Synthesis, bioactivity assessment, molecular docking and ADMET studies of new chromone congeners exhibiting potent anticancer activity.

In consideration of the chromones' therapeutic potential and anticancer activity, a new series of chromanone derivatives have been synthesized through a straightforward reaction between 6-formyl-7-hydroxy-5-methoxy-2-methylchromone (2) and various organic active compounds. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer), HCT-116 (colon cancer), HepG2 (liver cancer), and normal skin fibroblast cells (BJ1). The obtained data indicated that compounds 14b, 17, and 19 induce cytotoxic activity in the breast MCF7, while compounds 6a, 6b, 11 and 14c showed highly potent activity in the colon cancer cell lines. Overall, the results demonstrate that the potential cytotoxic effects of the studied compounds may be based on their ability to induce DNA fragmentation in cancer cell lines, down-regulate the expression level of CDK4 as well as the anti-apoptotic gene Bcl-2 and up-regulate the expression of the pro-apoptotic genes P53 and Bax. Furthermore, compounds 14b and 14c showed a dual mechanism of action by inducing apoptosis and cell cycle arrest. The docking studies showed that the binding affinity of the most active cytotoxic compounds within the active pocket of the CDK4 enzyme is stronger due to hydrophobic and H-bonding interactions. These results were found to be consistent with the experimental results.

Structure Activity Relationship and Molecular Docking of Some Quinazolines Bearing Sulfamerazine Moiety as New 3CLpro, cPLA2, sPLA2 Inhibitors.

The current work was conducted to synthesize several novel anti-inflammatory quinazolines having sulfamerazine moieties as new 3CLpro, cPLA2, and sPLA2 inhibitors. The thioureido derivative 3 was formed when compound 2 was treated with sulfamerazine. Also, compound 3 was reacted with NH2-NH2 in ethanol to produce the N-aminoquinazoline derivative. Additionally, derivative 4 was reacted with 4-hydroxy-3-methoxybenzaldehyde, ethyl chloroacetate, and/or diethyl oxalate to produce quinazoline derivatives 5, 6, and 12, respectively. The results of the pharmacological study indicated that the synthesized 4-6 and 12 derivatives showed good 3CLpro, cPLA2, and sPLA2 inhibitory activity. The IC50 values of the target compounds 4-6, and 12 against the SARS-CoV-2 main protease were 2.012, 3.68, 1.18, and 5.47 µM, respectively, whereas those of baicalein and ivermectin were 1.72 and 42.39 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against sPLA2 were 2.84, 2.73, 1.016, and 4.45 µM, respectively, whereas those of baicalein and ivermectin were 0.89 and 109.6 µM, respectively. The IC50 values of the target compounds 4-6, and 12 against cPLA2 were 1.44, 2.08, 0.5, and 2.39 µM, respectively, whereas those of baicalein and ivermectin were 3.88 and 138.0 µM, respectively. Also, incubation of lung cells with LPS plus derivatives 4-6, and 12 caused a significant decrease in levels of sPLA2, cPLA2, IL-8, TNF-α, and NO. The inhibitory activity of the synthesized compounds was more pronounced compared to baicalein and ivermectin. In contrast to ivermectin and baicalein, bioinformatics investigations were carried out to establish the possible binding interactions between the newly synthesized compounds 2-6 and 12 and the active site of 3CLpro. Docking simulations were utilized to identify the binding affinity and binding mode of compounds 2-6 and 12 with the active sites of 3CLpro, sPLA2, and cPLA2 enzymes. Our findings demonstrated that all compounds had outstanding binding affinities, especially with the key amino acids of the target enzymes. These findings imply that compound 6 is a potential lead for the development of more effective SARS-CoV-2 Mpro inhibitors and anti-COVID-19 quinazoline derivative-based drugs. Compound 6 was shown to have more antiviral activity than baicalein and against 3CLpro. Furthermore, the IC50 value of ivermectin against the SARS-CoV-2 main protease was revealed to be 42.39 µM, indicating that it has low effectiveness.

Chitosan Schiff base electrospun fabrication and molecular docking assessment for nonleaching antibacterial nanocomposite production.

In this work, new chitosan derivative nanofibers that exhibit antibacterial properties were successfully fabricated. The two CS Schiff base derivatives (CS-APC and CS-2APC) were prepared by incorporating 4-amino antipyrine moiety in two different ratios, followed by a reductive amination to obtain the corresponding derivatives CS-APCR and CS-2APCR. Spectral analyses were used to confirm the chemical structure. The molecular docking evaluation of CS-APC, CS-APCR, and CS was conducted on DNA topoisomerase IV, thymidylate kinase and SARS-CoV-2 main protease (3CLpro) active sites. CS-APCR showed a well-fitting into the three enzyme active sites with docking score values of - 32.76, - 35.43 and - 30.12 kcal/mol, respectively. The nanocomposites of CS derivatives were obtained by electrospinning the blends of CS-2APC and CS-2APCR with polyvinyl pyrrolidone (PVP) at 20 kV. The morphology of the nanofibers was investigated by scanning electron microscopy (SEM). It was found that fiber diameters were significantly decreased when CS-2APC and CS-2APCR were incorporated into pure PVP to reach 206-296 nm and 146-170 nm, respectively, compared to 224-332 nm for pure PVP. The derivatives of CS and their nanofibers with PVP were found to have antibacterial activities against two strains of Staphylococcus aureus and Escherichia coli. Data revealed that CS-2APC nanofibers showed antibacterial activity to the two strains of E. coli less than CS-2APCR nanofibers.

Phenolic Profiling and Therapeutic Potential of Certain Isolated Compounds from Parkia roxburghii against AChE Activity as well as GABAA α5, GSK-3ß, and p38α MAP-Kinase Genes.

Parkia roxburghii belongs to the family Mimosaceae; it has been used since ancient times as a cure for different health complications; such as inflammatory and gynecological diseases and hemiplegia. In this investigation, a reversed-phase-high-performance liquid chromatography (RP-HPLC) profile was carried out for P. roxburghii; also, the isolated bioactive compounds including quercetin, catechin, and biochaninA were individually and/or in combination investigated for their inhibitory effects on scopolamine-induced memory impairments in mice, implying that they have the ability to reduce the neurodegenerative effects of scopolamine and thus could be employed as a more effective therapeutic agent in the treatment of Alzheimer's disease (AD) in humans. The possible interactions of Parkia flavonoids with acetylcholinesterase (AChE), γ-aminobutyric acid A receptor, alpha5 (GABAA α5), glycogen synthase kinase-3 (GSK-3), p38 mitogen-activated protein kinase (p38MAP-kinase), signal-regulated kinase (ERK), and protein-serine/threonine kinase (Akt) were then determined using molecular docking.

Cardenolides and pentacyclic triterpenes isolated from Acokanthera oblongifolia leaves: their biological activities with molecular docking study.

Pentacyclic triterpenes and cardenolides were isolated from Acokanthera oblongifolia leaves. Their chemical structures were determined based on comprehensive 1D and 2D NMR spectroscopy. Their MIC was determined against 12 microorganisms. Their exerted cytotoxicity on the immortalized normal cells, hTERT-RPE1 was assessed by the sulforhodamine-B assay. The viral inhibitory effects of compounds against Newcastle disease virus (NDV) and H5N1 influenza virus IV were evaluated. Four in vitro antioxidant assays were performed in comparison with BHT and trolox and a weak activity was exhibited. Acovenoside A was with potent against H5N1-IV and NDV with IC50 ≤ 3.2 and ≤ 2.1 µg/ml and SI values of 93.75 and 95.23%, respectively, in comparison to ribavirin. Its CC50 record on Vero cells was > 400 and 200 µg/ml, respectively. Acobioside A was the most active compound against a broad range of microbes while Pseudomonas aeruginosa was the most sensitive. Its MIC (0.07 µg/ml) was 1/100-fold of the recorded CC50 (7.1 µg/ml/72 h) against hTERT-RPE1. The molecular docking of compounds on human DNA topoisomerase I (Top1-DNA) and IV glycoprotein hemagglutinin were studied using MOE program. This study has introduced the cardenolides rather than triterpenoids with the best docking score and binding interaction with the active site of the studied proteins.

Synthesis, Molecular Docking, and Biofilm Formation Inhibitory Activity of Bis(Indolyl)Pyridines Analogues of the Marine Alkaloid Nortopsentin.

An efficient and simple protocol for the synthesis of a new class of diverse bis(indolyl)pyridines analogues of the marine alkaloid nortopsentin has been reported. A one-pot four-component condensation of 3-cyanocarbomethylindole, various aldehyde, 3-acetylindole, and ammonium acetate in glacial acetic acid led to the formation of 2,6-bis(1H-indol-3-yl)-4-(substituted-phenyl)pyridine-5-carbonitriles. Additionally, 2,6-bis(1H-indol-3-yl)-4-(benzofuran) pyridine-5-carbonitriles were prepared via a one-pot four-component condensation of 3-cyanocarbomethylindole, various N-substituted-indole-3-aldehydes, 2-acetylbenzofuran, and ammonium acetate. The synthesized compounds were evaluated for their ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 6538 and the Gram-negative strain Escherichia coli ATCC 25922. Some of the new compounds showed a marked selectivity against the Gram-positive and Gram-negative strains. Remarkably, five compounds 4b, 7a, 7c, 7d and 8e demonstrated good antibiofilm formation against S. aureus and E. coli. On the other hand, the release of reducing sugars and proteins from the treated bacterial strains over the untreated strains was considered to explain the disruption effect of the selected compound on the contact cells of S. aureus and E. coli. Out of all studied compounds, the binding energies and binding mode of bis-indole derivatives 7c and 7d were theoretically the best thymidylate kinase, DNA gyrase B and DNA topoisomerase IV subunit B inhibitors.

Synthesis, Molecular Docking and Biological Evaluation of Novel Flavone Derivatives as Potential Anticancer Agents Targeting Akt.

BACKGROUND: Flavonoids are naturally occurring compounds with versatile healthpromoting effects against various diseases. OBJECTIVE: This aim of this paper is to synthesize and evaluate the biological activity of novel flavone derivatives against cancer. METHODS: A new series of 2-hydroxy-α,ß-unsaturated ketones 2a-h, was synthesized via the reaction of N-substituted-indole-3-carboxaldehyde 1a-h with 2-hydroxy acetophenone in the presence of piperidine. The oxidative cyclization of 2a-h using hydrogen peroxide/KOH and/or dimethyl sulfoxide/I2 produced the corresponding 2-(N-substituted-1H-indol-3-yl)-3-hydroxy-4H-chromen- 4-ones 3a-h and 2-(N-substituted-1H-indol-3-yl)-4H-chromen-4-ones 4a-h, respectively. Antiproliferative activities for synthesized series were investigated against HCT-116 colon and MCF- 7 breast cancer cell lines. Molecular downstream effects were evaluated using RT-PCR. Moreover, molecular docking was carried out to pinpoint the binding mode of the most active compounds into the active site of Akt enzyme (PDB ID: 3QKK). RESULTS: All compounds exhibited an anti-proliferative activity range of 52-97% and 67.2-99% against HCT-116 and MCF-7, respectively. Compounds 3b, 3h, 3g and 4h had a minimal inhibitory effect on normal BJ1 cells indicating their safety profile. Compounds 3b and 4h, in particular, exhibited the most potent antiproliferative activity against HCT116 and MCF7, meanwhile compounds 3g, 3h and 4g showed potent to moderate activity. Compound 3b had IC50 of 78.3 µM and 53.9 µM against HCT-116 and MCF-7 respectively with comparable IC50 for doxorubicin of 65.1 µM and 45.02 µM. Compound 3b exhibited significant down-regulation for Akt and significant up-regulation of CAS9 and CDKN1genes in all tested cell lines. CONCLUSION: The synthesized flavone derivatives and particularly compound 3b exhibited promising anticancer activity through Akt inhibition.

Synthesis and Bioactivity Assessment of Novel Spiro Pyrazole-Oxindole Congeners Exhibiting Potent and Selective in vitro Anticancer Effects.

The present work aims to design and synthesize novel series of spiro pyrazole-3,3'-oxindoles analogues and investigate their bioactivity as antioxidant and antimicrobial agents, as well as antiproliferative potency against selected human cancerous cell lines (i.e., breast, MCF-7; colon, HCT-116 and liver, HepG-2) relative to healthy noncancerous control skin fibroblast cells (BJ-1). The mechanism of their cytotoxic activity has been also examined by immunoassaying the levels of key anti- and proapoptotic protein markers. The analytical and spectral data of the all synthesized target congeners were compatible with their structures. Synthesized compounds showed diverse moderate to powerful antimicrobial and antioxidant activities. Results of MTT assay revealed that seven synthesized compounds (i.e., 11a, 11b, 12a, 12b, 13b, 13c and 13h) particularly exhibited significant cytotoxicity against the three cancerous cell lines under investigation. Ranges of IC50 values obtained were 5.7-21.3 and 5.8-37.4 µg/mL against HCT-116 and MCF-7, respectively; which is 3.8 and 6.5-fold (based on the least IC50 values) more significant relative to the reference chemotherapeutic drug doxorubicin. In HepG-2 cells, the analogue 13h the highest cytotoxicity with IC50 value of 19.2µg/mL relative to doxorubicin (IC50 = 21.6µg/mL). The observed cytotoxicity was specific to cancerous cells, as evidenced by the minimal toxicity in the noncancerous control skin-fibroblast cells. ELISA results indicated that the observed antiproliferative effect against examined cancer cell lines is mediated via engaging the activation of apoptosis as illustrated by the significant increase in proapoptotic protein markers (p53, bax and caspase-3) and reduction in the antiapoptotic marker bcl-2. Taken together, results of the present study emphasize the potential of spiro pyrazole-oxindole analogues as valuable candidate anticancer agents against human cancer cells.

Synthesis and biological activity of novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives.

A novel series of 4-methoxy, and 4,9-dimethoxy-5-substituted furo[2,3-g]-1,2,3-benzoxathiazine-7,7-dioxide derivatives 3a,b, 10a-g and 11a-g were prepared in good yields via the reaction of 4-methoxy (1a) and 4,7-dimethoxy-5-acetyl-6-hydroxybenzofurans (1b) and their α,ß-unsaturated keto derivatives 6a-g and 7a-g with chlorosulfonyl isocyanate (CSI). On the other hand, N-chlorosulfonyl carbamate derivatives 4a,b, 12a,b and 13a,b were prepared and allowed to react with piperidine to give the corresponding N-piperidinosulfonyl carbamate derivatives 5a,b, 14a,b and 15a,b, respectively. Sixteen new target compounds 3a,b, 10a-g, and 11a-g were tested for their DPPH radical-scavenging, and in vitro antiproliferative activity against A-549, MCF7 and HCT-116 cancer cell lines. Compounds 10a, 11c, 11e, and 11g showed moderate DPPH radical-scavenging activity compared to ascorbic acid at 100 µg/mL. 4,9-Dimethoxy-5-substituted styrylfuro[3,2-g]-1,2,3-benzoxathiazine-7,7-dioxides 11a, 11b, and 11c were found to be highly active against A-549 and HCT-116 cancer cell lines with IC50 values ranging from 0.02 to 0.08 µmol/mL compared to doxorubicin with IC50 = 0.04 and 0.06 µmol/mL, respectively.