Novel spectrophotometric method for determination of cinacalcet hydrochloride in its tablets via derivatization with 1,2-naphthoquinone-4-sulphonate

This study represents the first report on the development of a novel spectrophotometric method for determination of cinacalcet hydrochloride (CIN) in its tablet dosage forms. Studies were carried out to investigate the reaction between CIN and 1,2-naphthoquinone-4-sulphonate (NQS) reagent. In alkaline medium (pH 8.5), an orange red-colored product exhibiting maximum absorption peak (λmax) at 490 nm was produced. The stoichiometry and kinetic of the reaction were investigated and the reaction mechanism was postulated. This color-developing reaction was employed in the development of a simple and rapid visible-spectrophotometric method for determination of CIN in its tablets. Under the optimized reaction conditions, Beer's law correlating the absorbance with CIN concentration was obeyed in the range of 3 - 100 μg/ml with good correlation coefficient (0.9993). The molar absorptivity (ε) was 4.2 × 105 l/mol/cm. The limits of detection and quantification were 1.9 and 5.7 μg/ml, respectively. The precision of the method was satisfactory; the values of relative standard deviations (RSD) did not exceed 2%. No interference was observed from the excipients that are present in the tablets. The proposed method was applied successfully for the determination of CIN in its pharmaceutical tablets with good accuracy and precisions; the label claim percentage was 100.80 - 102.23 ± 1.27 - 1.62%. The results were compared favorably with those of a reference pre-validated method. The method is practical and valuable in terms of its routine application in quality control laboratories

Molecular structure, Hirshfeld surface analysis, spectroscopic (FT-IR, Laser-Raman, UV-vis. and NMR), HOMO-LUMO and NBO investigations on N-(12-amino-9,10-dihydro-9,10-ethanoanthracen-11-yl)-4-methylbenzenesulfonamide

Alasalvar, Can/0000-0002-4983-962X; , Nuri/0000-0001-8742-0160WOS: 000442193700078The structural geometry, vibrational wavenumbers (FT-IR and Raman), H-1 and C-13 NMR chemical shifts and UV-vis. electronic absorption wavelengths of N-(12-amino-9,10-dihydro-9,10-ethanoanthracen-11-yl)-4-methylbenzenesulfonamide (C23H22N2O2S) molecule were studied using experimental and computational methods. The theoretical investigations were performed by using DFT/B3LYP functional with the 6-311G(d,p) basis set in the ground state of the title molecule. The HOMO and LUMO analyses were theoretically investigated to support electronic transitions in UV-vis. spectrum of the compound. The vibrational band assignments of the calculated harmonic wavenumbers were obtained in terms of potential energy distribution (PED) analysis by using VEDA4 program. The Hirshfeld surface analysis was done to describe intermolecular interactions in crystal packing of the compound. The N-H center dot center dot center dot N intra-molecular hydrogen bonding interaction in the compound was investigated with NBO analysis. The experimental records on molecular geometry and spectral results have been showed that the correlation between experimental and theoretical data is in a good agreement. (C) 2018 Published by Elsevier B.V.Deanship of Scientific Research at King Saud UniversityDeanship of Scientific Research at King Saud University [RGP-163]The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-163

A Liquid Chromatography Tandem Mass Spectrometry Method for the Simultaneous Estimation of the Dopamine Receptor Antagonist LE300 and Its N-methyl Metabolite in Plasma: Application to a Pharmacokinetic Study

LE300 is a novel dopamine receptor antagonist used to treat cocaine addiction. In the current study, a sensitive and fast liquid chromatography–tandem mass spectrometry (LC-MS/MS) has been established and validated for the simultaneous analysis of LE300 and its N-methyl metabolite, MLE300, in rat plasma with an application in a pharmacokinetic study. The chromatographic elution of LE300, MLE300, and Ponatinib (IS, internal standard), was carried out on a 50 mm C18 analytical column (ID: 2.1 mm and particle size: 1.8 μm) maintained at 22 ± 2 °C. The run time was 5 min at a flow rate of 0.3 mL/min. The mobile phase consisted of 42% aqueous solvent (10 mM ammonium formate, pH: 4.2 with formic acid) and 58% organic solvent (acetonitrile). Plasma samples were pretreated using protein precipitation with acetonitrile. The electrospray ionization (ESI) source was used to generate an ion-utilizing positive mode. A multiple reaction monitoring mass analyzer mode was utilized for the quantification of analytes. The linearity of the calibration curves in rat plasma ranged from 1 to 200 ng/mL (r2 = 0.9997) and from 2 to 200 ng/mL (r2 = 0.9984) for LE300 and MLE300, respectively. The lower limits of detection (LLOD) were 0.3 ng/mL and 0.7 ng/mL in rat plasma for LE300 and MLE300, respectively. Accuracy (RE%) ranged from −1.71% to −0.07% and −4.18% to −1.48% (inter-day), and from −3.3% to −1.47% and −4.89% to −2.15% (intra-day) for LE300 and MLE300, respectively. The precision (RSD%) was less than 2.43% and 1.77% for the inter-day, and 2.77% and 1.73% for intra-day of LE300 and MLE300, respectively. These results are in agreement with FDA guidelines. The developed LC-MS/MS method was applied in a pharmacokinetic study in Wistar rats. Tmax and Cmax were 2 h and 151.12 ± 12.5 ng/mL for LE300, and 3 h and 170.4 ± 23.3 ng/mL for MLE300

Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

A new series of NSAID thioesters were synthesized and evaluated for their in vitro antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds 2b, 3b, 6a, 7a, 7b and 8a showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. In vitro COX-1/COX-2 enzyme inhibition assay results indicated that compounds 2b, 3b, 6a, 7a, 7b, 8a and 8 b selectively inhibited the COX-2 enzyme (IC50 = ∼0.20–0.69 μM), with SI values of (>72.5–250) compared with celecoxib (IC50 = 0.16 μM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC50 > 50 μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds 2a, 3b, 6a, 7a, 7b and 8a showed no activity to weak activity (% inhibition = ∼0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds

Synthesis, <i>in vitro</i> antitumour activity, and molecular docking study of novel 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinone analogues

<p>A novel series of 2-substituted mercapto-3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinones <b>1</b>–<b>20</b> was synthesised and evaluated for <i>in vitro</i> antitumour activity. <i>N</i>-(4-Chlorophenyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio)acetamide <b>(7)</b> and <i>N</i>-(3,4,5 trimethoxybenzyl)-2-[(3-(3,4,5-trimethoxybenzyl)-4(3H)-quinazolinon-2-yl)thio]propanamide <b>(19)</b> exhibited excellent antitumour properties, with mean growth inhibitory concentration (GI₅₀) of 17.90 and 6.33 µΜ, respectively, compared with those of 5-fluorouracil 5-FU, gefitinib, and erlotinib (mean GI₅₀: 18.60, 3.24, and 7.29 µΜ, respectively). Comparison of the GI₅₀ (µM) values of compounds <b>7</b> and <b>19</b> versus those of 5-FU, gefitinib, and erlotinib against an <i>in vitro</i> subpanel of tumour cells lines showed that compounds <b>7</b> and <b>19</b> have activities almost equal to or higher than that of those standard drugs, especially against lung, CNS, and breast cancer cells. However, compounds <b>5</b>, <b>10</b>, <b>14</b>, <b>15</b>, <b>16</b>, <b>17,</b> and <b>20</b> exhibited effective antitumour activity against the different cell lines tested, with growth inhibition percentage (MGI%) of 19, 24, 19, 17, 16, 15, and 16, respectively. A modelling study was performed for compounds <b>7</b> and <b>19</b> by docking them into the EGFR kinase enzyme to study their mode of binding with the putative binding site.</p

Synthesis, antitumour activities and molecular docking of thiocarboxylic acid ester-based NSAID scaffolds: COX-2 inhibition and mechanistic studies

<p>A new series of NSAID thioesters were synthesized and evaluated for their <i>in vitro</i> antitumor effects against a panel of four human tumor cell lines, namely: HepG2, MCF-7, HCT-116 and Caco-2, using the MTT assay. Compared to the reference drugs 5-FU, afatinib and celecoxib, compounds <b>2b</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b> and <b>8a</b> showed potent broad-spectrum antitumor activity against the selected tumour cell lines. Accordingly, these compounds were selected for mechanistic studies about COX inhibition and kinase assays. <i>In vitro</i> COX-1/COX-2 enzyme inhibition assay results indicated that compounds <b>2b</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b>, <b>8a</b> and <b>8 b</b> selectively inhibited the COX-2 enzyme (IC₅₀ = ∼0.20–0.69 μM), with SI values of (>72.5–250) compared with celecoxib (IC₅₀ = 0.16 μM, COX-2 SI: > 312.5); however, all the tested compounds did not inhibit the COX-1 enzyme (IC₅₀ > 50 μM). On the other hand, EGFR, HER2, HER4 and cSrc kinase inhibition assays were evaluated at a 10 μM concentration. The selected candidates displayed limited activities against the various tested kinases; the compounds <b>2a</b>, <b>3b</b>, <b>6a</b>, <b>7a</b>, <b>7b</b> and <b>8a</b> showed no activity to weak activity (% inhibition = ∼0–10%). The molecular docking study revealed the importance of the thioester moiety for the interaction of the drugs with the amino acids in the active sites of COX-2. The aforementioned results indicated that thioester based on NSAID scaffolds derivatives may serve as new antitumor compounds.</p

S-substituted 2-mercaptoquinazolin-4(3H)-one and 4-ethylbenzensulfonamides act as potent and selective human carbonic anhydrase IX and XII inhibitors

We evaluated the hCA (CA, EC 4.2.1.1) inhibitory activity of novel 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (compounds 2–20) towards the isoforms I, II, IX, and XII. hCA Isoforms were effectively inhibited by most of new compounds comparable to those of AAZ. Compounds 2 and 4 showed interestingly efficient and selective antitumor (hCA IX and hCA XII) inhibitor activities (KIs; 40.7, 13.0, and 8.0, 10.8 nM, respectively). Compounds 4 and 5 showed selective hCA IX inhibitory activity over hCA I (SI; 95 and 24), hCA IX/hCA II (SI; 23 and 5.8) and selective hCA XII inhibitory activity over hCA I (SI; 70 and 44), hCA XII/hCA II, (SI; 17 and 10) respectively compared to AAZ. Compounds 12–17, and 19–20 showed selective inhibitory activity towards hCA IX over hCA I and hCA II, with selectivity ranges of 27–195 and 3.2–19, respectively, while compounds 12, 14–17, and 19 exhibited selective inhibition towards hCA XII over hCA I and hCA II, with selectivity ratios of 48–158 and 5.4–31 respectively, compared to AAZ. Molecular docking analysis was carried out to investigate the selective interactions among the most active derivatives, 17 and 20 and hCAs isoenzymes. Compounds 17 and 20, which are highly selective CA IX and XII inhibitors, exhibited excellent interaction within the putative binding site of both enzymes, comparable to the co-crystallized inhibitors.Highlights Quinazoline-linked ethylbenzenesulfonamides inhibiting CA were synthesised. The new molecules potently inhibited the hCA isoforms I, II, IV, and IX. Compounds 4 and 5 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 4 and 5 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Compounds 12–17, 19, and 20 were found to be selective hCA IX/hCA I and hCA IX/hCA II inhibitors. Compounds 12, 14–17, 19 were found to be selective hCA XII/hCA I and hCA XII/hCA II inhibitors. Graphical Abstract Compounds 4 and 5 are selective hCA IX and XII inhibitors over hCA I (selectivity ratios of 95, 23, and 24, 5.8, respectively) and hCA II (selectivity ratios of 70, 17, and 44, 10 respectively). Compounds 12–17, and 19–20 are selective hCA IX inhibitors over hCA I (selectivity ratios of 27-195) and hCA II (selectivity ratios of 3.2-19). Compounds 12, 14–17 and 19 are also selective hCA XII inhibitors over hCA I (selectivity ratios of 48-158) and hCA II (selectivity ratios of 5.4-31)

A Rapid and Sensitive Liquid Chromatography-Tandem Mass Spectrometry Bioanalytical Method for the Quantification of Encorafenib and Binimetinib as a First-Line Treatment for Advanced (Unresectable or Metastatic) Melanoma&mdash;Application to a Pharmacokinetic Study

The combination regimen targeting BRAF and MEK inhibition, for instance, encorafenib (Braftovi&trade;, ENF) plus binimetinib (Mektovi&reg;, BNB), are now recommended as first-line treatment in patients with unresectable or metastatic melanoma with a BRAF V600-activating mutation. Patients treated with combination therapy of ENF and BNB demonstrated a delay in resistance development, increases in antitumor activity, and attenuation of toxicities compared with the activity of either agent alone. However, the pharmacokinetic profile of the FDA-approved ENF and BNB is still unclear. In this study, a rapid and sensitive LC-MS/MS bioanalytical method for simultaneous quantification of ENF and BNB in rat plasma was developed and validated. Chromatography was performed on an Agilent Eclipse plus C18 column (50 mm &times; 2.1 mm, 1.8 &micro;m), with an isocratic mobile phase composed of 0.1% formic acid in water/acetonitrile (67:33, v/v, pH 3.2) at a flow rate of 0.35 mL/min. A positive multiple reaction monitoring (MRM) mode was chosen for detection and the process of analysis was run for 2 min. Plasma samples were pre-treated using protein precipitation with acetonitrile containing spebrutinib as the internal standard (IS). Method validation was assessed as per the FDA guidelines for the determination of ENF and BNB over concentration ranges of 0.5&ndash;3000 ng/mL (r2 &ge; 0.997) for each drug (plasma). The lower limits of detection (LLOD) for both drugs were 0.2 ng/mL. The mean relative standard deviation (RSD) of the results for accuracy and precision was &le; 7.52%, and the overall recoveries of ENF and BNB from rat plasma were in the range of 92.88&ndash;102.28%. The newly developed approach is the first LC&ndash;MS/MS bioanalytical method that can perform simultaneous quantification of ENF and BNB in rat plasma and its application to a pharmacokinetic study. The mean result for Cmax for BNB and ENF was found to be 3.43 &plusmn; 0.46 and 16.42 &plusmn; 1.47 &micro;g/mL achieved at 1.0 h for both drugs, respectively. The AUC0-&infin; for BNB and ENF was found to be 18.16 &plusmn; 1.31 and 36.52 &plusmn; 3.92 &micro;g/mL.h, respectively. On the other hand, the elimination half-life (t1/2kel) parameters for BNB and ENF in the rat plasma were found to be 3.39 &plusmn; 0.43 h and 2.48 &plusmn; 0.24 h, and these results are consistent with previously reported values