyrosine Phosphatase 1B (PTP1B), a key role in the development of insulin resistance, diabetes (T2DM) and obesity, seems to have a substantial impact as a negative regulator of the insulin and leptin signaling pathways. Therefore, inhibiting PTP1B is a prospective therapeutic approach for the treatment of diabetes and obesity. However, the pyrazole scaffold is expected to be of significant pharmaceutical interest due to its broad spectrum of pharmacological actions. This study aims to focus on the significance of pyrazole scaffold in medicinal chemistry, the impact of PTP1B in diabetes and the therapeutic approach of pyrazole scaffold to treat T2DM. A comprehensive analysis of the published literature in several pharmaceutical and medical databases, such as the Web of Science (WoS), PubMed, ResearchGate, ScienceDirect etc., were indeed successfully completed and classified accordingly. Results: As reviewed, the various derivatives of the pyrazole scaffold exhibited prominent PTP1B inhibitory activity. The result showed that derivatives of oxadiazole and dibenzyl amine, chloro substituents, 1, 3-diaryl pyrazole derivatives with rhodanine-3-alkanoic acid groups, naphthalene and also 1, 3, 5-triazine-1H-pyrazole-triazolothiadiazole derivatives, octyl and tetradecyl derivative, indole- and N-phenylpyrazole-glycyrrhetinic acid derivatives with trifluoromethyl group, 2,3-pyrazole ring-substituted-4,4-dimethyl lithocholic acid derivatives with 4- fluoro phenyl substituted and additional benzene ring in the pyrazole scaffold significantly inhibits PTP1B. In silico study observed that pyrazole scaffold interacted with amino acid residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. Diabetes is a metabolic disorder that elevates the risk of mortality and severe complications. PTP1B is a crucial component in the management of diabetes and obesity. As a result, PTP1B is a promising therapeutic target for the treatment of T2DM and obesity in humans. We concluded that the pyrazole scaffold has prominent inhibitory potential against PTP1B.

Eco-friendly liquid chromatography method for the quantification of ibrutinib in a pharmaceutical dosage form.

The objective of this study was to quantitatively determine Bruton's tyrosine kinase inhibitor ibrutinib in its capsule dosage form and assess the homogeneity of the dosage form using green chromatography. The chromatographic method using gradient elution mode was optimized and validated in accordance with the International Council for Harmonization guidelines. The analysis was conducted on a Zodiac C18 column (75 × 4.6 mm and 3.5 µm) using a mobile phase consisting of pH 5.5 potassium phosphate buffer (mobile phase A) and 90% ethanol in milli-Q water (mobile phase B), with a flow rate set at 0.6 mL/min. Based on the validation data, the accuracy results fell within the range of 99.1%-100.6%. The relative standard deviation (% RSD) from precision for both the assays and the uniformity of dosage by content uniformity were determined to be 0.82 and 1.16, respectively. The correlation coefficient obtained from the linearity experiment was 0.999, indicating a strong linear relationship. The greenness of the developed method was assessed using various tools, including the National Environmental Methods Index (NEMI) pictogram, Modified NEMI, Analytical Eco-score calculation, Green Analytical Procedure Index (GAPI) pictogram, Analytical GREEnness (AGREE), and AGREE preparation (AGREEprep). The obtained greenness profile suggests that the optimized LC method is an excellent greener method, supported by the analytical eco-score of 86.

Design, Synthesis, Antimicrobial Evaluation of Novel 2-Oxo-4-Substituted Aryl-Azetidine Benzotriazole Derivatives.

A series of compounds was synthesized and characterized to explore new antimicrobial agents. These compounds were evaluated by using the agar cup plate method. The most active compound exhibited a zone of inhibition 18±0.09 mm and 19±0.09 mm against E. Coli and S. aureus, respectively. To gain insights into the intermolecular interactions, molecular docking studies were performed at the active site of the glucosamine fructose 6 phosphate synthase (GlcN 6 p) enzyme (PDB Id: 1XFF). The results of the molecular docking studies are in agreement with the pharmacological evaluation with potent compounds, exhibiting docking scores of -11.2. However, deformability, B-factor and covariance computations showed a result that the most active compound favored molecular connections with the protein. Therefore, our research is important for the development of antimicrobial agents.

Recent Developments in Proniosomal Transdermal Drug Delivery: An Overview.

Proniosomes are the stable carriers used for transdermal application as compared to other vesicular delivery systems like niosomes and liposomes. Oral administration of a drug is associated with severe GIT irritation and first-pass metabolism. The vesicular drug delivery system includes the basic concept of niosomes and proniosomes which describes their mechanism of action, structural formation, interactive study with skin, composition, and method of preparation. Gels contain a high aqueous component as compared to ointment and creams, due to which they can dissolve high concentrations of drugs, and thus help the drug to migrate easily through a vehicle, due to which, gels are considered to be superior in terms of use and patient compliance. This review will focus on the up-to-date research developments in the use of proniosomes, which are applicable to various diseases. Proniosomes are prepared mainly by different concentrations of nonionic surfactants, cholesterol, and lecithin by entrapping hydrophobic as well as hydrophilic drugs. In earlier studies, it was found that the non-ionic surfactants and phospholipids provided higher penetration and it has also been found that some phospholipids have the ability to fluidize the lipid bilayers of the stratum corneum and diffuse through it. In the future, proniosomes may gain more importance in the area of melanoma, brain targeting, protein and peptide drug delivery, gene delivery, hematological drug delivery, and also in cosmetics, and nutraceuticals.

The Severity of COVID-19 in Diabetes Patients.

AIMS: Diabetic patients are significantly stimulated by COVID-19 infection. The dreadful risk of COVID-19 mortality may be affected. In order to preserve precious lives, it is essential to comprehend how diabetes and COVID-19 are related, as well as how to manage diabetes. We aimed to focus on the mechanism, impact, and drug treatment of diabetes in COVID-19 patients. METHODS: A comprehensive scrutiny of the published literature in diverse pharmaceutical and medical databases such as Google Scholar, PubMed, Science Direct, DOAJ etc., were successfully conducted and classified accordingly. RESULTS: We discussed the severity of COVID-19 in diabetes patients. A patient with diabetes has a higher risk of COVID-19 mortality by influencing the development and prognosis of the disease. The recommended drugs for diabetes treatment in COVID-19 may reduce COVID-19 mortality. CONCLUSION: Metabolic syndrome diabetes is a risk factor enhancing the development and diagnosis of COVID-19. In order to treat diabetic patients who have COVID-19 infection, insulin is preferable over oral hypoglycemic medications.

Improvement in Bioavailability and Pharmacokinetic Characteristics of Efavirenz with Booster Dose of Ritonavir in PEGylated PAMAM G4 Dendrimers.

Efavirenz (EFV) with a booster dose of ritonavir (RTV) (EFV-RTV) inhibits the metabolism of EFV and improves its bioavailability. However, inadequate organ perfusion with surface permeability glycoprotein (P-gp) efflux sustains the viable HIV. Hence, the present investigations were aimed to evaluate the pharmacokinetics and tissue distribution efficiency of EFV by encapsulating it into PEGyalated PAMAM (polyamidoamine) G4 dendrimers with a booster dose of RTV (PPG4ER). The entrapment efficiency of PEGylated PAMAM G4 dendrimers was found to be 94% and 92.12% for EFV and RTV respectively with a zeta potential of 0.277 mV. The pharmacokinetics and tissue distribution behavior of EFV within PPG4ER was determined by developing and validating a simple, sensitive, and reliable bioanalytical method of RP-HPLC. The developed bioanalytical method was very sensitive with a quantification limit of 18.5 ng/ml and 139.2 ng/ml for EFV and RTV, respectively. The comparative noncompartmental pharmacokinetic parameters of EFV were determined by administrating a single intraperitoneal dose of EFV, EFV-RTV, and PPG4ER to Wistar rats. The PPG4ER produced prolonged release of EFV with a mean residential time (MRT) of 24 h with Cmax 7.68 µg/ml in plasma against EFV-RTV with MRT 11 h and Cmax 3.633 µg/ml. The PPG4ER was also detected in viral reservoir tissues (lymph node and spleen) for 3-4 days, whereas free EFV and EFV-RTV were cleared within 72 h. The pharmacokinetic data including Cmax, t1/2, AUCtot, and MRT were significantly improved in PPG4ER as compared with single EFV and EFV-RTV. This reveals that the PPG4ER has great potential to target the virus harbors tissues and improve bioavailability.