Utility of Cilefa Pink B, a foodstuff dye as a fluoro-substrate in the devising of the first facile green Molecular-mass-Related Fluorescence Sensor for quantifying amlodipine in batched material and dosage forms; content uniformity evaluation.

This study introduces the first and unique Molecular-mass-Related Fluorescence Sensor as the first fluorimetric strategy for determining amlodipine. An environmentally friendly, single-step, and direct spectrofluorimetric approach was utilized to evaluate the analyte. In an acidic setting, combining the amlodipine medication and the fluorescent dye Cilefa Pink B generated an instantaneous ultra-fluorescent product. An increase in dye response after adding amlodipine was proportional to the molecular weight of the generated complex, as measured at 329 nm. was the idea ofthe applied fluorimetric analysis. The complexing process increased the molecular mass from 879.86 to 1288.739 g mol-1. The medication's range of 0.050-1.00 µg mL-1 is directly correlated with this molecular massenlargement. The ideal settings for the changeable parameters of the system were established through an analysis of the response of the amlodipine-Cilefa Pink B system. Furthermore, the developed sensor complied with ICH (International Council for Harmonization) standards. The sensitivity limits were 0.0139 µg mL-1 (for the detection limit, LOD) and 0.042 µg mL-1 (for the quantification limit, LOQ). Additionally, this method effectively recovered the drug in its original and therapeutic dosage forms. Finally, the proposed process's environmental impact was also assessed through different modern greenness evaluation tools.

Lipase as a Chiral Selector Immobilised on Carboxylated Single-Walled Carbon Nanotubes and Encapsulated in the Organic Polymer Monolithic Capillary for Nano-High Performance Liquid Chromatography Enantioseparation of Racemic Pharmaceuticals.

Herein, we report the preparation of lipase immobilised on single-walled carbon nanotubes (SWCNTs) as an enantioselector for capillary monolithic columns and their application in the chiral separation of racemic pharmaceuticals. The columns were prepared through the encapsulation of functionalised SWCNTs (c-SWCNTs) within an organic monolithic polymer, followed by the immobilisation of lipase over the obtained monolith, over a three-day (L1) and five-day (L2) period. The prepared columns were tested for the enantioselective nano-HPLC separation of 50 racemic drugs. A suitable resolution was achieved for 25 drugs using nano-RP-HPLC conditions for both the L1 and L2 capillaries, while no specific resolution was detected under normal-phase HPLC conditions. The developed c-SWCNT-lipase-based polymeric monolithic capillaries are a promising expansion for separating pharmaceutical enantiomers' using nano-HPLC.

Central composite design driven optimization of sustainable stability indicating HPLC method for the determination of Tigecycline and greenness assessment.

Background: Tigecycline (TGC) is a recently developed antibiotic to battle resistant bacteria. The procedures outlined in the literature for analyzing TGC involve chemical solvents that could be hazardous. Therefore, this study aimed to create a sustainable and stable HPLC technique for quantifying Tigecycline in lyophilized powder. The powerful chemometric tool, experimental design (ED), will be applied to analyze the variables' interaction and impact on the selected analytical target profiles. Response surface methodology provides a tutorial on using the central composite design with three levels of variables and quadratic programming to optimize the design space of the developed method. Methods: The New HPLC method consisted of an aqueous buffer and ethanol as a green mobile phase run on a reversed-phase symmetry C18 column. A full resolution between the Tigecycline and its degradation product peaks was achieved in a short analytical runtime. Results: Further, the specificity, accuracy, precision, robustness and stability indicating power of the proposed approach were verified through stress degrading testing. Conclusions: Finally, the analytical eco-scale and the green Analytical Procedure Index (GAPI) were utilized to determine how environmentally friendly the recommended method was compared to other published approaches.

Novel 2-Thiouracil-5-Sulfonamide Derivatives: Design, Synthesis, Molecular Docking, and Biological Evaluation as Antioxidants with 15-LOX Inhibition.

New antioxidant agents are urgently required to combat oxidative stress, which is linked to the emergence of serious diseases. In an effort to discover potent antioxidant agents, a novel series of 2-thiouracil-5-sulfonamides (4-9) were designed and synthesized. In line with this approach, our target new compounds were prepared from methyl ketone derivative 3, which was used as a blocking unit for further synthesis of a novel series of chalcone derivatives 4a-d, thiosemicarbazone derivatives 5a-d, pyridine derivatives 6a-d and 7a-d, bromo acetyl derivative 8, and thiazole derivatives 9a-d. All compounds were evaluated as antioxidants against 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydrogen peroxide (H2O2), lipid peroxidation, and 15-lipoxygenase (15-LOX) inhibition activity. Compounds 5c, 6d, 7d, 9b, 9c, and 9d demonstrated significant RSA in all three techniques in comparison with ascorbic acid and 15-LOX inhibitory effectiveness using quercetin as a standard. Molecular docking of compound 9b endorsed its proper binding at the active site pocket of the human 15-LOX which explains its potent antioxidant activity in comparison with standard ascorbic acid.

Design, Synthesis, Molecular Modeling and Antitumor Evaluation of Novel Indolyl-Pyrimidine Derivatives with EGFR Inhibitory Activity.

Scaffolds hybridization is a well-known drug design strategy for antitumor agents. Herein, series of novel indolyl-pyrimidine hybrids were synthesized and evaluated in vitro and in vivo for their antitumor activity. The in vitro antiproliferative activity of all compounds was obtained against MCF-7, HepG2, and HCT-116 cancer cell lines, as well as against WI38 normal cells using the resazurin assay. Compounds 1-4 showed broad spectrum cytotoxic activity against all these cancer cell lines compared to normal cells. Compound 4g showed potent antiproliferative activity against these cell lines (IC50 = 5.1, 5.02, and 6.6 µM, respectively) comparable to the standard treatment (5-FU and erlotinib). In addition, the most promising group of compounds was further evaluated for their in vivo antitumor efficacy against EAC tumor bearing mice. Notably, compound 4g showed the most potent in vivo antitumor activity. The most active compounds were evaluated for their EGFR inhibitory (range 53-79%) activity. Compound 4g was found to be the most active compound against EGFR (IC50 = 0.25 µM) showing equipotency as the reference treatment (erlotinib). Molecular modeling study was performed on compound 4g revealed a proper binding of this compound inside the EGFR active site comparable to erlotinib. The data suggest that compound 4g could be used as a potential anticancer agent.

Grаdiеnt HPLC Mеthоd fоr Simultаnеоus Dеtеrminаtiоn оf Еight Sаrtаn аnd Stаtin Drugs in Thеir Purе аnd Dоsаgе Fоrms.

А grаdiеnt HPLC mеthоd was dеvеlоpеd аnd vаlidаtеd fоr rаpid simultаnеоus sеpаrаtiоn аnd dеtеrminаtiоn оf the following eight drugs оf sаrtаn аnd stаtin clаssеs in thеir purе аnd dоsаgе fоrms within 15 minutes: irbеsаrtаn (IRB), lоsаrtаn (LОS), vаlsаrtаn (VАL), оlmеsаrtаn (ОLM), rоsuvаstаtin (RОS), аtоrvаstаtin (АTR), lоvаstаtin (LОV), аnd simvаstаtin (SIM). Sеpаrаtiоn wаs cаrriеd оut оn а Kinеtеx C18 100А cоlumn (2.60 m, 4.60 mm × 100 mm) using а grаdiаnt binаrу mоbilе phаsе оf 0.05M pоtаssium dihуdrоgеn phоsphаtе buffеr (pH 3.50 аdjustеd bу оrthо-phоsphоric аcid) аnd аcеtоnitrilе аt rооm tеmpеrаturе. Thе flоw rаtе wаs 1.00 mL/min аnd mаximum аbsоrptiоn wаs mеаsurеd using a DАD dеtеctоr аt 280 nm. Thе rеtеntiоn timеs оf IRB, LОS, RОS, VАL, АTR, LОV, ОLM, аnd SIM wеrе rеcоrdеd tо bе 4.72, 5.32, 6.06, 7.19, 7.96, 9.30, 11.91, аnd 14.66 minutеs, rеspеctivеlу. Limits оf dеtеctiоn wеrе rеpоrtеd tо bе 2.01, 1.32, 1.10, 0.76, 0.21, 1.50, 0.38, аnd 0.55 mM fоr thе sаmе sеquеncе оf drugs, rеspеctivеlу, shоwing а high dеgrее оf mеthоd sеnsitivitу. Thе mеthоd wаs thеn vаlidаtеd аccоrding tо the intеrnаtiоnаl cоnfеrеncе оf hаrmоnizаtiоn (ICH) guidеlinеs fоr thе dеtеrminаtiоn оf thе drugs in thеir dоsаgе fоrms with highlу prеcisе rеcоvеriеs. Аlsо, a stаtisticаl cоmpаrisоn with rеfеrеncе mеthоds wаs pеrfоrmеd shоwing nо significаnt diffеrеncеs bеtwееn thе prоpоsеd mеthоd аnd rеpоrtеd оnеs in tеrms оf prеcisiоn аnd аccurаcу.

An LC-MS/MS spectrometry method for the simultaneous determination of Rosuvastatin and Irbesartan in rat plasma: Insight into pharmacokinetic and drug-drug interaction studies.

The synergistic vascular protective effect of statins and angiotensin receptor blockers (ARBs) is well known, however, the pharmacokinetic interaction among these classes is yet to be understood and the necessity of developing analytical methods for their determination in vivo is gradually increased. Herein, first chromatographic separation coupled tandem mass spectrometric was developed and fully validated for simultaneous measurement of rosuvastatin (ROS) and irbesartan (IRB) in rat plasma after oral administration. The two analytes were extracted from plasma sample using acetonitrile-induced protein precipitation then separated on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column by gradient elution using 6 mM ammonium formate/0.1% formic acid and ACN at a flow rate 0.4 mL min-1. Multiple reaction monitoring in positive ion mode was used for quantification of precursor to production at m/z 492.1 → 206.9 for IRB, 482.1 → 258.1 for ROS, and 409.2 → 238.2 for the internal standard, amlodipine (AML). Linearity was obeyed in the range of 1-10000 ng mL-1 and 1-5000 ng mL-1 with detection limits (S/N of 3) of 0.05 and 0.07 ng mL-1 for IRB and ROS, respectively. The current method was validated in terms of selectivity, recovery, accuracy, precision, matrix effects, and stability as per US-FDA bioanalytical guidelines. The application of our method reported her is the first to study pharmacokinetic interaction of IRB and ROS in rat plasma after a single oral dose. The area under the concentration-time curve (AUC), peak plasma concentrations (Cmax), half-life time (t1/2), and volume of distribution (Vd) of ROS and IRB were affected when the two drugs were co-administering. The current study provided a valuable tool for studying drug-drug interaction and might be useful for therapeutic drug monitoring and bioequivalence studies.

Synthesis, in vivo and in silico evaluation of novel 2,3-dihydroquinazolin-4(1H)-one derivatives as potential anticonvulsant agents.

In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)benzamide (4a-g) and N-(1-methyl-4-oxo-2-un/substituted-1,2-dihydroquinazolin-3[4H]-yl)-2-phenylacetamide (4h-n) derivatives were synthesized in two steps starting from the reaction of N-methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED50 ) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b, 4a, 4c, 4f, 4j, and 4i, showed very low ED50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABAA binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood-brain barrier. Hit, Lead & Candidate Discovery.

Design and synthesis of N4,N9-disubstituted spermines for non-viral siRNA delivery--structure-activity relationship studies of siFection efficiency versus toxicity.

PURPOSE: To study the effect of sequentially changing the chain length, oxidation level, and charge distribution in N4,N9-diacyl and N4,N9-dialkyl spermines on siRNA formulation, and then to compare their lipoplex transfection efficiency in cell lines. METHODS: Eight N4,N9-diacyl polyamines: N4,N9-[didecanoyl, dilauroyl, dimyristoyl, dimyristoleoyl, dipalmitoyl, distearoyl, dioleoyl and diretinoyl]-1,12-diamino-4,9-diazadodecane were synthesized. Their abilities to bind to siRNA and form nanoparticles were studied using a RiboGreen intercalation assay and particle sizing. Two diamides were also reduced to afford tetraamines N4,N9-distearyl- and N4,N9-dioleyl-1,12-diamino-4,9-diazadodecane. Delivery of fluorescein-labelled Label IT RNAi Delivery Control was studied in FEK4 primary skin cells and in an immortalized cancer cell line (HtTA), and compared with TransIT-TKO. RESULTS: The design, synthesis, and structure-activity relationship studies of a series of N4,N9-disubstituted spermines as efficient vectors for non-viral siRNA delivery to primary skin and cancer cell lines is reported. These non-liposomal cationic lipids are promising siRNA carriers based on the naturally occurring polyamine spermine showing that C-18 is a better chain length as shorter chains are more toxic. CONCLUSIONS: N4,N9-Distearoyl spermine and N4,N9-dioleoyl spermine are efficient siRNA formulation and delivery vectors, even in the presence of serum, comparable to TransIT-TKO. However, four positive charges distributed as in spermine was significantly more toxic.