Amer M. Alanazi

Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2

A group of cyclic imides (1-10) was designed for evaluation as a selective COX-2 inhibitors and investigated in vivo for their anti-inflammatory activity. Compounds 6a, 6b, 8a, 8b, 9a, 9b, 10a and 10b were proved to be potent COX-2 inhibitors with IC50 range of 0.1-4.0 μM. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 8a as a highly potent (IC50=0.1 μM), and an extremely selective [COX-2 (SI)>1000] comparable to celecoxib [COX-2 (SI)>384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50=72.4 mg/kg) relative to diclofenac (ED50=114 mg/kg). Molecular modeling 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. The study showed that the homosulfonamide fragment of 8a inserted deep inside the 2°-pocket of the COX-2 active site, where the SO2NH2 group underwent H-bonding interaction with Gln(192)(2.95 Å), Phe(518)(2.82 Å) and Arg(513)(2.63 and 2.73 Å). Docking study of the synthesized compound 8a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.

Fluorescence spectroscopic and molecular docking studies of the binding interaction between the new anaplastic lymphoma kinase inhibitor crizotinib and bovine serum albumin.

Binding of the recently introduced anti-cancer drug, crizotinib (CRB) with the bovine serum albumin (BSA) was comprehensively studied with the aid of fluorescence and UV-Vis spectroscopic as well as molecular docking techniques. The collective results of the study under the simulated physiological conditions proposed a static type of binding occurring between the CRB and BSA with binding constants of 104Lmol-1. BSA conformational changes were investigated using three dimensional (3D) and synchronous fluorescence measurements. Moreover, the results of site marker competitive experiments and molecular docking, it could be deduced that CRB was inserted into the subdomain IIA (site I) of BSA yielding a more stabilized system. This was further confirmed with the molecular docking results which revealed that CRB is located in the active site residues Try149, Glu152, Ser191, Arg194, Arg198, Trp213, Arg217, Arg256, His287, Ala290, Glu291, Ser343, Asp450 within a radius of 6Å. Combining the molecular docking studies and the computed thermodynamic parameters, it can be inferred that hydrophobic and electrostatic interactions are the major binding forces involved in formation of the CRB-BSA complex.

Design, synthesis and biological evaluation of 2-mercapto-3-phenethylquinazoline bearing anilide fragments as potential antitumor agents: Molecular docking study

A novel series of 2-(3-phenethyl-4(3H)quinazolin-2-ylthio)-N-substituted anilide and substituted phenyl 2-(3-phenethyl-4(3H) quinazolin-2-ylthio)acetate were designed, synthesized and evaluated for their in-vitro antitumor activity. Compound 15 possessed remarkable broad-spectrum antitumor activity which almost sevenfold more active than the known drug 5-FU with GI50 values of 3.16 and 22.60 μM, respectively. Compound 15 exhibited remarkable growth inhibitory activity pattern against renal cancer (GI50=1.77 μM), colon cancer (GI50=2.02 μM), non-small cell lung cancer (GI50=2.04 μM), breast cancer (GI50=2.77 μM), ovarian cancer (GI50=2.55 μM) and melanoma cancer (GI50=3.30 μM). Docking study was performed for compound 15 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib.

Design, synthesis, single-crystal and preliminary antitumor activity of novel arenesulfonylimidazolidin-2-ones.

Novel series of 1-(arenesulfonyl)imidazolidin-2-one (3a-i) and 1,3-bis(arenesulfonyl)imidazolidin-2-one (5a-i) have been synthesized and tested for their antitumor activity against 60 tumor cell lines taken from nine different organs. A significant inhibition for cancer cells was observed with series 5a-i compounds compared with the series 3a-i which showed a weak inhibition. Compounds 5a-i showed good inhibitory effect at the lung cancer HOP-92 and renal cancer CAKI-1 and UO-31 cell lines. Compound 5e showed remarkable broad-spectrum antitumor activity.

Synthesis, antitumor activity and molecular docking study of some novel 3-benzyl-4(3H)quinazolinone analogues

Abstract A novel series of 3-benzyl-substituted-4(3H)-quinazolinones were designed, synthesized and evaluated for their in vitro antitumor activity. The results of this study demonstrated that 2-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide, 2-(3-benzyl-6,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)acetamide and 3-(3-benzyl-6-methyl-4-oxo-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl)-propanamide have shown amazing broad spectrum antitumor activity with mean GI50 (10.47, 7.24 and 14.12 µM. respectively), and are nearly 1.5–3.0-fold more potent compared with the positive control 5-FU with mean GI50, 22.60 µM. On the other hand, compounds 6 and 10 yielded selective activities toward CNS, renal and breast cancer cell lines, whereas compound 9 showed selective activities towards leukemia cell lines. Molecular docking methodology was performed for compounds 7 and 8 into ATP binding site of EGFR-TK which showed similar binding mode to erlotinib, while compound 11 into ATP binding site of B-RAF kinase inhibited the growth of melanoma cell lines through inhibition of B-RAF kinase, similar to PLX4032.

Synthesis, antitumor and antimicrobial activity of some new 6-methyl-3-phenyl-4(3H)-quinazolinone analogues: in silico studies

Abstract Some new derivatives of substituted-4(3H)-quinazolinones were synthesized and evaluated for their in vitro antitumor and antimicrobial activities. The results of this study demonstrated that compound 5 yielded selective activities toward NSC Lung Cancer EKVX cell line, Colon Cancer HCT-15 cell line and Breast Cancer MDA-MB-231/ATCC cell line, while NSC Lung Cancer EKVX cell line and CNS Cancer SF-295 cell line were sensitive to compound 8. Additionally, compounds 12 and 13 showed moderate effectiveness toward numerous cell lines belonging to different tumor subpanels. On the other hand, the results of antimicrobial screening revealed that compounds 1, 9 and 14 are the most active against Staphylococcus aureus ATCC 29213 with minimum inhibitory concentration (MIC) of 16, 32 and 32 μg/mL respectively, while compound 14 possessed antimicrobial activities against all tested strains with the lowest MIC compared with other tested compounds. In silico study, ADME-Tox prediction and molecular docking methodology were used to study the antitumor activity and to identify the structural features required for antitumor activity.

Synthesis, molecular modeling study, preliminary antibacterial, and antitumor evaluation of N-substituted naphthalimides and their structural analogues

Carboxylic acid imides 1–26 have been synthesized and screened for their antibacterial against gram-positive and gram-negative organisms and their antitumor activity against 60 tumor cell lines taken from nine different organs. Compounds 12, 14, and 16 were the most active and broad-spectrum antibacterial member in this study. Compound 9 showed the most cytotoxicity with a significant inhibition for renal cancer cells. 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 compounds 12, 14, and 16 into the active site of the topoisomerase II DNA gyrase enzymes revealed a similar binding mode to bound inhibitor Clorobiocin.Graphical Abstract

A Spectroscopic Approach to Investigate the Molecular Interactions between the Newly Approved Irreversible ErbB blocker "Afatinib" and Bovine Serum Albumin

The interaction of afatinib (AFB) with bovine serum albumin (BSA) was examined via fluorescence and UV-Vis spectroscopy. Spectrofluorimetric measurements revealed that AFB can strongly quench the BSA intrinsic fluorescence through producing a non-fluorescent complex. This quenching mechanism was thoroughly investigated with regard to the type of quenching, binding constant, number of binding locations and the fundamental thermodynamic parameters. Subsequently, the association constant of AFB with BSA was computed at three different temperatures and was found to range from 7.34 to 13.19 x105 L mol-1. Thermodynamic parameters calculations demonstrated a positive ΔSƟvalue with both negative ΔHϴand ΔGϴvalues for AFB–BSA complex, which in turn infers thata spontaneous binding is taking place with both electrostatic bonding and hydrophobic interactions participating in the binding of AFB and BSA. Similarly, the UV absorption spectra of AFB-BSA system were studied and confirmed the interaction. Conformational alteration of the protein upon binding to AFB was elaborated with the aid of three dimensional fluorescence measurements as well as synchronous fluorescence spectra.

HPLC-fluorescence method for the enantioselective analysis of propranolol in rat serum using immobilized polysaccharide-based chiral stationary phase.

A stereoselective high-performance liquid chromatographic (HPLC) method was developed and validated to determine S-(-)- and R-(+)-propranolol in rat serum. Enantiomeric resolution was achieved on cellulose tris(3,5-dimethylphenylcarbamate) immobilized onto spherical porous silica chiral stationary phase (CSP) known as Chiralpak IB. A simple analytical method was validated using a mobile phase consisted of n-hexane-ethanol-triethylamine (95:5:0.4%, v/v/v) at a flow rate of 0.6 mL min(-1) and fluorescence detection set at excitation/emission wavelengths 290/375 nm. The calibration curves were linear over the range of 10-400 ng mL(-1) (R = 0.999) for each enantiomer with a detection limit of 3 ng mL(-1). The proposed method was validated in compliance with ICH guidelines in terms of linearity, accuracy, precision, limits of detection and quantitation, and other aspects of analytical validation. Actual quantification could be made for propranolol isomers in serum obtained from rats that had been intraperitoneally (i.p.) administered a single dose of the drug. The proposed method established in this study is simple and sensitive enough to be adopted in the fields of clinical and forensic toxicology. Molecular modeling studies including energy minimization and docking studies were first performed to illustrate the mechanism by which the active enantiomer binds to the β-adrenergic receptor and second to find a suitable interpretation of how both enantiomers are interacting with cellulose tris(3,5-dimethylphenylcarbamate) CSP during the process of resolution. The latter interaction was demonstrated by calculating the binding affinities and interaction distances between propranolol enantiomers and chiral selector.

Potentiometric determination of moxifloxacin in some pharmaceutical formulation using PVC membrane sensors

BackgroundThe construction and electrochemical response characteristics of Poly (vinyl chloride) membrane sensors for moxifloxacin HCl (MOX) are described. The sensing membranes incorporate ion association complexes of moxifloxacin cation and sodium tetraphenyl borate (NaTPB) (sensor 1), phosphomolybdic acid (PMA) (sensor 2) or phosphotungstic acid (PTA) (sensor 3) as electroactive materials.ResultsThe sensors display a fast, stable and near-Nernstian response over a relative wide moxifloxacin concentration range (1 × 10-2 - 4.0 × 10-6, 1 × 10-2 - 5.0 × 10-6, 1 × 10-2 - 5.0 × 10-6 M), with detection limits of 3 × 10-6, 4 × 10-6 and 4.0 × 10-6 M for sensor 1, 2 and 3, respectively over a pH range of 6.0 - 9.0. The sensors show good discrimination of moxifloxacin from several inorganic and organic compounds. The direct determination of 400 μg/ml of moxifloxacin show an average recovery of 98.5, 99.1 and 98.6% and a mean relative standard deviation of 1.8, 1.6 and 1.8% for sensors 1, 2 and 3 respectively.ConclusionsThe proposed sensors have been applied for direct determination of moxifloxacin in some pharmaceutical preparations. The results obtained by determination of moxifloxacin in tablets using the proposed sensors are comparable favorably with those obtained using the US Pharmacopeia method. The sensors have been used as indicator electrodes for potentiometric titration of moxifloxacin.