Yousif A. Asiri

Design, synthesis, and biological evaluation of substituted hydrazone and pyrazole derivatives as selective COX-2 inhibitors: Molecular docking study.

New arylhydrazone derivatives and a series of 1,5-diphenyl pyrazoles were designed and synthesized from 1-(4-chlorophenyl)-4,4,4-trifuorobutane-1,3-dione 1. The newly synthesized compounds were investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw oedema model. Moreover, they were tested for their inhibitory activity against ovine COX-1 and COX-2 using an in vitro cyclooxygenase (COX) inhibition assay. Some of the new compounds (2f, 6a and 6d) showed a reasonable in vitro COX-2 inhibitory activity, with IC₅₀ value of 0.45 μM and selectivity index of 111.1. A virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Docking study of the synthesized compounds 2f, 6a and 6d into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Synthesis, anti-inflammatory activity and COX-1/COX-2 inhibition of novel substituted cyclic imides. Part 1: Molecular docking study.

A group of cyclic imides (1-13) was designed for evaluation as selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activities using carrageenan-induced rat paw edema model. Compounds 5b, 6b, 11b, 11c, 12b and 12c were proved to be potent COX-2 inhibitors with IC50 range of 0.1-1.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 5b as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)=400] comparable to celecoxib [COX-2 (SI)>333.3], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=104 mg/kg) relative to diclofenac (ED50=114 mg/kg). A Virtual screening was carried out through docking the designed compounds into the COX-2 binding site to predict if these compounds have analogous binding mode to the COX-2 inhibitors. Molecular modeling (docking) study showed that the CH3O substituents of 5b inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such group underwent a H-bonding interaction with His90 (2.43, 2.83 Å), Arg513 (2.89 Å) and Tyr355 (3.34 Å). Docking study of the synthesized compound 5b into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

In vivo evaluation of hydrochlorothiazide liquisolid tablets in beagle dogs

This study was carried out to evaluate the absorption characteristics of experimentally developed hydrochlorothiazide liquisolid tablets using six male beagle dogs. Comparison with reference commercial tablets was made. As no bibliographic data were found for the pharmacokinetic parameters of the drug in dogs, an intravenous drug administration was included in the study. The drug was administered orally as a single 25 mg dose of commercial and liquisolid tablets on two occasions in a randomized two-way crossover design. The pharmacokinetic parameters of the drug post intravenous dosing were reported for the first time. The results of the oral administration revealed statistically significant differences between the liquisolid and the commercial tablets in the area under the plasma concentration-time curve, the peak plasma concentration, and the absolute bioavailability. On the other hand, no significant differences were observed between the two formulations with regard to the mean residence time, the mean absorption time, and the rate of absorption. The absolute bioavailability of the drug from the liquisolid tablets was 15% higher than that from the commercial one. The parametric 90% confidence intervals for the different parameters were higher than the commonly expected intervals for bioequivalency, indicating greater bioavailability of the liquisolid tablets.

Design, synthesis and antibacterial activity of fluoroquinolones containing bulky arenesulfonyl fragment: 2D-QSAR and docking study

Here in, we report the design, synthesis, and antibacterial activity of series of bulky arenesulfonamido derivatives using ciprofloxacin and norfloxacin as scaffolds. All the synthesized compounds were investigated in vitro for their antibacterial activities against two Gram-positive and two Gram-negative organisms using dilution broth method. Among the tested compounds examined, compounds 3-7 showed significance difference from the standard drug ciprofloxacin. 2D-QSAR study provides details on the fine relationship linking structure and activity and offers clues for structural modifications that can improve the activity. Docking study of the compound 3b into the active site of the topoisomerase II DNA-gyrase enzymes revealed a similar binding mode to ciprofloxacin with additional classical and nonclassical hydrogen bonds.

Effect of long-term human exposure to environmental heavy metals on the expression of detoxification and DNA repair genes.

The present study was designed to evaluate the influence of long-term environmental human exposure to three heavy metals, lead (Pb), cadmium (Cd), and mercury (Hg), on the expression of detoxifying, xenobiotic metabolizing, and DNA repair genes in Mahd Ad-Dahab city. The study groups consisted of 40 healthy male residents (heavy metal-exposed) and 20 healthy male from Riyadh city, 700 km away, and served as control group. The heavy metal-exposed group with high exposure to Pb, Cd, or Hg was divided into three subgroups Pb-, Cd-, and Hg-exposed groups, respectively. The mRNA expression levels of detoxifying, NQO1, HO-1, GSTA1, MT-1, and HSP70, were significantly decreased in all heavy metal-exposed group as compared to control group. This was accompanied with a proportional decrease in the expression of xenobiotic metabolizing gene, cytochrome P4501A1. On the other hand, the DNA repair gene OGG1 and the 8-OHdG level were dramatically inhibited in Cd-exposed group only.

Rapid determination of canagliflozin in rat plasma by UHPLC-MS/MS using negative ionization mode to avoid adduct-ions formation.

Canagliflozin is the first sodium-glucose co-transporter-2 inhibitor, approved by the US Food and Drug Administration for the treatment of type 2 diabetes mellitus. In this study, a sensitive UHPLC-MS/MS assay for rapid determination of canagliflozin in rat plasma was developed and validated for the first time. Chromatographic separation of canagliflozin and zafirlukast (IS) was carried out on Acquity BEH C18 column (100×2.1 mm, i.d. 1.7 µm) using acetonitrile-water (80:20, v/v) as mobile phase at a flow rate of 0.3 mL min(-1). Canagliflozin and IS were extracted from plasma by protein precipitation method using acetonitrile. The mass spectrometric detection was performed using electrospray ionization source in negative mode to avoid canagliflozin adduct ions formation. Multiple reaction monitoring were used for quantitation of precursor to product ion at m/z 443.16 >364.96 for canagliflozin and m/z 574.11>462.07 for IS, respectively. The assay was fully validated in terms of selectivity, linearity, accuracy, precision, recovery, matrix effects and stability. The validated method was successfully applied to the characterization of oral pharmacokinetic profiles of canagliflozin in rats. The mean maximum plasma concentration of canagliflozin of 1616.79 ng mL(-1) was achieved in 1.5 h after oral administration of 20 mg kg(-1) in rats.

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Abstract The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1–14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI50; 2.63–3.09 µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI50; 22.60 µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI50; 3.24 µM) and are nearly 2-fold more potent compared to erlotinib (mean GI50; 7.29 µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

Polypharmacy and patterns in drug prescribing at a primary healthcare centre in the Riyadh region of Saudi Arabia

Objective  To elucidate the various patterns in drug prescribing in a non‐Ministry of Health‐affiliated primary healthcare centre model (Riyadh Kharj Military Hospital) in Saudi Arabia.

Effects of Green Tea Extracts on the Pharmacokinetics of Quetiapine in Rats

Quetiapine is an atypical antipsychotic, used clinically in the treatment of schizophrenia, acute mania in bipolar disorders, and bipolar depression in adults. In this study, the effect of green tea extracts (GTE) on the pharmacokinetics of quetiapine (substrate of CYP3A4) was investigated in rats. Male Wistar albino rats received GTE (175 mg/kg) or saline (control) by oral gavage for 7 days before a single intragastric administration of 25 mg/kg quetiapine. Plasma concentrations of quetiapine were measured up to 12 h after its administration by a validated ultraperformance liquid chromatography-tandem mass spectroscopy. Pretreatment with GTE produced significant reductions in the maximum plasma concentration and area under the curve of quetiapine by 45% and 35%, respectively, compared to quetiapine alone. However, GTE did not produce significant change in elimination half-life and oral clearance of quetiapine. This study concluded that GTE may decrease the bioavailability of quetiapine when coadministered.

Chapter 8 – Tadalafil

Tadalafil is PDE5 inhibitor that has recently been approved for the treatment of ED. The mechanism of action of tadalafil is similar to sildenafil and vardenafil through the inhibition of PDE. In both chemical structure and PDE subtype selectivity profile, tadalafil differs markedly from sildenafil and vardenafil. Compared with sildenafil and vardenafil, tadalafil exhibits a prolonged plasma residence and window of therapeutic response. The physical properties, spectroscopic data and chromatographic methods of determination of tadalafil are documented.