New hydrazide derivatives of N-amino-11-azaartemisinin as promising epidermal growth factor receptor inhibitors for therapeutic development in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) treatments, such as DNA-damaging agents like carboplatin, pose considerable human toxicity and may contribute to cancer relapse. Artemisinin derivatives offer a less toxic alternative; however, their specific role in TNBC management remains to be established. To address this gap, computational models were employed to design and evaluate artemisinin-based prototypes as potential TNBC therapeutics, aiming to provide safer and more effective treatment options for this aggressive cancer subtype. Among the series of hydrazide derivatives of azaartemisinin (10a-l) reported herein, compound 10j emerged as the most promising, exhibiting notable cytotoxicity with IC50 values of 1.74 and 1.64 µM against MDA-MB-231 and MDA-MB-468 cells, respectively. The clinically useful drug doxorubicin provided IC50 values of 0.29 and 0.29 µM against MDA-MB-231 and MDA-MB-468 cells, while artemisinin provided IC50 values of 107.30 and 116.60 µM, respectively. Furthermore, putative interactions between the synthesized compounds and the epidermal growth factor receptor (EGFR) were identified using molecular docking studies, suggesting a possible mechanism for their anticancer effect. Additionally, to determine the thermodynamic parameters of the interactions between artemisinin, azaartemisinin, and biomolecules, isothermal titration calorimetry experiments were performed. The binding constant value on the order of 104 indicates a comparatively stronger binding affinity of azaartemisinin with human serum albumin (HSA) compared to artemisinin with HSA. These findings support the potential of azaartemisinin derivatives as promising EGFR inhibitors for therapeutic development in TNBC, offering a new avenue for less toxic and more effective cancer treatments.

Novel saturated 1,2,4-trioxanes and their antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in Swiss mice model via oral route.

Novel saturated 6-(4'-aryloxy phenyl) vinyl 1,2,4-trioxanes 12a(1-3)-12d(1-3) and 13a(1-3)-13d(1-3) have been designed and synthesized, in one single step from diimide reduction of 11a(1-3)-11d(1-3). All the newly synthesized trioxanes were evaluated for their antimalarial activity against multi-drug resistant Plasmodium yoelii nigeriensis via oral route. Cyclopentane-based trioxanes 12b1, 12c1 and 12d1, provided 100 % protection to the infected mice at 24 mg/kg × 4 days. The most active compound of the series, trioxane 12b1, provided 100 % protection even at 12 mg/kg × 4 days and 60 % protection at 6 mg/kg × 4 days. The currently used drug, ß-arteether provides only 20 % protection at 24 mg/kg × 4 days.

Zirconium oxide nano-catalyzed synthesis of pharmacologically important bis(indolyl)methanes: a highly efficient and mild approach.

We report herein a highly efficient and mild approach for synthesizing pharmacologically active bis(indolyl)methanes 3a-z, utilizing ZrO2 nanoparticles as a catalyst. The method involves a condensation reaction between indole and diverse aromatic aldehydes in acetonitrile under mild conditions. The ZrO2 nano-catalyst prepared via a co-precipitation method demonstrates exceptional efficacy, leading to favourable yields of the target bis(indolyl)methanes 3a-z. The versatility of this methodology is highlighted through substrate screening, showcasing its applicability to various aromatic aldehydes.

An overview on the antimalarial activity of 1,2,4-trioxanes, 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes.

The demand for novel, fast-acting, and effective antimalarial medications is increasing exponentially. Multidrug resistant forms of malarial parasites, which are rapidly spreading, pose a serious threat to global health. Drug resistance has been addressed using a variety of strategies, such as targeted therapies, the hybrid drug idea, the development of advanced analogues of pre-existing drugs, and the hybrid model of resistant strains control mechanisms. Additionally, the demand for discovering new potent drugs grows due to the prolonged life cycle of conventional therapy brought on by the emergence of resistant strains and ongoing changes in existing therapies. The 1,2,4-trioxane ring system in artemisinin (ART) is the most significant endoperoxide structural scaffold and is thought to be the key pharmacophoric moiety required for the pharmacodynamic potential of endoperoxide-based antimalarials. Several derivatives of artemisinin have also been found as potential treatments for multidrug-resistant strain in this area. Many 1,2,4-trioxanes, 1,2,4-trioxolanes, and 1,2,4,5-tetraoxanes derivatives have been synthesised as a result, and many of these have shown promise antimalarial activity both in vivo and in vitro against Plasmodium parasites. As a consequence, efforts to develop a functionally straight-forward, less expensive, and vastly more effective synthetic pathway to trioxanes continue. This study aims to give a thorough examination of the biological properties and mode of action of endoperoxide compounds derived from 1,2,4-trioxane-based functional scaffolds. The present system of 1,2,4-trioxane, 1,2,4-trioxolane, and 1,2,4,5-tetraoxane compounds and dimers with potentially antimalarial activity will be highlighted in this systematic review (January 1963-December 2022).

Electrochemical Post-Ugi Cyclization for the Synthesis of Highly Functionalized Spirolactams.

The combination of the Ugi reaction and electro-organic synthesis can aid in the creation of novel heterocycles that have not been previously explored. In this study, a new strategy utilizing bis-amides from the Ugi reaction has been developed, which can produce C-S, C-Se, and C-C═O functionalized five-membered spirolactams mediated by electricity under catalyst- and metal-free conditions. Notably, this approach can be applied using a microelectro-flow reactor (µ-EFR) for gram-scale synthesis. The described strategy can synthesize complex azaspiro-fused tricyclic scaffolds with high diastereo- and regioselectivity, highlighting its versatility and potential.

Cell Voltage-Dependent Structural Dichotomy: Electrochemical C-H Acyloxylation and N-Acylation of 2H-Indazoles.

A simple and efficient electrochemical method that utilizes modulation of the cell voltage to cause structural alterations in 2H-indazole is introduced. This method enables the C-3 acyloxylation of 2H-indazole and promotes the transfer of the acyl group from C-3 to N-1, allowing the N-acylation of 2H-indazoles. Additionally, the application of the µ-electro flow reactor was demonstrated, showcasing its effectiveness in achieving gram-scale production of 3x within a short residence time.

Merging Electrochemical Synthesis and Post-Ugi Cyclization for the Synthesis of Diverse 4-Imidazolidinones.

Despite the appreciation for electro-organic synthesis, postmulticomponent reaction transformation chemistry rarely exploits this powerful technology. Herein, we explore post-Ugi cyclization reactions using N-centered radical-mediated intramolecular ipso cyclization to synthesize diverse spirocyclic variants of 4-imidazolidinones through the use of electrochemically generated amidyl radicals from the bis-amides of the Ugi adducts. This protocol features an undivided cell setup under constant-current conditions with carbon-platinum electrodes. These metal- and reagent-free reactions are scalable and have broad substrate scope.

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. Herein, we introduce new series of spirooxindoles via hybridization of the chemically stable core spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one and the pyrazole motif inspired by lead pyrazole-based p53 activators, the MDM2 inhibitor BI-0252 and promising molecules previously reported by our group. Single crystal X-ray diffraction analysis confirmed the chemical identity of a representative derivative. Fifteen derivatives were screened for cytotoxic activities via MTT assay against a panel of four cancer cell lines expressing wild-type p53 (A2780, A549, HepG2) and mutant p53 (MDA-MB-453). The hits were 8h against A2780 (IC50 = 10.3 µM) and HepG2 (IC50 = 18.6 µM), 8m against A549 (IC50 = 17.7 µM), and 8k against MDA-MB-453 (IC50 = 21.4 µM). Further MTT experiments showed that 8h and 8j potentiated doxorubicin activity and reduced its IC50 by at least 25% in combinations. Western blot analysis demonstrated that 8k and 8m downmodulated MDM2 in A549 cells. Their possible binding mode with MDM2 were simulated by docking analysis.

Calixarene-Metal Complexes in Lactide Polymerization: The Story so Far.

Polylactide synthetic procedures have lately gained attention, possibly due to their biocompatibility and the environmental problems associated with fossil-fuel-based polymers. Polylactides can be obtained from natural sources such as cassava, corn, and sugar beet, and polylactides can be manufactured in a laboratory using a variety of processes that begin with lactic acid or lactide. One of the most effective synthetic pathways is through a Lewis acid catalyzed ring-opening polymerization of lactides to obtain a well-defined polymer. In this regard, calixarenes, because of their easy functionalization and tunable properties, have been widely considered to be a suitable 3D molecular scaffold for new metal complexes that can be used for lactide polymerization. This review summarizes the progress made in applying some metal-calixarene complexes in the ring-opening polymerization of lactide.

An overview of synthetic methods and applications of photoluminescence properties of carbon quantum dots.

Carbon quantum dots (CQDs) are promising carbonaceous nanomaterials fortuitously discovered in 2004. CQDs are the rising stars in the nanotechnology ensemble because of their unique properties and widespread applications in sensing, imaging, medicine, catalysis, and optoelectronics. CQDs are notable for their excellent solubility and effective luminescence and, as a result, they are also known as carbon nanolights. Many strategies are used for the efficient and economical preparation of CQDs; however, CQDs prepared from waste or green sustainable methods have greater requirements due to their safety and ease of synthesis. Sustainable chemical strategies for CQDs have been developed, emphasizing green synthetic methodologies based on 'top-down' and 'bottom-up' approaches. This review summarizes many such studies relevant to the development of sustainable methods for photoluminescent CQDs. Furthermore, we have emphasized recent advances in CQDs' photoluminescence applications in chemical and biological fields. Finally, a brief overview of synthetic processes using the green source and their associated applications are tabulated, providing a clear understanding of the new optoelectronic materials.

Correction: Pd-Catalysed [3 + 2]-cycloaddition towards the generation of bioactive bis-heterocycles/identification of COX-2 inhibitors via in silico analysis.

Correction for 'Pd-Catalysed [3 + 2]-cycloaddition towards the generation of bioactive bis-heterocycles/identification of COX-2 inhibitors via in silico analysis' by Elagandhula Sathish et al., Org. Biomol. Chem., 2022, 20, 4746-4752, https://doi.org/10.1039/D2OB00467D.

Electrochemical Regioselective Sulfenylation of 2H-Indazoles with Thiols in Batch and Continuous Flow.

A novel electrochemical cross-dehydrogenative C-S bond coupling of aryl thiols with 2H-indazole is reported. Thiol-functionalized 2H-indazoles were synthesized under catalyst-, oxidant-, and metal-free conditions with innocuous hydrogen as the sole byproduct at ambient temperature. Furthermore, continuous electrochemical flow conditions using a graphite/Ni flow cell were used to obtained 3-(arylthio)-2H-indazole compounds on a gram scale within the residence time of 39 min. Detailed mechanistic studies including control experiments and cyclic voltammetry are provided to support the radical-radical cross-coupling pathway.

Dithiophosphonate Anchored Heterometallic (Ag(I)/Fe(II)) Molecular Catalysts for Electrochemical Hydrogen Evolution Reaction.

The dichalcogenide ligated molecules in catalysis to produce molecular hydrogen through electroreduction of water are rarely explored. Here, a series of heterometallic [Ag4(S2PFc(OR)4] [where Fc = Fe(η5-C5H4)(η5-C5H5), R = Me, 1; Et, 2; nPr, 3; isoAmyl, 4] clusters were synthesized and characterized by IR, absorption spectroscopy, NMR (1H, 31P), and electrospray ionization mass spectrometry. The molecular structures of 1, 2, and 3 clusters were established by single-crystal X-ray crystallographic analysis. The structural elucidation shows that each triangular face of a tetrahedral silver(I) core is capped by a ferrocenyl dithiophosphonate ligand in a trimetallic triconnective (η3; µ2, µ1) pattern. A comparative electrocatalytic hydrogen evolution reaction of 1-5 (R = iPr, 5) was studied in order to demonstrate the potential of these clusters in water splitting activity. The experimental results reveal that catalytic performance decreases with increases in the length of the carbon chain and branching within the alkoxy (-OR) group of these clusters. Catalytic durability was found effective even after 8 h of a chronoamperometric stability test along with 1500 cycles of linear sweep voltammetry performance, and only 15 mV overpotential was increased at 5 mA/cm2 current density for cluster 1. A catalytic mechanism was proposed by applying density functional theory (DFT) on clusters 1 and 2 as a representative. Here, a µ1 coordinated S-site between Ag4 core and ligand was found a reaction center. The experimental results are also in good accordance with the DFT analysis.

Synthesis of a Zirconium Complex of an N,O-type p-tert-Butylcalix[4]arene and Its Application in Some Multicomponent Reactions.

The synthesis and characterization of a new octahedral Zr(IV) complex of oxygen-depleted N,O-type calixarene ligand comprising two distal-functionalized pyrazole rings have been reported. The cone shape and structure of the prepared complex were confirmed univocally by single-crystal X-ray diffraction and NMR studies. The Zr metal lies at 2.091 Å from the plane of the calixarene ring. This complex has been utilized as an efficient catalyst for the synthesis of Biginelli adducts, bis(indolyl)methanes, and coumarins. This complex (Cl2Zr-calixarene) showed superior activity for these multicomponent reactions in comparison to the corresponding Ti(IV) and Zn(II) analogues. Ferrocene-appended bis(indolyl)methane, prepared using this catalyst, was also evaluated for its anticancer activity against the A-172 cell line.

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. In this work, synthetic arylvinyl-1,2,4-trioxanes 1a-u have been evaluated under various acidic conditions to mimic the milieu of the stomach (pH between 1.5 and 3.5) through which they have to pass when administered orally. The effect of acid on trioxanes led to their degradation into corresponding ketones and glyoxal. Under such acidic conditions glyoxal polymerized to form a nonisolable condensate product. The study indicates that the actual bioavailability of the drug is far less than the administered dose.

Pd-Catalysed [3 + 2]-cycloaddition towards the generation of bioactive bis-heterocycles/identification of COX-2 inhibitors via in silico analysis.

In the current research, we envisaged the synthesis of bis-heterocycles containing the dihydroisoxazole ring by [3 + 2] cycloaddition of VECs (vinyl ethylene carbonates) and nitrile oxides, assisted by a Pd catalyst. Herein we explored hydroximoyl chlorides as versatile precursors for the in situ generation of nitrile oxides that were exploited to achieve the cycloaddition reaction on a vinyl group of VECs to generate bis-heterocycles. In silico-based studies of bis-heterocycles on the cyclooxygenase (COX) enzyme displayed selective COX-2 inhibition.

Electro-Oxidative sp3 C-H Bond Functionalization and Annulation Cascade: Synthesis of Novel Heterocyclic Substituted Indolizines.

Indolizine derivatives are prevalent in many synthetic intermediates, pharmaceuticals, and organic materials. Herein, we report a novel electro-oxidative cascade cyclization reaction that uses electricity as the primary energy input to promote the reaction, leading to a series of heterocyclic substituted indolizine derivatives under exogenous-oxidant-free conditions. It is noteworthy that this electrochemical method provides a novel strategy for generating heterocyclic diversity of quinazolinones and quinolines on indolizines. In addition, the sole byproduct in the reaction was molecular hydrogen.

Novel hydrazone derivatives of N-amino-11-azaartemisinin with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice via intramuscular route.

Novel hydrazone derivatives 10a-m were prepared from N-Amino-11-azaartemisinin (9) and screened for their antimalarial activity by oral and intramuscular (i.m.) routes against multidrug-resistant Plasmodium yoelii in Swiss mice model. Several of the hydrazone derivatives showed higher order of antimalarial activity. Compounds 10b, 10g, 10m provided 100% protection to the infected mice at the dose of 24 mg/kg × 4 days via oral route. Fluorenone based hydrazone 10m the most active compound of the series, provided 100% protection at the dose of 6 mg/kg × 4 days via intramuscular route and also provided 100% protection at the dose of 12 mg/kg × 4 days via oral route. While artemisinin gave 100% protection at 48 mg/kg × 4 days and only 60% protection at 24 mg/kg × 4 days via intramuscular (i.m.) route. Compound 10m found to be four-fold more active than artemisinin via intramuscular route.

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

Twenty-five new hits of spirooxindole analogs 8a-y engrafted with indole and pyrazole scaffolds were designed and constructed via a [3+2]cycloaddition (32CA) reaction starting from three components: new chalcone-based indole and pyrazole scaffolds 5a-d, substituted isatins 6a-c, and secondary amines 7a-d. The potency of the compounds were assessed in modulating cholinesterase (AChE) activity using Ellman's method. Compounds 8i and 8y showed the strongest acetylcholine esterase inhibition (AChEI) with IC50 values of 24.1 and 27.8 µM, respectively. Molecular docking was used to study their interaction with the active site of hAChE.

Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model.

Novel 6-arylethyl-1,2,4-trioxanes6a-i and 7a-i are easily accessible in one step from the diimide reduction of 6-arylvinyl-1,2,4-trioxanes 5a-i. All of these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in a Swiss mice model. Most of the saturated trioxanes 6c, 6f, 6g, 6h, and 6i, the active compounds of the series, provided 100% protection to the malaria-infected mice at a dose of 24 mg/kg × 4 days. Further, trioxane 6i, the most active compound of the series, also showed 100% protection even at a dose of 12 mg/kg × 4 days and 20% protection at a dose of 6 mg/kg × 4 days. In this model, ß-arteether provided 100% protection at a dose of 48 mg/kg × 4 days and only 20% protection at a dose of 24 mg/kg × 4 days via the oral route, which was found to exhibit 4-fold antimalarial activity compared with the currently used drug ß-arteether.