Maha Habash

Ligand-based modelling followed by synthetic exploration unveil novel glycogen phosphorylase inhibitory leads.

Glycogen phosphorylase (GP) is a valid anti-diabetic target. Accordingly, we applied a drug discovery workflow to unveil novel inhibitory GP leads via combining pharmacophore modeling, QSAR analysis and in silico screening, followed by synthetic exploration of active hits. Virtual screening identified six low micromolar inhibitory leads from the National Cancer Institute (NCI) list of compounds. The most potent hits exhibited anti-GP IC(50) values of 3.2 and 4.1 μM. Synthetic exploration of hit 59 (IC(50)=4.1 μM) yielded 25 lead inhibitors with the best illustrating IC(50) of 3.0 μM. Interestingly, we prepared several novel mixed oxalyl amide anti-GP leads employing new chemical reaction involving succinic acid-based adducts.

Ligand-based modeling followed by in vitro bioassay yielded new potent glucokinase activators

Glucokinase (GK) has received recent interest as a valid antidiabetic target. With this in mind, we applied a computational workflow based on combining pharmacophore modeling and QSAR analysis followed by in silico screening toward the discovery of novel GK activators. Virtual screening identified 10 promising bioactivators from the National Cancer Institute (NCI) list of compounds. The most potent NCI hit illustrated 6.3-fold GK activation at 10 μM. These results demonstrated that our virtual screening protocol was able to identify novel GK activator leads for subsequent development into potential antidiabetic agents.

In Vitro and In Vivo Evaluation of Casein as a Drug Carrier for Enzymatically Triggered Dissolution Enhancement from Solid Dispersions

Due to its unique properties, such as biodegradability, biocompatibility, high amphiphilic property, and micelle formation, casein (CS) has been increasingly studied for drug delivery. We used CS as a drug carrier in solid dispersions (SDs) and evaluated the effect of its degradation by trypsin on drug dissolution from the dispersions. SDs of CS and mefenamic acid (MA) were prepared by physical mixing, kneading, and coprecipitation methods. In comparison to pure MA, the dispersions were evaluated for drug–protein interaction, loss of drug crystalinity, and drug morphology by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Drug dissolution from the dispersions was evaluated in simulated intestinal fluid as enzyme free and trypsin-enriched media. Furthermore, in vivo drug absorption of MA from CS-MA coprecipitate was evaluated in rats, in comparison with a reference SD of polyethylene glycol and MA (PEG-MA SD). Relative to other CS preparations, CS-MA coprecipitate showed the highest loss of drug crystallinity, drug micronization, and CS-MA interaction. CS remarkably enhanced the dissolution rate and extent of MA from the physical and kneaded mixtures. However, the highest dissolution enhancement was obtained when MA was coprecipitated with CS. Trypsin that can hydrolyze CS during dissolution resulted in further enhancement of MA dissolution from the physical and kneaded mixtures. However, a corresponding retardation effect was obtained for the coprecipitate. In correlation with in vitro drug release, CS-MA coprecipitate also showed significantly higher MA bioavailability in rats than PEG-MA SD.

Preparation and in vitro characterization of glibenclamide-loaded alginate hexyl-amide beads: a novel drug delivery system to improve the dissolution rate

Abstract Objective: This investigation aimed to synthesize amphiphilic hexyl amidic derivative of alginate to be used in the preparation of glibenclamide-loaded release system of improved dissolution rate. Materials and methods: Hexyl amine was associated to the activated carboxylic acid moieties of alginate to synthesize alginate hexyl amide polymer (AHAP). This polymer in comparison to alginate was used in different concentrations for preparing beads containing glibenclamide by an ionic gelation using Ca++ as gelling ion. The prepared beads were characterized by DSC, FTIR and scanning electron microscope. The swelling behavior, drug loading capacity and release behavior were studied. Results and discussion: The results showed that the prepared AHAP beads were smaller in size and more spherical. The surface was highly corrugated with much and wider pore size. The beads showed a high drug loading capacity and efficacy that was affected by the polymer concentration. The drug release rate from AHAP beads reached 100% after 4, 8 and 12 hours in comparison to 75.3%, 73.2% and 69.2% from alginate beads at 3%, 2% and 1% polymer concentrations, respectively. Conclusion: It can thus be concluded that the amphiphilic AHAP-based bead is a simple and efficient delivery system of promising industrial significance for the improvement of the dissolution rate.

Synthesis and evaluation of novel diphenylthiazole derivatives as potential anti-inflammatory agents

In the presented study, we synthesized a novel series of 18 diphenylthiazole derivatives and tested their anti-inflammatory properties. They showed significant anti-inflammatory properties in inflamed mice paws animal model. Docking-based analysis suggested that they act as COX enzyme inhibitors. The most potent compound 9e is significantly more active in reducing inflamed animal paws compared to diclofenac. Accordingly, we believe these compounds are good leads for further development into potent anti-inflammatory drugs.

Docking-based comparative intermolecular contacts analysis and in silico screening reveal new potent acetylcholinesterase inhibitors

The positive impact of acetylcholinesterase enzyme inhibitors on neurodegenerative diseases impelled continuous attempts to discover and optimize new acetylcholinesterase enzyme inhibitors. The combined recent interest inacetylcholinesterase enzyme inhibitors, together with known shortages of docking and docking validation methods prompted us to use our new 3D-QSAR method, namely, docking-based comparative intermolecular contacts analysis, to identify optimal docking conditions required to dock certain group of inhibitors into acetylcholinesterase enzyme binding site. Additionally, optimal docking-based comparative intermolecular contacts analysis models were converted into pharmacophore models, which were validated by receiver operating characteristic curve analysis. The pharmacophores were subsequently used as search queries to mine the national cancer institute list of compounds for new acetylcholinesterase enzyme inhibitors. Five low micromolar acetylcholinesterase enzyme inhibitors were identified. The most potent gave IC50 value of 2.55 μM.

Research advances in kinase enzymes and inhibitors for cardiovascular disease treatment

The targeting of protein kinases has great future potential for the design of new drugs against cardiovascular diseases (CVDs). Enormous efforts have been made toward achieving this aim. Unfortunately, kinase inhibitors designed to treat CVDs have suffered from numerous limitations such as poor selectivity, bad permeability and toxicity. So, where are we now in terms of discovering effective kinase targeting drugs to treat CVDs? Various drug design techniques have been approached for this purpose since the discovery of the inhibitory activity of Staurosporine against protein kinase C in 1986. This review aims to provide context for the status of several emerging classes of direct kinase modulators to treat CVDs and discuss challenges that are preventing scientists from finding new kinase drugs to treat heart disease.

Synthesis and Antibacterial Activity of Some Novel N,N-Di-Oxalamide Derivatives

Novel N,N-di-oxalamide derivatives 1-6 were synthesized and characterized by the spectroscopic techniques. These derivatives showed good antibacterial activities against Gram-negative organism Escherichia coli and Gram-positive organisms Staphylococcus aureus and Bacillus subtilus. However, compounds 3 and 4 showed potent antibacterial activity against Gram-negative organism Escherichia coliand Gram-positive organism Staphylococcus aureus. In addition to that, we compared their antibacterial profiles with previously synthesized N,N-di-oxalamide derivatives 7-9. The new compounds showed superior antibacterial activities compared to moderate activities for 7-9.