Visible-light-mediated flow protocol for Achmatowicz rearrangement.

The batch processes of APIs/pharmaceutical synthesis are prone to suffer significant limitations, including longer process time, shortage of skilled manpower, laborious post-synthetic work-up, etc. To address the inherent limitations of batch processes, a novel approach was undertaken, resulting in the establishment and development of a visible light-assisted modular photo-flow reactor with a seamlessly integrated post-synthetic work-up procedure enabling the efficient synthesis of dihydropyranones from furfuryl alcohols. The reaction uses sun light as green energy source, and the novel photo-flow reactor platform developed with an integrated system enabling a downstream process in a time and labor-efficient manner which facilitates the Achmatowicz rearrangement, resulting in a fast (10 min) formation of the dihydropyranone products.

One flask cascade approach to a complex pyrano[2,3-]pyrazole-pyrazolone hybrid heterocyclic system and its initiatory neurobiological profiling.

A one-pot multicomponent approach towards a hybrid heterocyclic pyrano[2,3-]pyrazole-pyrazolone framework involving tandem Knoevenagel condensation, sequential intermolecular 1,6-Michael addition, and 6- cyclization between diynones and pyrazolones, mediated by DBU, has been discovered. This process embodies several green and sustainable chemistry features. Preliminary bioactivity profiling of the new chemical entities indicates neuroprotective and AChE inhibitory activities.

Glucosyltriazole amphiphile treatment attenuates breast cancer by modulating the AMPK signaling.

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells.

Natural products from the human microbiome: an emergent frontier in organic synthesis and drug discovery.

Often referred to as the "second genome", the human microbiome is at the epicenter of complex inter-habitat biochemical networks like the "gut-brain axis", which has emerged as a significant determinant of cognition, overall health and well-being, as well as resistance to antibiotics and susceptibility to diseases. As part of a broader understanding of the nexus between the human microbiome, diseases and microbial interactions, whether encoded secondary metabolites (natural products) play crucial signalling roles has been the subject of intense scrutiny in the recent past. A major focus of these activities involves harvesting the genomic potential of the human microbiome bioinformatics guided genome mining and culturomics.

A protocol for directly accessing geminal C-4 diarylated pyrazol-5(4)-ones tandem C-H aryne insertion and their inceptive neurobiological evaluation.

Geminal C-4 diarylation of substituted pyrazol-5(4)-ones with generated arynes as the aryl source has been achieved in a one-flask operation. All the newly accessed C4--diarylated pyrazolone entities were found to be non-cytotoxic with varying AChE enzyme inhibitory activities and BBB permeability attributes that augur well for further advancement towards CNS therapeutics for untreatable disorders.

Design, synthesis and biological evaluation of novel cationic liposomes loaded with melphalan for the treatment of cancer.

Therapeutically active lipids in drug delivery systems offer customization for enhanced pharmaceutical and biological effects, improving safety and efficacy. Biologically active N, N-didodecyl-3,4-dimethoxy-N-methylbenzenaminium lipid (Q) was synthesized and employed to create a liposome formulation (FQ) encapsulating melphalan (M) through a thin film hydration method. Synthesized cationic lipids and their liposomal formulation underwent characterization and assessment for additive anti-cancer effects on myeloma and melanoma cancer cell lines.

Diversified Stitching of Ynones with Oxindole-3-oxy acrylates: One-Flask Spiro-annulation Protocol toward Assorted 3/5-Spiro[furan-2,3'-indolin]-2'-ones.

Spiroannulation of oxindole-3-oxy acrylates with ynones involving two overlapping, base differentiated cascades has been observed. Initial exposure of ynones and oxindole 3-oxy acrylates to KCO triggered a tandem Michael-Michael cascade to deliver a pair of spiroannulated diastereomers. Further exposure to LiHMDS led to deep restructuring through a second multistep cascade involving stereoselective recreation of the C3 quaternary center to furnish 3-spiro[furan-2,3'-indolin]-2'-ones with functional amplification and scrambling.

C-H modification of natural products: a minimalist enabling tactic for drug discovery, API processing and bioconjugation.

Intrusion into the C-H chemical space of natural products through the strategic deployment of C-H functionalization reactions could lead to incredibly new molecular diversities with an unforeseen impact on biological functions. Based on this hypothesis, semisynthetic C-H modification of natural products is emerging as a minimalist tactic in natural product based drug discovery. Several examples of C-H modification of natural products, resulting in functional gains in key pharmacological attributes potency, aqueous solubility and DMPK profile, along with opportunities in allied areas such as API processing, bioconjugation, and target deconvolution, continue to surface in the recent literature.

Accessing spiropiperidines from dihydropyridones through tandem triflation-allylation and ring-closing metathesis (RCM).

A novel approach to build 2-spiropiperidine moieties starting from dihydropyridones was developed. The triflic anhydride-promoted conjugate addition of allyltributylstannane onto dihydropyridones allowed for the formation of bis-alkenyl intermediates that were converted to the corresponding spirocarbocycles with excellent yields ring closing metathesis. The vinyl triflate group generated on these 2-spiro-dihydropyridine intermediates could be successfully used as a chemical expansion vector for further transformations namely Pd-catalyzed cross-coupling reactions.

Synthesis and Characterization of a New Cationic Lipid: Efficient siRNA Delivery and Anticancer Activity of Survivin-siRNA Lipoplexes for the Treatment of Lung and Breast Cancers.

Survivin has been shown to be widely expressed in most tumor cells, including lung and breast cancers. Due to limited siRNA delivery, it is more challenging to target survivin using knockdown-based techniques. Designing and developing new, bifunctional chemical molecules with both selective anti-proliferative activity and effective siRNA transfection capabilities by targeting a particular gene is important to treat aggressive tumors like triple-negative breast tumors (TNBC).

An Approach to Functionally Embellished -Alkynylbenzoates or Furan-3(2)-ones from Diynones and DMAD: Controlled Divergence and Product Selectivity.

The discovery of reaction regime controlled product diversification in a one-pot reaction between diynones and dimethyl-1,3-acetonedicarboxylate (DMAD) to selectively furnish either functionally unique pentasubstituted -alkynylbenzoates or fully substituted furan-3(2)-ones is delineated. The potential of these two versatile platforms to enter new utilitarian chemical space has also been explored.

Correction: Sulphonated graphene oxide catalyzed continuous flow synthesis of pyrazolo pyrimidinones, sildenafil and other PDE-5 inhibitors.

[This corrects the article DOI: 10.1039/D1RA08220E.].

Total synthesis of antiviral drug, nirmatrelvir (PF-07321332).

The emergence and rapid spread of coronavirus disease 2019 (COVID-19), a potentially fatal disease, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has swiftly led to public health crisis worldwide. Hence vaccines and antiviral therapeutics are an important part of the healthcare response to combat the ongoing threat by COVID-19. Here, we report an efficient synthesis of nirmatrelvir (PF-07321332), an orally active SARS-CoV-2 main protease inhibitor.

Anticancer effect and apoptosis induction by azaflavanone derivative in human prostate cancer cells.

Polyphenols are naturally occurring organic compounds with varying structures represented by four major groups: flavonoids, phenolic acids, lignans and stilbenes. Several studies suggested that these secondary metabolites have health benefits due to its anti-tumorigenic effect. Therefore, substantial effort has been put forward to isolate and characterize these natural compounds and synthesize analogues that may serve as potential anti-cancer therapeutics.

Regioselective C-3-alkylation of quinoxalin-2(1)-ones C-N bond cleavage of amine derived Katritzky salts enabled by continuous-flow photoredox catalysis.

An efficient, transition metal-free visible-light-driven continuous-flow C-3-alkylation of quinoxalin-2(1)-ones has been demonstrated by employing Katritzky salts as alkylating agents in the presence of eosin-y as a photoredox catalyst and DIPEA as a base at room temperature. The present protocol was accomplished by utilizing abundant and inexpensive alkyl amine (both primary and secondary alkyl) and as well as this a few amino acid feedstocks were converted into their corresponding redox-active pyridinium salts and subsequently into alkyl radicals. A wide variety of C-3-alkylated quinoxalin-2(1)-ones were synthesized in moderate to high yields.

Sulphonated graphene oxide catalyzed continuous flow synthesis of pyrazolo pyrimidinones, sildenafil and other PDE-5 inhibitors.

Sulphonated graphene oxide was used for cascade condensation and cyclization reactions towards accessing substituted pyrazolo pyrimidinones. Further, sulphonation and amination reactions were integrated through continuous flow chemistry to access PDE-5 inhibitors. Herein, we report a simple continuous synthetic platform that reduce tedious manual operations and accelerate the synthesis of several potent inhibitors of phosphodiesterase type-5.

Tandem Michael--Michael Addition-Mediated Orthogonal Strapping of Diynones: Regioselective Spirocyclopentannulation of Oxindoles and Pyrazolones and DFT Validation.

An efficient protocol involving the transformation of sequentially generated recursive anions from heterocyclic precursors to orthogonally strap diynones through one pot transition-metal-free spirocyclopentannulation has been devised, employing oxindoles and pyrazolones as prototypical platforms. Insights into these regioselective tandem Michael--Michael processes have been gleaned through DFT calculations.

-Flavanone Diminishes Parkinsonism in the Mutant.

Parkinson's disease is a chronic and progressive neurodegenerative disease, induced by slow and progressive death of the dopaminergic (DA) neurons from the midbrain region called substantia nigra (SNc) leading to difficulty in locomotion. At present, very few potential therapeutic drugs are available for treatment, necessitating an urgent need for development. In the current study, the transgenic model that induces selective loss in dopaminergic neurons and impairment of locomotory functions has been used to see the effect of the aza-flavanone molecule.

Stitching Ynones with Nitromethanes: Domino Synthesis of Functionally Enriched Benzofurans and Benzothiophenes.

A convenient one-pot benzannulation of regioisomeric 2- or 3-substituted furan and thiophene ynones with a range of nitromethanes has been discovered to directly access densely and diversely functionalized benzofurans and benzothiophenes. In this protocol, the nitro group in nitromethanes functions as recursive carbanion activator to setup tandem Michael addition-6π-electrocyclization, and its eventual sacrificial elimination facilitates aromatization and overall benzannulation. This benzannulation was also explored with furan/thiophene based -halo ynones wherein a Michael addition-SAr process operates and nitromethanes leave their imprint to deliver nitro substituted benzo-furans and -thiophenes.

Identification and characterization of forced degradation products of vortioxetine by LC/MS/MS and NMR.

Vortioxetine (VTX) is a novel multimodal antidepressant drug that affects the serotoninergic and noradrenergic systems. In this work, the forced degradation of VTX was studied according to (ICH) Q1A (R2) guidelines. The study revealed that VTX was stable under thermal stress conditions and hydrolytic stress conditions i.

Access to 2-Alkyl/Aryl-4-(1)-Quinolones via Orthogonal "NH" Insertion into -Haloaryl Ynones: Total Synthesis of Bioactive Pseudanes, Graveoline, Graveolinine, and Waltherione F.

An efficient one-pot synthesis of 4-(1)-quinolones through an orthogonal engagement of diverse -haloaryl ynones with ammonia in the presence of Cu(I), involving tandem Michael addition and ArCsp-N coupling, is presented. The substrate scope of this convenient protocol, wherein ammonium carbonate acts as both an in situ ammonia source and a base toward diverse 2-substituted 4-(1)-quinolones, has been mapped and its efficacy validated through concise total synthesis of bioactive natural products pseudanes (IV, VII, VIII, and XII), graveoline, graveolinine, and waltherione F.

Synthesis and evaluation of a novel quinoline-triazole analogs for antitubercular properties via molecular hybridization approach.

Towards a quest for establishing new antitubercular agents, we have designed new quinoline-triazole hybrid analogs in a six-step reaction sequence involving versatile reactions like Vilsmeier-Haack and click reaction protocol. The design is based on the structural modification of bedaquiline moiety and involves molecular hybridization approach. The structure of the synthesized product was elucidated by single crystal X-ray diffraction study.

Micro-electro-flow reactor (μ-EFR) system for ultra-fast arene synthesis and manufacture of daclatasvir.

The World Health Organization (WHO) has listed daclatasvir (DCV), symmetrical arene, as one of the essential medicines for human health. DCV manufacturing is usually carried out in a non-continuous or "batch" approach over multiple locations and is severely limited by long production times (3-10 days), resulting in non-affordability (highly expensive) and disruption of the potential chain supply. Here, we report the total process system including the development of a novel electro-flow reactor containing patterned electrodeposited Ni or Pt nanoparticles over a copper electrode for a C-C coupling reaction in a co-reductant/oxidant-free, ultra-fast process for symmetrical substituted/unsubstituted biphenyl synthesis.

A General Carbazole Synthesis via Stitching of Indole-Ynones with Nitromethanes: Application to Total Synthesis of Carbazomycin A, Calothrixin B, and Staurosporinone.

A new, one-pot domino benzannulation reaction between indole-3-ynones and various nitromethane derivatives has been explored for a general entry to diversely functionalized carbazole frameworks (28 examples). The scope of this new benzannulation has been extended to variants like 2-chloroindole-3-ynones to eventuate in chemo-differentiated 1,2,3,4-tetrasubstituted carbazoles with retention of the nitro group. The efficacy of this strategy has been demonstrated through concise total synthesis of natural products, viz.