Exploiting spirooxindoles for dual DNA targeting/CDK2 inhibition and simultaneous mitigation of oxidative stress towards selective NSCLC therapy; synthesis, evaluation, and molecular modelling studies.

The unique structure of spirooxindoles and their ability to feature various pharmacophoric motifs render them privileged scaffolds for tailoring new multitarget anticancer agents. Herein, a stereoselective multicomponent reaction was utilized to generate a small combinatorial library of pyrazole-tethered spirooxindoles targeting DNA and CDK2 with free radical scavenging potential as an extra bonus. The designed spirooxindoles were directed to combat NSCLC inducing apoptosis and alleviating oxidative stress.

Activation of p53 signaling and regression of breast and prostate carcinoma cells by spirooxindole-benzimidazole small molecules.

This study discusses the synthesis and use of a new library of spirooxindole-benzimidazole compounds as inhibitors of the signal transducer and activator of p53, a protein involved in regulating cell growth and cancer prevention. The text includes the scientific details of the [3 + 2] cycloaddition (32CA) reaction between azomethine ylide and ethylene within the framework of Molecular Electron Density Theory. The mechanism of the 32CA reaction proceeds through a process, with emphasis on the highly asynchronous transition state structure.

New spiro-indeno[1,2-]quinoxalines clubbed with benzimidazole scaffold as CDK2 inhibitors for halting non-small cell lung cancer; stereoselective synthesis, molecular dynamics and structural insights.

Despite the crucial role of CDK2 in tumorigenesis, few inhibitors reached clinical trials for managing lung cancer, the leading cause of cancer death. Herein, we report combinatorial stereoselective synthesis of rationally designed spiroindeno[1,2-]quinoxaline-based CDK2 inhibitors for NSCLC therapy. The design relied on merging pharmacophoric motifs and biomimetic scaffold hopping into this privileged skeleton cost-effective one-pot multicomponent [3 + 2] cycloaddition reaction.

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity.

A new series of spirooxindoles based on benzimidazole, triazole, and isatin moieties were synthesized via a [3+2] cycloaddition reaction protocol in one step. The single X-ray crystal structure of the intermediate triazole-benzimidazole was solved. The new chemical structures of these spirooxindole molecules have been achieved for the first time.

Synthesis and SARs study of novel spiro-oxindoles as potent antiproliferative agents with CDK-2 inhibitory activities.

A series of 16 novel spirooxindole analogs 8a-p were designed and constructed via cost-effective single-step multicomponent [3+2] cycloaddition reaction of azomethine ylide (AY) generated in situ from substituted isatin (6a-d) with suitable amino acids (7a-c) and ethylene-engrafted pyrazole derivatives (5a,b). The potency of all compounds was assayed against a human breast cancer cell line (MCF-7) and a human liver cell line (HepG2). Spiro compound 8c was the most active member among the synthesized candidates, with exceptional cytotoxicity against the MCF-7 and HepG2 cell lines, with IC values of 0.

Optimized spirooxindole-pyrazole hybrids targeting the p53-MDM2 interplay induce apoptosis and synergize with doxorubicin in A549 cells.

Recently, cancer research protocols have introduced clinical-stage spirooxindole-based MDM2 inhibitors. However, several studies reported tumor resistance to the treatment. This directed efforts to invest in designing various combinatorial libraries of spirooxindoles.

Design, Synthesis and In Vitro Evaluation of Spirooxindole-Based Phenylsulfonyl Moiety as a Candidate Anti-SAR-CoV-2 and MERS-CoV-2 with the Implementation of Combination Studies.

The search for an effective anti-viral to inhibit COVID-19 is a challenge for the specialized scientific research community. This work investigated the anti-coronavirus activity for spirooxindole-based phenylsulfone cycloadducts in a single and combination protocols. The newly designed anti-SARS-CoV-2 therapeutics spirooxindoles synthesized by [3 + 2] cycloaddition reactions represent an efficient approach.

Mechanistic Evaluation of the Stability of Arylvinyl-1,2,4-trioxanes under Acidic Conditions for Their Oral Administration as an Antimalarial Drug.

A mechanistic approach to understand the course of metabolism for synthetic 1,2,4-trioxanes, potent antimalarial compounds, to evaluate their bioavailability for antimalarial action has been studied in the present work. It is an important parameter to study the course of metabolism of a drug candidate molecule when administered via oral route during its journey from oral intake to its target site. From the pharmacokinetics point of view, it determines the bioavailability of an active drug or a prodrug at the target point.

Cu(ii)-thiophene-2,5-bis(amino-alcohol) mediated asymmetric Aldol reaction and Domino Knoevenagel Michael cyclization: a new highly efficient Lewis acid catalyst.

The highly efficient Lewis acid-catalytic system Cu(ii)-thiophene-2,5-bis(amino-alcohol) has been developed for enantioselective Aldol reaction of isatin derivatives with ketones. The new catalytic system also proved to be highly enantioselective for the one pot three-component Domino Knoevenagel Michael cyclization reaction of substituted isatin with malononitrile and ethylacetoacetate. The chiral ligand (2,2')-2,2'-((thiophene-2,5-diylbis(methylene))bis(azanediyl))bis(3-phenylpropan-1-ol) (L1) in combination with Cu(OAc)·HO employed as a new Lewis acid catalyst, furnished 3-substituted-3-hydroxyindolin-2-ones derivatives (3a-s) in good to excellent yields (81-99%) with high enantioselectivities (up to 96% ee) and spiro[4-pyran-3,3-oxindole] derivatives (6a-l) in excellent yields (89-99%) with high ee (up to 95%).

Exploiting the Chiral Ligands of (imidazolinyl)- and (oxazolinyl)thiophenes-Synthesis and Application in Cu-Catalyzed Friedel-Crafts Asymmetric Alkylation.

Five new -symmetric chiral ligands of 2,5-(imidazolinyl)thiophene () and 2,5-(oxazolinyl)thiophene ( and ) were synthesized from thiophene-2,5-dicarboxylic acid () with enantiopure amino alcohols (-) in excellent optical purity and chemical yield. The utility of these new chiral ligands for Friedel-Crafts asymmetric alkylation was explored. Subsequently, the optimized tridentate ligand and Cu(OTf) catalyst (15 mol%) in toluene for 48 h promoted Friedel-Crafts asymmetric alkylation in moderate to good yields (up to 76%) and with good enantioselectivity (up to 81% ).

Straightforward Regio- and Diastereoselective Synthesis, Molecular Structure, Intermolecular Interactions and Mechanistic Study of Spirooxindole-Engrafted Rhodanine Analogs.

Straightforward regio- and diastereoselective synthesis of bi-spirooxindole-engrafted rhodanine analogs - were achieved by one-pot multicomponent [3 + 2] cycloaddition (32CA) reaction of stabilized azomethine ylide (AYs -) generated in situ by condensation of L-thioproline and 6-chloro-isatin with ()-2-(5-(4-chlorobenzylidene)-2,4-dioxothiazolidin-3-yl)--(2-morpholinoethyl)acetamide. The bi-spirooxindole-engrafted rhodanine analogs were constructed with excellent diastereo- and regioselectivity along with high chemical yield. X-ray crystallographic investigations for hybrid revealed the presence of four contiguous stereocenters related to C11, C12, C19 and C22 of the spiro structure.

Construction of Spirooxindole Analogues Engrafted with Indole and Pyrazole Scaffolds as Acetylcholinesterase Inhibitors.

Twenty-five new hits of spirooxindole analogs engrafted with indole and pyrazole scaffolds were designed and constructed a [3+2]cycloaddition (32CA) reaction starting from three components: new chalcone-based indole and pyrazole scaffolds , substituted isatins , and secondary amines . The potency of the compounds were assessed in modulating cholinesterase (AChE) activity using Ellman's method. Compounds and showed the strongest acetylcholine esterase inhibition (AChEI) with IC values of 24.

Stereoselective Synthesis of the Di-Spirooxindole Analogs Based Oxindole and Cyclohexanone Moieties as Potential Anticancer Agents.

A new series of di-spirooxindole analogs, engrafted with oxindole and cyclohexanone moieties, were synthesized. Initially, azomethine ylides were generated via reaction of the substituted isatins (isatin, , 6-chloroisatin, , 5-fluoroisatin, , 5-nitroisatin, , 5-methoxyisatin, , and 5-methylisatin, , and (2)-octahydro-1-indole-2-carboxylic acid , in situ azomethine ylides reacted with the cyclohexanone based-chalcone to afford the target di-spirooxindole compounds . This one-pot method provided diverse structurally complex molecules, with biologically relevant spirocycles in a good yields.

Bimetallic Iron-Palladium Catalyst System as a Lewis-Acid for the Synthesis of Novel Pharmacophores Based Indole Scaffold as Anticancer Agents.

The Friedel-Crafts reaction between substituted indoles as nucleophiles with chalcones-based benzofuran and benzothiophene scaffolds was carried out by employing a highly efficient bimetallic iron-palladium catalyst system. This catalytic approach produced the desired -heteroaryl products with low catalyst loading, a simple procedure, and with acceptable yield. All synthesized indole scaffolds - were initially evaluated for their cytotoxic effect against human fibroblast BJ cell lines and appeared to be non-cytotoxic.

Synthesis of a New Class of Spirooxindole-Benzo[]Thiophene-Based Molecules as Acetylcholinesterase Inhibitors.

A series of new oxindole-based spiro-heterocycles bearing the benzo[]thiophene motif were synthesized via a 1,3-dipolar cycloaddition reaction and their acetylcholinesterase (AChE) inhibitory activity was evaluated. All the synthesized compounds exhibited moderate inhibitory activities against AChE, while was found to be the most active analog with an IC value of 20,840 µM·L. Its molecular structure was a 5-chloro-substituted oxindole bearing benzo[]thiophene and octahydroindole moieties.

Spiroindolone analogues bearing benzofuran moiety as a selective cyclooxygenase COX-1 with TNF-α and IL-6 inhibitors.

To design and discover a new compound can used as a COX with TNF-α and IL-6 inhibitors is highly challenge. A series of spiroindolone-bearing benzofuran moieties were resynthesized from the chalcone-based benzo[]furan with substituted isatin, and amino acids. The requisite spiroindolone analogues were tested for their potential inhibitory activities against lipid metabolizing enzymes such as cyclooxygenase COX-1, COX-2, and the release of pro-inflammatory cytokines interleukin IL-6, and tumor necrosis factor TNF-α.

Synthesis and characterisation of thiobarbituric acid enamine derivatives, and evaluation of their α-glucosidase inhibitory and anti-glycation activity.

A new series of thiobarbituric (thiopyrimidine trione) enamine derivatives and its analogues barbituric acid derivatives was synthesised, characterised, and screen for evaluation of α-glucosidase enzyme inhibition and anti-glycation activity. This series of compounds were found to inhibit α-glucosidase activity in a reversible mixed-type manner with IC between 264.07 ± 1.

Synthesis and Inhibitory Effect of Some Indole-Pyrimidine Based Hybrid Heterocycles on α-Glucosidase and α-Amylase as Potential Hypoglycemic Agents.

The Michael addition reaction of barbituric acid with chalcones incorporating the indole scaffold was achieved by using a highly efficient bimetallic Iron-palladium catalyst in the presence of acetylacetone (acac). This catalytic approach produced the desired products in a simple operation and low catalyst loading with acceptable yield of the new hybrids. All tested compounds were subjected for biological activity on α-glucosidase and α-amylase.

Anticancer Indole-Based Chalcones: A Structural and Theoretical Analysis.

The crystal structures of five new chalcones derived from -ethyl-3-acetylindole with different substituents were investigated: ()-3-(4-bromophenyl)-1-(1-ethyl-1-indol-3-yl)prop-2-en-1-one (); ()-3-(3-bromophenyl)-1-(1-ethyl-1-indol-3-yl)prop-2-en-1-one (); ()-1-(1-ethyl-1-indol-3-yl)-3-(4-methoxyphenyl)prop-2-en-1-one (); ()-1-(1-ethyl-1-indol-3-yl)-3-mesitylprop-2-en-1-one (); and ()-1-(1-ethyl-1-indol-3-yl)-3-(furan-2-yl)prop-2-en-1-one (). The molecular packing of the studied compounds is controlled mainly by C-H⋅⋅⋅O hydrogen bonds, C-H⋅⋅⋅π interactions, and π···π stacking interactions, which were quantitatively analyzed using Hirshfeld topology analysis. Using density functional theory (DFT) calculations, the order of polarity () was determined.

Vibrational spectral analysis, XRD-structure, computation, exo⇔endo isomerization and non-linear optical crystal of 5-((5-chloro-1-indol-2-yl)methylene)-1,3-diethyl-2-thioxodihy-dropyrimidine-4,6 (1,5)-dione.

This work deals with the synthesis and characterization of the novel 5-((5-chloro-1-indol-2-yl)methylene)-1,3-diethyl-2-thioxodihydro-pyrimidine-4,6(1,5)-dione π-bridge (D-A-D) donor-acceptor-donor compound. Its exo-isomer structure has been proven by XRD-single-crystal analysis for the first time. The IR, UV-Vis.

Spiroindolone Analogues as Potential Hypoglycemic with Dual Inhibitory Activity on α-Amylase and α-Glucosidase.

Inhibition of α-amylase and α-glucosidase by specified synthetic compounds during the digestion of starch helps control post-prandial hyperglycemia and could represent a potential therapy for type II diabetes mellitus. A new series of spiroheterocyclic compounds bearing oxindole/benzofuran/pyrrolidine/thiazolidine motifs were synthesized via a 1,3-dipolar cyclo-addition reaction approach. The specific compounds were obtained by reactions of chalcones having a benzo[]furan scaffold (compounds ), with a substituted isatin (compounds ) and heterocyclic amino acids (compounds ).

Synthesis of Pyridine-Dicarboxamide-Cyclohexanone Derivatives: Anticancer and α-Glucosidase Inhibitory Activities and In Silico Study.

An efficient and practical method for the synthesis of 2,6-diaryl-4-oxo-,'-di(pyridin-2-yl)cyclohexane-1,1-dicarboxamide is described in this present study, which occurs through a double Michael addition reaction between diamide and various dibenzalacetones. The reaction was carried out in dichloromethane (DCM) in the presence of 1,8-diazabicyclo[5.4.