Publications by authors named "Mohammad M Al-Sanea"

36 Publications

Targeting 3CLpro and SARS-CoV-2 RdRp by sp. Metabolites: A Computational Study.

Molecules 2021 Jun 21;26(12). Epub 2021 Jun 21.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, Universities Zone, New Minia City 61111, Egypt.

Since December 2019, novel coronavirus disease 2019 (COVID-19) pandemic has caused tremendous economic loss and serious health problems worldwide. In this study, we investigated 14 natural compounds isolated from sp. via a molecular docking study, to examine their ability to act as anti-COVID-19 agents. Moreover, the pharmacokinetic properties of the most promising compounds were studied. The docking study showed that virtually screened compounds were effective against the new coronavirus via dual inhibition of SARS-CoV-2 RdRp and the 3CL main protease. In particular, nakinadine B (), 20-hepacosenoic acid () and amphimedoside C () were the most promising compounds, as they demonstrated good interactions with the pockets of both enzymes. Based on the analysis of the molecular docking results, compounds and were selected for molecular dynamics simulation studies. Our results showed sp. to be a rich source for anti-COVID-19 metabolites.
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http://dx.doi.org/10.3390/molecules26123775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8235472PMC
June 2021

Elevated CO differently suppresses the arsenic oxide nanoparticles-induced stress in C3 (Hordeum vulgare) and C4 (Zea maize) plants via altered homeostasis in metabolites specifically proline and anthocyanin metabolism.

Plant Physiol Biochem 2021 Jun 6;166:235-245. Epub 2021 Jun 6.

Botany and Microbiology Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62511, Egypt; Integrated Molecular Plant Physiology Research, Department of Biology, University of Antwerp, Antwerp, Belgium.

Nano-sized arsenic oxide nanoparticles (AsO-NP) limit crop growth and productivity. AsO-NP represent a strong environmental hazard. The predicted rise in future atmospheric CO could boost plant growth both under optimal and heavy metal stress conditions. So far, the phytotoxicity of AsO-NP and their interaction with eCO were not investigated at physiological and metabolic levels in crop species groups such as C3 and C4. We investigated how eCO level (620 ppm) alleviated soil AsO-NP toxicity induced growth and mitigated oxidative damages through analysing photosynthetic parameters, primary (sugars and amino acids) and secondary (phenolics, flavonoids and anthocyanins) metabolism in C3 (barley) and C4 (maize) plants. Compared to maize, barley accumulated higher AsO-NP level, which inhibited growth and induced oxidative damage particularly in barley (increased HO and lipid peroxidation). Interestingly, eCO differently mitigated AsO-NP toxicity on photosynthesis, which consequently improved sugar metabolism. Moreover, high carbon availability in eCO treated plants directed to produce osmo-protectant (soluble sugars and proline) and antioxidants (anthocyanins and tocopherols). In the line with increased proline and anthocyanins, their metabolism was also improved. Notable differences occurred between the two plant species. The ornithine pathway was preferred in maize while in barley proline accumulation was mainly through glutamate pathway. Moreover, under AsO-NP stress, barley preferentially accumulated anthocyanins while maize accumulated total phenolics and flavonoids. This work contributes to improving our understanding of the differences in growth, physiological and biochemical responses of major crops of two functional photosynthetic groups (C3 and C4 plants) under ambient and elevated CO grown under AsO-NP stress.
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http://dx.doi.org/10.1016/j.plaphy.2021.05.036DOI Listing
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 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

Antiulcer Potential of L. cv. Arbequina Leaf Extract Supported by Metabolic Profiling and Molecular Docking.

Antioxidants (Basel) 2021 Apr 22;10(5). Epub 2021 Apr 22.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia City, Minia 61111, Egypt.

Gastric ulceration is among the most serious humanpublic health problems. L. cv. Arbequina is one of the numerous olive varieties which have scarcely been studied. The reported antioxidant and anti-inflammatory potential of the olive plant make it a potential prophylactic natural product against gastric ulcers. Consequently, the main goal of this study is to investigate the gastroprotective effect of L. cv. Arbequina leaf extract. LC-HRMS-based metabolic profiling of the alcoholic extract of L. cv. Arbequina led to the dereplication of 18 putative compounds (-). In vivo indomethacin-induced gastric ulcer in a rat model was established and the extract was tested at a dose of 300 mg kg compared to cimetidine (100 mg kg). The assessment of gastric mucosal lesions and histopathology of gastric tissue was done. It has been proved that significantly decreased the ulcer index and protected the mucosa from lesions. The antioxidant potential of the extract was evaluated using three in vitro assays, HO scavenging, xanthine oxidase inhibitory, and superoxide radical scavenging activities and showed promising activities. Moreover, an in silico based study was performed on the putatively dereplicated compounds, which highlighted that 3-hydroxy tyrosol () and oleacein () can target the 5-lipoxygenase enzyme (5-LOX) as a protective mechanism against the pathogenesis of ulceration. Upon experimental validation, both compounds 3-hydroxy tyrosol (HT) and oleacein (OC) ( and , respectively) exhibited a significant in vitro 5-LOX inhibitory activity with IC values of 8.6 and 5.8 µg/mL, respectively. The present study suggested a possible implication of leaves as a potential candidate having gastroprotective, antioxidant, and 5-LOX inhibitory activity for the management of gastric ulcers.
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http://dx.doi.org/10.3390/antiox10050644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146603PMC
April 2021

Potential Anticancer Lipoxygenase Inhibitors from the Red Sea-Derived Brown Algae : An In-Silico-Supported In-Vitro Study.

Antibiotics (Basel) 2021 Apr 10;10(4). Epub 2021 Apr 10.

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

LC-MS-assisted metabolomic profiling of the Red Sea-derived brown algae "Sargassaceae" dereplicated eleven compounds -. Further phytochemical investigation afforded two new aryl cresol -, along with eight known compounds -. Both new metabolites, along with showed moderate in vitro antiproliferative activity against HepG2, MCF-7, and Caco-2. Pharmacophore-based virtual screening suggested both 5-LOX and 15-LOX as the most probable target linked to their observed antiproliferative activity. The in vitro enzyme assays revealed and were able to inhibit 5-LOX more preferentially than 15-LOX, while showed a convergent inhibitory activity toward both enzymes. Further in-depth in silico investigation revealed the molecular interactions inside both enzymes' active sites and explained the varying inhibitory activity for and toward 5-LOX and 15-LOX.
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http://dx.doi.org/10.3390/antibiotics10040416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069941PMC
April 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

Metabolomic profiling of three species, and their possible potential role against COVID-19.

J Biomol Struct Dyn 2021 Feb 18:1-13. Epub 2021 Feb 18.

Department of Pharmacognosy, Faculty of Pharmacy, MTI University, Cairo, Egypt.

The COVID-19 pandemic in Egypt is a part of the worldwide global crisis of coronavirus 2 (SARS-CoV-2). The contagious life-threatening condition causes acute respiratory syndrome. The present study aimed to assess the compounds identified by LC-MS of the methanolic leaves extracts from three conifers trees cultivated in Egypt ( and ) via docking technique as potential inhibitor of COVID-19 virus on multiple targets; viral main protease (M, 6LU7), non-structural protein-16 which is a methyl transferase (nsp16, 6W4H) and RNA dependent RNA polymerase (nsp12, 7BV2). Among the three targets, nsp16 was the best target recognized by the tested compounds as can be deduced from docking studies. Moreover, the methanolic extract of showed the highest radical-scavenging activity using (DPPH test) with 53.7 µg/mL comparable to ascorbic acid with IC = 46 µg/mL The anti-inflammatory potential carried using enzyme linked immunoassay showed the highest activity for and followed by with IC = 23.20 ± 1.17 µg/mL, 82.83 ± 3.21 µg/mL and 221.13 ± 6.7 µg/mL, respectively (Celecoxib was used as a standard drug with IC = 141.92 ± 4.52 µg/mL). Moreover, a molecular docking study was carried for the LC-MS annotated metabolites to validate their anti-inflammatory inhibitory effect using Celecoxib as a reference compound and showed a high docking score (-7.7 kcal/mol) for Octadecyl () -coumarate and (-7.3 kcal/mol) for secoisolariciresinol rhamnoside.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1885494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899166PMC
February 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

Multitarget studies of , family against SARS-CoV-2 supported by molecular dynamics simulation.

J Biomol Struct Dyn 2020 Dec 15:1-11. Epub 2020 Dec 15.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia City, Egypt.

The novel strain of human coronavirus, emerged in December 2019, which has been designated as SARS-CoV-2, causes a severe acute respiratory syndrome. Since then, it has arisen as a serious threat to the world public health. Since no approved vaccines or drugs has been found to efficiently stop the virulent spread of the virus, progressive inquiries targeting these viruses are urgently needed, especially those from plant sources. Metabolic profiling using LC-HR-ESI-MS of the butanol extract of () aerial parts yielded 10 compounds including flavonoids, iridoids and phenolics. As it has been previously reported that some flavonoids can be used as anti-SARS drugs by targeting SARS-CoV-1 3CLpro, we chose to examine 14 flavonoids (detected by metabolomics and other compounds isolated several chromatographic techniques). We investigated their potential binding interactions with the 4 main SARS-CoV-2 targets: M, nsp16/nsp10 complex, ACE2-PD and RBD-S-protein molecular docking. Docking results indicated that the nsp16/nsp10 complex has the best binding affinities where the strongest binding was detected with apigenin-7--rutinoside, prunin and acaciin with -9.4, -9.3 and -9.3 kcal/mol binding energy, respectively, compared to the control (SAM) with -8.2 kcal/mol. Furthermore, the stability of these complexes was studied using molecular dynamics of 150 ns, which were then compared to their complexes in the other three targets. MM-PBSA calculations suggested the high stability of acaciin-nsp16 complex with binding energy of -110 kJ/mol. This study sheds light on the structure-based design of natural flavonoids as anti-SARS-CoV-2 drugs targeting the nsp16/10 complex.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2020.1852964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7784784PMC
December 2020

Molecular Characterization of Hepatitis C Virus for Developed Antiviral Agents Resistance Mutations and New Insights into in-silico Prediction Studies.

Infect Drug Resist 2020 23;13:4235-4248. Epub 2020 Nov 23.

Department of Microbiology and Immunology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt.

Background: Identification and characterization of developed antiviral drug resistance mutations are key to the success of antiviral therapies against hepatitis C virus (HCV), which remains a worldwide highly prevalent pathogenic disease. Although most studies focus on HCV genotypes 1, 2 or 3, the investigation of drug resistance in HCV genotype 4, predominant in North Africa, is especially significant in Egypt.

Methods: We performed mutational and genotypic analysis of the untranslated region (UTR) and nonstructural protein 5B (NS5B) drug resistance-associated regions of HCV for patients in the surrounding villages of Mansoura city, who were not responding to different antiviral treatments (sofosbuvir (SOF), ribavirin, and interferon). Furthermore, molecular modelling approaches (homology modelling and docking studies) were used to investigate the significance of the identified NS5B mutations for SOF and ribavirin binding in the HCV genotype 4a NS5B active site.

Results: Genotypic analysis confirmed all samples to have genotype 4 with sub-genotype 4a predominant. Partial sequencing of the UTR and NS5B resistance-associated regions identified D258E, T282S and A307G mutations in all isolates of NS5B. The UTR mutation site at position 243 was associated with interferon resistance, whereas the NS5B T282S mutation was considered as significant for SOF and ribavirin resistance. Docking studies in the HCV genotype 4a homology model predict SOF and ribavirin to accommodate a nucleotide-like binding mode, in which the T282 residue does interfere with the binding as it would in HCV genotypes 1 and 2. Mutation energy calculations predict T282S to moderately destabilize the binding of SOF and ribavirin by 0.57 and 0.47 kcal/mol, respectively.

Conclusion: The performed study identified and characterized several antiviral drug resistance mutations of HCV genotype 4a and proposed a mechanism by which the T282S mutation may contribute to SOF and ribavirin resistance.
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http://dx.doi.org/10.2147/IDR.S267809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696641PMC
November 2020

Inhibition of Bruton tyrosine kinase by acalabrutinib dampens lipopolysaccharide/galactosamine-induced hepatic damage.

Biomed Pharmacother 2020 Nov 17;131:110736. Epub 2020 Sep 17.

Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt.

Bruton tyrosine kinase (BTK) sits at the crossroads of adaptive and innate immunities. Nevertheless, the detailed role of BTK activation in hepatic inflammatory disorders is still elusive to date. Accordingly, we investigated the impact of blocking BTK activation by acalabrutinib (ACB) on lipopolysaccharide/galactosamine (LPS/D-GaIN)-induced deleterious manifestations in the liver. This was achieved by pretreating mice with ACB (6, 12 or 24 mg/kg, oral) 2 h before challenge with LPS/D-GaIN (70 μg/kg and 700 mg/kg, respectively, i.p.) for 6 h. The results showed that ACB (6 and 12 mg/kg) (i) curbed LPS/D-GaIN-induced rise in biochemical (serum ALT, AST and LDH) and histological (necrosis, degeneration and congestion scores) indices of hepatocellular injury; (ii) attenuated LPS/D-GaIN-induced elevation in parameters of hepatocellular apoptosis (cleaved caspase 3) and proliferation (PCNA); and (iii) importantly, mitigated LPS/D-GaIN-induced recruitment and infiltration of the inflammatory cells to the liver evidenced by lowering elevated serum MCP-1 concentration and hepatic F4/80 immunostaining. These effects were linked to ACB dose-dependent inhibition of NF-κB nuclear translocation that subsequently reduced LPS/D-GaIN-mediated release of TNF-α, IL-1β and IL-22 in the blood circulation. However, a dose of 12 mg/kg of ACB elevated the hepatic TNF-α, IL-1β and IL-22 concentrations that arose from a compensatory activation of ERK and JNK. Inhibition of BTK also attenuated LPS/D-GaIN-induced overexpression of CD98, which is another contributor alongside cytokines for monocyte recruitment. Therapeutically, targeting BTK by ACB is an efficient approach for hitting multiple points with one agent that can dampen hepatocellular injury, death, immune cell recruitment and inflammation cascade.
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http://dx.doi.org/10.1016/j.biopha.2020.110736DOI Listing
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

3-Methylthiazolo[3,2-a]benzimidazole-benzenesulfonamide conjugates as novel carbonic anhydrase inhibitors endowed with anticancer activity: Design, synthesis, biological and molecular modeling studies.

Eur J Med Chem 2020 Dec 22;207:112745. Epub 2020 Aug 22.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795, Cairo, Egypt.

Herein we describe design and synthesis of different series of novel small molecules featuring 3-methylthiazolo[3,2-a]benzimidazole moiety (as a tail) connected to the zinc anchoring benzenesulfonamide moiety via ureido (7), enaminone (12), hydrazone (14), or hydrazide (15) linkers. The newly prepared conjugates have been screened for their inhibitory activities toward four human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoforms: hCA I, II, IX and XII. Thereafter, the urea and enaminone linkers were elongated by one- or two-atoms spacers to afford the elongated counterparts 9 and 13, respectively. Finally, the zinc anchoring sulfonamide group was replaced by the carboxylic acid group to afford acids 17. Compounds 12d, 13b and 15 displayed single-digit nanomolar CA IX inhibitory activities (Ks = 6.2, 9.7 and 5.5 nM, respectively), along with good selectivity towards hCA IX over hCA I and II. Subsequently, they were screened for their growth inhibitory actions against breast cancer MCF-7 and MDA-MB-231 cell lines, and for their impact on cell cycle progression and induction of apoptosis. Moreover, a molecular docking study was conducted to gain insights for the plausible binding interactions of target sulfonamides within hCA isoforms II, IX and XII binding sites.
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http://dx.doi.org/10.1016/j.ejmech.2020.112745DOI Listing
December 2020

Novel [(-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and studies.

J Enzyme Inhib Med Chem 2020 Dec;35(1):1300-1309

Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt.

As a continuation for our previous work, a novel set of -alkylindole-isatin conjugates (, , and ) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on -1 of indole motif, with subsequent conjugation with different -unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead . The best results were obtained with -propylindole -5-methylisatin hybrid which displayed broad spectrum anti-proliferative action with efficient sub-panel GI (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid in CDK2 and Bcl-2 active sites unveiled that -propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate as a promising lead for further development and optimisation as an efficient antitumor drug.
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http://dx.doi.org/10.1080/14756366.2020.1773814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717600PMC
December 2020

Benzofuran-Based Carboxylic Acids as Carbonic Anhydrase Inhibitors and Antiproliferative Agents against Breast Cancer.

ACS Med Chem Lett 2020 May 18;11(5):1022-1027. Epub 2020 Mar 18.

Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy.

Pursuing our effort for developing effective inhibitors of the cancer-related hCA IX isoform, here we describe the synthesis of novel benzofuran-based carboxylic acid derivatives, featuring the benzoic (-) or hippuric () acid moieties linked to 2-methylbenzofuran or 5-bromobenzofuran tails via an ureido linker. The target carboxylic acids were evaluated for the potential inhibitory action against hCAs I, II, IX, and XII. Superiorly, benzofuran-containing carboxylic acid derivatives , , and acted as submicromolar hCA IX inhibitors with KIs = 0.91, 0.79, and 0.56 μM, respectively, with selective inhibitory profile against the target hCA IX over the off-target isoforms hCA I and II (s: 2 to >63 and 4-47, respectively). Compounds , , and were examined for their antiproliferative action against human breast cancer (MCF-7 and MDA-MB-231) cell lines. In particular, displayed promising antiproliferative (IC = 2.52 ± 0.39 μM), cell cycle disturbance, and pro-apoptotic actions in MDA-MB-231 cells.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236537PMC
May 2020

Genotoxic potential of a novel PDE-4B inhibitor Apremilast by chromosomal aberration and micronucleus assay in mice.

Saudi Pharm J 2020 May 2;28(5):615-620. Epub 2020 Apr 2.

Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakakah-72341, Saudi Arabia.

Objective: Researchers have confirmed that chronic administration of drugs at high doses causes genotoxicity which serve as first step in development of cancers. Apremilast, a phosphodiesterase-4 inhibitor is Food and Drug Administration (FDA) approved drug for Psoriatic Arthritis. The present study designed to conduct genotoxicity testing using the genotoxic study which give simple, sensitive, economical and fast tools for the assessment of damage of genetic material.

Methods: To conduct genotoxicity study of Apremilast, 60 Swiss albino male mice divided into 6 groups (n = 10). Group1 served as a normal control group without any treatment, Group 2 treated as a disease control and administered with cyclophosphamide 40 mg/kg, IP. Group 3, 4, 5 and 6 treated as test groups and received 10, 20, 40 and 80 mg/kg/day Apremilast respectively. The total duration of study was 13 weeks. At termination day animals were sacrificed and chromosomal aberration assay (BMCAA) and micronucleus assay (BMMNA) were performed to know the genotoxicity potential of Apremilast.

Results: The results indicates significant rise in chromosomal aberrations (CA) frequency in bone marrow cells and decrease in the MI of the disease control animals as well as Apremilast treated groups. Further significant (p < 0.001; p < 0.0001) increase in score of micronucleated polychromatic erythrocytes (MNPCEs) and percentage of micronucleated PCEs per 1000 PCEs and decrease in the ratio of polychromatic/normochromatic erythrocytes (PCE/NCE) was observed in micronucleus assay. Genotoxic effect increases with the increase of Apremilast dose. Finding of present indicates that Apremilast shows genotoxic potential on high administration although further detailed toxicity studies required for confirmations.
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http://dx.doi.org/10.1016/j.jsps.2020.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229325PMC
May 2020

New Cytotoxic Natural Products from the Red Sea Sponge .

Mar Drugs 2020 May 3;18(5). Epub 2020 May 3.

Department of Pharmacognosy, Faculty of Pharmacy, Deraya University, New Minia 61111, Egypt.

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (), and a cerebroside, stylissoside A (), from the methanol extract of the Red Sea sponge . Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, and , displayed strong cytotoxicity against the MCF-7 cell line, with IC values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC at 36.8 ± 0.16 µM for and IC 30.5 ± 0.23 µM for compared to the standard drug cisplatin. Molecular docking experiments showed that and displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents.
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http://dx.doi.org/10.3390/md18050241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281077PMC
May 2020

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

Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity.

J Enzyme Inhib Med Chem 2020 Dec;35(1):831-839

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt.

In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 µM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3.
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http://dx.doi.org/10.1080/14756366.2020.1743281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144320PMC
December 2020

Synthesis and biological evaluation of small molecule modulators of CDK8/Cyclin C complex with phenylaminoquinoline scaffold.

PeerJ 2020 13;8:e8649. Epub 2020 Mar 13.

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

Background: CDK8/CycC complex has kinase activity towards the carboxyterminal domain of RNA polymerase II, and contributes to the regulation of transcription via association with the mediator complex. Different human malignancies, mainly colorectal and gastric cancers, were produced as a result of overexpression of CDK8/CycC in the mediator complex. Therefore, CDK8/CycC complex represents as a cancer oncogene and it has become a potential target for developing CDK8/CycC modulators.

Methods: A series of nine 4-phenylaminoquinoline scaffold-based compounds was synthesized, and biologically evaluated as potential CDK8/CycC complex inhibitors.

Results: The scaffold substituent effects on the intrinsic inhibitory activity toward CDK8/CycC complex are addressed trying to present a novel outlook of CDK8/CycC Complex inhibitors with 4-phenylaminoquinoline scaffold in cancer therapy. The secondary benzenesulfonamide analogues proved to be the most potent compounds in suppressing CDK8/CycC enzyme, whereas, their primary benzenesulfonamide analogues showed inferior activity. Moreover, the benzene reversed sulfonamide analogues were totally inactive.

Discussion: The titled scaffold showed promising inhibitory activity data and there is a crucial role of un/substituted sulfonamido group for CDK8/CycC complex inhibitory activity. Compound showed submicromolar potency against CDK8/CycC (IC = 0.639 µM) and it can be used for further investigations and to design another larger library of phenylaminoquinoline scaffold-based analogues in order to establish detailed SARs.
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http://dx.doi.org/10.7717/peerj.8649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075364PMC
March 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

Aptamers in Drug Design: An Emerging Weapon to Fight a Losing Battle.

Curr Drug Targets 2019 ;20(16):1624-1635

Division of Drug Design and Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Ahalia School of Pharmacy, Palakkad 678557, Kerala, India.

Implementation of novel and biocompatible polymers in drug design is an emerging and rapidly growing area of research. Even though we have a large number of polymer materials for various applications, the biocompatibility of these materials remains as a herculean task for researchers. Aptamers provide a vital and efficient solution to this problem. They are usually small (ranging from 20 to 60 nucleotides, single-stranded DNA or RNA oligonucleotides which are capable of binding to molecules possessing high affinity and other properties like specificity. This review focuses on different aspects of Aptamers in drug discovery, starting from its preparation methods and covering the recent scenario reported in the literature regarding their use in drug discovery. We address the limitations of Aptamers and provide valuable insights into their future potential in the areas regarding drug discovery research. Finally, we explained the major role of Aptamers like medical imaging techniques, application as synthetic antibodies, and the most recent application, which is in combination with nanomedicines.
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http://dx.doi.org/10.2174/1389450120666190729121747DOI Listing
September 2020

Novel aryl carboximidamide and 3-aryl-1,2,4-oxadiazole analogues of naproxen as dual selective COX-2/15-LOX inhibitors: Design, synthesis and docking studies.

Bioorg Chem 2019 04 20;85:577-584. Epub 2019 Feb 20.

Pharmacology Department, College of Pharmacy, Jouf University, Sakaka, Aljouf 2014, Saudi Arabia; Biochemistry Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.

A series of novel naproxen analogues containing 3-aryl-1,2,4-oxadiazoles moiety (4b-g) and their reaction intermediates aryl carboximidamides moiety (3b-g) was synthesized and evaluated in vitro as dual COXs/15-LOX inhibitors. Compounds 3b-g exhibited superior inhibitory activity than celecoxib as COX-2 inhibitors. Compounds 3b-d and 3g were the most potent COX-2 inhibitors with IC range of 6.4 - 8.13 nM and higher selectivity indexes (3b, SI = 26.19; 3c, SI = 13.73; 3d, SI = 29.27; 3g, SI = 18.00) comparing to celecoxib (IC = 42.60 nM, SI = 8.05). Regarding 15-LOX inhibitory activity, compounds belonging to aryl carboximidamide backbone 3b-e and 3g were the most potent with IC range of 1.77-4.91 nM comparing to meclofenamate sodium (IC = 5.64 µM). Data revealed that The levels of NO released by aryl carboximidamides 3b-g were more higher than 3-aryl-1,2,4-oxadiazole derivatives 4b-g, which correlated well with their COX-2 inhibitory activities.
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http://dx.doi.org/10.1016/j.bioorg.2019.02.043DOI Listing
April 2019

Fruit-Derived Polysaccharides and Terpenoids: Recent Update on the Gastroprotective Effects and Mechanisms.

Front Pharmacol 2018 22;9:569. Epub 2018 Jun 22.

Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Malaysia.

Ulceration in the stomach develops in peptic ulcer disease when there is a loss of protective mucosal layers, particularly in infection. Antibiotic therapy has failed to eradicate and impede the colonization of . Despite given treatment, recurrent bleeding can occur and lead to death in the affected individual. The disease progression is also related to the non-steroidal inflammatory drug and stress. There are extensive research efforts to identify the gastroprotective property from various alkaloids, flavonoids, and tannins compounds from plants and marine. These natural products are believed to be safe for consumption. However, not much attention was given to summarize the carbohydrate and terpenoidal anti-ulcer compounds. Hence, this review will cover the possible mechanisms and information about acidic hydroxylans, arabinogalactan and rhamnogalacturon; and limonene, pinene, lupeol, citral, ursolic acid and nomilin to exemplify on the gastroprotective properties of polysaccharides and terpenoid, respectively, obtained from fruits. These compounds could act as a prebiotic to prevent the inhabitation of , modulate the inflammation, suppress gastric cancer growth, and capable of stimulating the reparative mechanisms on the affected regions. Finally, this review provides the future research prospects of these natural compounds in an effort to develop new therapy for gastrointestinal tissue healing.
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http://dx.doi.org/10.3389/fphar.2018.00569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6024987PMC
June 2018

Anti-nociceptive mechanisms of flavonoids-rich methanolic extract from Terminalia coriacea (Roxb.) Wight & Arn. leaves.

Food Chem Toxicol 2018 May 17;115:523-531. Epub 2018 Mar 17.

Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, 43400, Selangor Darul Ehsan, Malaysia; Genetics and Regenerative Medicine Research Centre, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University University, Sakaka, Al Jouf Province, Saudi Arabia.

In view of the report on anti-nociceptive activity of Leathery Murdah, Terminalia coriacea {Roxb.} Wight & Arn. (Combretaceae) leaves, the present study was conducted to isolate the active constituents and identify the underlying mechanisms. The methanolic extract of T. coriacea leaves (TCLME) at doses 125, 250 and 500 mg/kg orally, was subjected to various in-vivo assays in acetic acid induced writhing and formalin induced paw-licking tests with aspirin (100 mg/kg) and morphine (5 mg/kg) as reference drugs. Three flavonoids, rutin, robinin and gossypetin 3-glucuronide 8-glucoside were isolated and characterized from TCLME for the first time. The extract showed significant (p < 0.001) dose-dependent anti-nociceptive activity in glutamate induced paw licking in mice. The involvement of opioid pathway was confirmed as naloxone (5 mg/kg, i.p) treatment blocked the analgesic activity of the test extract. Similarly, glibenclamide (an ATP - sensitive potassium channel inhibitor) at dose of 10 mg/kg, i.p increased writhing in acetic acid model. It reversed the inhibitory effects of TCLME when administered in combination. Treatment of TCLME alone and in combination with l-arginine (100 mg/kg, i.p) significantly (p < 0.001) reduced writhing while pre-treatment with l-NAME (20 mg/kg, i.p) further enhanced the analgesic action of TCLME indicating involvement of nitric oxide pathway.
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http://dx.doi.org/10.1016/j.fct.2018.03.021DOI Listing
May 2018
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