Adnan A. Kadi

Synthesis, analgesic and anti-inflammatory evaluation of some novel quinazoline derivatives

Two series of some new 2,4,6-trisubstituted-quinazoline derivatives were prepared and screened for their analgesic, anti-inflammatory activity and acute toxicity. Four compounds were more potent analgesic agents than the reference drug Indomethacin and thirteen compounds showed significant anti-inflammatory activity. Seven compounds showed combined ability to inhibit both pain and inflammation. Compounds tested for acute toxicity showed no toxic symptoms or mortality rates 24 h post-administration implying their good safety margin.

Synthesis, Analgesic and Anti-Inflammatory Evaluation of Some New 3H-Quinazolin-4-one Derivatives

In this study, we have synthesized a series of 3H‐quinazolin‐4‐ones in order to obtain new compounds with potential analgesic and anti‐inflammatory activity. The structures of the newly synthesized compounds were confirmed by means of infrared, nuclear magnetic resonance and mass spectroscopy. Some compounds were evaluated for their analgesic and anti‐inflammatory activities by writhing and carrageenan‐induced rat paw edema tests, respectively. In comparison to the standard drug indomethacine, compounds 4, 6c, 12–14, 16, 18, 19, and 22 induced significant reduction in the writhing response while compounds 6c, 12, 14, 16, 18, and 22 produced a good dose‐dependent anti‐inflammatory activity. The best dual analgesic / anti‐inflammatory relative activity was observed with compounds 6c, 14, 16, 18, and 22.

Synthesis and anticonvulsant activity of some new thiazolo[3,2-a][1,3]diazepine, benzo[d]thiazolo[5,2-a][12,6]diazepine and benzo[d]oxazolo[5,2-a][12,6]diazepine analogues

A new series of 6,7-dihydro-thiazolo[3,2-a][1,3]diazepines (9-12), benzo[d]thiazolo[5,2-a][12,6]diazepines (19-21) and benzo[d]oxazolo[5,2-a][12,6]diazepine (24) analogues were synthesized and evaluated for their anticonvulsant activity. Compounds (E)-2-bromo-6,7-dihydro-thiazolo[3,2-a][1,3]diazepine-8(5H)-thione (12), 3-chloro-benzo[d]thiazolo[5,2-a][12,6]diazepin-10-one (20), and 4-chloro-benzo[d]oxazolo[5,2-a][12,6] diazepin-10-one (24) showed 100% protection against PTZ- and bicuculline-induced seizures; 70%, 33%, 70% protection against MES-induced tonic extension; and 70%, 66%, 100% protection against picrotoxin-induced convulsions, respectively. Compounds 12, 20, and 24 proved to act as GABA(A) receptor agonists, with ED(50) values of 252, 380, 251 mg/kg; TD(50) values of 398, 417, 355 mg/kg; PI values of 1.58, 1.09, 1.41; LD(50) values of 380, 617, 537 mg/kg and TI values of 1.51, 1.62, 2.14, respectively.

Identification and characterization of in vitro phase I and reactive metabolites of masitinib using a LC-MS/MS method: bioactivation pathway elucidation

Masitinib is a selective tyrosine kinase inhibitor (TKI). It is currently registered in Europe for the treatment of mast cell tumors in dogs. The current study reports the identification and characterization of fourteen phase I metabolites of masitinib by reversed phase liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS). Phase I metabolic reactions were reduction, demethylation, hydroxylation, oxidation and N-oxide formation. Structures of the proposed phase I metabolites showed high lability to form reactive metabolites. So incubation was performed in the presence of 1.0 mM GSH or 1.0 mM KCN to check for reactive metabolites. No GSH adduct was found, while eight cyano adduct structures were determined based on full MS scan and MS2 scan data for each metabolite. Interestingly, a literature review showed no previous studies have been made on the in vitro metabolism of masitinib or detailed structural identification of the formed metabolites.

Microwave-Assisted One-Step Synthesis of Fenamic Acid Hydrazides from the Corresponding Acids

A facile and efficient method for synthesis of fenamic acid hydrazides from their acids in one-step reaction under microwave irradiation and solvent-free conditions was developed. Compared with the two-step conventional heating method, the process was simple, the reaction time was very short and the yields were almost quantitative.

Validated LC-MS/MS Method for the Quantification of Ponatinib in Plasma: Application to Metabolic Stability.

In the current work, a rapid, specific, sensitive and validated liquid chromatography tandem mass-spectrometric method was developed for the quantification of ponatinib (PNT) in human plasma and rat liver microsomes (RLMs) with its application to metabolic stability. Chromatographic separation of PNT and vandetanib (IS) were accomplished on Agilent eclipse plus C18 analytical column (50 mm × 2.1 mm, 1.8 μm particle size) maintained at 21±2°C. Flow rate was 0.25 mLmin-1 with run time of 4 min. Mobile phase consisted of solvent A (10 mM ammonium formate, pH adjusted to 4.1 with formic acid) and solvent B (acetonitrile). Ions were generated by electrospray (ESI) and multiple reaction monitoring (MRM) was used as basis for quantification. The results revealed a linear calibration curve in the range of 5–400 ngmL-1 (r2 ≥ 0.9998) with lower limit of quantification (LOQ) and lower limit of detection (LOD) of 4.66 and 1.53 ngmL-1 in plasma, 4.19 and 1.38 ngmL-1 in RLMs. The intra- and inter-day precision and accuracy in plasma ranged from1.06 to 2.54% and -1.48 to -0.17, respectively. Whereas in RLMs ranged from 0.97 to 2.31% and -1.65 to -0.3%. The developed procedure was applied for quantification of PNT in human plasma and RLMs for study metabolic stability of PNT. PNT disappeared rapidly in the 1st 10 minutes of RLM incubation and the disappearance plateaued out for the rest of the incubation. In vitro half-life (t1/2) was 6.26 min and intrinsic clearance (CLin) was 15.182± 0.477.

Synthesis, Ultra-Short Acting Hypnotic Activity, and Metabolic Profile of Ethyl 8-Oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a] [1,3]diazepin-3-carboxylate (HIE-124)

The synthesis and biological evaluation of ethyl 8‐oxo‐5,6,7,8‐tetrahydro‐thiazolo[3,2‐a][1,3]diazepin‐3‐carboxylate (HIE‐124, 4), as a member of a new generation of ultra‐short acting hypnotics is described. HIE‐124 4 exhibited potent in‐vivo activity with a very rapid onset of action and a shorter duration of action with no acute tolerance or noticeable side effects than thiopental sodium. The rat in‐vivo and in‐vitro metabolic profile of 4 is also described. Urine was pooled from a number of animals and analyzed using electrospray liquid chromatography mass spectrometry (ESI LC‐MS). HIE‐124 4 was incubated with rat‐liver microsomal and rat‐liver hepatocyte preparations then similarly analyzed. The only metabolic product of both in‐vitro and in‐vivo experiments is the carboxylic acid derivative 5. HIE‐124 4 has the potential use not only as a pre‐anesthetic medication and as anesthesia inducer but also has the potential to be used with thiopental sodium to maintain anesthesia for longer duration.

Detection and characterization of ponatinib reactive metabolites by liquid chromatography tandem mass spectrometry and elucidation of bioactivation pathways

Ponatinib (PNT), as a multi-targeted tyrosine kinase inhibitor, is active against T315I and other BCR-ABL mutants. PNT is registered in the U.S. and EU under the trade name of Iclusig®. The current study reports the identification and characterization of in vitro metabolites of PNT, which were produced by its incubation with rat liver microsomes (RLMs). PNT and its metabolites were extracted from the incubation mixture by the protein precipitation procedure and the supernatants were injected into high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) equipment. Reversed phase liquid chromatography resolved seven in vitro PNT metabolites. Each metabolite displayed one or more metabolic reaction pathways including N-demethylation, N-oxide formation, oxidation, reduction and hydroxylation. Structures of the PNT metabolites showed high liability to form reactive metabolites. Since bioactivation is often speculated to be responsible for observed idiosyncratic toxicities including hepatotoxicity, incubation of PNT with RLMs was carried out in the presence of 1.0 mM GSH or 1.0 mM KCN to check its reactive metabolites. No GSH adduct was found while four cyano adduct metabolites were determined and their structures were proposed based on the mass scan and product ion data for each metabolite.

Microwave-Assisted Solution-Phase Synthesis and DART-Mass Spectrometric Monitoring of a Combinatorial Library of Indolin-2,3-dione Schiff Bases with Potential Antimycobacterial Activity

A combinatorial library composed of eleven hydrazides A-K and eleven indolin-1,2-dione derivatives 1-11 has been designed to formally generate sublibraries of 22 mixtures, M1-M22 comprising of 121 Schiff bases, A-K(1-11). The designed library has been synthesized by the solution-phase method and microwave-assisted synthetic techniques. The formation of individual compounds of each mixture was confirmed by Direct Analysis in Real Time (DART) as ionization technique connected to an Ion Trap as a mass detector. The synthesized mixtures were evaluated for their antimycobacterial activity against four Mycobacterium strains; M. intercellulari, M. xenopi, M. cheleneoi and M. smegmatis. Variable antimycobacterial activity was revealed with the investigated mixtures and maximum activity was shown by M8, M10, M11, and M15 with MIC values of 1.5, 3.1, 6.2 and 0.09 μg/mL, respectively. Application of the indexed method of analysis on these active mixtures revealed that compounds D8, D10 and D11 may contribute to the activity of the tested mixtures.

An LC‐MS/MS method for rapid and sensitive high‐throughput simultaneous determination of various protein kinase inhibitors in human plasma

A reliable, high-throughput and sensitive LC-MS/MS procedure was developed and validated for the determination of five tyrosine kinase inhibitors in human plasma. Following their extraction from human plasma, samples were eluted on a RP Luna®-PFP 100 Å column using a mobile phase system composed of acetonitrile and 0.01 m ammonium formate in water (pH ~4.1) with a ratio of (50:50, v/v) flowing at 0.3 mL min-1 . The mass spectrometer was operating with electrospray ionization in the positive ion multiple reaction monitoring mode. The proposed methodology resulted in linear calibration plots with correlation coefficients values of r2  = 0.9995-0.9999 from concentration ranges of 2.5-100 ng mL-1 for imatinib, 5.0-100 ng mL-1 for sorafenib, tofacitinib and afatinib, and 1.0-100 ng mL-1 for cabozantinib. The procedure was validated in terms of its specificity, limit of detection (0.32-1.71 ng mL-1 ), lower limit of quantification (0.97-5.07 ng mL-1 ), intra- and inter assay accuracy (-3.83 to +2.40%) and precision (<3.37%), matrix effect and recovery and stability. Our results demonstrated that the proposed method is highly reliable for routine quantification of the investigated tyrosine kinase inhibitors in human plasma and can be efficiently applied in the rapid and sensitive analysis of their clinical samples.