Publications by authors named "Mohamed A Abdelgawad"

36 Publications

Navigating into the Chemical Space of Monoamine Oxidase Inhibitors by Artificial Intelligence and Cheminformatics Approach.

ACS Omega 2021 Sep 1;6(36):23399-23411. Epub 2021 Sep 1.

Department of Pharmaceutical Chemistry and Analysis, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi 682041, India.

The monoamine oxidase (MAO) enzyme class is a prevalent target for many neurodegenerative and depressive disorders. Even though scrutinization of many promising drugs for the treatment of MAO inhibition has been carried out in recent times, a conclusive structural requirement for potent activity needs to be developed. Numerous approaches have been examined for the identification of structural features for potent MAO inhibitors (MAOIs) that mainly involve an array of computational studies, synthetic approaches, and biological evaluation. In this paper, we have analyzed ∼2200 well-known MAOIs to expand perceptions in the chemical space of MAOIs. The physicochemical properties of the MAOIs disclosed a discernible hydrophobic feature making a bunch discrete from the central nervous system (CNS) acting drugs, as exposed using the principal component analysis (PCA). The Murcko scaffold structure study revealed unfavorable and favorable scaffold structures, in both data sets, with the highest biological activity shown by the 3-phenyl-2-chromen-2-one scaffold. This scaffold showed a polypharmacological effect. R-group disintegration and automatic structure-activity relationship (SAR) study resulted in identification of substructures responsible for the inhibitory bioactivity of the MAO-A and MAO-B enzymes. Moreover, with activity cliff analysis, significant biological activity was detected by simple molecular conversion in the chemical compound structure. In addition, we used the machine learning tool to generate a hypothesis wherein pyrazole, benzene ring, and amide containing structural functionalities can exhibit potential biological activities. This hypothesis revealed that CNS target drugs, C4155, C13390, C21265, C43862, C31524, C24810, C37100, C42075, and C43644, could be repurposed as valuable candidates for the MAO-B enzyme. For researchers, this study will bring new perceptions in the discovery and development of MAOIs and direct lead and hit optimization for the progress of small molecules beneficial for MAO-targeting associated diseases.
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http://dx.doi.org/10.1021/acsomega.1c03250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444296PMC
September 2021

Chemical characteristics and targeted encapsulated fruits extracts nanoparticles for antioxidant and cytotoxicity potentials.

Saudi J Biol Sci 2021 Sep 29;28(9):5349-5358. Epub 2021 May 29.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.

A promising fruit (CMF) extract targets an additional incorporation in functional foods. It retains appropriate health welfares owing to its antioxidant properties with limited incorporation in food matrices due its hydrophobicity. Therefore, CMF extract micro- and nanocapsulation was performed to protect and facilitate consistency of produced hydrophobic foods matrices. Furthermore, to determine its phytochemicals, antioxidant, and cytotoxic effects by applying analytical HPLC, FRAP and SRB assay, respectively. HPLC analysis of the tested extracts revealed the presence of, 25.59 ± 1.78 mg catechin/g, 69.68 ± 4.20 mg quercetin/g, and 112.72 ± 8.38 mg gallic acid/g extract. The CMF extract displayed a potent DPPH radicals' scavenger and FRAP high reduction capability in a dose-dependent manner. The potent pharmacological activities of CMF extract may be ascribed to high concentration of polyphenolics including flavonoids which strongly reported to possess an antitumor and antioxidant activities. To confirm the efficient CMF incorporation in micro- and nanosystems and their thermal stabilities to withstand the high temperatures applied during some food processing. DSC of the apparent melt of non-capsulated CMF and encapsulated forms (MCMF and NCMF) in sodium alginate gel and beads was studied. Results showed that melting point of CMF extract (86.17 °C) indicating its inability whereas the MCMF and NCMF melting points (226.45 and 383.87 °C, respectively) demonstrating the capability of expending alginate - packaging material to shield the vital active compounds of fruit to be applied in different targeted delivery products especially that disclosed to high thermal treatments.
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http://dx.doi.org/10.1016/j.sjbs.2021.05.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381057PMC
September 2021

Strawberry and Ginger Silver Nanoparticles as Potential Inhibitors for SARS-CoV-2 Assisted by In Silico Modeling and Metabolic Profiling.

Antibiotics (Basel) 2021 Jul 6;10(7). Epub 2021 Jul 6.

Department of Pharmacognosy, Faculty of Pharmacy, Modern University for Technology and Information, Cairo 11865, Egypt.

SARS-CoV-2 (COVID-19), a novel coronavirus causing life-threatening pneumonia, caused a pandemic starting in 2019 and caused unprecedented economic and health crises all over the globe. This requires the rapid discovery of anti-SARS-CoV-2 drug candidates to overcome this life-threatening pandemic. Strawberry ( Duch.) and ginger () methanolic extracts were used for silver nanoparticle (AgNPs) synthesis to explore their SARS-CoV-2 inhibitory potential. Moreover, an in silico study was performed to explore the possible chemical compounds that might be responsible for the anti-SARS-CoV-2 potential. The characterization of the green synthesized AgNPs was carried out with transmission electron microscope (TEM), Fourier-transform infrared, spectroscopy ultraviolet-visible spectroscopy, zeta potential, and a dynamic light-scattering technique. The metabolic profiling of strawberry and ginger methanolic extract was assessed using liquid chromatography coupled with high-resolution mass spectrometry. The antiviral potential against SARS-CoV-2 was evaluated using an MTT assay. Moreover, in silico modeling and the molecular dynamic study were conducted via AutoDock Vina to demonstrate the potential of the dereplicated compounds to bind to some of the SARS-CoV-2 proteins. The TEM analysis of strawberry and ginger AgNPs showed spherical nanoparticles with mean sizes of 5.89 nm and 5.77 nm for strawberry and ginger, respectively. The UV-Visible spectrophotometric analysis showed an absorption peak at λmax of 400 nm for strawberry AgNPs and 405 nm for ginger AgNPs. The Zeta potential values of the AgNPs of the methanolic extract of strawberry was -39.4 mV, while for AgNPs of ginger methanolic extract it was -42.6 mV, which indicates a high stability of the biosynthesized nanoparticles. The strawberry methanolic extract and the green synthesized AgNPs of ginger showed the highest antiviral activity against SARS-CoV-2. Dereplication of the secondary metabolites from the crude methanolic extracts of strawberry and ginger resulted in the annotation of different classes of compounds including phenolic, flavonoids, fatty acids, sesquiterpenes, triterpenes, sterols, and others. The docking study was able to predict the different patterns of interaction between the different compounds of strawberry and ginger with seven SARS-CoV-2 protein targets including five viral proteins (Mpro, ADP ribose phosphatase, NSP14, NSP16, PLpro) and two humans (AAK1, Cathepsin L). The molecular docking and dynamics simulation study showed that neohesperidin demonstrated the potential to bind to both human AAK1 protein and SARS-CoV-2 NSP16 protein, which makes this compound of special interest as a potential dual inhibitor. Overall, the present study provides promise for Anti-SARS-CoV-2 green synthesized AgNPs, which could be developed in the future into a new anti-SARS-CoV-2 drug.
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http://dx.doi.org/10.3390/antibiotics10070824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300822PMC
July 2021

Identification of non-classical hCA XII inhibitors using combination of computational approaches for drug design and discovery.

Sci Rep 2021 Jul 30;11(1):15516. Epub 2021 Jul 30.

Pharmaceutical Chemistry Department, College of Pharmacy, Jouf University, Sakaka, 72341, Aljouf, Saudi Arabia.

Human carbonic anhydrase XII (hCA XII) isozyme is of high therapeutic value as a pharmacological target and biomarker for different types of cancer. The hCA XII is one of the crucial effectors that regulates extracellular and intracellular pH and affects cancer cell proliferation, invasion, growth and metastasis. Despite the fact that interaction features of hCAs inhibitors with the catalytic site of the enzyme are well described, lack in the selectivity of the traditional hCA inhibitors based on the sulfonamide group or related motifs is an urgent issue. Moreover, drugs containing sulfanomides can cause sulfa allergies. Thus, identification of novel non-classical inhibitors of hCA XII is of high priority and is currently the subject of a vast field of study. This study was devoted to the identification of novel potential hCA XII inhibitors using comprehensive set of computational approaches for drug design discovery: generation and validation of structure- and ligand-based pharmacophore models, molecular docking, re-scoring of virtual screening results with MMGBSA, molecular dynamics simulations, etc. As the results of the study several compounds with alternative to classical inhibitors chemical scaffolds, in particular one of coumarins derivative, have been identified and are of high interest as potential non-classical hCA XII inhibitors.
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http://dx.doi.org/10.1038/s41598-021-94809-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324906PMC
July 2021

Trimethoxylated Halogenated Chalcones as Dual Inhibitors of MAO-B and BACE-1 for the Treatment of Neurodegenerative Disorders.

Pharmaceutics 2021 Jun 8;13(6). Epub 2021 Jun 8.

Department of Pharmaceutical Chemistry, AIMS Health Sciences Campus, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, Kochi 682041, India.

Six halogenated trimethoxy chalcone derivatives (CH1-CH6) were synthesized and spectrally characterized. The compounds were further evaluated for their inhibitory potential against monoamine oxidases (MAOs) and β-secretase (BACE-1). Six compounds inhibited MAO-B more effectively than MAO-A, and the 2',3',4'-methoxy moiety in CH4-CH6 was more effective for MAO-B inhibition than the 2',4',6'-methoxy moiety in CH1-CH3. Compound CH5 most potently inhibited MAO-B, with an IC value of 0.46 µM, followed by CH4 (IC = 0.84 µM). In 2',3',4'-methoxy derivatives (CH4-CH6), the order of inhibition was -Br in CH5 > -Cl in CH4 > -F in CH6 at the -position in ring B of chalcone. CH4 and CH5 were selective for MAO-B, with selectivity index (SI) values of 15.1 and 31.3, respectively, over MAO-A. CH4 and CH5 moderately inhibited BACE-1 with IC values of 13.6 and 19.8 µM, respectively. When CH4 and CH5 were assessed for their cell viability studies on the normal African Green Monkey kidney cell line (VERO) using MTT assays, it was noted that both compounds were found to be safe, and only a slightly toxic effect was observed in concentrations above 200 µg/mL. CH4 and CH5 decreased reactive oxygen species (ROS) levels of VERO cells treated with HO, indicating both compounds retained protective effects on the cells by antioxidant activities. All compounds showed high blood brain barrier permeabilities analyzed by a parallel artificial membrane permeability assay (PAMPA). Molecular docking and ADME prediction of the lead compounds provided more insights into the rationale behind the binding and the CNS drug likeness. From non-test mutagenicity and cardiotoxicity studies, CH4 and CH5 were non-mutagenic and non-/weak-cardiotoxic. These results suggest that CH4 and CH5 could be considered candidates for the cure of neurological dysfunctions.
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http://dx.doi.org/10.3390/pharmaceutics13060850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226672PMC
June 2021

Cytotoxic Potential, Metabolic Profiling, and Liposomes of sp. Crude Extract Supported by in silico Analysis.

Int J Nanomedicine 2021 4;16:3861-3874. Epub 2021 Jun 4.

Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.

Introduction: Sponge- sp. (Family: Spongiidae) is a coastal sponge that possesses a broad variety of natural-products. However, the exact chemical constituents and cytotoxic activity of the extract are still undefinable.

Methodology: In the present study, the metabolomic profiling of sp. dereplicated 20 compounds, utilizing liquid chromatography coupled with high-resolution mass spectrometry (LC-HRESIMS). derived crude extract, before and after encapsulation within nanosized liposomes, was in vitro screened against hepatic, breast, and colorectal carcinoma human cell lines (HepG2, MCF-7, and Caco-2, respectively).

Results: The identified metabolites were fit to diverse chemical classes, covering diterpenes, an indole alkaloid, sesterterpenoid, sterol, and methylherbipoline salt. Comprehensive in silico experiments predicted several compounds in the sponge-derived extract (eg, compounds -) to have an anticancer potential via targeting multiple targets. The crude extract showed moderate antiproliferative activities towards studied cell lines with IC values range from 10.7 to 12.4 µg/mL. The formulated extract-containing liposomes (size 141±12.3nm, PDI 0.222, zeta potential 20.8 ± 2.3), significantly enhanced the in vitro anticancer activity of the entrapped extract (IC values ranged from 1.7 to 4.1 µg/mL).

Discussion: Encapsulation of both the hydrophilic and the lipophilic components of the extract within the lipid-based nanovesicles enhanced the cellular uptake and accessibility of the entrapped cargo. This study introduces liposomal nano-vesicles as a promising approach to improve the therapeutic potential of sponge-derived extracts.
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http://dx.doi.org/10.2147/IJN.S310720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8187037PMC
June 2021

Novel Phenolic Compounds as Potential Dual EGFR and COX-2 Inhibitors: Design, Semisynthesis, in vitro Biological Evaluation and in silico Insights.

Drug Des Devel Ther 2021 31;15:2325-2337. Epub 2021 May 31.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72341, Saudi Arabia.

Introduction: Epidermal growth factor receptor (EGFR) inhibition is an imperative therapeutic approach targeting various types of cancer including colorectal, lung, breast, and pancreatic cancer types. Moreover, cyclooxygenase-2 (COX-2) is frequently overexpressed in different types of cancers and has a role in the promotion of malignancy, apoptosis inhibition, and metastasis of tumor cells. Combination therapy has been emerged to improve the therapeutic benefit against cancer and curb intrinsic and acquired resistance.

Methods: Three semi-synthetic series of compounds (, , and ) were prepared and evaluated biologically as potential dual epidermal growth factor receptor (EGFR) and COX-2 inhibitors. The main phenolic constituents of L. (-coumaric, caffeic and gallic) acids have been isolated and subsequently subjected to diazo coupling with various amines to get novel three chemical scaffolds with potential anticancer activities.

Results: Compounds and showed superior inhibitory activity against EGFR (IC: 0.9 and 0.5 µM, respectively) and displayed good COX-2 inhibition (IC: 4.35 and 2.47 µM, respectively). Moreover, the final compounds were further evaluated for their cytotoxic activity against human colon cancer (HT-29), pancreatic cancer (PaCa-2), human malignant melanoma (A375), lung cancer (H-460), and pancreatic ductal cancer (Panc-1) cell lines. Interestingly, compounds and exhibited the highest cytotoxic activity with average IC values of 1.5 µM and 2.8 µM against H-460 and Panc-1, respectively. The virtual docking study was conducted to gain proper understandings of the plausible-binding modes of target compounds within EGFR and COX-2 binding sites.

Discussion: The NMR of prepared compounds showed characteristic peaks that confirmed the structure of the target compounds. The synthesized benzoxazolyl scaffold containing compounds showed inhibitory activities for both COXs and EGFR which are consistent with the virtual docking study.
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http://dx.doi.org/10.2147/DDDT.S310820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178614PMC
May 2021

Olive Oil/Pluronic Oleogels for Skin Delivery of Quercetin: In Vitro Characterization and Ex Vivo Skin Permeability.

Polymers (Basel) 2021 May 31;13(11). Epub 2021 May 31.

Department of Pharmaceutics, Faculty of Pharmacy, Ahram Canadian University, Giza 14756, Egypt.

The main objective of this study was to prepare and characterize oleogel as potential carrier for quercetin skin delivery. The formulations were prepared by adding olive oil (5-30%) to Pluronic F127 hydrogel and were evaluated for particle size, zeta potential, viscosity in vitro quercetin release and stability, and were compared with that of Pluronic F127 hydrogel. The selected formulation was characterized for its interaction possibility, ex vivo skin permeation and skin histological changes and safety. The particle sizes ranged from 345.3 ± 5.3 nm to 401.5 ± 2.8 nm, and possessed negative charges. The viscosities of the formulations were found in the range of 6367-4823 cps with inverse proportionality to olive oil percentage while the higher percentages showed higher quercetin release. Percentages of 25% and 30% olive oil showed instability pattern under the conditions of accelerated stability studies. Differential scanning calorimetry verified the existence of quercetin in micellar aggregation and the network in the case of hydrogel and oleogel respectively. Ex vivo skin permeation showed an improved skin permeation of quercetin when 20% olive oil containing oleogel was used. Skin histology after 10 days of application showed stratum corneum disruption and good safety profile. Based on these findings, the proposed oleogel containing 20% olive oil denotes a potential carrier for topical delivery of quercetin.
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http://dx.doi.org/10.3390/polym13111808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198417PMC
May 2021

Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach.

Molecules 2021 May 28;26(11). Epub 2021 May 28.

Department of Pharmacy, Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea.

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1-pyrazole () showed the highest potency against MAO-B with an IC value of 0.063 µM. The potencies against MAO-B were increased in the order of -F (in ) > -Cl () > -Br () > -H (). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for and (IC = 8.38 and 4.31 µM, respectively). showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by at > 55.8. was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of to MAO-B. Thus, can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.
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http://dx.doi.org/10.3390/molecules26113264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198649PMC
May 2021

Development of 3-methyl/3-(morpholinomethyl)benzofuran derivatives as novel antitumor agents towards non-small cell lung cancer cells.

J Enzyme Inhib Med Chem 2021 Dec;36(1):987-999

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

As one of the most lethal malignancies, lung cancer is considered to account for approximately one-fifth of all malignant tumours-related deaths worldwide. This study reports the synthesis and biological assessment of two sets of 3-methylbenzofurans (, , and ) and 3-(morpholinomethyl)benzofurans (, , and ) as potential anticancer agents towards non-small cell lung carcinoma A549 and NCI-H23 cell lines, with VEGFR-2 inhibitory activity. The target benzofuran-based derivatives efficiently inhibited the growth of both A549 and NCI-H23 cell lines with IC spanning in ranges 1.48-47.02 and 0.49-68.9 µM, respectively. The three most active benzofurans (, and ) were further investigated for their effects on the cell cycle progression and apoptosis in A549 (for ) and NCI-H23 (for and ) cell lines. Furthermore, benzofurans , and displayed good VEGFR-2 inhibitory activity with IC equal 77.97, 132.5 and 45.4 nM, respectively.
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http://dx.doi.org/10.1080/14756366.2021.1915302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128204PMC
December 2021

Identification of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides as new SLC-0111 analogues: Synthesis and evaluation of the carbonic anhydrase inhibitory activities.

Eur J Med Chem 2021 Jun 13;218:113360. Epub 2021 Mar 13.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia.

As a front-runner selective CA IX inhibitor currently in Phase Ib/II clinical trials, SLC-0111 has been herein exploited as a lead molecule for development of new different sets of N-phenyl-2-(phenylsulfonyl)acetamides/propanamides incorporating different functionalities; primary sulfonamide (5a-f), free carboxylic (8a, 8d), ethyl ester (8b, 8e), acetyl (8c, 8f) and nitro (10a, 10b), as potential carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. All the prepared analogues have been examined for their CA inhibitory activities towards four human (h) isoenzymes, hCA I, II, IX and XII. Interestingly, replacement of SLC-0111 ureido linker with the flexible sulfonyl acetamide linker, as well as linker branching and elongation strategies successfully enhanced the inhibitory action toward hCA IX isoform, such as in sulfones 5a-d and 5f which displayed better activity than SLC-0111. Furthermore, sulfonamide-based sulfone (5f) and carboxylic acid-based sulfones (8a and 8d) demonstrated interesting selectivity toward the tumor-related hCA IX isoform over both hCA I and hCA II, which suggests them as promising candidates for further development as potential anticancer candidates. Thereafter, the anti-proliferative action for sulfones 5f, 8a and 8d was examined against breast (MCF-7) and colon (HCT-116) cancer cell lines. Also, sulfone 5f was further assessed for its impact on the cell cycle progression and apoptosis in HCT-116 cells.
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http://dx.doi.org/10.1016/j.ejmech.2021.113360DOI Listing
June 2021

A New CDK2 Inhibitor with 3-Hydrazonoindolin-2-One Scaffold Endowed with Anti-Breast Cancer Activity: Design, Synthesis, Biological Evaluation, and In Silico Insights.

Molecules 2021 Jan 14;26(2). Epub 2021 Jan 14.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72341, Aljouf Province, Saudi Arabia.

Background: Cyclin-dependent kinases (CDKs) regulate mammalian cell cycle progression and RNA transcription. Based on the structural analysis of previously reported CDK2 inhibitors, a new compound with 3-hydrazonoindolin-2-one scaffold () was well designed, synthesized, and biologically evaluated as a promising anti-breast cancer hit compound.

Methods: The potential anti-cancerous effect of was evaluated using cytotoxicity assay, flow cytometric analysis of apoptosis and cell cycle distribution, ELISA immunoassay, in vitro CDK2/cyclin A2 activity, and molecular operating environment (MOE) virtual docking studies.

Results: The results revealed that exhibits pronounced CDK2 inhibitory activity and cytotoxicity in human breast cancer MCF-7 cell line. The cytotoxicity of was found to be intrinsically mediated apoptosis, which in turn, is associated with low Bcl-2 expression and high activation of caspase 3 and p53. Besides, blocked the proliferation of the MCF-7 cell line and arrested the cell cycle at the G2/M phase. The docking studies did not confirm which one of geometric isomers ( and ) is responsible for binding affinity and intrinsic activity of . However, the molecular dynamic studies have confirmed that the -isomer has more favorable binding interaction and thus is responsible for CDK2 inhibitory activity.

Discussion: These findings displayed a substantial basis of synthesizing further derivatives based on the 3-hydrazonoindolin-2-one scaffold for favorable targeting of breast cancer.
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http://dx.doi.org/10.3390/molecules26020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830330PMC
January 2021

Morpholine-based chalcones as dual-acting monoamine oxidase-B and acetylcholinesterase inhibitors: synthesis and biochemical investigations.

J Enzyme Inhib Med Chem 2021 Dec;36(1):188-197

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon, Republic of Korea.

Nine compounds () containing the morpholine moiety were assessed for their inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Most of the compounds potently inhibited MAO-B; most potently inhibited with an IC value of 0.030 µM, followed by (0.25 µM). most potently inhibited AChE (IC = 6.1 µM), followed by (IC = 12.01 µM) and most potently inhibited MAO-A (IC = 7.1 µM). was a reversible mixed-type inhibitor of MAO-B ( = 0.018 µM); reversibly competitively inhibited AChE ( = 2.52 µM); and reversibly noncompetitively inhibited AChE ( = 7.04 µM). , and crossed the blood-brain barrier, and were non-toxic to normal VERO cells. These results show that is a selective inhibitor of MAO-B and that is a dual-acting inhibitor of AChE and MAO-B, and that both should be considered candidates for the treatment of Alzheimer's disease.
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http://dx.doi.org/10.1080/14756366.2020.1842390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808749PMC
December 2021

Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors.

Molecules 2020 Nov 17;25(22). Epub 2020 Nov 17.

Department of Pharmacy, and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Korea.

Twelve pyridazinones (-) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. was found to be the most potent MAO-B inhibitor with an IC value of 0.013 µM, followed by (IC = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by bromo substitution () than by bromo substitution (). For substitution, inhibitory potencies for MAO-B were as follows: -Cl () > -N(CH) () > -OCH () > Br () > F () > -CH () > -H (). and efficiently inhibited MAO-A with IC values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). and were found to be reversible and competitive inhibitors of MAO-B with K values of 0.014 and 0.0071, respectively. Moreover, was less toxic to healthy fibroblast cells (L929) than . Molecular docking simulations with MAO binding sites returned higher docking scores for and with MAO-B than with MAO-A. These results suggest that and are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.
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http://dx.doi.org/10.3390/molecules25225371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698448PMC
November 2020

Evaluation of ligustrazine based synthetic compounds for mechanism based antiproliferative effects.

Med Chem 2020 Sep 5. Epub 2020 Sep 5.

Department of Chemistry, University of Sargodha, Sargodha 40100. Pakistan.

Background: Ligustrazine and chalcones have been reported previously for various biological activities including anticancer effects.

Objectives: Based on the multitargeted biological activities approach of ligustrazine based chalcones, in current study 18 synthetic ligustrazine-containing α, β-unsaturated carbonyl-based 1, 3-Diphenyl-2-propen-1-one derivatives were evaluated for their inhibitory effects on growth of five different types of cancer cells.

Methods: All compounds were evaluated for anticancer effects on various cancer cell lines by propidium iodide fluorescence assay and various other assays were performed for mechanistic studies.

Results: Majority of compounds exhibited strong inhibition of cancer cells especially synthetic compounds 4a and 4b bearing 1-Pyridin-3-yl-ethanone as a ketone moiety in main structural backbone were found most powerful inhibitors of cancer cell growth. Most active 9 compounds among whole series were selected for further studies related to different cancer targets including EGFR TK kinases, tubulin polymerization, KAF and BRAFV600E.

Conclusion: Synthetic derivatives including 4a-b and 5a-b showed multitarget approach and showed strong inhibitory effects on EGFR, FAK and BRAF while three compounds including 3e bearing methoxy substitution, 4a and 4b with 1- pyridin-3-yl-ethanone moiety showed the inhibition of tubulin polymerization.
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http://dx.doi.org/10.2174/1573406416666200905125038DOI Listing
September 2020

Revealing the role of fluorine pharmacophore in chalcone scaffold for shifting the MAO-B selectivity: investigation of a detailed molecular dynamics and quantum chemical study.

J Biomol Struct Dyn 2021 Oct 24;39(16):6126-6139. Epub 2020 Jul 24.

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad, Kerala, India.

The development of highly selective monoamine oxidase-B (MAO-B) inhibitors has great therapeutic benefit in treatment of various neurodegenerative disorders. Recent study documented that shifting of fluorine atom from to position on the phenyl B ring of heteroaryl chalcones shown a remarkable shift in the selectivity and potency between MAO-A and MAO-B isoforms. Despite the large plethora of the design of new selective MAO-B inhibitors, the current paper illustrates the role and orientation of fluorine atom with remarkable MAO-B selectivity of three compounds (O23, O24 and O25), which differ from all other substituents encountered in the chalcone scaffolds is recently reported by our group. Conformational analyses of differential inhibitory effects of O23, O24 and O25 on MAO-A and MAO-B, differential analyses of complementary interactions at MAO-A/-B active sites and differential analysis of affinity binding and per-residue energy contributions are calculated by molecular dynamics study. Density functional theory based electronic structure calculations were employed with special emphasis to electrostatic potential and frontier molecular orbitals. Results of the current study can be used for lead modification and a new insight for the development of novel fluorinated chalcones for the treatment of various neurodegenerative disorders. Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1796803DOI Listing
October 2021

Sulfonamide-based 4-anilinoquinoline derivatives as novel dual Aurora kinase (AURKA/B) inhibitors: Synthesis, biological evaluation and in silico insights.

Bioorg Med Chem 2020 07 25;28(13):115525. Epub 2020 Apr 25.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Beni-Suef University, Beni-Suef 62514, Egypt. Electronic address:

Aurora kinases (AURKs) were identified as promising druggable targets for targeted cancer therapy. Aiming at the development of novel chemotype of dual AURKA/B inhibitors, herein we report the design and synthesis of three series of 4-anilinoquinoline derivatives bearing a sulfonamide moiety (5a-d, 9a-d and 11a-d). The % inhibition of AURKA/B was determined for all target quinolines, then compounds showed more than 50% inhibition on either of the enzymes, were evaluated further for their IC on the corresponding enzyme. In particular, compound 9d displayed potent AURKA/B inhibitory activities with IC of 0.93 and 0.09 µM, respectively. Also, 9d emerged as the most efficient anti-proliferative analogue in the US-NCI anticancer assay toward the NCI 60 cell lines panel, with broad spectrum activity against different cell lines from diverse cancer subpanels. Docking studies, confirmed that, the sulfonamide SO oxygen was involved in a hydrogen bond with Lys162 and Lys122 in AURKA and AURKB, respectively, whereas, the sulfonamide NH could catch hydrogen bond interaction with the surrounding amino acid residues Lys141, Glu260, and Asn261 in AURKA and Lys101, Glu177, and Asp234 in AURKB. Furthermore, N1 nitrogen of the quinoline scaffold formed an essential hydrogen bond with the hinge region key amino acids Ala213 and Ala173 in AURKA and AURKB, respectively.
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http://dx.doi.org/10.1016/j.bmc.2020.115525DOI Listing
July 2020

Design, Synthesis and Biological Evaluation of New HDAC1 and HDAC2 Inhibitors Endowed with Ligustrazine as a Novel Cap Moiety.

Drug Des Devel Ther 2020 4;14:497-508. Epub 2020 Feb 4.

Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

Introduction: Histone deacetylases (HDACs) represent one of the most validated cancer targets. The inhibition of HDACs has been proven to be a successful strategy for the development of novel anticancer candidates.

Methods: This work describes design and synthesis of a new set of HDAC inhibitors ( and ) utilizing ligustrazine as a novel cap moiety, and achieving the pharmacophoric features required to induce the desired inhibition.

Results: The newly synthesized derivatives were evaluated for their potential inhibitory activity toward two class I histone deacetylases, namely HDAC1 and HDAC2. The tested ligustrazine-based compounds were more potent toward HDAC2 (IC range: 53.7-205.4 nM) than HDAC1 (IC range: 114.3-2434.7 nM). Furthermore, the antiproliferative activities against two HDAC-expressing cancer cell lines; HT-29 and SH-SY5Y were examined by the MTT assay. Moreover, a molecular docking study of the designed HDAC inhibitors ( and ) was carried out to investigate their binding pattern within their prospective targets; HDAC1 (PDB-ID: 4BKX) and HDAC2 (PDB-ID: 6G3O).

Discussion: Compound was found to be the most potent analog in this study toward HDAC1 and HDAC2 with IC values equal 114.3 and 53.7 nM, respectively. Moreover, it was the most effective counterpart (IC = 1.60 µM), with 4.7-fold enhanced efficiency than reference drug Gefitinib (IC = 7.63 µM) against SH-SY5Y cells. Whereas, compound (IC = 1.96 µM) was the most active member toward HT-29 cells, being 2.5-times more potent than Gefitinib (IC = 4.99 µM). Collectively, these results suggest that merits further optimization and development as an effective new HDACI lead compound.
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http://dx.doi.org/10.2147/DDDT.S237957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008064PMC
October 2020

New pyrimidine-benzoxazole/benzimidazole hybrids: Synthesis, antioxidant, cytotoxic activity, in vitro cyclooxygenase and phospholipase A2-V inhibition.

Bioorg Chem 2019 11 26;92:103218. Epub 2019 Aug 26.

Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.

To enhance the cytotoxicity of benzimidazole and/or benzoxazole core, the benzimidazole/benzoxazole azo-pyrimidine were synthesized through diazo-coupling of 3-aminophenybenzimidazole (6a) or 3-aminophenylbenzoxazole (6b) with diethyl malonate. The new azo-molanates 6a&b mixed with urea in sodium ethoxide to afford the benzimidazolo/benzoxazolopyrimidine 7a&b. The structure elucidation of new synthesized targets was proved using spectroscopic techniques NMR, IR and elemental analysis. The cytoxicity screening had been carried out against five cancer cell lines: prostate cancer (PC-3), lung cancer (A-549), breast cancer (MCF-7), pancreas cancer (PaCa-2) and colon cancer (HT-29). Furthermore, the antioxidant activity, phospholipase A2-V and cyclooxygenases inhibitory activities of the target compounds 7a&b were evaluated and the new compounds showed potent activity (cytotoxicity IC range from 4.3 to 9.2 µm, antioxidant activity from 40% to 80%, COXs or LOX inhibitory activity from 1.92 µM to 8.21 µM). The docking of 7a&b was made to confirm the mechanism of action.
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http://dx.doi.org/10.1016/j.bioorg.2019.103218DOI Listing
November 2019

Synthesis and biological evaluation of novel 3-(quinolin-4-ylamino)benzenesulfonamidesAQ3 as carbonic anhydrase isoforms I and II inhibitors.

J Enzyme Inhib Med Chem 2019 Dec;34(1):1457-1464

d Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence , Firenze , Italy.

Carbonic anhydrases (CAs, EC 4.2.1.1) are crucial metalloenzymes that are involved in diverse bioprocesses. We report the synthesis and biological evaluation of novel series of benzenesulfonamides incorporating un/substituted ethyl quinoline-3-carboxylate moieties. The newly synthesised compounds were evaluated as inhibitors of the cytosolic human (h) isoforms hCA I and II. Both isoforms hCA I and II were inhibited by the quinolines reported here in variable degrees: hCA I was inhibited with s in the range of 0.966-9.091 μM, whereas hCA II in the range of 0.083-3.594 μM. The primary 7-chloro-6-flouro substituted sulphfonamide derivative ( = 0.083 μM) proved to be the most active quinoline in inhibiting hCA II, whereas, its secondary sulfonamide analog failed to inhibit the hCA II up to 10 μM, confirming the crucial role of the primary sulphfonamide group, as a zinc-binding group for CA inhibitory activity.
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http://dx.doi.org/10.1080/14756366.2019.1652282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713088PMC
December 2019

Design, synthesis, analgesic, anti-inflammatory activity of novel pyrazolones possessing aminosulfonyl pharmacophore as inhibitors of COX-2/5-LOX enzymes: Histopathological and docking studies.

Bioorg Chem 2018 08 8;78:103-114. Epub 2018 Mar 8.

Department of Pathology, Faculty of Veterinary Medicine, Beni-Suef University, Beni-Suef 62511, Egypt.

A series of newly synthesized 4-aryl-hydrazonopyrazolones were designed and their structures were confirmed by spectral and elemental analyses. All synthesized compounds were evaluated for their in vitro COXs, 5-LOX inhibition, in vivo analgesic and anti-inflammatory activities. Compounds 5d, 5f and 5i were found to be the most potent COX-2/5-LOX inhibitors with superior COX-2 selectivity index values (SI = 5.29-5.69) to reference standard celecoxib (SI = 3.52). Four compounds; 5b, 5c, 5d and 5f showed excellent anti-inflammatory activity (% edema inhibition = 72.72-54.54%) and perfect ED values (ED = 0.044-0.104 mmol/kg) relative to celecoxib (ED = 0.032 mmol/kg). To explore the most active compounds, ulcerogenic effect on stomach in comparison with indomethacin and celecoxib in addition to histopathological investigations were performed. Compound 5f showed better gastric profile (UI = 2.33) than celecoxib (UI = 3.00). Also, 5f caused 50% increase in thermal pain threshold close to reference drug indomethacin (53.13%). Docking study of all the target compounds into COX-2 and 5-LOX active sites was performed to rational their anti-inflammatory activities.
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http://dx.doi.org/10.1016/j.bioorg.2018.03.011DOI Listing
August 2018

Novel pyrimidine-pyridine hybrids: Synthesis, cyclooxygenase inhibition, anti-inflammatory activity and ulcerogenic liability.

Bioorg Chem 2018 04 31;77:339-348. Epub 2018 Jan 31.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.

Some derivatives containing pyrido[2,3-d:6,5d']dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC = 0.25-0.89 µM) than celecoxib (IC = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.
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http://dx.doi.org/10.1016/j.bioorg.2018.01.028DOI Listing
April 2018

Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production.

Eur J Med Chem 2018 Feb 31;146:260-273. Epub 2018 Jan 31.

Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka, 2014, Saudi Arabia. Electronic address:

A series of novel compounds carrying pyrazino[1,2-a]indol-1(2H)-one scaffold (5a-g) and their reaction intermediates, indole-2-carboxamides, (3a-g) were synthesized and evaluated for their ability to inhibit reactive oxygen species (ROS) generation, antioxidant activity and anticancer activity against a panel of cancer cell lines using MTT assay. The results showed that these compounds can inhibit ROS generation during the metabolic phase of phagocytosis in a dose-dependent manner where compounds 5d and 5e were the most potent samples with higher inhibitory activities (IC values 3.3 and 1.4 μM, respectively) than that of the reference acetylsalicylic acid (IC = 9.7 μM). Results for the determination of potential antioxidant properties of the synthesized compounds showed that compounds 5d and 5e containing pyrazino[1,2-a]indol-1-one backbone were the most acive and even comparable to Trolox. Compounds 3d-f and 5d-f with the least IC values in MTT assay were tested against three known anticancer targets EGFR, BRAF and Tubulin. Histopathological and immunohistochemical study were performed to determine the consequence of exposure to chronic low dose of chlorpyrifos on the testis of male mice and results revealed that these effects can be ameliorated by co-treatment with the most active antioxidant compounds 5d and 5e. Finally, molecular docking studies were performed to explore the binding mode of the most active compounds against EGFR and BRAF kinases.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.042DOI Listing
February 2018

Discovery of a COX-2 selective inhibitor hit with anti-inflammatory activity and gastric ulcer protective effect.

Future Med Chem 2017 10 27;9(16):1899-1912. Epub 2017 Oct 27.

Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Sakaka, Aljouf 2014, Kingdom of Saudi Arabia.

Aim: A novel series of 2-arylimino-5-arylidenethiazolidin-4-ones 12a-n were synthesized and all the target compounds were fully characterized by IR, H NMR, C NMR, mass spectroscopy and elemental analysis. Materials & methods: All the target compounds were evaluated for their COX inhibition by enzyme immunoassay kit and in vivo anti-inflammatory activity.

Results: Tested compounds were found more potent inhibitors of COX-2 (IC = 0.54-3.14 µM) than COX-1 (IC = 4.97-11.52 µM). The ulcerogenic liability of compounds 12(d, e, f, h, k, m) was performed and showed gastric safety more than or comparable to celecoxib.

Conclusion: In addition, docking study of the most potent and selective compound 12h into COX-2 active site revealed that this target compound assumed interactions and binding pattern similar to that of as a cocrystallized ligand bromocelecoxib (S-58).
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http://dx.doi.org/10.4155/fmc-2017-0115DOI Listing
October 2017

Pyrazole-hydrazone derivatives as anti-inflammatory agents: Design, synthesis, biological evaluation, COX-1,2/5-LOX inhibition and docking study.

Bioorg Chem 2017 10 30;74:212-220. Epub 2017 Aug 30.

Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt.

A new series of pyrazole-hydrazone derivatives 4a-i were designed and synthesized, their chemical structures were confirmed by IR, H NMR, C NMR, MS spectral data and elemental analysis. IC values for all prepared compounds to inhibit COX-1, COX-2 and 5-LOX enzymes were determined in vitro. Compounds 4a (IC=0.67μM) and 4b (IC=0.58μM) showed better COX-2 inhibitory activity than celecoxib (IC=0.87μM) with selectivity index (SI=8.41, 10.55 in sequent) relative to celecoxib (SI=8.85). Also, compound 4a and 4b exhibited superior inhibitory activity against 5-LOX (IC=1.92, 2.31μM) higher than zileuton (IC=2.43μM). All target pyrazoles were screened for their ability to reduce nitric oxide production in LPS stimulated peritoneal macrophages. Compounds 4a, 4b, 4f and 4i displayed concentration dependent reduction and were screened for in vivo anti-inflammatory activity using carrageenan-induced rat paw edema assay. Compound 4f showed the highest anti-inflammatory activity (% edema inhibition=15-20%) at all doses when compared to reference drug celecoxib (% edema inhibition=15.7-17.5%). Docking studies were carried out to investigate the interaction of target compounds with COX-2 enzyme active site.
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http://dx.doi.org/10.1016/j.bioorg.2017.08.014DOI Listing
October 2017

Design, synthesis and biological evaluation of some novel benzothiazole/benzoxazole and/or benzimidazole derivatives incorporating a pyrazole scaffold as antiproliferative agents.

Bioorg Chem 2017 10 15;74:82-90. Epub 2017 Jul 15.

Sharjah Institute for Medical Research, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates; Department of Pharmacology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.

In an aim at developing new antiproliferative agents, new series of benzothiazole/benzoxazole and/or benzimidazole substituted pyrazole derivatives 11a-c, 12a-c and 13a-c were prepared and evaluated for their antiproliferative activity against breast carcinoma (MCF-7) and non-small cell lung cancer (A549) cell lines. The target compound, 2-acetyl-4-[(3-(1H-benzimidazol-2-yl)-phenyl]-hydrazono-5-methyl-2,4-dihydropyrazol-3-one (12a) was the most active compound against both MCF-7 and A549 cell lines with half maximal inhibitory concentrations (IC)=6.42 and 8.46μM, respectively. Furthermore, the inhibitory activity of the all the target compounds against COX enzymes was recorded as a proposed mechanism for their antiproliferative activity. The obtained results revealed that the benzothiazolopyrazolone derivative 13c was the most potent COX-2 inhibitor (IC=0.10μM), while the 5-acetylbenzimidazolylpyrazolone derivative 12a was the most COX-2 selective (S.I.=104.67) in comparison with celecoxib (COX-2 IC=1.11μM, S.I.=13.33). Docking simulation on the most active compounds 12a and 13c had been performed to investigate the binding interaction of these active compounds within the binding site of COX-2 enzyme.Collectively, this work demonstrated the promising activity of the newly designed compounds as leads for further development into antiproliferative agents.
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http://dx.doi.org/10.1016/j.bioorg.2017.07.007DOI Listing
October 2017

Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors.

Arch Pharm (Weinheim) 2017 Aug 12;350(8). Epub 2017 Jun 12.

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.

New series of diarylpyrazoles 8a-f and triarylimidazoline-5-ones 11a-g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77-5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h).
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http://dx.doi.org/10.1002/ardp.201600386DOI Listing
August 2017

Design, synthesis and biological screening of some novel celecoxib and etoricoxib analogs with promising COX-2 selectivity, anti-inflammatory activity and gastric safety profile.

Bioorg Chem 2017 02 26;70:173-183. Epub 2016 Dec 26.

Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Beni Suef University, Beni Suef 62514, Egypt; Pharmaceutical Sciences Department, Ibn Sina National College for Medical Studies, Jeddah 21418, Kingdom of Saudi Arabia.

Two new series of 4,6-diaryl-3-cyanopyridine 4a-r and 1,3,5-triaryl-2-pyrazolines 6a-f and were prepared. The new compounds were evaluated for their in vitro COX-2 selectivity and in vivo anti-inflammatory activity. Compounds 4o,r and 6d,f had moderate to high selectivity index (S.I.) compared to celecoxib (selectivity indexes of 4.5, 3.14, 4.79 and 3.21, respectively) and also, showed in vivo anti-inflammatory activity approximately equal to or higher than celecoxib (edema inhibition %=60.5, 64.5, 59.3 and 59.3, after 3h, respectively) and the effective anti-inflammatory doses were (ED=10.1, 7.8, 8.46 and 10.7mg/kg respectively, celecoxib ED=10.8mg/kg) and ulcerogenic liability were determined for these compounds which showed promising activity by being more potent than celecoxib with nearly negligible ulcerogenic liability compared to celecoxib (reduction in ulcerogenic liability versus celecoxib=85, 82, 74 and 67%, respectively).
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http://dx.doi.org/10.1016/j.bioorg.2016.12.008DOI Listing
February 2017

Synthesis, biological evaluation, docking study and ulcerogenicity profiling of some novel quinoline-2-carboxamides as dual COXs/LOX inhibitors endowed with anti-inflammatory activity.

Eur J Med Chem 2017 Feb 5;127:972-985. Epub 2016 Nov 5.

Department of Pharmaceutical Chemistry, College of Pharmacy, Aljouf University, Aljouf, Sakaka2014, Saudi Arabia. Electronic address:

A series of novel quinoline-2-carboxamides 15-28 was synthesized and evaluated in vitro as dual COXs/LOX inhibitors. Compounds 19 and 27 exhibited the highest potency and selectivity for COX-2 inhibitory activity (IC = 1.21 and 1.13 μM, respectively; selectivity index (COX-1/COX-2) = 6.52 and 7.61, respectively) in comparison to the reference drug celecoxib (COX-2 IC = 0.88 μM; selectivity index (COX-1/COX-2) = 8.31). The anti-inflammatory activity of the newly synthesized compounds was further assessed in vivo using carrageenan induced paw edema assay. Interestingly, the in vitro results of COXs inhibitory assay were consistent with that of the in vivo assay where compounds 19 and 27 showed the highest anti-inflammatory activity with edema inhibition percentages of 59.38% and 65.03%, respectively compared to celecoxib (71.21%) after 5 h. Moreover, it was found that compounds 19 and 27 have a superior gastric safety profile comparable to indomethacin. The molecular docking study of compounds 19 and 27 into COX-2 active site suggested that these hits assumed binding pattern and interactions similar to that of bromocelecoxib (S-58) as a cocrystallized ligand explaining their remarkable COX-2 inhibitory activity and selectivity. Taken together, these results indicated that these derivatives are good leads for subsequent development into potential anti-inflammatory agents with least gastric damage.
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http://dx.doi.org/10.1016/j.ejmech.2016.11.006DOI Listing
February 2017

DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NEW PYRROLOAZEPINES WITH POTENTIAL AND SELECTIVE ANTITUMOR ACTIVITY.

Acta Pol Pharm 2016 Mar-Apr;73(2):359-68

2-Chloroacetylamino-pyrrolo[1,2-a]azepine-3-ethyl ester 3 was synthesized, condensed with ammonium thiocyanate to obtain a hybrid molecule of pyrrolo [1,2-a]azepine and thiazolidinone moiety 4. Coupling of the obtained hybrid molecule with the appropriate aldehydes or diazonium salt afforded novel substituted hybrids 5a,b and 6. Chemical structures were confirmed by spectral and elemental analysis. The synthesized compounds were tested on liver Hep3B, lung A549, breast MCF7 cancer cell lines and normal fibroblast cells as well, using sulforhodamine-B assay method. Compound 5a showed to be potent and selective to lung A549 cancer cell line (IC50 = 13 nM/mL, S.I. = 2.9). The most potent one against MCF7 was compound 4 with IC50 value equals 12 nM/mL and S.I. = 1.4. Compounds 5b, 6 exhibited high potency and selectivity towards Hep3B cancer cells with IC50 and S.I. equal 15 nM/mL, 10.8 and 9 nM/mL, 285, respectively. The ability of the synthesized compounds 3-6 to act as modulators for cyclin dependent kinases was explored through molecular docking studies.
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June 2016
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