New 2-oxoindole derivatives as multiple PDGFRα/ß and VEGFR-2 tyrosine kinase inhibitors.

Two new series of N-aryl acetamides 6a-o and benzyloxy benzylidenes 9a-p based 2-oxoindole derivatives were designed as potent antiproliferative multiple kinase inhibitors. The results of one-dose NCI antiproliferative screening for compounds 6a-o and 9a-p elucidated that the most promising antiproliferative scaffolds were 6f and 9f, which underwent five-dose testing. Notably, the amido congener 6f was the most potent derivative towards pancreatic ductal adenocarcinoma MDA-PATC53 and PL45 cell lines (IC50 = 1.73 µM and 2.40 µM, respectively), and the benzyloxy derivative 9f was the next potent one with IC50 values of 2.85 µM and 2.96 µM, respectively. Both compounds 6f and 9f demonstrated a favorable safety profile when tested against normal prostate epithelial cells (RWPE-1). Additionally, compound 6f displayed exceptional selectivity as a multiple kinase inhibitor, particularly targeting PDGFRα, PDGFRß, and VEGFR-2 kinases, with IC50 values of 7.41 nM, 6.18 nM, and 7.49 nM, respectively. In contrast, the reference compound Sunitinib exhibited IC50 values of 43.88 nM, 2.13 nM, and 78.46 nM against the same kinases. The derivative 9f followed closely, with IC50 values of 9.9 nM, 6.62 nM, and 22.21 nM for the respective kinases. Both 6f and 9f disrupt the G2/M cell cycle transition by upregulating p21 and reducing CDK1 and cyclin B1 mRNA levels. The interplay between targeted kinases and these cell cycle regulators underpins the G2/M cell cycle arrest induced by our compounds. Also, compounds 6f and 9f fundamentally resulted in entering MDA-PATC53 cells into the early stage of apoptosis with good percentages compared to the positive control Sunitinib. The in silico molecular-docking outcomes of scaffolds 6a-o and 9a-p in VEGFR-2, PDGFRα, and PDGFRß active sites depicted their ability to adopt essential binding interactions like the reference Sunitinib. Our designed analogs, specifically 6f and 9f, possess promising antiproliferative and kinase inhibitory properties, making them potential candidates for further therapeutic development.

Dexmedetomidine in Fluoroscopic Guided Splanchnic Nerve Neurolysis for Pain Control: A Randomized, Controlled Trial.

BACKGROUND: Splanchnic nerve neurolysis (SNN) shows beneficial effects in reducing malignancy-associated refractory abdominal pain. Using adjuvants, such as dexmedetomidine to improve the pain was studied. OBJECTIVE: To detect any role of dexmedetomidine as an additive to local anesthetics with an alcohol injection in the chemical SNN process to improve pain in patients having upper-abdominal cancer. STUDY DESIGN: Double-blinded, prospective randomized study. SETTING: Department of Anesthesia and Intensive Care, faculty of medicine, Minia University,Egypt. METHODS: Forty patients with upper-abdominal malignancy-associated refractory abdominal pain underwent fluoroscopic guided SNN were divided into 2 groups. The SNN was performed by using 1.5 mL lidocaine 1%, dexmedetomidine 2 µg/kg, and then an injection of 4.5 mL of ethanol 96% on each side in group D and without dexmedetomidine in group C is done. Patients gave the score of abdominal pain expressed by the Visual Analog Scale (VAS), which measures the pain intensity. Scors were recorded prior to injection, during injection, after injection by 5 min, and after 2, 6, 12, 24, 72 hours, one week (W), 2 W, one month (M), and 2 M. Also, we recorded the amount of morphine required to relieve the residual pain after injection, the effect of procedure on quality of life (QOL), and any complication after injection. RESULTS: VAS scores showed a significant increase in group C in comparison to group D during injection, after injection by 5 min, 2, 6, 12, 24 hours, one and 2 months (P < 0.0001, 0.0001, 0.029, 0.031, 0.025, 0.040, 0.020, 0.015), respectively. The morphine requirement was significantly increased at one W, one M, and 2 M in group C in comparison to Group D (P < 0.044, 0.017, 0.033) with no significant change in the QOL observed between groups. LIMITATIONS: The limitations of this study were a relatively small sample size and short period of follow-up. CONCLUSIONS: This study revealed that using dexmedetomidine in the chemical SNN process improves the pain results from injection of alcohol and refractory cancer related pain with reduction in the consumption of morphine in patients with upper-abdominal malignancy.

Combination of an Oxindole Derivative with (-)-ß-Elemene Alters Cell Death Pathways in FLT3/ITD+ Acute Myeloid Leukemia Cells.

Acute myeloid leukemia (AML) is one of the cancers that grow most aggressively. The challenges in AML management are huge, despite many treatment options. Mutations in FLT3 tyrosine kinase receptors make the currently available therapies less responsive. Therefore, there is a need to find new lead molecules that can specifically target mutated FLT3 to block growth factor signaling and inhibit AML cell proliferation. Our previous studies on FLT3-mutated AML cells demonstrated that ß-elemene and compound 5a showed strong inhibition of proliferation by blocking the mutated FLT3 receptor and altering the key apoptotic genes responsible for apoptosis. Furthermore, we hypothesized that both ß-elemene and compound 5a could be therapeutically effective. Therefore, combining these drugs against mutated FLT3 cells could be promising. In this context, dose-matrix combination-based cellular inhibition analyses, cell morphology studies and profiling of 43 different apoptotic protein targets via combinatorial treatment were performed. Our studies provide strong evidence for the hypothesis that ß-elemene and compound 5a combination considerably increased the therapeutic potential of both compounds by enhancing the activation of several key targets implicated in AML cell death.

Indole-based FLT3 inhibitors and related scaffolds as potential therapeutic agents for acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation mechanisms are among the most common genetic abnormalities detected in about 30% of acute myeloid leukemia (AML) patients. These mutations are accompanied by poor clinical response, although all these progressions in identifying and interpreting biological AML bio-targets. Several small structured FLT3 inhibitors have been ameliorated to struggle against AML. Despite all these developments regarding these inhibitors, the Overall survival rate is about five years or more in less than one-third of diagnosed AML patients. Midostaurin was the first FDA-approved FLT3 inhibitor in 2017 in the United States and Europe for AML remedy. Next, Gilteritinib was an FDA-approved FLT3 inhibitor in 2018 and in the next year, Quizartinib was approved an as FLT3 inhibitor in Japan. Interestingly, indole-based motifs had risen as advantaged scaffolds with unusual multiple kinase inhibitory activity. This review summarises indole-based FLT3 inhibitors and related scaffolds, including FDA-approved drugs, clinical candidates, and other bioactive compounds. Furthermore, their chemotypes, mechanism of action, and interaction mode over both wild and mutated FLT3 target proteins had been judgmentally discussed. Therefore, this review could offer inspiring future perspectives into the finding of new FLT3-related AML therapies.

Biosynthesizing Cassia fistula Extract-Mediated Silver Nanoparticles for MCF-7 Cell Lines Anti-Cancer Assay.

The unique consequence of green synthesis is that the mediator plant is able to release chemicals that are efficacious as reducing as well as stabilizing agents. In this work, the fruit pulp and leaf essences of Cassia fistula have been used to manufacture silver nanoparticles through the green synthesis technique. The sculpturing of nanoparticles was accomplished by utilizing the reduction phenomenon that ensued due to the reaction between plant essences and the precursor solution. These biosynthesized silver nanoparticles were examined, where we used scanning electron microscopy, UV-vis spectroscopy, and X-ray diffraction techniques as means to analyze the structure, optical properties, and crystalline behavior, respectively. The absorption spectra for fruit and leaf extracts obtained from the UV-vis analyses peaked at 401 and 397 nm, and these peaks imply the appearance of optical energy gaps of 2.12 and 2.58 eV, accompanying spherical shapes of particles with diameters in the ranges of 12-20 and 50-80 nm, respectively. These silver nanoparticles together with the adopted green technique have a vast array of applications, specifically in the biomedical realm. In particular, they are being used to treat several diseases and are manifested as strong anti-tumor agents to medicate MCF-7 breast cancer cell lines in order to minimize the cell growth rate depending on their concentrations.

In silico drug discovery of SIRT2 inhibitors from natural source as anticancer agents.

Sirtuin 2 (SIRT2) is a member of the sirtuin protein family, which includes lysine deacylases that are NAD+-dependent and organize several biological processes. Different forms of cancer have been associated with dysregulation of SIRT2 activity. Hence, identifying potent inhibitors for SIRT2 has piqued considerable attention in the drug discovery community. In the current study, the Natural Products Atlas (NPAtlas) database was mined to hunt potential SIRT2 inhibitors utilizing in silico techniques. Initially, the performance of the employed docking protocol to anticipate ligand-SIRT2 binding mode was assessed according to the accessible experimental data. Based on the predicted docking scores, the most promising NPAtlas molecules were selected and submitted to molecular dynamics (MD) simulations, followed by binding energy computations. Based on the MM-GBSA binding energy estimations over a 200 ns MD course, three NPAtlas compounds, namely NPA009578, NPA006805, and NPA001884, were identified with better ΔGbinding towards SIRT2 protein than the native ligand (SirReal2) with values of - 59.9, - 57.4, - 53.5, and - 49.7 kcal/mol, respectively. On the basis of structural and energetic assessments, the identified NPAtlas compounds were confirmed to be steady over a 200 ns MD course. The drug-likeness and pharmacokinetic characteristics of the identified NPAtlas molecules were anticipated, and robust bioavailability was predicted. Conclusively, the current results propose potent inhibitors for SIRT2 deserving more in vitro/in vivo investigation.

Vanillin-Based Indolin-2-one Derivative Bearing a Pyridyl Moiety as a Promising Anti-Breast Cancer Agent via Anti-Estrogenic Activity.

The structure-based design introduced indoles as an essential motif in designing new selective estrogen receptor modulators employed for treating breast cancer. Therefore, here, a series of synthesized vanillin-substituted indolin-2-ones were screened against the NCI-60 cancer cell panel followed by in vivo, in vitro, and in silico studies. Physicochemical parameters were evaluated with HPLC and SwissADME tools. The compounds demonstrated promising anti-cancer activity for the MCF-7 breast cancer cell line (GI = 6-63%). The compound with the highest activity (6j) was selective for the MCF-7 breast cancer cell line (IC50 = 17.01 µM) with no effect on the MCF-12A normal breast cell line supported by real-time cell analysis. A morphological examination of the used cell lines confirmed a cytostatic effect of compound 6j. It inhibited both in vivo and in vitro estrogenic activity, triggering a 38% reduction in uterine weight induced by estrogen in an immature rat model and hindering 62% of ER-α receptors in in vitro settings. In silico molecular docking and molecular dynamics simulation studies supported the stability of the ER-α and compound 6j protein-ligand complex. Herein, we report that indolin-2-one derivative 6j is a promising lead compound for further pharmaceutical formulations as a potential anti-breast cancer drug.

New antiproliferative 3-substituted oxindoles inhibiting EGFR/VEGFR-2 and tubulin polymerization.

New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a-j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC50 value of 14.77 µM compared to 5-fluorouracil (5FU) (IC50 = 2.02 µM). Notably, compound 6f hampered receptor tyrosine EGFR fundamentally with an IC50 value of 1.38 µM, compared to the reference sunitinib with an IC50 value of 0.08 µM. Moreover, compound 6f afforded anti-tubulin polymerization activity with an IC50 value of 7.99 µM as an outstanding observable activity compared with the reference combretastatin A4 with an IC50 value of 2.64 µM. In silico molecular-docking results of compound 6f in the ATP-binding site of EGFR agreed with the in vitro results. Besides, the investigation of the physicochemical properties of compound 6f via the egg-boiled method clarified good lipophilicity, GIT absorption, and blood-brain barrier penetration properties.

Discovery of oxindole-based FLT3 inhibitors as a promising therapeutic lead for acute myeloid leukemia carrying the oncogenic ITD mutation.

FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a-c inhibited 68%-73% and 83%-91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%-2% and 27%-39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-ß. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

Secondary metabolites of Livistona decipiens as potential inhibitors of SARS-CoV-2.

In late December 2019, a pandemic coronavirus disease 2019 (COVID-19) emerged in Wuhan, China and spread all over the globe. One of the promising therapeutic techniques of viral infection is to search for enzyme inhibitors among natural phytochemicals using molecular docking to obtain leads with the least side effects. The COVID-19 virus main protease (Mpro) is considered as an attractive target due to its pivotal role in controlling viral transcription and replication. Metabolic profiling of the crude extract of Livistona decipiens Becc. (Arecaceae) leaves and fruit dereplicated twelve metabolites using LC-HRESIMS. Molecular docking simulation and in silico ADME profiling of these annotated compounds proposed that tricin is a promising lead against COVID-19 virus Mpro. The alcoholic extract was shown to inhibit SARS-CoV-2 through in vitro culture and RT-PCR testing with EC50 = 0.122 and 1.53 µg mL-1 for leaves and fruit extracts, respectively, when compared with that of the FDA-approved anti-COVID-19 remdesivir (0.002 µg mL-1). Preliminary steps were also performed including the 3CL-protease inhibition assay and cytotoxicity study. It is worthwhile to find a cheap, safe, natural source for promising anti-SARS-CoV-2 agents that can be further tested in vivo against the COVID-19 virus Mpro. This study provides scientific basis for demonstrating beneficial effects of L. decipiens application on human health during the corona pandemic.

Effective Microorganism Solution and High Volume of Fly Ash Blended Sustainable Bio-Concrete.

Currently, the production of sustainable concrete with high strength, durability, and fewer environmental problems has become a priority of concrete industries worldwide. Based on this fact, the effective microorganism (EM) solution was included in the concrete mixtures to modify the engineering properties. Concrete specimens prepared with 50% fly ash (FA) as an ordinary Portland cement (OPC) replacement were considered as the control sample. The influence of EM solution inclusion (at various contents of 0, 5, 10, 15, 20, and 25% weight) in the cement matrix as water replacement was examined to determine the optimum ratio that can enhance the early and late strength of the proposed bio-concrete. The compressive strength, porosity, carbonation depth, resistance to sulphuric acid attack, and the environmental benefits of the prepared bio-concrete were evaluated. The results showed that the mechanical properties and durability performance of the bio-concrete were improved due to the addition of EM and FA. Furthermore, the inclusion of 10% EM could increase the compressive strength of the bio-concrete at 3 (early) and 28 days by 42.5% and 14.6%, respectively. The durability performance revealed a similar trend wherein the addition of 50% FA and 10% EM into the bio-concrete could improve its resistance against acid attack by 35.1% compared to the control specimen. The concrete mix designed with 10% EM was discerned to be optimum, with approximately 49.3% lower carbon dioxide emission compared to traditional cement.

Novel Inhibitor for Downstream Targeting of Transforming Growth Factor-ß Signaling to Suppress Epithelial to Mesenchymal Transition and Cell Migration.

Cancer metastasis accounts for most of the mortality associated with solid tumors. However, antimetastatic drugs are not available on the market. One of the important biological events leading to metastasis is the epithelial to mesenchymal transition (EMT) induced by cytokines, namely transforming growth-factor-ß (TGF-ß). Although several classes of inhibitors targeting TGF-ß and its receptor have been developed, they have shown profound clinical side effects. We focused on our synthetic compound, HPH-15, which has shown anti-fibrotic activity via the blockade of the TGF-ß Smad-dependent signaling. In this study, 10 µM of HPH-15 was found to exhibit anti-cell migration and anti-EMT activities in non-small-cell lung cancer (NSCLC) cells. Although higher concentrations are required, the anti-EMT activity of HPH-15 has also been observed in 3D-cultured NSCLC cells. A mechanistic study showed that HPH-15 inhibits downstream TGF-ß signaling. This downstream inhibition blocks the expression of cytokines such as TGF-ß, leading to the next cycle of Smad-dependent and -independent signaling. HPH-15 has AMPK-activation activity, but a relationship between AMPK activation and anti-EMT/cell migration was not observed. Taken together, HPH-15 may lead to the development of antimetastatic drugs with a new mechanism of action.

Discovery of Azaindolin-2-One as a Dual Inhibitor of GSK3ß and Tau Aggregation with Potential Neuroprotective Activity.

The inhibition of glycogen synthase kinase 3ß (GSK3ß) activity through pharmacological intervention represents a promising approach for treating challenging neurodegenerative disorders like Alzheimer's disease. Similarly, abnormal tau aggregate accumulation in neurons is a hallmark of various neurodegenerative diseases. We introduced new dual GSK3ß/tau aggregation inhibitors due to the excellent clinical outcome of multitarget drugs. Compound (E)-2f stands out among the synthesized inhibitors as a promising GSK3ß inhibitor (IC50 1.7 µM) with a pronounced tau anti-aggregation effect in a cell-based model of tauopathy. Concurrently, (E)-2f was demonstrated to be non-toxic to normal cells, making it a promising neuroprotective lead compound that needs further investigation.

NS3 helicase inhibitory potential of the marine sponge Spongia irregularis.

In the current study, an investigation of the activity of the total extract of the marine sponge Spongia irregularis and its different fractions against the hepatitis C virus (HCV) was pursued. The results revealed that the ethyl acetate fraction exhibited the highest anti-HCV activity, with an IC50 value of 12.6 ± 0.05 µg ml-1. Chromatographic resolution of the ethyl acetate fraction resulted in the isolation of four known compounds, 1,3,7-trimethylguanine (1), 3,5-dihydroxyfuran-2(5H)-one (2), thymidine (3), and 1H-indazole (4). By using LC-HR-ESI-MS metabolic profiling, compounds 5-14 were also identified in the same fraction. Molecular docking calculations revealed the high binding affinity of compound 14 against the allosteric pocket of HCV NS3-NS4A and the active site of HCV NS3 helicase (-10.1 and -7.4 kcal mol-1, respectively). Molecular dynamics simulations, followed by molecular mechanics-generalized Born surface area energy calculations, demonstrated the structural and energetic stability of compound 14 in complex with HCV targets.

Antiproliferative potential of moluccella laevis L. aerial parts family lamiaceae (labiatae), supported by phytochemical investigation and molecular docking study.

The current biologically guided study aimed the in vitro investigation of cytotoxic activity, identification of the phytochemical content of Moluccella laevis L. aerial parts and supporting this activity by a molecular docking study. Aqueous fraction demonstrated the most potent cytotoxic effect against CACO-2 with IC50 = 0.067 ± 0.01 µg/mL. Furthermore, EtOAc fraction showed a remarkable cytotoxic activity against MCF-7 cell line with IC50 = 0.35 ± 0.02 µg/mL. Consequently, total ethanolic extract (TEE) and its fractions were subjected to LC-HR-ESI-MS metabolic profiling to discover the constituents that possibly underlie their cytotoxicity. Twenty compounds were tentatively identified from metabolic analysis. Furthermore, eight compounds were isolated. In silico docking study revealed that stachydrine is more likely to account for the antiproliferative activity of both EtOAc and aqueous fractions, probably via its moderate inhibition of receptor tyrosine kinases. [Formula: see text].

New Multi-Targeted Antiproliferative Agents: Design and Synthesis of IC261-Based Oxindoles as Potential Tubulin, CK1 and EGFR Inhibitors.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 µM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 µM. A mechanistic study demonstrated 4b's efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 µM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 µg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 µg/mL and 0.40 µg/mL compared to Gifitinib (IC50 = 0.05 µg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

Selective SIRT2 inhibitors as promising anticancer therapeutics: An update from 2016 to 2020.

Sirtuin 2 (SIRT2) is a member of the human sirtuins, which regulates various biological processes and is deemed as a novel biomarker for different cancers. Depending on the tumor type, SIRT2 knockout leads to a controversial role in tumorigenesis, however, pharmacological inhibition of SIRT2 results exclusively in growth inhibition of various cancer cells. In this respect, selective SIRT2 inhibitors hold therapeutic promise in a wide range of tumors. The literature has a batch of successful stories of SIRT2 modulators discovery. This review presents our perspective on the up-to-date selective SIRT2 inhibitors and their antiproliferative activity.

Telerehabilitation Guidelines in Saudi Arabia.

Rehabilitation needs are increasing globally due to population growth, aging population, high survival rates for people with disability, and severe health conditions. In the past few years, new telecommunication-based practices, including various forms of e-rehabilitation have gained attention all over the world, including the Kingdom of Saudi Arabia (KSA). Telerehabilitation is an alternative way of delivering rehabilitation services in which information and communication technologies are used to expedite communication between the health care professional and the patient at a distant location. It can be beneficial to people in rural areas, especially individuals in isolated communities. At present, the COVID-19 pandemic has forced speedy adoption of telerehabilitation due to restricted traditional in-person visits all over the world, including KSA; however, no telerehabilitation guidelines are available in the country. Since specialized rehabilitation services are limited to main cities of the country, the provision of care by reaching out the underserved areas using telemedicine technology is deemed important. These guidelines were established collaboratively by panel of various rehabilitation experts with input from other practitioners in the field and strategic stakeholders. It will facilitate rehabilitation clinicians practicing in KSA providing consultation, counseling, education, assessment, monitoring, therapy, or follow-up to a patient remotely using telemedicine communication technologies. This document includes administrative, clinical, and technical guidelines, which are aimed to standardize telerehabilitation practice across the country. The core principles are based on standards set forth by American Telemedicine Association and are guided by telemedicine policy in KSA. Additionally, ethical considerations of telerehabilitation practice pertinent to Saudi culture and health care system are elaborated as well. This document serves as a general guide for the provision of telerehabilitation services and do not describe a specialty-specific clinical practice guideline.

NS3/4A helicase inhibitory alkaloids from Aptenia cordifolia as HCV target.

Chemical investigation of Aptenia cordifolia roots extract, using chromatographic and spectroscopic techniques, resulted in isolation and identification of eight known compounds. The basic ethyl acetate fraction (alkaloidal fraction) afforded O-methylsceletenone, epinine, 4-methoxy phenethylamine, and N-methyl tyramine while, the acidic ethyl acetate fraction (non-alkaloidal fraction) afforded only cis-N-coumaroyl tyramine. Moreover, the petroleum ether fraction afforded capric acid, tricosanol, and a mixture of ß-sitosterol & stigma sterol. Upon screening of anti HCV activity of these three fractions, only the basic ethyl acetate fraction had high activity against HCV with an IC50 value equal to 2.4 µg mL-1 which provoked us to carry out structure based in silico virtual screening on the drug targets of HCV of isolated alkaloidal compounds as well as the previously dereplicated alkaloids through metabolomics from the antiviral active fraction. The tortuosamine compound exhibited the strongest binding to the active site of NS3/4A helicase with a binding affinity (-7.1 kcal mol-1) which is very close to the native ligand (-7.7 kcal mol-1).

Antidepressant potential of Mesembryanthemum cordifolium roots assisted by metabolomic analysis and virtual screening.

Depression is a common mental disturbance that can be categorized as mild, moderate or severe. Mesemberine alkaloids, the main recognized phytoconstituents of some plants belonging to family Mesembryanthemaceae, are well-known as serotonin reuptake inhibitors. Therefore, the objective of this study is to evaluate the antidepressant activity of the alkaloidal fraction of Mesembryanthemum cordifolium L.f. (Aptenia cordifolia) roots, family Mesembryanthemaceae using forced swimming test, assisted by metabolomic analysis and in silico ligand-based and structure-based screening. Results showed that the alkaloidal fraction displayed an antidepressant activity superior to imipramine hydrochloride, a standard antidepressant agent. Nine alkaloids were annotated from the metabolomic analysis. Interestingly, among the dereplicated constituents, mesembrane (5) displayed strong binding affinity to SERT protein, which is slightly higher than the antidepressant drug venlafaxine. In conclusion, the alkaloidal fraction of the M. cordifolium (A. cordifolia) root exhibits an antidepressant activity which can be attributed in part to mesembrane (5).