Design, synthesis, and biochemical and computational screening of novel oxindole derivatives as inhibitors of Aurora A kinase and SARS-CoV-2 spike/host ACE2 interaction

Medicinal Chemistry Research, Год журнала: 2024, Номер 33(4), С. 620 - 634

Опубликована: Март 5, 2024

Abstract Isatin (indol-2,3-dione), a secondary metabolite of tryptophan, has been used as the core structure to design several compounds that have tested and identified potent inhibitors apoptosis, potential antitumor agents, anticonvulsants, antiviral agents. In this work, analogs isatin hybrids synthesized characterized, their activities were established both Aurora A kinase severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike/host angiotensin-converting enzyme II (ACE2) interactions. Amongst hybrids, 6a , 6f 6g 6m exhibited inhibitory (with IC 50 values < 5 $$\mu$$ μ M), with GScore −7.9, −7.6, −8.2 −7.7 kcal/mol, respectively. Compounds 6i showed in blocking SARS-CoV-2 spike/ACE2 binding range 30 −6.4 −6.6 capable inhibiting kinase. Pharmacophore profiling indicated compound tightly fits pharmacophores, while 6d 6l pharmacophore. This work is proof concept some existing cancer drugs may possess properties. Molecular modeling active for each protein adopted different modes, hence interacting set amino acid residues site. The weaker against could be explained by small sizes ligands fail address important interactions ACE2 receptor

Язык: Английский

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Investigation of some plant stilbenoids and their fragments for the identification of inhibitors of SARS-CoV-2 viral spike/ACE2 protein binding

The Microbe, Год журнала: 2024, Номер 3, С. 100059 - 100059

Опубликована: Март 23, 2024

In silico binding studies were conducted on the known plant-derived polyphenolic tetrameric stilbenoids, (–)-hopeaphenol (1), vaticanol B (2) and vatalbinoside A (3) their monomeric derivative resveratrol (8), identified from several plant species. The natural products 1–3 had been previously evaluated against SARS-CoV-2 protein targets responsible for viral transmission infection. two isomeric compounds displayed a high affinity blocking of spike with human angiotensin-converting enzyme 2 (ACE2). Molecular docking molecular dynamics simulations have used to attempt explain spike/ACE2 complex. hydrophobic properties respective target sites computed compared physicochemical each compound toward site. ADMET/DMPK profiles also demonstrate potential fragments as lead antiviral discovery. These results reported here support experimental data obtained date clearly identify stilbenoid structure class one worthy future during chemical biology and/or drug discovery efforts.

Язык: Английский

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An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 interaction: synthesis, biological evaluation and computational analysis

Medicinal Chemistry Research, Год журнала: 2025, Номер unknown

Опубликована: Фев. 23, 2025

Язык: Английский

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Synthesis, Spectroscopic Characterization, DFT Analysis and Molecular Docking of Mn(II), Co(II) and Ni(II) complexes of Hydrazone Derived from 5-chloroisatin and 2,4-dinitrophenylhydrazine

Journal of Organometallic Chemistry, Год журнала: 2024, Номер 1013, С. 123184 - 123184

Опубликована: Май 17, 2024

Язык: Английский

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Computer-aided design, synthesis, and biological evaluation of 4-chloro-N-(2-oxo-3-(2-pyridin-4-yl)hydrazineylidene)indolin-5yl)benzamide and 1-(4-bromobenzyl)-5-indoline-2,3-dione against SARS-CoV-2 spike/ACE2

The Microbe, Год журнала: 2024, Номер 4, С. 100143 - 100143

Опубликована: Авг. 15, 2024

The emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2) as a global threat has driven urgent need for identification bioactive molecules capable controlling or completely eradicating this virus. Our group been investigating isatin hybrids that block binding human angiotensin-converting enzyme (ACE2) and viral spike protein. This work describes synthesis biological evaluation two derivatives (indol-2,3-dione) based on computational approach. Isatin, secondary metabolite tryptophan, used core structure is versatile favorable precursor privileged scaffold against complex. new compound scaffolds AVS-01 AVS-02 were designed by modifications at C-3 N-1 positions, respectively, according to various reagents available in our lab. Molecular docking compounds was explore their interactions with target protein shown article showed quite distinct glide scores (GScore = −3.657 −4.534 AVS-02, respectively). Several analogs synthesized tested quest find plausible further synthesis. While inhibition spike/ACE2 an IC50 value 8.8 µM, reference hopeaphenol inhibited interaction 0.3 µM. Compound rather no SARS-CoV-2 spike/host ACE2 > 32 An estimation free energy (ΔGbind), solvation (ΔGsolv) MM-GBSA calculations carried out re-evaluate affinity gain insights into observed activity non-activity. calculation ΔGbind −35.91 kcal/mol and-25.32 ΔGsolv 25.56 16.92 respectively. leads conclusion position indole-2,3-dione moiety favors blockage compared position. Analysis GScores, per-residue energies, energies van der Waals should favor towards

Язык: Английский

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Effects of some anti-ulcer and anti-inflammatory natural products on cyclooxygenase and lipoxygenase enzymes: insights from in silico analysis

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Май 22, 2024

Gastric and duodenal ulcers are increasingly becoming global health burdens. The side effects of conventional treatments such as non-steroid anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), antibiotics, histamine H2 receptor antagonists (H2RAs), cytoprotective agents have necessitated the search for new medications. Plants a rich source active metabolites herbal medicines been used in treatment cancers. In this study, we in silico methods to evaluate some anti-ulcer phytochemicals on key enzymes, cyclooxygenase (COX), lipoxygenase (LOX) which implicated protection destruction gastric mucosa. Five compounds, rhamnetin, kaempferol, rutin, rosmarinic acid, chlorogenic acid were identified putatively bind 2 (COX-2) 5-lipoxygenase (5-LOX) but not 1 (COX-1). interaction mechanisms between these target proteins discussed. drug metabolism, pharmacokinetics, toxicity compounds evaluated assess their suitability potential next-generation drugs.

Язык: Английский

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An evaluation of spirooxindoles as blocking agents of SARS-CoV-2 spike/ACE2 fusion and M pro inhibitory agents: Synthesis, biological evaluation and computational analysis

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Июнь 21, 2024

Both tetrahydroisoquinolines (THIQs) and oxindoles (OXs) display a broad range of biological activities, including antiviral activity. They are, therefore, recognized as privileged scaffolds in drug discovery. Here, we describe the synthesis spirofused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) their evaluation potential blocking agents both SARS-CoV-2 spike/ACE fusion inhibitors main protease (M^pro). The most active synthesized compound showed 50% inhibitory concentration (IC₅₀) 3.6 µM against fusion. None tested compounds was shown to be M^pro. possesses bulky naphthyl group, which addresses voluminous hydrophobic regions ACE2 binding site interacts with residues target; this finding agrees previous studies revealing that block spike/ACE2 fusion, e.g., natural product hopeaphenol. Therefore, spirooxindoles may provide useful leads search for agents.

Язык: Английский

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Effects of some anti-ulcer and anti-inflammatory natural products on cyclooxygenase and lipoxygenase enzymes: insights from in silico analysis

In Silico Pharmacology, Год журнала: 2024, Номер 12(2)

Опубликована: Ноя. 2, 2024

Язык: Английский

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