Ismail Salama

Design, synthesis, and biological evaluation of novel thiazolidinediones as PPARγ/FFAR1 dual agonists.

Diabetes mellitus is a chronic metabolic disorder that affects more than 180 million people worldwide. Peroxisome proliferator activated receptors (PPARs) are a group of nuclear receptors that have been targeted by the thiazolidinedione (TZD) class of compounds for the management of type II diabetes. PPARγ is known to regulate adipogenesis and glucose metabolism. Another emerging target for the design of antidiabetic agents is the free fatty acid receptor 1 (FFAR1), previously known as GPR40. Agonists of this receptor were found to enhance insulin secretion in diabetic patients. It has been reported that some thiazolidinediones (TZDs) activate FFAR1 with micromolar potency. In this study, based on docking studies into the crystal structure of PPARγ and a homology model of FFAR1, nineteen compounds were designed, synthesized, and biologically tested for agonistic activity on both receptors. Nine compounds showed promising dual activity, with two compounds, 11a and 5b, having affinities in the low micromolar range on both targets. These molecules represent the first antidiabetic agents that could act as insulin sensitizers as well as insulin secretagogues.

HPLC and Chemometric Methods for the Simultaneous Determination of Miconazole Nitrate and Nystatin

High-performance liquid chromatography (HPLC) and chemometric methods were applied to the simultaneous determination of the two nonsteroidal antifungal drugs, miconazole (MIC) and nystatin (NYS). The applied chemometric techniques are multivariate methods including classical least squares, principal component regression and partial least squares methods. The ultraviolet (UV) absorption spectra of the standard solutions of the training and validation sets in methanol are recorded in the range of 280-320 nm at 0.2-nm intervals. The HPLC method depends on reversed-phase separation using a C18 column. The mobile phase consists of a mixture of methanol-acetonitrile-ammonium acetate buffer (pH 6; 50 mM) (60:30:10 v/v/v). The UV detector was set at 230 nm. The developed methods were validated and successfully applied to the simultaneous determination of MIC and NYS in their tablets. The assay results obtained using the chemometric methods were statistically compared to those of the HPLC method and good agreement was observed.

1,4-Disubstituted aromatic piperazines with high 5-HT2A/D2 selectivity: Quantitative structure-selectivity investigations, docking, synthesis and biological evaluation

Simultaneous targeting of dopamine D2 and 5-HT2A receptors for the treatment of schizophrenia is one key feature of typical and atypical antipsychotics. In most of the top-selling antipsychotic drugs like aripiprazole and risperidone, high affinity to both receptors can be attributed to the presence of 1,4-disubstituted aromatic piperazines or piperidines as primary receptor recognition elements. Taking advantage of our in-house library of phenylpiperazine-derived dopamine receptor ligands and experimental data, we established highly significant CoMFA and CoMSIA models for the prediction of 5-HT2A over D2 selectivity. Subsequently, the models were applied to identify the selective candidates 55-57 from our newly synthesized library of GPCR ligands comprising a pyrazolo[1,5-a]pyridine head group and a 1,2,3-triazole based linker unit. The test compound 57 showed subnanomolar a Ki value (0.64 nM) for 5-HT2A and more than 10- and 30-fold selectivity over the dopamine receptor isoforms D2S and D2L, respectively.

RP-HPLC/Pre-Column Derivatization for Analysis of Omeprazole, Tinidazole, Doxycycline and Clarithromycin

A validated, reliable and accurate reversed-phase high performance liquid chromatographic method using pre-column derivatization was adopted for the simultaneous determination of two ternary mixtures containing omeprazole, tinidazole and doxycycline hyclate or clarithromycin. Separation was achieved on a C18 column, through a gradient elution system using acetonitrile-methanol-water adjusted to pH = 6.60. Drugs were detected at 277 nm over concentration ranges of 1-112, 5-125, 2.5-550 and 2.5-100 µg/mL for omeprazole, tinidazole, doxycycline hyclate and clarithromycin, respectively. This is the first method that has isolated and identified clarithromycin derivative by infrared and mass spectroscopy. This method is the first study for the simultaneous determination of omeprazole, tinidazole, doxycycline hyclate and clarithromycin in combined mixtures and pharmaceutical formulations.

Synthesis and binding profile of haloperidol-based bivalent ligands targeting dopamine D(2)-like receptors.

Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the pathophysiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsychotics. This study describes the development of a series of novel bivalent molecules with a pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investigated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diagnostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simultaneous occupancy of two neighboring binding sites.

Development and validation of a sensitive UHPLC-MS/MS method for the simultaneous analysis of tramadol, dextromethorphan chlorpheniramine and their major metabolites in human plasma in forensic context: application to pharmacokinetics

The prerequisites for forensic confirmatory analysis by LC/MS/MS with respect to European Union guidelines are chromatographic separation, a minimum number of two MS/MS transitions to obtain the required identification points and predefined thresholds for the variability of the relative intensities of the MS/MS transitions (MRM transitions) in samples and reference standards. In the present study, a fast, sensitive and robust method to quantify tramadol, chlorpheniramine, dextromethorphan and their major metabolites, O-desmethyltramadol, dsmethyl-chlorpheniramine and dextrophan, respectively, in human plasma using ibuprofen as internal standard (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction method using ethyl acetate-diethyl-ether (1:1). Extracted samples were analyzed by ultra-high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase containing acetonitrile, water and formic acid (89.2:11.7:0.1) for 2.0 min at a flow rate of 0.25 μL/min into a Hypersil-Gold C18 column, 20 × 2.0 mm (1.9 µm) from Thermoscientific, New York, USA. The calibration curve was linear for the six analytes. The intraday precision (RSD) and accuracy (RE) of the method were 3-9.8 and -1.7-4.5%, respectively. The analytical procedure herein described was used to assess the pharmacokinetics of the analytes in 24 healthy volunteers after a single oral dose containing 50 mg of tramadol hydrochloride, 3 mg chlorpheniramine maleate and 15 mg of dextromethorphan hydrobromide.

STABILITY-INDICATING CHROMATOGRAPHIC METHOD FOR THE DETERMINATION OF BENZONATATE, DIPHENHYDRAMINE, GUAIFENESIN, AND PHENYLEPHRINE

A high-performance liquid chromatographic method has been developed for the simultaneous analysis of benzonatate (BNZ), diphenhydramine hydrochloride (DPH), guaifenesin (GFN), and phenylephrine hydrochloride (PEP). The separation was achieved using a Thermo C18 reversed-phase column (250 mm × 4.6 mm ID, particle size 5 µ). Dual mode gradient elution was used for the separation and UV detection was carried out at 222 nm. The method was specific and stability indicating as chromatographic conditions provided adequate separation of degradation products. The method showed good linearity in the range of 5–400, 1–120, 3–300, and 2–100 µg/mL for BNZ, DPH, GFN, and PEP, respectively. All the square of the correlation coefficients are 0.999. The degradation products were isolated and identified by NMR, IR, and mass spectroscopy. The proposed method proved to be accurate, precise, selective, and robust. The applicability of the method was evaluated in commercial dosage form analysis as well as in stability studies.

Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-γ/FFAR1 agonists

Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-γ (PPAR-γ) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue.

Discovery of tetrahydro-ß-carboline derivatives as a new class of phosphodiesterase 4 inhibitors

Phosphodiesterase 4 is the primary enzyme responsible for degradation of the second messenger cAMP in many of the cells releasing proinflammatory mediators. Inhibition of this enzyme could help in the management of various inflammatory conditions such as asthma, chronic obstructive pulmonary disorder, arthritis, and psoriasis. In this study, two novel series of tetrahydro-β-carbolines were designed by combining the pharmacophoric features of both tadalafil and piclamilast. Twenty-two compounds were synthesized and assessed for Phosphodiesterase 4 inhibition, four of them showed superior activity to the reference compound IBMX. Docking studies showed that the prepared compounds interact with the crucial Gln443 with variable interactions with the hydrophobic pocket Q2. This is the first report of tetrahydro-β-carbolines as a scaffold for Phosphodiesterase 4 inhibition. Currently, further optimization of the substituents is carried out to fine-tune the hydrophobic interactions and enhance the potency of this novel series of inhibitors.Graphical abstract

Comparative Study of New Hplc And Hptlc Methods For Simultaneous Determination of Dipyrone And Camylofin Dihydrochloride Using Hyoscine Butyl Bromide As Internal Standard

Two new methods are developed for simultaneous determination of dipyrone (Dip) and camylofin dihydrochloride (Cam) in bulk and in pharmaceutical formulation (Spasmopyralgin M ® tablet) using hyoscine butyl bromide as internal standard (I.S.) to further increase the applicability of the methods. The first method was based on HPLC separation of studied compounds using 250 x 4.6 mm (i.d.) phenomenex (5μm particle size) C18 column as stationary phase and mixture of 50 mM ammonium acetate (pH adjusted to 5.3 using acetic acid) and acetonitrile as mobile phase. The second one was HPTLC method where the separation was achieved on Merck HPTLC aluminium plates of silica gel 60 F254 using acetone: methanol: acetic acid (52: 28: 20, v/v/v) as mobile phase. Comparative study was performed to argue the advantage of each method and determine which one is better for routine analysis of studied drugs.