Papers by Muhammad Khattab
The world of Benzimidazoles is fascinating. It exhibit multitude of pharmacological activities. H... more The world of Benzimidazoles is fascinating. It exhibit multitude of pharmacological activities. Here, where 2-phenylbenzimidazoles are focused on, the anticancer activities against four different cancer lines are proved. Besides, the molecular docking of the most active compounds into the active site of the target receptor is performed. Keep in mind, the world of Benzimidazoles is endless.
The effect of twenty-one solvents on the UV-Vis spectrum of the tyrosine kinase inhibitor AG-1478... more The effect of twenty-one solvents on the UV-Vis spectrum of the tyrosine kinase inhibitor AG-1478 was investigated. The absorption spectrum in the range 300-360 nm consisted of two partially overlapping bands at approximately 340 nm and 330 nm. The higher energy absorption band was more sensitive to solvent and exhibited a peak position that varied from 327 nm to 336 nm, while the lower energy absorption band demonstrated a change in peak position from 340 nm to 346 nm in non-chlorinated solvents. The fluorescence spectrum of AG-1478 was particularly sensitive to solvent. The wavelength of peak intensity varied from 409 nm to 495 nm with the corresponding Stokes shift in the range of 64 nm to 155 nm (4536 cm −1 to 9210 cm −1 ). We used a number of methods to assess the relationship between spectroscopic properties and solvent properties. The detailed analysis revealed that for aprotic solvents, the peak position of the emission spectrum in wavenumber scale correlated with the polarity (dielectric constant or E T (30)) of the solvent. In protic solvents, a better correlation was observed between the hydrogen bonding power of the solvent and the position of the emission spectrum. Moreover, the fluorescence quantum yields were larger in aprotic solvents as compared to protic solvents. This analysis underscores the importance of polarity and hydrogen-bonding environment on the spectroscopic properties of AG-1478. These studies will assume relevance in understanding the interaction of AG-1478 in vitro and in vivo.
AG-1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine) shows promising in vitro and in vivo... more AG-1478 (N-(3-chlorophenyl)-6,7-dimethoxy-4-quinazolinamine) shows promising in vitro and in vivo antiproliferative activity and has gained global interest due to its potent and broad biopharmaceutical activities. An important step towards understanding its spatial and temporal distribution is to determine whether the inhibitors have spectral signatures that might assist in determining the relevant targets and interactions. Its UV-Vis absorption spectra in various solutions have been measured [Khattab et al., Spectrochimica Acta A, 2016, 164, 128]. The present study correlates the UV-Vis spectral signatures with the structure of the drug. Two stable conformers AG-1478B and AG-1478A with close energy values (DE = 1.58 kcal mol À1 ) were located on the potential energy surface through rotation of the single C-N bond of the C-NH-C chain of the drug. The present density functional theory (DFT) study reveals that both conformers contribute to the measured UV-Vis absorption spectrum of AG-1478. The conformers, AG-1478B and AG-1478A, were subjected to further study using molecular orbital theory. It is found that although the conformers are close in energy, the anisotropic properties, such as the shape in three dimensional (3D) space, the dipole moment and the orbitals, are apparently different. The excess orbital energy spectrum (EOES) indicates that six core orbitals exhibit significant conformational changes, exhibiting the signatures of the N atoms, i.e., the NH linker N (25) and the quinazoline N . The valence orbitals with significant configurational changes are either due to the local distribution (30a) or delocalization (46a, 76a and 82a (highest occupied molecular orbital (HOMO))).
A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as gly... more A series of (benzimidazol-2-yl)-aniline (1) derivatives has been synthesized and evaluated as glycogen phosphorylase (GP) inhibitors. Kinetics studies revealed that compounds displaying a lateral heterocyclic residue with several heteroatoms (series 3 and 5) exhibited modest inhibitory properties with IC 50 values in the 400-600 lM range. Arylsulfonyl derivatives 7 (Ar: phenyl) and 9 (Ar: o-nitrophenyl) of 1 exhibited the highest activity (series 2) among the studied compounds (IC 50 324 lM and 357 lM, respectively) with stronger effect than the p-tolyl analogue 8.
We studied the spectroscopic characteristics of SKF86002, an anti-inflammatory and tyrosine kinas... more We studied the spectroscopic characteristics of SKF86002, an anti-inflammatory and tyrosine kinase inhibitor drug candidate. Two conformers SKF86002A and SKF86002B are separated by energy barriers of 19.68 kJ·mol −1 and 6.65 kJ·mol −1 due to H-bonds, and produce the three major UV-Vis absorption bands at 325 nm, 260 nm and 210 nm in cyclohexane solutions. This environment-sensitive fluorophore exhibited emission in the 400-500 nm range with a marked response to changes in environment polarity. By using twenty-two solvents for the solvatochromism study, it was noticed that solvent polarity, represented by dielectric constant, was well correlated with the emission wavelength maxima of SKF86002. Thus, the SKF86002 fluorescence peak red shifted in aprotic solvents from 397.5 nm in cyclohexane to 436 nm in DMSO. While the emission maximum in hydrogen donating solvents ranged from 420 nm in t-butanol to 446 nm in N-methylformamide. Employing Lippert-Mataga, Bakhshiev and Kawski models, we found that one linear correlation provided a satisfactory description of polarity effect of 18 solvents on the spectral changes of SKF86002 with R 2 values 0.78, 0.80 and 0.80, respectively. Additionally, the multicomponent linear regression analysis of Kamlet-Taft (R 2 = 0.94) revealed that solvent acidity, basicity and polarity accounted for 31%, 24% and 45% of solvent effects on SKF86002 emission, respectively. While Catalán correlation (R 2 = 0.92) revealed that solvatochromic change of SKF86002 emission was attributed to changes in solvent dipolarity (71%), solvent polarity (12%), solvent acidity (11%) and solvent basicity (6%). Plot of Reichardt transition energies and emission energies of SKF86002 in 18 solvents showed also a linear correlation with R 2 = 0.90. The dipole moment difference between excited and ground state was calculated to be 3.4-3.5 debye.
The benzimidazole nucleus is an important pharmacophore in drug discovery, being a good bioisoste... more The benzimidazole nucleus is an important pharmacophore in drug discovery, being a good bioisostere of naturally occurring nucleotides. This heterocycle may represent a type of privileged substructure which can interact with proteins and enzymes; it has, hence, been extensively utilized as a drug scaffold in medicinal chemistry. The connection between wide ranging biological activity and compounds containing the benzimidazole nucleus is known, and well documented in the literature. Benzimidazole derivatives have a multitude of interesting pharmacological activity, including antiviral, antitumor, antihypertensive, proton pump inhibitory, anthelmintic, antimicrobial, and anti-inflammatory activity. Accordingly, a brief survey is given below covering the synthesis of 2-phenybenzimidazole derivatives and their biological importance.
Tyrosine kinase inhibitors (TKI) are an important class of molecules. Specific interactions of TK... more Tyrosine kinase inhibitors (TKI) are an important class of molecules. Specific interactions of TKI with water are of interest since they appear in high resolution X-ray structures of TKI-protein complexes and are thought to be important determinants of drug efficacy. Methods for determining the specific interactions of TKI with water molecules in solution are therefore highly desirable. Recently, we revealed that the TKI, AG1478, exhibits absorbance and fluorescence spectra which are sensitive to the conformation of the molecule and the polarity of the surrounding environment. In the present work, we investigated the potential hydrogen bond binding sites of AG1478 using spectroscopic measurements of acetonitrilewater solutions. UV-Vis absorbance spectroscopy of AG1478 revealed H-bond interactions between water molecules and AG1478 in the ground state, as evidenced by changes in spectral shape and optical density with increases in water fraction. The fluorescence spectra of AG1478 in acetonitrile were also greatly influenced by water interactions, revealing fluorescence quenching (by 80%) with the addition of 2% by volume of water. The AG1478 fluorescence quantum yield decreased with increasing temperature in neat acetonitrile but revealed an unorthodox increase with increasing temperature in acetonitrilewater solution. Taken together, these changes are consistent with a specific complex or complexes formed between AG1478 and water molecules. Potential AG1478-water clusters were investigated using ab initio calculations. The effects of explicit hydrogen bonding on vertical excitation, topology and electronic configuration of AG1478 were examined computationally.
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Papers by Muhammad Khattab