Two Stability Indicating Chromatographic Methods: TLC Densitometric versus HPLC Method for the Simultaneous Determination of Brinzolamide and Timolol Maleate in Ophthalmic Formulation in the Presence of Probable Carcinogenic Oxidative Degradation Product of Timolol Maleate

A comparative study between two stability-indicating chromatographic methods for the assay of brinzolamide and timolol maleate in the co-existence of the probable carcinogenic oxidative degradation product of timolol maleate in their ophthalmic formulation was demonstrated. The first method established the thin-layer chromatography coupled with the densitometric determination of the analyzed spots, using silica gel TLC aluminum plates F254 and a developing system of chloroform: methanol: ammonia (6:1:0.1, in volumes) at room temperature to give good separation for the three investigated components, where retardation factors for the oxidative degradation product of timolol maleate, brinzolamide and timolol maleate were (Rf 0.21), (Rf 0.46), and (Rf 0.55), respectively. The linear ranges were 2–10 and 3–16 μg/band for brinzolamide and timolol maleate, respectively. In the second method, high performance liquid chromatography (HPLC), photo diode array detection was used on a Eurospher 5 µm C18 100 Å (4.6 × 250 mm) column, using triethylamine pH 3.5, adjusted by glacial acetic acid: acetonitrile (20:80, v/v) at a rate of 0.5 mL per minute. An acceptable separation was achieved, where the retention times for timolol maleate, the oxidative degradation product of timolol maleate and brinzolamide, were (Rt 3.6), (Rt 4.7), and (Rt 5.6), respectively. Linearity covered a range of 20–120 μg/mL for both drugs. It has been proved previously that timolol maleate is liable to oxidation, giving a high-probability carcinogenic product in female mice. The validation for the new proposed stability-indicating methods was optimized in line with the ICH guidelines with good outcomes. It is worth noting that the HPLC-DAD method showed superior separation, economic and time-saving results, while TLC method was more sensitive

An Update on JAK Inhibitors

Janus kinases (JAKs) are a family of non-receptor tyrosine kinases, composed by four members, JAK1, JAK2, JAK3 and TYK2. JAKs are involved in different inflammatory and autoimmune diseases, as well as in malignancies, through the activation of the JAK/STAT signalling pathway. Furthermore, the V617F mutation in JAK2 was identified in patients affected by myeloproliferative neoplasms. This knowledge prompted researchers from academia and pharmaceutical companies to investigate this field in order to discover small molecule JAK inhibitors. These efforts recently afforded to the market approval of four JAK inhibitors. Despite the fact that all these drugs are pyrrolo[2,3-d]pyrimidine derivatives, many compounds endowed with different heterocyclic scaffolds have been reported in the literature as selective or multi-JAK inhibitors, and a number of them is currently being evaluated in clinical trials. In this review we will report many representative compounds that have been published in articles or patents in the last five years (period 2013-2017). The inhibitors will be classified on the basis of their chemical structure, focusing, when possible, on their structure activity relationships, selectivity and biological activity. For every class of derivatives, compounds disclosed before 2013 that have entered clinical trials will also be briefly reported, to underline the importance of a particular chemical scaffold in the search for new inhibitors

Flow Injection Sensing Strategy for Determining Cationic Surfactants in Commodity and Water Samples

The formation of stable binary water-soluble sub-micellar aggregates of cetyltrimethylammonium bromide-copper-pyrocatechol violet complex (CTAB-Cu-PCV) diminishes the stability and absorbance of the Cu-PCV complex. A new flow injection spectrophotometric sensing strategy used for the determination of CTAB in commodity personal care antiseptics and water samples has been established relying on the above-mentioned concept. Based on the reduction of the absorption of the Cu-PCV solution by the injection of CTAB solution at pH 6.0 and 430 nm, a linear absorbance decrease was observed over the CTAB concentration range of 2.0 to 100.0 µg mL−1 (r = 0.987). The analysis method showed limits of detection (3.3 ơ) and quantification (10 ơ) of 0.08 and 0.27 µg mL−1, respectively. The precision (RSD) for five replicate determinations was 7.9 and 3.7% at 10 and 50 µg mL−1, respectively. The developed method was applied successfully to the determination of CTAB in personal care products, namely skin lotion and vaginal wash, in addition to water samples. The corresponding RSD (n = 5) values were ≤8.2%

Synthesis, Spectroscopic Characterization, Antibacterial Activity, and Computational Studies of Novel Pyridazinone Derivatives

In this work, a novel series of pyridazinone derivatives (3–17) were synthesized and characterized by NMR (1H and 13C), FT-IR spectroscopies, and ESI-MS methods. All synthesized compounds were screened for their antibacterial activities against Staphylococcus aureus (Methicillin-resistant), Escherichia coli, Salmonella typhimurium, Pseudomonas aeruginosa, and Acinetobacter baumannii. Among the series, compounds 7 and 13 were found to be active against S. aureus (MRSA), P. aeruginosa, and A. baumannii with the lowest MIC value range of 3.74–8.92 µM. Afterwards, DFT calculations of B3LYP/6-31++G(d,p) level were carried out to investigate geometry structures, frontier molecular orbital, molecular electrostatic potential maps, and gap energies of the synthesized compounds. In addition, the activities of these compounds against various bacterial proteins were compared with molecular-docking calculations. Finally, ADMET studies were performed to investigate the possibility of using of the target compounds as drugs

Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals

Male infertility is significantly influenced by the plasma-protein sex hormone-binding globulin (SHBG). Male infertility, erectile dysfunction, prostate cancer, and several other male reproductive system diseases are all caused by reduced testosterone bioavailability due to its binding to SHBG. In this study, we have identified 345 phytochemicals from 200 literature reviews that potentially inhibit severe acute respiratory syndrome coronavirus 2. Only a few studies have been done using the SARS-CoV-2 inhibitors to identify the SHBG inhibitor, which is thought to be the main protein responsible for male infertility. In virtual-screening and molecular-docking experiments, cryptomisrine, dorsilurin E, and isoiguesterin were identified as potential SHBG inhibitors with binding affinities of −9.2, −9.0, and −8.8 kcal/mol, respectively. They were also found to have higher binding affinities than the control drug anastrozole (−7.0 kcal/mol). In addition to favorable pharmacological properties, these top three phytochemicals showed no adverse effects in pharmacokinetic evaluations. Several molecular dynamics simulation profiles’ root-mean-square deviation, radius of gyration, root-mean-square fluctuation, hydrogen bonds, and solvent-accessible surface area supported the top three protein–ligand complexes’ better firmness and stability than the control drug throughout the 100 ns simulation period. These combinatorial drug-design approaches indicate that these three phytochemicals could be developed as potential drugs to treat male infertility

Integrated Computational Approaches for Inhibiting Sex Hormone-Binding Globulin in Male Infertility by Screening Potent Phytochemicals

Male infertility is significantly influenced by the plasma-protein sex hormone-binding globulin (SHBG). Male infertility, erectile dysfunction, prostate cancer, and several other male reproductive system diseases are all caused by reduced testosterone bioavailability due to its binding to SHBG. In this study, we have identified 345 phytochemicals from 200 literature reviews that potentially inhibit severe acute respiratory syndrome coronavirus 2. Only a few studies have been done using the SARS-CoV-2 inhibitors to identify the SHBG inhibitor, which is thought to be the main protein responsible for male infertility. In virtual-screening and molecular-docking experiments, cryptomisrine, dorsilurin E, and isoiguesterin were identified as potential SHBG inhibitors with binding affinities of −9.2, −9.0, and −8.8 kcal/mol, respectively. They were also found to have higher binding affinities than the control drug anastrozole (−7.0 kcal/mol). In addition to favorable pharmacological properties, these top three phytochemicals showed no adverse effects in pharmacokinetic evaluations. Several molecular dynamics simulation profiles’ root-mean-square deviation, radius of gyration, root-mean-square fluctuation, hydrogen bonds, and solvent-accessible surface area supported the top three protein–ligand complexes’ better firmness and stability than the control drug throughout the 100 ns simulation period. These combinatorial drug-design approaches indicate that these three phytochemicals could be developed as potential drugs to treat male infertility