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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 metal- and oxidant-free synthesis of S-thiocarbamates.

An expeditious synthetic strategy to access functionalized S-thiocarbamates was developed in good to excellent yields and with high current efficiencies. Readily available isocyanides and thiols were used as the starting materials under simple metal- and oxidant-free reaction conditions avoiding an inert atmosphere. The practical application of the present methodology was achieved by electrochemical synthesis of the herbicides prosulfocarb and pebulate. Furthermore, continuous electrochemical flow conditions using a graphite/Pt flow cell were used to obtain S-thiocarbamate compounds on a gram scale within a residence time of 35 min.

Synthesis of quinazoline-3-oxides via a Pd(ii) catalyzed azide-isocyanide coupling/cyclocondensation reaction.

A novel and efficient protocol concerning palladium catalyzing the three-component reaction of 2-azidobenzaldehyde, isocyanide, and hydroxylamine hydrochloride is developed. This method allows the rapid elaboration of quinazoline 3-oxides in a one-pot fashion. The 3-CR mainly involves concatenation of azide-isocyanide denitrogenative coupling, condensation with hydroxylamine and 6-exo-dig cyclization. The salient features of the methodology are operational simplicity, use of milder reaction conditions, being devoid of any additives such as oxidants (redox neutral) or base, and releasing N2 and H2O as the byproducts.

Establishment of Guidelines for the Control of Glycosylation Reactions and Intermediates by Quantitative Assessment of Reactivity.

Stereocontrolled chemical glycosylation remains a major challenge despite vast efforts reported over many decades and so far still mainly relies on trial and error. Now it is shown that the relative reactivity value (RRV) of thioglycosides is an indicator for revealing stereoselectivities according to four types of acceptors. Mechanistic studies show that the reaction is dominated by two distinct intermediates: glycosyl triflates and glycosyl halides from N-halosuccinimide (NXS)/TfOH. The formation of glycosyl halide is highly correlated with the production of α-glycoside. These findings enable glycosylation reactions to be foreseen by using RRVs as an α/ß-selectivity indicator and guidelines and rules to be developed for stereocontrolled glycosylation.

Catalyst-Controlled Structural Divergence: Selective Intramolecular 7-endo-dig and 6-exo-dig Post-Ugi Cyclization for the Synthesis of Benzoxazepinones and Benzoxazinones.

Metal catalyzed post-Ugi cyclization of bis-amides is reported in this study. Exposure of bis-amides to Pd(II) catalyst triggered the formation of seven-membered benzoxazepinones. This investigation established that changing the catalyst to a Echavarren's gold(I) turned off cyclization to seven member ring and turned on 6-exo-dig annulations to afford family of six-membered benzoxazinones. To support the proposed mechanisms, quantum chemical based density functional theory calculations have been performed and validated. This novel method obtained molecular complexity up to four modular inputs and divergence of two different skeletons. 2D NMR spectroscopic techniques and single crystal X-ray diffraction established the proposed structures.

Highly stereoselective glycosyl-chloride-mediated synthesis of 2-deoxyglucosides.

Cl intermediates: The glycosylation of per-O-benzylated 2-deoxy- and 2,6-dideoxythioglycosides, promoted by the combination of para-toluenesulfenyl chloride (p-TolSCl) and silver triflate (AgOTf), furnished the products in high yields and high stereoselectivity. The glycosyl chloride was the intermediate (see scheme).

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.

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.

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.