UPLC/MS-MS assay development for estimation of mozavaptan in plasma and its pharmacokinetic study in rats.

AIM: Mozavaptan is a nonpeptide vasopressin receptor antagonist approved for the treatment of ectopic antidiuretic hormone secretion syndrome. METHODS & RESULTS: A simple, rapid and fully validated UPLC/MS-MS method was developed for the quantitation of mozavaptan in rat plasma. The chromatographic separation was conducted on an Acquity UPLC BEH™ C18 column with an optimum mobile phase of 10 mM ammonium acetate buffer and 0.1% formic acid in acetonitrile (30:70 v/v) at a flow rate of 0.3 ml/min. The multiple reaction monitoring transitions were performed at m/z 428.16→119.03 for mozavaptan and m/z 237.06→179.10 for carbamazepine (internal standard). CONCLUSION: The method was effectively applied for the determination of mozavaptan pharmacokinetic parameters after the oral administration of 3 mg/kg mozavaptan in rats.

A validated UPLC-MS/MS method for flibanserin in plasma and its pharmacokinetic interaction with bosentan in rats.

AIM: The purpose of this study was development, validation and application of ultra-performance liquid chromatography (UPLC)-ESI-MS/MS method for quantitation of flibanserin in plasma samples. METHOD & RESULTS: After extraction of analyte from plasma by diethyl ether, separation was performed on UPLC C18 column using mobile phase composition of 10 mM ammonium formate-acetonitrile (30:70, v/v) by isocratic elution of 0.3 ml/min. The multiple reaction monitoring transitions of m/z 391.13 → 161.04 and 384.20 → 253.06 were used for detection of analyte and internal standard (quetiapine), respectively. The calibration curves were linear (r ≥ 0.995) between 0.22 and 555 ng/ml concentration and all validation results were within the acceptable range as per US FDA guidelines. CONCLUSION: The assay procedure was fully validated and successfully applied in pharmacokinetic interaction study of flibanserin with bosentan in rats.

Method development for quantification of quizartinib in rat plasma by liquid chromatography/tandem mass spectrometry for pharmacokinetic application.

Quizartinib is a highly potent inhibitor of the fms-like tyrosine kinase receptor, which is one of the most commonly mutated genes in acute myeloid leukemia. Quizartinib has shown a significant antileukemic clinical influence among relapsed/refractory acute myeloid leukemia patients. This study aimed at developing and validating an analytical method for the measurement of quizartinib in rat plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was validated according to US Food and Drug Administration guidelines, and the results obtained in this work met the set criteria. Liquid-liquid extraction was used and chromatographic separation was achieved on a BEHTM C18 column. Detection of quizartinib was achieved in multiple reaction monitoring mode using positive-ion mode electrospray ionization. The MS/MS ion transitions at mass-to-charge ratios (m/z) of 561.129/114.09 and 441.16/84.03 were monitored for quizartinib and ibrutinib, respectively. The linear detection range was 2-1000 ng/mL (r > 0.998), with intra- and inter-day assay precisions ≤13.07 and 13.17%, respectively. This rapid, simple and sensitive method was validated and successfully applied to the pharmacokinetic study of quizartinib in rat samples.

Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation.

Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 µM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC50 = 21 and 29 µM, respectively) and MDA-MB-468 (IC50 = 23 and 24 µM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d.

2-((Benzimidazol-2-yl)thio)-1-arylethan-1-ones: Synthesis, crystal study and cancer stem cells CD133 targeting potential.

In order to develop a potent anti-tumor agent that can target both cancer stem cells and the bulk of tumor cells, a series of 2-((benzimidazol-2-yl)thio)-1-arylethan-1-ones 5a-o was synthesized. All compounds were evaluated for their anti-proliferative activity towards colon HT-29 cancer cell line. In addition, their inhibitory effect against cell surface expression of CD133, a potent cancer stem cells (CSCs) marker, in the same cells was evaluated by flow cytometry at 10 µM. Compound 5l emerged as the most active anti-proliferative analog against HT-29 (IC50 = 18.83 ± 1.37 µM), that almost equipotent as 5-fluorouracil (IC50 = 15.83 ± 1.63 µM) with 50.11 ± 4.05% inhibition effect on CD133 expression, suggested dual targeted effect. Also, compounds 5h, 5j, 5k and 5m-o inhibited the expression of CD133 with more than 50%. The SAR study pointed out the significance of substitution of the pendent phenyl group with lipophilic electron-donating groups or replacing it by 2-thienyl or 2-furyl groups.

Synthesis, biological evaluation and 2D-QSAR study of halophenyl bis-hydrazones as antimicrobial and antitubercular agents.

In continuation of our endeavor towards the development of potent and effective antimicrobial agents, three series of halophenyl bis-hydrazones (14a-n, 16a-d, 17a and 17b) were synthesized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the identification of five molecules 14c, 14g, 16b, 17a and 17b (MIC range from 0.12 to 7.81 µg/mL) with broad antimicrobial activity against Mycobacterium tuberculosis; Aspergillus fumigates; Gram positive bacteria, Staphylococcus aureus, Streptococcus pneumonia, and Bacillis subtilis; and Gram negative bacteria, Salmonella typhimurium, Klebsiella pneumonia, and Escherichia coli. Three of the most active compounds, 16b, 17a and 17b, were also devoid of apparent cytotoxicity to lung cancer cell line A549. Amphotericin B and ciprofloxacin were used as references for antifungal and antibacterial screening, while isoniazid and pyrazinamide were used as references for antimycobacterial activity. Furthermore, three Quantitative Structure Activity Relationship (QSAR) models were built to explore the structural requirements controlling the different activities of the prepared bis-hydrazones.

Synthesis and anticancer potential of certain novel 2-oxo-N'-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazides.

Treatment of ethyl 3-hydrazinyl-3-oxopropanoate (6) with indoline-2,3-dione derivatives 7a-g gave ethyl 3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propanoates 8a-g which were allowed to react with the appropriate salicyaldehyde 9a and/or 9b to furnish the chromene-based hydrazones 10a-i. Compounds 10a-i displayed a significant activity against HT-29 colon cancer cell line and a moderate activity against leukemia K562 cell line. Compound 10f emerged as the most active congener toward HT-29 colon cancer cell line with IC50 = 7.98 ± 0.05 µM whereas compound 10c exhibited the best antiproliferative activity against leukemia K562 cell line with IC50 = 9.44 ± 0.02 µM. Moreover, compound 1e showed 87.81 ± 7% inhibition of side population (SP) HT-29 colon cancer stem cells.

Thiazolo[3,2-a]benzimidazoles: synthetic strategies, chemical transformations and biological activities.

The present review covers the recent synthetic strategies and chemical transformations of thiazolo[3,2-a]benzimidazoles and it also presents the highlights of the biological activities of these compounds.