Anti-SARS-CoV-2 activities of tanshinone IIA, carnosic acid, rosmarinic acid, salvianolic acid, baicalein, and glycyrrhetinic acid between computational and in vitro insights

RSC Advances, Год журнала: 2021, Номер 11(47), С. 29267 - 29286

Опубликована: Янв. 1, 2021

Six compounds namely, tanshinone IIA (1), carnosic acid (2), rosmarinic (3), salvianolic B (4), baicalein (5), and glycyrrhetinic (6) were screened for their anti-SARS-CoV-2 activities against both the spike (S) main protease (Mpro) receptors using molecular docking studies. Molecular recommended superior affinities of (4) as common results from previously published computational articles. On other hand, actual tested in vitro plaque reduction assay to calculate IC50 values after measuring CC50 MTT on Vero E6 cells. Surprisingly, (1) was most promising member with equals 4.08 ng μl-1. Also, (2) (3) showed 15.37 25.47 μl-1, respectively. However, a weak activity an value 58.29 Furthermore, dynamics simulations 100 ns performed active compound point view (salvianolic 4), besides, one biologically (tanshinone 1) S Mpro complexes them (four different processes) confirm give more insights regarding stability inside SARS-CoV-2 mentioned receptors, understand mechanism action towards inhibition it necessary examine mode two compounds, (2). Both (1 2) very virucidal prominent inhibitory effect viral adsorption rather than its replication. This predicted protein protein. Our could be rearrange based search reasons behind great differences between silico SARS-CoV-2. Finally, we recommend further advanced preclinical clinical studies especially rapidly applied COVID-19 management either alone or combination and/or (4).

Язык: Английский

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Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2

Bioorganic Chemistry, Год журнала: 2022, Номер 123, С. 105770 - 105770

Опубликована: Апрель 2, 2022

Язык: Английский

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Synthesis, Molecular Docking, and Dynamic Simulation Targeting Main Protease (Mpro) of New, Thiazole Clubbed Pyridine Scaffolds as Potential COVID-19 Inhibitors

Current Issues in Molecular Biology, Год журнала: 2023, Номер 45(2), С. 1422 - 1442

Опубликована: Фев. 7, 2023

Many biological activities of pyridine and thiazole derivatives have been reported, including antiviral activity and, more recently, as COVID-19 inhibitors. Thus, in this paper, we designed, synthesized, characterized a novel series N-aminothiazole-hydrazineethyl-pyridines, beginning with N'-(1-(pyridine-3-yl)ethylidene)hydrazinecarbothiohydrazide derivative various hydrazonoyl chlorides phenacyl bromides. Their Schiff bases were prepared from the condensation N-aminothiazole 4-methoxybenzaldehyde. FTIR, MS, NMR, elemental studies used to identify new products. The binding energy for non-bonding interactions between ligand (studied compounds) receptor was determined using molecular docking against SARS-CoV-2 main protease (PDB code: 6LU7). Finally, best docked pose highest (8a = -8.6 kcal/mol) selected further dynamics (MD) simulation verify outcomes comprehend thermodynamic properties binding. Through additional vitro vivo research on newly synthesized chemicals, it is envisaged that achieved results will represent significant advancement fight COVID-19.

Язык: Английский

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Pimenta dioica (L.) Merr. Bioactive Constituents Exert Anti-SARS-CoV-2 and Anti-Inflammatory Activities: Molecular Docking and Dynamics, In Vitro, and In Vivo Studies

Molecules, Год журнала: 2021, Номер 26(19), С. 5844 - 5844

Опубликована: Сен. 27, 2021

In response to the urgent need control Coronavirus disease 19 (COVID-19), this study aims explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses viral infection could lead acute respiratory distress which is considered a critical and life-threatening complication associated with infection. Therefore, anti-viral anti-inflammatory can be key management of patients COVID-19. Four bioactive compounds, namely ferulic acid 1, rutin 2, gallic 3, chlorogenic 4 were isolated leaves Pimenta dioica (L.) Merr (ethyl acetate extract) identified using spectroscopic evidence. Furthermore, molecular docking dynamics simulations performed for compounds (1–4) against SARS-CoV-2 main protease (Mpro) as proposed mechanism action. all tested their half-maximal cytotoxicity (CC50) inhibitory concentrations (IC50). Additionally, lung toxicity was induced in rats by mercuric chloride effects treatment P. dioca aqueous extract, recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, genetic expression miRNA 21-3P miRNA-155 levels assess essential COVID-19 patients. Interestingly, showed remarkable activities IC50 values 31 µg/mL, 108 μg/mL, 360 respectively. found better 1 2 treatments. Our results promising more advanced preclinical clinical studies especially on either alone or combination other isolates management.

Язык: Английский

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Naturally Available Flavonoid Aglycones as Potential Antiviral Drug Candidates against SARS-CoV-2

Molecules, Год журнала: 2021, Номер 26(21), С. 6559 - 6559

Опубликована: Окт. 29, 2021

Flavonoids are important secondary plant metabolites that have been studied for a long time their therapeutic potential in inflammatory diseases because of cytokine-modulatory effects. Five flavonoid aglycones were isolated and identified from the hydrolyzed aqueous methanol extracts Anastatica hierochuntica L., Citrus reticulata Blanco, Kickxia aegyptiaca (L.) Nabelek. They as taxifolin (1), pectolinarigenin (2), tangeretin (3), gardenin B (4), hispidulin (5). These structures elucidated based on chromatographic spectral analysis. In this study, molecular docking studies carried out compounds against SARS-CoV-2 main protease (Mpro) compared to co-crystallized inhibitor Mpro (α-ketoamide (KI), IC50 = 66.72 µg/mL) reference standard. Moreover, vitro screening was evaluated. Compounds 2 3 showed highest virus inhibition with 12.4 2.5 µg/mL, respectively. Our findings recommend further advanced vivo examined flavonoids, especially either alone or combination each other identify promising lead target effectively. This is first report activity these SARS-CoV-2.

Язык: Английский

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Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors

RSC Advances, Год журнала: 2021, Номер 11(50), С. 31339 - 31363

Опубликована: Янв. 1, 2021

Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on worldwide finance, healthcare system, even daily life. Even with introduction of different preventive vaccines, there is still dire need for effective antiviral therapeutics. Nature been considered as historical trove drug discovery development, particularly cases crises. Herein, comprehensive

Язык: Английский

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In Silico and In Vitro Studies for Benzimidazole Anthelmintics Repurposing as VEGFR-2 Antagonists: Novel Mebendazole-Loaded Mixed Micelles with Enhanced Dissolution and Anticancer Activity

ACS Omega, Год журнала: 2021, Номер 7(1), С. 875 - 899

Опубликована: Дек. 22, 2021

Cancer is a leading cause of death worldwide and its incidence unfortunately anticipated to rise in the next years. On other hand, vascular endothelial growth factor receptor 2 (VEGFR-2) highly expressed tumor-associated cells, where it affects tumor-promoting angiogenesis. Therefore, VEGFR-2 considered one most promising therapeutic targets for cancer treatment. Furthermore, some FDA-approved benzimidazole anthelmintics have already shown potential anticancer activities. repurposing them against can provide rapid effective alternative that be implicated safely Hence, 13 anthelmintic drugs were subjected molecular docking receptor. Among tested compounds, fenbendazole (FBZ, 1), mebendazole (MBZ, 2), albendazole (ABZ, 3) proposed as antagonists. dynamics simulations carried out at 200 ns, giving more information on their thermodynamic dynamic properties. Besides, activity aforementioned was vitro three different cell lines, including liver (HUH7), lung (A549), breast (MCF7) lines. The results depicted cytotoxic especially both HUH7 A549 improve aqueous solubility MBZ, formulated form mixed micelles (MMs) which showed an enhanced drug release with better cytotoxicity compared crude MBZ. Finally, quantification concentration treated cells has been conducted based enzyme-linked immunosorbent assay. disclosed FBZ, ABZ significantly (p < 0.001) reduced VEGFR-2, while lowest inhibition achieved MBZ-loaded MMs, even much than reference sorafenib. Collectively, investigated could encountered lead compounds further structural modifications thus activity, accomplished through studying structure–activity relationships.

Язык: Английский

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Topo II inhibition and DNA intercalation by new phthalazine-based derivatives as potent anticancer agents: design, synthesis, anti-proliferative, docking, and in vivo studies

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2021, Номер 37(1), С. 299 - 314

Опубликована: Дек. 11, 2021

This research presents the design and synthesis of a novel series phthalazine derivatives as Topo II inhibitors, DNA intercalators, cytotoxic agents. In vitro testing new compounds against HepG-2, MCF-7, HCT-116 cell lines confirmed their potent activity with low IC50 values. inhibition intercalating activities were evaluated for most members. values determination demonstrated inhibitory affinities tested at micromolar level. Amongst, compound 9d was member. It inhibited enzyme value 7.02 ± 0.54 µM 26.19 1.14 µM. Compound then subjected to an in vivo antitumor examination. tumour proliferation reducing solid volume mass. Additionally, it restored liver enzymes, proteins, CBC parameters near-normal, indicating remarkable amelioration functions along histopathological examinations.

Язык: Английский

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Pharmacophore‐linked pyrazolo[3,4‐d]pyrimidines as EGFR‐TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies

Archiv der Pharmazie, Год журнала: 2021, Номер unknown

Опубликована: Авг. 31, 2021

Abstract Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4‐ d ]pyrimidine is versatile scaffold that exploited for developing anticancer agents. On basis of fragment‐based drug discovery, considering essential pharmacophoric features potent EGFR tyrosine kinase (TK) inhibitors, herein, we report design and synthesis new hybrid pyrazolo[3,4‐ linked diverse fragments reported potential. These include hydrazone, indoline‐2‐one, phthalimide, thiourea, oxadiazole, pyrazole, dihydropyrazole. The synthesized were evaluated their activity against human breast cell line, MCF‐7. obtained results revealed comparable antitumor reference drugs doxorubicin toceranib. Docking studies performed along EGFR‐TK ADMET profiling studies. docking showed ability designed compounds to interact key residues through number covalent noncovalent interactions. compound 25 (IC 50 = 2.89 µM) suggested it may serve lead further optimization development.

Язык: Английский

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Design and Synthesis of New Quinoxaline Derivatives as Potential Histone Deacetylase Inhibitors Targeting Hepatocellular Carcinoma: In Silico, In Vitro, and SAR Studies

Frontiers in Chemistry, Год журнала: 2021, Номер 9

Опубликована: Сен. 22, 2021

Guided by the structural optimization principle and promising anticancer effect of quinoxaline nucleus, a new series novel HDAC inhibitors were designed synthesized. The synthesized compounds to bear reported pharmacophoric features in addition an extra moiety occupy non-used vacant deep pocket receptor. newly prepared evaluated for their vitro anti-proliferative activities against HepG-2 HuH-7 liver cancer cell lines. tested showed both most active ten candidates ( 6 c , d f g k l 7 b 8 10 h 12 ) further on gene expression levels Bax as apoptotic marker Bcl-2 anti-apoptotic one. Moreover, they ability inhibit histone deacetylase (HDAC1, HDAC4, HDAC6) activities. Compound achieved best cytotoxic lines with IC 50 values 1.53 3.06 µM, respectively, also it inhibitory HDAC1, HDAC6 1.76, 1.39, 3.46 compared suberoylanilide hydroxamic acid (SAHA) reference drug (IC = 0.86, 0.97, 0.93 respectively). Furthermore, more characteristic arrest growth population at G0/G1 S phases 1.23-, 1.18-fold, that control, determined cycle analysis. Also, compound marked elevation AnxV-FITC cells percentage early late increasing total apoptosis 9.98-, 10.81-fold, control. docking studies carried out identify proposed binding mode towards prospective target (HDAC4). In silico ADMET toxicity revealed have accepted profiles drug-likeness low toxicity. Finally, interesting SAR analysis was concluded help future design potent HDACIs medicinal chemists.

Язык: Английский

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