Mohammad A. Hassan

Improvement of the in vitro dissolution characteristics of famotidine by inclusion in β-cyclodextrin

Abstract An inclusion complex between famotidine and β-cyclodextrin was prepared by mixing the two components in a millimolar ratio in distilled water and heating under reflux for l h followed by stirring at room temperature for 5 days. Phase-solubility studies revealed the formation of a 1:1 complex of the AL type with a rate constant of 74.96 M−1. The formation of the complex in the solid state was confirmed by infrared spectroscopy and differential scanning calorimetry. The inclusion complex was shown by X-ray powder diffraction to be significantly less crystalline than any of the pure components. More significantly, the dissolution rate of the complex from constant surface-area discs was determined to be about twice and six times higher than that of the physical mixture and the pure drug, respectively.

Characterization of glibenclamide glassy state

Abstract Glibenclamide crystals were converted to the glassy state by cooling the melt on an ice bath. The glass state formation was confirmed by differential scanning calorimetry (DSC) measurements. Further evidence was provided by other techniques such as infrared spectroscopy (IR), X-ray powder diffraction, equilibrium solubility and dissolution studies. X-ray diffraction patterns of pulverized glassy glibenclamide stored up to 4 months at room temperature indicated no transformation to the crystalline state. The IR studies showed that the characteristic peaks of glibenclamide at 3310, 3100, 1725 and 1610 cm −1 decreased in intensity in the glassy state which was attributed to the partial transformation of the most stable keto form to the enol form during glass formation. storing glassy glibenclamide at different temperatures resulted in a decrease in its equilibrium solubility. This decrease was attributed to the partial transformation of the glassy form to a crystalline form. The kinetics of the transformation process were pseudo first order in nature. Dissolution studies showed that glassy glibenclamide exhibits a higher dissolution rate than either crystalline glibenclamide or a commercially available product (Daonil).

Generation of the First Structure-Based Pharmacophore Model Containing a Selective “Zinc Binding Group” Feature to Identify Potential Glyoxalase-1 Inhibitors

Within this study, a unique 3D structure-based pharmacophore model of the enzyme glyoxalase-1 (Glo-1) has been revealed. Glo-1 is considered a zinc metalloenzyme in which the inhibitor binding with zinc atom at the active site is crucial. To our knowledge, this is the first pharmacophore model that has a selective feature for a “zinc binding group” which has been customized within the structure-based pharmacophore model of Glo-1 to extract ligands that possess functional groups able to bind zinc atom solely from database screening. In addition, an extensive 2D similarity search using three diverse similarity techniques (Tanimoto, Dice, Cosine) has been performed over the commercially available “Zinc Clean Drug-Like Database” that contains around 10 million compounds to help find suitable inhibitors for this enzyme based on known inhibitors from the literature. The resultant hits were mapped over the structure based pharmacophore and the successful hits were further docked using three docking programs with different pose fitting and scoring techniques (GOLD, LibDock, CDOCKER). Nine candidates were suggested to be novel Glo-1 inhibitors containing the “zinc binding group” with the highest consensus scoring from docking.

A Stability-Indicating Hplc Analysis of Famotidine and Its Application to Kinetic Studies

Abstract A stability-indicating HPLC analytical method has been developed for the determination of the H2-receptor antagonist, famotidine in the presence of its degradation products. the method utilizes reversed phase chromatography with UV detection and internal calibration techniques. the mobile phase was comprised of 84% ammonium acetate buffer (pH 2.9) and 16% acetonitrile and pumped at a flow rate of 1.5 ml/min. Quantitation was performed by measuring the peak height ratio of drug to internal standard (salicylic acid). the limit of famotidine detection was determined to be 10 ng (0.4 ug/ml) with a signal to noise ratio of 3:1. Within day coefficient of variation of the method was 2.22% (2.5 μg/ml) and 0.82% (10 μg/ml). Between day coefficient of variation based on the slopes of daily prepared standard curves was 4.70%. the developed method was used to determine the drug content of famotidine tablets. Further, it was used to investigate the kinetics of degradation of the drug in an acidic solution.

Virtual lead identification of farnesyltransferase inhibitors based on ligand and structure-based pharmacophore techniques.

Farnesyltransferase enzyme (FTase) is considered an essential enzyme in the Ras signaling pathway associated with cancer. Thus, designing inhibitors for this enzyme might lead to the discovery of compounds with effective anticancer activity. In an attempt to obtain effective FTase inhibitors, pharmacophore hypotheses were generated using structure-based and ligand-based approaches built in Discovery Studio v3.1. Knowing the presence of the zinc feature is essential for inhibitor’s binding to the active site of FTase enzyme; further customization was applied to include this feature in the generated pharmacophore hypotheses. These pharmacophore hypotheses were thoroughly validated using various procedures such as ROC analysis and ligand pharmacophore mapping. The validated pharmacophore hypotheses were used to screen 3D databases to identify possible hits. Those which were both high ranked and showed sufficient ability to bind the zinc feature in active site, were further refined by applying drug-like criteria such as Lipiniski’s “rule of five” and ADMET filters. Finally, the two candidate compounds (ZINC39323901 and ZINC01034774) were allowed to dock using CDOCKER and GOLD in the active site of FTase enzyme to optimize hit selection.

Kinetics of the acid-catalyzed hydrolysis of famotidine

Abstract The kinetics of hydrolysis of famotidine were studied in 0.01–0.10 M hydrochloric acid solutions of 2 mg/ml using a stability-indicating high-performance liquid Chromatographic assay with ultraviolet detection. The hydrolysis followed pseudo-first order kinetics with respect to famotidine concentration. The observed rate constant was found to depend on hydrogen ion concentration and was not influenced by the ionic strength. The specific hydrogen ion catalytic rate constant was calculated to be 3.427 M −1 · h −1 at 37° C. The temperature dependence of famotidine hydrolysis was investigated in 0.1 M hydrochloric acid solutions having an ionic strength of 0.2 in the temperature range 37–55° C. The activation energy was determined to be 63.7 kJ/mol. The impact of the acid-catalyzed hydrolysis on the stability of famotidine in the stomach was discussed. It was estimated that in the gastric pH 1–2 and with a gastric emptying half-life of 50 min in normal young adults about 5.3–35.8% of an oral dose of famotidme would undergo degradation in the stomach. This percentage might be even increased to 12.0–57.8% in the elderly.

Novel N-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-IV enzyme

Background The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP-IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels. Methods In this study, computer-aided drug design was used to help establish a novel N-substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP-IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point. Results Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 μM concentration. Conclusion The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold.

Synthesis and Anticandidal Activity of Azole-Containing Sulfonamides

Twenty five benzenesulfonamides containing one imidazole or triazole ring, or two imidazole or triazole rings have been synthesized and evaluated as anticandidal agents. The most active compounds were 5c, 6b, 6c, 6e, and 17b, which exhibited MIC values of 4.55–24.39 mM depending on the clinical isolate. Comparing imidazole to triazole derivatives did not show a clear effect on activity. Compounds containing a N‐benzyl group also showed no clear evidence on activity given the fact that they have an extra aromatic ring. Secondary sulfonamides, 5l, 5m, and 5n showed activities that were proportional to their lipophilicity. The activities of N‐aryl‐substituted derivatives 5j, 5k, 5l, 5m, 5n, and 6j were also proportional to their lipophilicity. Halogenation enhanced the activity as a result of improvement of lipophilicity. The presence of two imidazole or triazole rings in the same compound did not show a clear enhancement of activity.

Physico-chemical characterization of a new salt of ibuprofen

A new salt of ibuprofen was prepared by reaction with t-butylamine; its formation was confirmed by IR and 1H-NMR spectroscopy. The salt was characterized by thermoanalytical, X-ray powder diffraction and solubility studies. The salt was found to be 1.5 times more soluble in water than was ibuprofen, with an enthalpy of solution of -8.84 kcal mol-1.

Methoxyphenylcipro induces antitumor activity in human cancer cells.

To examine the antitumor activity of a new derivative of ciprofloxacin called methoxyphenylcipro (CMPP). Cell viability was assessed using the MTT assay and apoptotic cells and reactive oxygen species were evaluated using flow cytometry. Results revealed that CMPP induces antiproliferative activity against breast cancer cells and melanoma and to a lesser extent against colorectal cancer cells. Interestingly, compared to ciprofloxacin, CMPP-induced a selective cytotoxicity against human cancer cells but not human normal fibroblasts. The potential of CMPP to inhibit cellular growth in MD-MB-486 breast cancer cells and MV3 melanoma cells was largely due to induction of caspase-dependent apoptosis, as confirmed by caspase-3 activation and cleavage of its substrate PARP. In addition, results indicated that CMPP-induced apoptosis is mediated by generation of reactive oxygen species. These findings revealed that CMPP has a selective antitumor activity against cancer cells and warrants further clinical evaluation.