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The COVID-19 pandemic has posed a significant threat to society in recent times, endangering human health, life, and economic well-being. The disease quickly spreads due to the highly infectious SARS-CoV-2 virus, which has undergone numerous mutations. Despite intense research efforts by the scientific community since its emergence in 2019, no effective therapeutics have been discovered yet. While some repurposed drugs have been used to control the global outbreak and save lives, none have proven universally effective, particularly for severely infected patients. Although the spread of the disease is generally under control, anti-SARS-CoV-2 agents are still needed to combat current and future infections. This study reviews some of the most promising repurposed drugs containing indolyl heterocycle, which is an essential scaffold of many alkaloids with diverse bio-properties in various biological fields. The study also discusses natural and synthetic indole-containing compounds with anti-SARS-CoV-2 properties and computer-aided drug design (in silico studies) for optimizing anti-SARS-CoV-2 hits/leads.

Chemoprevention is one of the accessible strategies for preventing, delaying or reversing cancer processing utilizing chemical intervention of carcinogenesis. NAD(P)H quinone oxidoreductase 1 (NQO1) is a xenobiotic metabolizing cytosolic enzyme/protein with important functional properties towards oxidation stress, supporting its ability in detoxification/chemoprotective role. A set of 3,5-diylidene-4-piperidones (as curcumin mimics) bearing alkyl sulfonyl group were synthesized with potential NQO1 induction properties. Compounds 5ab (R = 2-MeOC 6 H 4 , R’ = Me) and 5ac (R = 2-MeOC 6 H 4 , R’ = Et) are the most promising agents synthesized (% induction of NQO1 = 51.562, 45.793) relative to that of 4’-bromoflavone (4’-BF, reference standard) at 10 µM. LPS-induced iNOS production in RAW264.7 macrophages of the most promising agents discovered ( 5ab and 5ac ) displayed concentration-dependent with comparable activities to the reference anti-inflammatory drug indomethacin. Molecular modeling studies (including QSAR, molecular docking and molecular dynamics) were accessed supporting the observed biological profiles.

Targeted therapy is preferable over other therapeutics due to its limitation of drawbacks and better pharmaceutical outcomes. VEGF and its receptors have been observed to be hyper-activated in many cancer types and are considered promising targets for assigning anticancer agents. The current study is directed towards synthesis of novel antiproliferative 2-oxoindolin-3-ylidenes incorporating urea function with VEGFR-2 properties. The targeted agents were obtained through a two-step reaction. Addition of the appropriate 1-(acetylphenyl)-3-phenylurea 9a,b to the corresponding isatin 10a–f in ethanol containing a quantitative amount of Et 2 NH followed by acidic dehydration (AcOH/HCl) afforded the targeted agents 12a–j . Promising antiproliferation properties (MTT assay) were observed for most of the synthesized agents against HCT116 (colon), MCF7 (breast) and PaCa2 (pancreatic) cancer cell lines relative to sunitinib. VEGFR-2 inhibitory properties are consistent with the antiproliferation properties exhibited against the tested cell lines. Compound 12b (R = 4-NHCONHPh, R′ = H; % inhibition = 87.2) is the most promising/potent anti-VEGFR-2 agent synthesized with activity close to that of sunitinib (% inhibition = 89.4) at 10 μM. Molecular docking studies (PDB: 3WZE and 3AGD) support the antiproliferation effects against cancer cell lines tested with VEGFR-2 inhibitory properties. The results are consistent with collaboration of the pharmacophores considered (2-oxoindolyl heterocycle and urea) in improving the bio-properties.

The p53, often referred to as the “guardian of the genome”, is a well-established tumor-suppressor protein that plays a critical role in regulating the cell cycle, DNA repair, differentiation, and apoptosis, with its activity primarily modulated by the MDM2 protein (murine double minute 2, also known as HDM2 in humans). Disrupting the protein-protein interaction between p53 and MDM2 represents a promising therapeutic strategy for developing anticancer agents. Recent studies have shown that several spirooxindole-containing compounds exhibit significant antitumor properties, primarily by inhibiting the p53–MDM2 interaction. This review provides an overview of structure-based spirooxindoles that could have therapeutic potential. It highlights findings from the past decade concerning their antiproliferative properties and implications for interfering with the p53–MDM2 interaction. The discussion includes various analogs of spirooxindoles as promising candidates for optimizing leads in drug discovery programs aimed at developing novel and clinically effective agents.