Publications by authors named "Mohamed I Attia"

51 Publications

Development of novel univariate and multivariate validated chemometric methods for the analysis of dasatinib, sorafenib, and vandetanib in pure form, dosage forms and biological fluids.

Spectrochim Acta A Mol Biomol Spectrosc 2022 Jan 28;264:120336. Epub 2021 Aug 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

New precise, responsive and selective univariate and multivariate chemometric spectrophotometric methods were developed and validated for determination of vandetanib (VTB), dasatinib (DTB), and sorafenib (SFB) in pure form, tablets, spiked human (plasma and urine). Determination of these drugs is essential because of their therapeutic benefits. These methods included double divisor ratio spectra derivative univariate method and chemometric multivariate method including partial least-squares (PLS) and principal component regression (PCR). A novel univariate method was developed for the estimation of these drugs. This method depends on the UV-Spectrophotometric data for simultaneous analysis of a ternary overlapped mixture. The Double divisor ratio spectra derivative absorption minima at 358.4 nm was used for quantification of VTB, absorption maxima at 300.3 nm for quantification of DTB and absorption maxima at 259.8 nm for quantification of SFB. This method shown a linearity in the extent of 2-9 μg/mL for VTB and DTB and over the concentration range of 3-9 μg/mL SFB within correlation coefficient (r2) of 0.9999. This method was successfully applied to pure form, tablet dosage form, spiked human (urine and plasma). Chemometric PLS and PCR models were found to be linear in the range of 2-9, 2-9, and 3-9 μg/mL for VTB, DTB and SFB, respectively. These models were estimated using eighteen mixtures as calibration set and seven mixtures as validation set. In the original data, the minimum root mean square error of prediction (RMSEP) was 0.11, 0.09 and 0.09 for VTB, DTB and SFB by PLS and 0.05, 0.04 and 0.03 by PCR while in the derivative data, the RMSEP was 0.09, 0.10 and 0.09 by PLS and 0.06, 0.06 and 0.03, by PCR for VTB, DTB and SFB, respectively. These methods were applied for the determination of the drugs in pure form and dosage form. Updating PLS model permitted the determination of the VTB, DTB and SFB in spiked human urine, plasma and drug-dissolution test of their tablet.
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http://dx.doi.org/10.1016/j.saa.2021.120336DOI Listing
January 2022

Design, Synthesis, and Antimicrobial Activity of Certain New Indole-1,2,4 Triazole Conjugates.

Molecules 2021 Apr 15;26(8). Epub 2021 Apr 15.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

The increasing prevalence of microbial infections and the emergence of resistance to the currently available antimicrobial drugs urged the development of potent new chemical entities with eminent pharmacokinetic and/or pharmacodynamic profiles. Thus, a series of new indole-triazole conjugates was designed and synthesized to be assessed as new antimicrobial candidates using the diameter of the inhibition zone and minimum inhibitory concentration assays against certain microbial strains. Their in vitro antibacterial evaluation revealed good to moderate activity against most of the tested Gram-negative strains with diameter of the inhibition zone (DIZ) values in the range of 11-15 mm and minimum inhibition concentration (MIC) values around 250 µg/mL. Meanwhile, their in vitro antifungal evaluation demonstrated a potent activity against with MIC value as low as 2 µg/mL for most of the tested compounds. Moreover, compound is the most potent congener with an MIC value of 2 µg/mL against .
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http://dx.doi.org/10.3390/molecules26082292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071222PMC
April 2021

A validated RP-HPLC method for the determination of piperidone analogue of curcumin.

Pak J Pharm Sci 2020 Mar;33(2):685-694

Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Curcumin (Diferuloylmethane) is a natural product extracted from the root of Curcuma longa. 5-Bis (4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone, the piperidone analogue of curcumin (PAC), was one of the analogues that, demonstrated potential anticancer effects against breast and colon cancers compared with native curcumin. A simple, accurate, and rapid isocratic reverse phase high performance liquid chromatography (HPLC) analytical method utilizing UV detection was developed and validated for the determination of PAC utilizing C column with run time was 7 min. Chromatogram showed a peak of PAC at retention time of 5.8±0.92 min. The method was validated for linearity, accuracy, precision, limit of detection, limit of quantitation and robustness. Linear relationship (r > 0.99) was observed between AUP of PAC and the corresponding concentrations over 100-10000μg/mL. The LOQ of this assay was 3.9ng/mL with a corresponding relative standard deviation of 4.8 and 4.0%. The LOD was 13.1ng/mL at a signal-to-noise ratio of >3.
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March 2020

Antiestrogenic Activity and Possible Mode of Action of Certain New Nonsteroidal Coumarin-4-acetamides.

Molecules 2020 Mar 28;25(7). Epub 2020 Mar 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

The preparation of certain 2-(2-oxo-2-chromen-4-yl)--substituted acetamides was planned as a step in the development of new modified nonsteroidal antiestrogens. The purity of target compounds was checked by thin-layer chromatography (TLC), and their structures were confirmed using various spectroscopic tools including IR, H-NMR, C-NMR, and MS spectroscopy. Viability tests were applied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effect of the synthesized compounds against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound proved the most active against MCF-7 cells, with an IC value of 0.32 μM. The results of an analysis of in vitro antiestrogenic activity indicated that only compound exhibited antiestrogenic activity; its IC value of 29.49 μM was about twice as potent as that of the reference compound, MIBP. The aromatase activity was evaluated for the synthesized target compounds and the intermediates and . A significant aromatase inhibition was observed for the intermediate and compound , with IC values of 14.5 and 17.4 μM, respectively. Compound , namely 7-methoxy-4-(2-oxo-2-(piperidin-1-yl)ethyl)-2H-chromen-2-one, could be used as an antiestrogen and/or cytotoxic agent with selective activity against tumor cells.
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http://dx.doi.org/10.3390/molecules25071553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181245PMC
March 2020

New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity.

Drug Des Devel Ther 2020 3;14:483-495. Epub 2020 Feb 3.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Background: Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates ( against three human cancer cell lines.

Methods: The antiproliferative activities of compounds were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds .

Results: The in vitro antiproliferative activities of compounds against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound had an IC value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC = 8.11 µM). In-depth pharmacological testing was conducted with compound to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds .

Conclusion: Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds and provided a detailed insight into the pharmacological profile of compound . Thus, compounds can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.
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http://dx.doi.org/10.2147/DDDT.S227862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006853PMC
January 2021

Antiproliferative activity and possible mechanism of action of certain 5-methoxyindole tethered C-5 functionalized isatins.

Drug Des Devel Ther 2019 27;13:3069-3078. Epub 2019 Aug 27.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Background: Cancer is one of the most dreaded human diseases, that has become an ever-increasing health problem and is a prime cause of death globally. The potential antiproliferative activity of certain indole-isatin molecular hybrids was evaluated in vitro against three human cancer cell lines.

Methods: Standard protocols were adopted to examine the antiproliferative potential and mechanisms of compounds . Western blot analysis was carried out on compound .

Results: Compounds demonstrated in vitro antiproliferative activity in the range of 22.6-97.8%, with compounds and being the most active antiproliferative compounds   with IC values of 1.69 and 1.91 µM, which is fivefold and fourfold more potent than sunitinib (IC=8.11 µM), respectively. Compound was selected for in-depth pharmacological testing to understand its possible mechanism of antiproliferative activity. It caused a lengthening of the G1 phase and a reduction in the S and G2/M phases of the cell cycle and had an IC value of 10.4 μM with the resistant NCI-H69AR cancer cell line. Moreover, compound significantly decreased the amount of phosphorylated Rb protein in a dose-dependent fashion, which was confirmed via Western blot analysis.

Conclusion: The current investigation highlighted the potential antiproliferative activity of compounds as well as the antiproliferative profile of compound . These compounds can be harnessed as new lead antiproliferatives in the preclinical studies of cancer chemotherapy.
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http://dx.doi.org/10.2147/DDDT.S208241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718129PMC
March 2020

Synthesis, structure elucidation, and antifungal potential of certain new benzodioxole-imidazole molecular hybrids bearing ester functionalities.

Drug Des Devel Ther 2019 26;13:775-789. Epub 2019 Feb 26.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia,

Background: The incidence of fungal infections is a growing serious global health burden. There is an urgent medical demand to acquire new antifungal drug-like compounds having azole nuclei to get rid of the drawbacks of the currently available azole antifungal agents.

Methods: The target compounds were synthesized in a four-step reaction sequence using the appropriate acetophenone derivative as a starting material. The antifungal potential of the title compounds was assessed using DIZ and MIC assays according to the reported standard procedures.

Results: The newly synthesized oximino esters were identified with the aid of various spectroscopic approaches. Their assigned chemical structures were confirmed via single-crystal X-ray structure of compound . The molecular structure of compound was crystallized in the triclinic, -1, =9.898 (3) Å, =10.433 (3) Å, =11.677 (4) Å, =86.886 (6)°, =87.071 (7)°, =64.385 (6)°, =1,085.2 (6) Å3, =2. The synthesized compounds were in vitro evaluated for antifungal potential against four fungal strains. Compounds and bearing a trifluoromethylphenyl moiety showed the best anti- activity with minimum inhibitory concentration (MIC) value of 0.148 μmol/mL, while compound displayed the best activity toward with MIC value of 0.289 μmol/mL. Compounds and were the most active congeners against Candida parapsilosis and , respectively.

Conclusion: Single-crystal X-ray analysis of compound confirmed without doubt the assigned chemical structures of the title compounds as well as confirmed the ()-configuration of their oximino group. Compounds and emerged as the most active compounds against the tested fungi and they could be considered as new antifungal lead candidates.
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http://dx.doi.org/10.2147/DDDT.S199135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396673PMC
July 2019

Synthesis and Spectroscopic Identification of Certain Imidazole-Semicarbazone Conjugates Bearing Benzodioxole Moieties: New Antifungal Agents.

Molecules 2019 Jan 7;24(1). Epub 2019 Jan 7.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

During the last three decades the extent of life-threatening fungal infections has increased remarkably worldwide. Synthesis and structure elucidation of certain imidazole-semicarbazone conjugates ⁻ are reported. Single crystal X-ray analysis of compound unequivocally confirmed its assigned chemical structure and the ()-configuration of its imine double bond. Compound crystallized in the triclinic system, P-1, a = 6.3561 (3) Å, b = 12.5095 (8) Å, c = 14.5411 (9) Å, α = 67.073 (4)°, β = 79.989 (4)°, γ =84.370 (4)°, V = 1048.05 (11) ų, Z = 2. In addition, DIZ and MIC assays were used to examine the in vitro antifungal activity of the title conjugates ⁻ against four fungal strains. Compound , bearing a 4-ethoxyphenyl fragment, showed the best MIC value (0.304 µmol/mL) against both and species, while compounds (MIC = 0.311 µmol/mL), , and (MIC = 0.287 µmol/mL) exhibited the best anti- activity.
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http://dx.doi.org/10.3390/molecules24010200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6337076PMC
January 2019

Synthesis, Spectroscopic Identification and Molecular Docking of Certain -(2-{[2-(1-Indol-2-ylcarbonyl) Hydrazinyl](oxo)Acetylphenyl)Acetamides and -[2-(2-{[2-(Acetylamino)Phenyl](oxo)Acetylhydrazinyl)-2-Oxoethyl]-1-Indole-2-Carboxamides: New Antimicrobial Agents.

Molecules 2018 Apr 29;23(5). Epub 2018 Apr 29.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

-(2-{[2-(1-Indol-2-ylcarbonyl)hydrazinyl](oxo)acetyl}phenyl)acetamides () and -[2-(2-{[2-(acetylamino)phenyl](oxo)acetyl}hydrazinyl)-2-oxoethyl]-1-indole-2-carboxamides () were synthesized and characterized with different analytical tools. -Acetylisatines were subjected to ring opening at their C2 carbons with the aid of different indole-bearing hydrazides and to afford the respective glyoxylamides . The antimicrobial activity of the target compounds was assessed with the aid of Diameter of the Inhibition Zone (DIZ) and Minimum Inhibitory Concentration (MIC) assays against a panel of Gram-positive and Gram-negative bacteria and certain fungal strains. The antimicrobial screening revealed that , , and are the most sensitive microorganisms towards the synthesized compounds . In addition, compounds and emerged as the most active congeners towards and , respectively. Molecular docking studies revealed the possible binding mode of compounds and to their target proteins.
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http://dx.doi.org/10.3390/molecules23051043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102541PMC
April 2018

Synthesis and biological evaluation of certain hydrazonoindolin-2-one derivatives as new potent anti-proliferative agents.

J Enzyme Inhib Med Chem 2018 Dec;33(1):867-878

b Department of Pharmaceutical Chemistry, College of Pharmacy , King Saud University , Riyadh , Saudi Arabia.

In connection with our research program on the development of novel indolin-2-one-based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC values of 4.37, 2.53, 2.14, and 4.66 µM, respectively, which are superior to Sunitinib (average IC = 8.11 µM). Furthermore, compounds 7b and 10e were evaluated for their effects on cell cycle progression and levels of phosphorylated retinoblastoma (Rb) protein in the A-549 cancer cell line. Moreover, 7b and 10e inhibited the cell growth of the multidrug-resistant lung cancer NCI-H69AR cell line with IC = 16 µM. In addition, the cytotoxic activities of 7b and 10e were assessed towards three non-tumorigenic cell lines (Intestine IEC-6, Breast MCF-10A, and Fibroblast Swiss-3t3) where both compounds displayed mean tumor selectivity index (1.6 and 1.8) higher than that of Sunitinib (1.4).
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http://dx.doi.org/10.1080/14756366.2018.1462802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011955PMC
December 2018

Synthesis, Spectroscopic Characterization and Antimicrobial Potential of Certain New Isatin-Indole Molecular Hybrids.

Molecules 2017 Nov 15;22(11). Epub 2017 Nov 15.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Molecular hybridization has a wide application in medicinal chemistry to obtain new biologically active compounds. New isatin-indole molecular hybrids - have been synthesized and characterized by various spectroscopic tools. The in vitro antimicrobial potential of the prepared compounds - was assessed using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against a panel of Gram-negative bacteria, Gram-positive bacteria and fungi. Most of the synthesized compounds - showed weak activities against Gram-negative bacteria while compounds and exhibited good activities against Gram-positive bacteria. On the other hand, compound emerged as the most active compound towards (), with an MIC value of 3.9 µg/mL, and compound as the most active congener towards (), with an MIC value of 15.6 µg/mL. Moreover, compound manifested the best anti- effect, with an MIC value of 7.8 µg/mL, making it equipotent with compound .
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http://dx.doi.org/10.3390/molecules22111958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150181PMC
November 2017

Synthesis, Single Crystal X-ray Analysis, and Antifungal Profiling of Certain New Oximino Ethers Bearing Imidazole Nuclei.

Molecules 2017 Nov 3;22(11). Epub 2017 Nov 3.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Fungal infections threaten human health, particularly in immune-compromised patients worldwide. Although there are a large number of antifungal agents available, the desired clinical attributes for the treatment of fungal infections have not yet been achieved. Azoles are the mainstay class of the clinically used antifungal agents. In the current study, the synthesis, spectroscopic characterization, and antifungal activity of certain new oximino ethers - bearing imidazole nuclei are reported. The ()-configuration of the imine double bond of the synthesized compounds - has been confirmed via single crystal X-ray analysis of compound as a representative example of this class of compounds. The molecular structure of compound was crystallized in the monoclinic, 2₁/, = 18.7879(14) Å, 5.8944(4) Å, = 16.7621(12) Å, = 93.063(3)°, = 1855.5(2) ų, = 4. The in vitro antifungal activity of the synthesized compounds - were evaluated using diameter of the inhibition zone (DIZ) and minimum inhibitory concentration (MIC) assays against different fungal strains. Compound manifested anti- activity with an MIC value of 0.050 µmol/mL, being almost equipotent with the reference antifungal drug fluconazole (FLC),while compounds and are the most active congeners against , being equipotent and about twenty-three times more potent than FLC with an MIC value of 0.002 µmol/mL. The results of the current report might support the development of new potent and safer antifungal azoles.
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http://dx.doi.org/10.3390/molecules22111895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150221PMC
November 2017

Isatin-benzoazine molecular hybrids as potential antiproliferative agents: synthesis and in vitro pharmacological profiling.

Drug Des Devel Ther 2017 9;11:2333-2346. Epub 2017 Aug 9.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

In continuation of our endeavor with respect to the development of potent and effective isatin-based anticancer agents, we adopted the molecular hybridization approach to design and synthesize four different sets of isatin-quinazoline ( and )/phthalazine ()/quinoxaline () hybrids. The antiproliferative activity of the target hybrids was assessed towards HT-29 (colon), ZR-75 (breast) and A-549 (lung) human cancer cell lines. Hybrids emerged as the most active antiproliferative congener in this study. Compound induced apoptosis via increasing caspase 3/7 activity by about 5-fold in the A-549 human cancer cell line. In addition, it exhibited an increase in the G1 phase and a decrease in the S and G2/M phases in the cell cycle effect assay. Furthermore, it displayed an inhibitory concentration 50% value of 9.5 µM against multidrug-resistant NCI-H69AR lung cancer cell line. The hybrid was also subjected to in vitro metabolic investigations through its incubation with rat liver microsomes and analysis of the resulting metabolites with the aid of liquid chromatography-mass spectrometry.
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http://dx.doi.org/10.2147/DDDT.S140164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557401PMC
May 2018

New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres.

PLoS One 2017 25;12(7):e0181241. Epub 2017 Jul 25.

Department of Applied Organic Chemistry, National Res earch Centre, (ID: 60014618), Dokki, Giza, Egypt.

The synthesis and molecular characterization of new isatin-based hydrazonoindolin-2-ones 4a-o and 7a-e are reported. The in vitro anti-proliferative potential of the synthesized compounds 4a-o and 7a-e was examined against HT-29 (colon), ZR-75 (breast) and A549 (lung) human cancer cell lines. Compounds 7b, 7d and 7e were the most active congeners against the tested human cancer cell lines with average IC50 values of 4.77, 3.39 and 2.37 μM, respectively, as compared with the reference isatin-based drug, sunitinib, which exhibited an average IC50 value of 8.11 μM. Compound 7e was selected for further pharmacological evaluation in order to gain insight into its possible mechanism of action. It increased caspase 3/7 activity by 2.4- and 1.85-fold between 4 and 8 h of treatment, respectively, at 10 μM and it caused a decrease in the percentage of cells in the G1 phase of the cell cycle with a corresponding increase in the S-phase. In addition, compound 7e increased phosphorylated tyrosine (p-Tyr) levels nearly two-fold with an apparent IC50 value of 3.8 μM. The 7e-loaded PLGA microspheres were prepared using a modified emulsion-solvent diffusion method. The average encapsulation efficiency of the 7e-loaded PLGA microspheres was 85% ± 1.3. While, the in vitro release profile of the 7e-loaded microspheres was characterized by slow and continuous release of compound 7e during 21 days and the release curve was fitted to zero order kinetics. Incorporation of 7e into PLGA microspheres improved its in vitro anti-proliferative activity toward the human cancer cell line A549 after 120 h incubation period with an IC50 value less than 0.8 μM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181241PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526551PMC
October 2017

Erratum to: New spectrofluorimetric methods for determination of melatonin in the presence of -{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1-indol-2-yl}methyl)-5-methoxy-1-indol-3-yl]-ethyl}acetamide: a contaminant in commercial melatonin preparations.

Chem Cent J 2016 28;10:57. Epub 2016 Sep 28.

Department of Pharmaceutical Chemistry, Institute of Pharmacy and Food Chemistry, Würzburg University, Am Hubland, 97074 Würzburg, Germany ; Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, The German University in Cairo, New Cairo City, Egypt.

[This corrects the article DOI: 10.1186/1752-153X-6-36.].
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http://dx.doi.org/10.1186/s13065-016-0203-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039883PMC
September 2016

Synthesis, X-ray Single Crystal Structure, Molecular Docking and DFT Computations on N-[(1E)-1-(2H-1,3-Benzodioxol-5-yl)-3-(1H-imidazol-1-yl)propylidene]-hydroxylamine: A New Potential Antifungal Agent Precursor.

Molecules 2017 Feb 28;22(3). Epub 2017 Feb 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Mycoses are serious health problem, especially in immunocompromised individuals. A new imidazole-bearing compound containing an oxime functionality was synthesized and characterized with different spectroscopic techniques to be used for the preparation of new antifungal agents. The stereochemistry of the oxime double bond was unequivocally determined via the single crystal X-ray technique. The title compound , CHN₃O₃·C₃H₈O, crystallizes in the monoclinic space group 2₁with = 9.0963(3) Å, = 14.7244(6) Å, = 10.7035(4) Å, β = 94.298 (3)°, = 1429.57(9) ų, = 2. The molecules were packed in the crystal structure by eight intermolecular hydrogen bond interactions. A comprehensive spectral analysis of the title molecule has been performed based on the scaled quantum mechanical (SQM) force field obtained by density-functional theory (DFT) calculations. A molecular docking study illustrated the binding mode of the title compound into its target protein. The preliminary antifungal activity of the title compound was determined using a broth microdilution assay.
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http://dx.doi.org/10.3390/molecules22030373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155236PMC
February 2017

A Stability-Indicating HPLC-DAD Method for Determination of Stiripentol: Development, Validation, Kinetics, Structure Elucidation and Application to Commercial Dosage Form.

J Anal Methods Chem 2014 14;2014:638951. Epub 2014 Oct 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

A rapid, simple, sensitive, and accurate isocratic reversed-phase stability-indicating high performance liquid chromatography method has been developed and validated for the determination of stiripentol and its degradation product in its bulk form and pharmaceutical dosage form. Chromatographic separation was achieved on a Symmetry C18 column and quantification was achieved using photodiode array detector (DAD). The method was validated in accordance with the ICH requirements showing specificity, linearity (r (2) = 0.9996, range of 1-25 μg/mL), precision (relative standard deviation lower than 2%), accuracy (mean recovery 100.08 ± 1.73), limits of detection and quantitation (LOD = 0.024 and LOQ = 0.081 μg/mL), and robustness. Stiripentol was subjected to various stress conditions and it has shown marked stability under alkaline hydrolytic stress conditions, thermal, oxidative, and photolytic conditions. Stiripentol degraded only under acidic conditions, forming a single degradation product which was well resolved from the pure drug with significantly different retention time values. This degradation product was characterized by (1)H-NMR and (13)C-NMR spectroscopy as well as ion trap mass spectrometry. The results demonstrated that the method would have a great value when applied in quality control and stability studies for stiripentol.
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http://dx.doi.org/10.1155/2014/638951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4211168PMC
November 2014

Anticonvulsant profiles of certain new 6-aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones.

Int J Mol Sci 2014 Sep 23;15(9):16911-35. Epub 2014 Sep 23.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Misr University for Science & Technology, 6th of October City 12566, Egypt.

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a-l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5] undecane-3,5-diones (6m-x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino] cycloalkanecarboxamides (3a-f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a-f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a-f which were cyclized under mild conditions to give the spiro compounds 5a-f. Ultimately, compounds 5a-f were alkylated or aralkylated to give the target compounds 6a-i and 6m-u. On the other hand, compounds 6j-l and 6v-x were synthesized from the intermediates 5a-f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a-x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a-x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.
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http://dx.doi.org/10.3390/ijms150916911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200821PMC
September 2014

FT-IR, FT-Raman, molecular structure, first order hyperpolarizability, HOMO and LUMO analysis, MEP and NBO analysis of 3-(adamantan-1-yl)-4-(prop-2-en-1-yl)-1H-1,2,4-triazole-5(4H)-thione, a potential bioactive agent.

Spectrochim Acta A Mol Biomol Spectrosc 2014 Nov 14;132:295-304. Epub 2014 May 14.

Department of Chemistry, University of Antwerp, B2610 Antwerp, Belgium.

The optimized molecular structure, vibrational frequencies, corresponding vibrational assignments of 3-(adamantan-1-yl)-4-(prop-2-en-1-yl)-1H-1,2,4-triazole-5(4H)-thione have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of normal modes vibrations was done using GAR2PED program. The HOMO and LUMO analysis are used to determine the charge transfer within the molecule. The stability of the molecule arising from hyperconjugative interaction and charge delocalization has been analyzed using NBO analysis. The calculated geometrical parameters are in agreement with the XRD data. The calculated first hyperpolarizability is high and the title compound is an attractive candidate for further studies in nonlinear optical applications. To estimate the chemical reactivity of the molecule, the molecular electrostatic potential is calculated for the optimized geometry of the molecule.
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http://dx.doi.org/10.1016/j.saa.2014.04.177DOI Listing
November 2014

Anticonvulsant potential of certain new (2E)-2-[1-Aryl-3-(1H-imidazol-1-yl)propylidene]-N-(aryl/H)hydrazinecarboxamides.

ScientificWorldJournal 2014 12;2014:357403. Epub 2014 Jan 12.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Anticonvulsant potential and neurotoxicity of certain new imidazole-containing arylsemicarbazones 6a-p are reported. The test compounds 6a-p exhibited anticonvulsant activity mainly in the scPTZ screen. Compound 6p emerged as the most active surrogate displaying 100% protection at a dose level of 636 μ mol/kg in the scPTZ screen without any neurotoxicity. The assigned (E)-configuration of the title compounds 6a-p was confirmed via single crystal X-ray structure of compound 6g.
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http://dx.doi.org/10.1155/2014/357403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913509PMC
December 2014

Synthesis of novel 2-(substituted amino)alkylthiopyrimidin-4(3H)-ones as potential antimicrobial agents.

Molecules 2013 Dec 27;19(1):279-90. Epub 2013 Dec 27.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh 11451, Saudi Arabia.

5-Alkyl-6-(substituted benzyl)-2-thiouracils 3a,c were reacted with (2-chloroethyl) diethylamine hydrochloride to afford the corresponding 2-(2-diethylamino)ethylthiopyrimidin- 4(3H)-ones 4a,b. Reaction of 3a-c with N-(2-chloroethyl)pyrrolidine hydrochloride and/or N-(2-chloroethyl)piperidine hydrochloride gave the corresponding 2-[2-(pyrrolidin-1-yl)ethyl]-thiopyrimidin-4(3H)-ones 5a-c and 2-[2-(piperidin-1-yl)ethyl]thiopyrimidin-4(3H)-ones 6a,b, respectively. Treatment of 3a-d with N-(2-chloroethyl)morpholine hydrochloride under the same reaction conditions formed the corresponding 2-[2-(morpholin-4-yl)ethyl]thiopyrimidines 6c-f. On the other hand, 3a,b were reacted with N-(2-bromoethyl)phthalimide and/or N-(3-bromopropyl)phthalimide to furnish the corresponding 2-[2-(N-phthalimido)ethyl]-pyrimidines 7a,b and 2-[3-(N-phthalimido)-propyl]pyrimidines 7c,d, respectively. Compounds 3a-d, 4a,b, 5a-c, 6a-f and 7a-d were screened against Gram-positive bacteria (Staphylococcus aureus ATCC 29213, Bacillus subtilis NRRL 4219 and Bacillus cereus), yeast-like pathogenic fungus (Candida albicans ATCC 10231) and a fungus (Aspergillusniger NRRL 599). The best antibacterial activity was displayed by compounds 3a, 3b, 4a, 5a, 5b, 6d, 6f, 7b and 7d, whereas compounds 4b, 5b, 5c, 6a, 6b and 6f exhibited the best antifungal activity.
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http://dx.doi.org/10.3390/molecules19010279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6271362PMC
December 2013

Synthesis and anticancer potential of certain novel 2-oxo-N'-(2-oxoindolin-3-ylidene)-2H-chromene-3-carbohydrazides.

Eur J Med Chem 2013 16;70:358-63. Epub 2013 Oct 16.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt. Electronic address:

Treatment of ethyl 3-hydrazinyl-3-oxopropanoate (6) with indoline-2,3-dione derivatives 7a-g gave ethyl 3-oxo-3-(2-(2-oxoindolin-3-ylidene)hydrazinyl)propanoates 8a-g which were allowed to react with the appropriate salicyaldehyde 9a and/or 9b to furnish the chromene-based hydrazones 10a-i. Compounds 10a-i displayed a significant activity against HT-29 colon cancer cell line and a moderate activity against leukemia K562 cell line. Compound 10f emerged as the most active congener toward HT-29 colon cancer cell line with IC₅₀ = 7.98 ± 0.05 μM whereas compound 10c exhibited the best antiproliferative activity against leukemia K562 cell line with IC₅₀ = 9.44 ± 0.02 μM. Moreover, compound 1e showed 87.81 ± 7% inhibition of side population (SP) HT-29 colon cancer stem cells.
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http://dx.doi.org/10.1016/j.ejmech.2013.09.060DOI Listing
September 2014

1-Aryl-3-(1H-imidazol-1-yl)propan-1-ol esters: synthesis, anti-Candida potential and molecular modeling studies.

Chem Cent J 2013 Oct 25;7(1):168. Epub 2013 Oct 25.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P,O, Box 2457, Riyadh 11451, Saudi Arabia.

Background: An increased incidence of fungal infections, both invasive and superficial, has been witnessed over the last two decades. Candida species seem to be the main etiology of nosocomial fungal infections worldwide with Candida albicans, which is commensal in healthy individuals, accounting for the majority of invasive Candida infections with about 30-40% of mortality.

Results: New aromatic and heterocyclic esters 5a-k of 1-aryl-3-(1H-imidazol-1-yl)propan-1-ols 4a-d were successfully synthesized and evaluated for their anti-Candida potential. Compound 5a emerged as the most active congener among the newly synthesized compounds 5a-k with MIC value of 0.0833 μmol/mL as compared with fluconazole (MIC value >1.6325 μmol/mL). Additionally, molecular modeling studies were conducted on a set of anti-Candida albicans compounds.

Conclusion: The newly synthesized esters 5a-k showed more potent anti-Candida activities than fluconazole. Compounds 7 and 8 revealed significant anti-Candida albicans activity and were able to effectively satisfy the proposed pharmacophore geometry, using the energy accessible conformers (Econf < 20 kcal/mol).
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http://dx.doi.org/10.1186/1752-153X-7-168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3819650PMC
October 2013

In vitro anti-Candida activity of certain new 3-(1H-imidazol-1-yl)propan-1-one oxime esters.

Molecules 2013 Sep 30;18(10):12208-21. Epub 2013 Sep 30.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Anti-Candida activities of certain new oximes 4a-d and their respective aromatic esters 5a-l are reported. The tested compounds 4a-d and 5a-l exhibited better anti-Candida profiles than fluconazole. Compound 5j, namely (E)-3-(1H-imidazol-1-yl)-1-phenylpropan-1-one O-4-chlorobenzoyl oxime emerged as the most active congener, with a MIC value of 0.0054 µmol/mL being more potent than both fluconazole (MIC > 1.6325 µmol/mL) and miconazole (MIC value = 0.0188 µmol/mL) as a new anti-Candida albicans agent.
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http://dx.doi.org/10.3390/molecules181012208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270279PMC
September 2013

GABA(B)-agonistic activity of certain baclofen homologues.

Molecules 2013 Aug 22;18(9):10266-84. Epub 2013 Aug 22.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Baclofen (1) is a potent and selective agonist for bicuculline-insensitive GABA(B) receptors and is used clinically as an antispastic and muscle relaxant agent. In the search for new bioactive chemical entities that bind specifically to GABA(B) receptors, we report here the synthesis of certain baclofen homologues, namely (R,S)-5-amino-3-arylpentanoic acid hydrochlorides (R,S)-1a-h as well as (R,S)-5-amino-3-methylpentanoic acid [(RS)-1i] to be evaluated as GABA(B)R agonists. Compound 1a is an agonist to GABA(B) receptors with an EC₅₀ value of 46 μM on tsA201 cells transfected with GABA(B1b)/GABA(B2)/Gqz5, being the most active congener among all the synthesized compounds.
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http://dx.doi.org/10.3390/molecules180910266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270091PMC
August 2013

The reaction of ethyl 2-oxo-2H-chromene-3-carboxylate with hydrazine hydrate.

Molecules 2013 Feb 6;18(2):2084-95. Epub 2013 Feb 6.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.

Although salicylaldehyde azine (3) was reported in 1985 as the single product of the reaction of ethyl 2-oxo-2H-chromene-3-carboxylate (1) with hydrazine hydrate, we identified another main reaction product, besides 3, which was identified as malono-hydrazide (4). In the last two decades, however, some articles have claimed that this reaction afforded exclusively hydrazide 2 and they have reported the use of this hydrazide 2 as a precursor in the syntheses of several heterocyclic compounds and hydrazones 6. We reported herein a study of the formation of 2 and a facile route for the synthesis of the target compounds N'-arylidene-2-oxo-2H-chromene-3-carbohydrazides 6a-f.
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http://dx.doi.org/10.3390/molecules18022084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270269PMC
February 2013

Comparative ANNs with different input layers and GA-PLS study for simultaneous spectrofluorimetric determination of melatonin and pyridoxine HCl in the presence of melatonin’s main impurity.

Molecules 2013 Jan 14;18(1):974-96. Epub 2013 Jan 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.

Melatonin (MLT) has many health implications, therefore it is important to develop specific analytical methods for the determination of MLT in the presence of its main impurity, N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]ethyl}acetamide (DMLT) and pyridoxine HCl (PNH) as a co-formulated drug. This work describes simple, sensitive, and reliable four multivariate calibration methods, namely artificial neural network preceded by genetic algorithm (GA-ANN), principal component analysis (PCA-ANN) and wavelet transform procedures (WT-ANN) as well as partial least squares preceded by genetic algorithm (GA-PLS) for the spectrofluorimetric determination of MLT and PNH in the presence of DMLT. Analytical performance of the proposed methods was statistically validated with respect to linearity, accuracy, precision and specificity. The proposed methods were successfully applied for the assay of MLT in laboratory prepared mixtures containing up to 15% of DMLT and in commercial MLT tablets with recoveries of no less than 99.00%. No interference was observed from common pharmaceutical additives and the results compared favorably with those obtained by a reference method.
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http://dx.doi.org/10.3390/molecules18010974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6270584PMC
January 2013

2-(2,3-Dimethyl-anilino)benzohydrazide.

Acta Crystallogr Sect E Struct Rep Online 2012 Aug 25;68(Pt 8):o2527-8. Epub 2012 Jul 25.

In the title compound, C(15)H(17)N(3)O, the dihedral angle between the benzene rings is 58.05 (9)°. The non-H atoms of the hydrazide group lie in a common plane (r.m.s. deviation = 0.0006 Å) and are close to coplanar with their attached benzene ring [dihedral angle = 8.02 (9)°]. An intra-molecular N-H⋯O hydrogen bond generates an S(6) ring motif in the mol-ecule, and a short intra-molecular contact (H⋯H = 1.88 Å) is also observed. In the crystal, mol-ecules are linked by pairs of N-H⋯N hydrogen bonds into inversion dimers. The crystal packing also features C-H⋯π inter-actions.
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http://dx.doi.org/10.1107/S1600536812032576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414975PMC
August 2012

5-(Adamantan-1-yl)-3-[(4-benzyl-piperazin-1-yl)meth-yl]-1,3,4-oxadiazole-2(3H)-thione.

Acta Crystallogr Sect E Struct Rep Online 2012 Jul 23;68(Pt 7):o2172-3. Epub 2012 Jun 23.

The mol-ecule of the title compound, C(24)H(32)N(4)OS, is a functionalized 1,3,4-oxadiazole-2-thione with substituted piperazine and adamantanyl substituents attached at the 3- and 5-positions, respectively, of the oxadiazole spacer with an approximately C-shaped conformation. In the crystal, mol-ecules form dimers via C-H⋯S inter-action. The piperazine ring has a chair conformation; the substituents S, methyl-ene C and adamantane C of the essentially planar oxadiazole ring are approximately in the same plane, with distances of -0.046 (2), -0.085 (5) and 0.003 (4) Å, respectively. The dihedral angle between the planes of the phenyl and oxadiazole rings is 31.3 (3)°.
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http://dx.doi.org/10.1107/S1600536812027249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393978PMC
July 2012

1-{[(2,3-Dihydro-1H-inden-2-yl)-oxy]meth-yl}quinazoline-2,4(1H,3H)-dione.

Acta Crystallogr Sect E Struct Rep Online 2012 Jun 23;68(Pt 6):o1866-7. Epub 2012 May 23.

In the title mol-ecule, C(18)H(16)N(2)O(3), the five-membered ring has an envelope conformation, with the substituted C atom deviating by 0.342 (4) Å from the mean plane P calculated for the remainder of the non-H atoms of the 2,3-dihydro-1H-indene fragment. The mean planes of quinazoline-2,4(1H,3H)-dione fragment and P form a dihedral angle of 59.08 (4)°. In the crystal, pairs of N-H⋯O hydrogen bonds link mol-ecules into inversion dimers, and weak C-H⋯O hydrogen bonds and π-π inter-actions between the benzene rings of the quinazoline ring systems [centroid-centroid distance = 3.538 (3) Å] further consolidate the packing.
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http://dx.doi.org/10.1107/S1600536812022350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3379431PMC
June 2012
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