4-Isopropylnitrobenzene (4-IPNB) is a nitroaromatic compound commonly employed as an intermediate in pesticide synthesis and chemical manufacturing. Despite its potential environmental persistence and ecological risks, the microbial degradation pathway of 4-IPNB remains largely unknown. In this study, a Gram-negative bacterium, designated Sphingobium yanoikuyae strain SG1, was isolated from a pesticide manufacturing site in Brazil for its ability to utilize 4-IPNB as the sole added source of carbon, nitrogen, and energy. Aerobic degradation of 4-IPNB by strain SG1 was accompanied by nitrite release, and intermediate-trapping experiments revealed the transient accumulation of 4-isopropylcatechol (4-IPC). Together, these findings support the initial conversion of 4-IPNB to 4-IPC through oxidative denitration and dihydroxylation. Genomic and transcriptomic analyses further inferred several candidate nitroarene dioxygenases that may catalyze this initial reaction. Furthermore, the downstream metabolism of 4-IPC proceeded via both meta- and ortho-cleavage pathways, with cell-extract enzyme assays demonstrating predominant meta-cleavage activity under the tested conditions. Strain SG1 also degraded 4-IPNB in nonsterile soil slurry microcosms, extending its degradation capability beyond defined liquid culture. This study provides the first comprehensive insight into the microbial aerobic degradation of 4-IPNB, advances our understanding of the environmental fate of emerging nitroaromatic contaminants, and supports the potential of strain SG1 in 4-IPNB biodegradation and removal.

A novel Rh(III)-catalyzed method has been established for the concise synthesis of highly functionalized indolizino[2,3-b]quinolinone derivatives (IZQLOs). This strategy proceeds through a complex cascade reaction between N-pyridin-2-yl enaminones and pyridotriazoles, involving traceless directing group-assisted C-H activation, β-carbon activation of enaminone, and the formation of an oxidized N-C bond to construct the key pyrrole ring framework, followed by intramolecular cyclization to form the lactam. The reaction sequence is flexible, allowing either initial formation of the pyrrole ring, followed by construction of the six-membered pyrimidinone ring, or vice versa. This one-pot process efficiently forges three new bonds, one C-C and two C-N, to build the complex polycyclic frameworks of pyrido[1',2':1,2]pyrimido[5,4-a]indolizin-13-ones 3, under [Cp*RhCl2]2 catalysis with 1-AdCO2H as an additive in DCE at 120 °C. Moreover, by employing ortho-halo-substituted enaminones in the presence of NaOAc at 100 °C, the reaction pathway can be redirected to exclusively afford another class of indolizino[2,3-b]quinolinone derivatives 4. This intramolecular SNAr transformation enables efficient and combinatorial access to a diverse array of biologically relevant complex structures based on the IZQLO scaffold.

A synthetic protocol for the construction of 3,4-disubstituted cinnoline scaffolds was described, which allowed for the transformation of ortho-alkynyl arylhydrazides via iron-catalyzed cascade C-H functionalization/cycloaddition. Furthermore, the practical utility of this method had been validated by easily scale-up synthesis, substrates derived from bioactive molecules and versatile derivatization of the target products. Mechanistic studies revealed that the reaction possibly proceeds via twice iron-mediated single-electron transfer (SET) processes. Furthermore, the resulting 3,4-disubstituted cinnolines exhibited significant anti-inflammatory effects from LPS stimulation experiment.

Herein, we report a green and sustainable approach for the de novo synthesis of ortho-halo N-aryl α-keto amides via a room-temperature, metal-free, visible-light-induced pathway from readily available feedstocks. This protocol involves the formation of an N-aryl α-keto amide followed by regioselective ortho halogenation, without the need of pre-installation of a directing group. Here, phenacyl halide has been utilized as a source of halogen for the first time. Mechanistic investigation indicates the formation of a halide radical under visible-light-mediated conditions from hydrogen halide, generated in situ from phenacyl halide. This atom-economical protocol tolerates diverse functional groups, delivering excellent yields of the desired products. Gram-scale synthesis, product diversification and application to the synthesis of bromo-quinolines are other highlights of our protocol.

This study reports the synthesis of a range of novel peptide-mimicking antimicrobials with conjugated ortho-hindered nitroarenes (CONAs) for nitric oxide release. These peptide-mimics were rationally designed, building from a previously established anthranilamide peptide-mimicking scaffold and synergistically substituting aromatic capping groups for aromatic CONAs. CONAs were synthesised via a novel synthetic pathway, avoiding the use of highly toxic CrO3 and red fuming nitric acid, in fewer steps and good-excellent yields compared to previously reported methods. Of the synthesised peptide-mimics, one formed a self-assembling low molecular weight hydrogel, and their gel properties were characterised by rheology, atomic force microscopy and circular dichroism. The synthesised compounds released NO when exposed to 530 nm light, and their antimicrobial activity was measured via a minimum inhibitory concentration assay, with one compound exhibiting activity against Gram-positive Staphylococcus aureus at 8 µg mL[-1].

Silacycles have attracted significant attention due to their broad applications in synthetic chemistry, medicinal chemistry, and materials science. However, the synthesis of silacyclesparticularly medium-sized ringsremains a formidable challenge. Herein, we report a general and efficient method for accessing a new family of nine- to eleven-membered benzodisilacycles bearing an additional heteroatom (O, S, N, or Si) on the ring scaffolds via palladium-catalyzed intermolecular silylation of primary and secondary C-(sp3)-H bonds. Readily available ortho-ether, thioether, tertiary amine, and silyl-substituted aryl iodides, as well as cyclic disilanes, serve as the building blocks, laying the foundation for diversity-oriented synthesis of these novel silacyclic scaffolds (>100 examples). Other salient features include excellent chemoselectivities, broad functional group tolerance, simple reaction conditions, low catalyst loading, and scalability. The key to the high efficiency of this disilylation reaction lies in the employment of cyclic disilanes as the silylation reagents. The synthetic practicality of the current strategy is further proven by the late-stage modification of pharmaceuticals and bioactive compounds.

Gliomas remain one of the most lethal malignancies, with limited therapeutic options and poor prognosis under current standard-of-care regimens. Copper-based metallodrugs represent an emerging therapeutic strategy, but their clinical translation is hampered by rapid speciation in biological media and poor tumor selectivity. In this work, eight novel copper(II) Schiff-base complexes were synthesized from four diamine backbones (1,3-diaminopropane, 2,2-dimethyl-1,3-propanediamine, 2,2'-(ethylenedioxy)bis(ethylamine) and 1,3-diaminopropan-2-ol) and four aldehydes (3,4-dimethoxybenzaldehyde, vanillin, ethyl vanillin, and ortho-vanillin), and characterized by IR, UV-Vis, EPR, elemental analysis, and mass spectrometry. EPR spectroscopy revealed distinct coordination geometries across the series, ranging from distorted tetrahedral to a unique square-planar N2O2 geometry in [Cu(OVDP)](ClO4)2 (compound OVDPCu, where OV = ortho-vanillin and DP = 1,3-diaminopropane). All complexes were encapsulated in liposomal nanocarriers by solvent nanoprecipitation, yielding monodisperse vesicles with incorporation efficiencies of 20-60%. Cytotoxicity was assessed by MTT assay against the glioblastoma cell line LN-18 and the non-tumorigenic hippocampal line mHippoE-2. Free ligands were low in activity, confirming that cytotoxicity is copper-dependent. OVDPCu was the most potent free complex against LN-18 cells, consistent with its square-planar geometry enhanced DNA-targeting capacity. Liposomal encapsulation of OVDPCu enhanced potency 3.8-fold over the free complex (EC50 = 3.4 μM against LN-18), while maintaining a selectivity index of 5.1 over non-tumorigenic cells, attributed differential endocytic uptake by tumor cells and protection of the intact complex from premature serum protein interaction. These findings establish a clear structure-geometry-activity relationship in copper(II) Schiff-base chemistry and support encapsulated OVDPCu as a compelling candidate for further preclinical validation in glioblastoma models.

Di(silylamido)stannylenes find application in chemical synthesis, catalysis and deposition of thin film materials. Homoleptic bis(N-alkyl-substituted-silylamido)stannylenes (i.e. [Sn{N[t]Bu(TMS)}2], TMS = trimethylsilyl) have previously been reported to possess limited thermal stability. Here, we describe the experimental and computational investigation of the thermal decomposition of [Sn{NR(TMS)}2] [R = [i]Pr, Cy, [t]Bu, Ad (Ad = 1-adamantyl), CPh3]. For aliphatic N-alkyl groups, DFT calculations support an intramolecular C(sp[3])-H activation by deprotonation of the TMS group via σ-bond metathesis (σBM), which forms a reactive four-membered heterocycle that is followed by disproportionation. When the N-alkyl group is substituted for the trityl group (-CPh3), the homoleptic stannylene could not be isolated, with the deprotonation of a neighbouring ortho-phenyl C(sp[2])-H position via σBM occurring at room temperature. The resultant five-membered heterocyclic Sn(II) intermediate rapidly tetramerises into [Sn{κ[2]-Ph'CPh2N(TMS)}]4, which is stable with respect to disproportionation.

Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors have shown limited clinical translation, partly because IDO1 blockade can be bypassed by tryptophan 2,3-dioxygenase (TDO) and may stabilize nonenzymatic IDO1 signaling states that promote tumor progression. Here, we report compound 66, an ortho-benzamidourea derivative obtained through the optimization of VS-15. Compound 66 displayed improved metabolic stability, balanced IDO1/TDO inhibition, and spectroscopic behavior consistent with apo-enzyme targeting. In tumor cells, 66 reduced kynurenine-pathway output and attenuated the IDO1/SHP-2 interaction, counteracting IDO1-driven noncatalytic signaling. This multimodal profile was associated with the inhibition of cancer cell proliferation and migration. Compound 66 therefore represents a chemical probe for dissecting enzymatic and signaling functions within the IDO1/TDO axis and supports small-molecule modulation of both catalytic and noncatalytic immune-metabolic pathways as an alternative to purely catalytic IDO1 inhibition or complete IDO1 degradation.

Leishmaniasis remains a major unmet medical need, and the development of new selective antileishmanial chemotypes is still urgently required. Herein, we report the design, synthesis, and biological evaluation of two series of benzofuranyl chalcones as antileishmanial agents against L. mexicana. Primary screening at 5 µg/mL identified 25 compounds that inhibited parasite metabolism by more than 50%, supporting the benzofuranyl chalcone framework as a productive antileishmanial scaffold. Dose-response studies revealed several low-micromolar leads, with compound 14l as the most potent analog (IC50 = 2.1 µM), followed by 13e (IC50 = 3.3 µM), 14p (IC50 = 4.2 µM), 13h (IC50 = 4.3 µM), and 14c (IC50 = 4.4 µM). All prioritized compounds displayed low cytotoxicity toward J774A.1 murine macrophages, resulting in high selectivity indices, with 14l showing SI > 666.7. Structure-activity relationship analysis indicated that activity is strongly influenced by both substituent identity and scaffold orientation; ortho-chloro and ortho-nitro substitution were favored in one series, whereas meta-CF3 and 3,4,5-trimethoxy substitution were particularly beneficial in the complementary framework. Computational studies suggest a plausible interaction with the FAD-associated region of L. mexicana fumarate reductase, although direct biochemical validation remains necessary.

Poly(ADP-ribose) polymerase-1 (PARP-1) plays a critical role in DNA damage repair and has emerged as a synthetic lethal target for BRCA mutant cancers. Herein, we report the discovery of novel PARP-1 inhibitors based on the natural stilbene scaffold through structural modification and ROS-responsive prodrug optimization. A series of stilbene derivatives with ortho-hydroxybenzamide scaffold were designed and synthesized. Among them, compound 24c demonstrated potent antiproliferative activity against BRCA1-deficient cell lines (SUM149PT, MDA-MB-436, and HCC1937) and the BRCA2-deficient cell line (Capan-1). Mechanistic studies revealed that 24c effectively inhibited intracellular PARP-1 activity, exacerbated DNA double-strand breaks, induced ROS generation, and decreased mitochondrial membrane potential, ultimately leading to cell cycle arrest and apoptosis. To enhance in vivo efficacy, ROS-responsive prodrugs were designed and synthesized, with P-24c demonstrating excellent antitumor activity (TGI = 69.3%) and low toxicity in a SUM149PT xenograft model. This work provides a valuable paradigm for developing novel antitumor agents from privileged natural scaffolds.

Herein, we disclose a tertiary amine-promoted domino reaction enabling facile one-pot synthesis of quinazolinones and benzoxazinones in moderate to excellent yields (up to 97%). This transition-metal-free protocol operates under simple reaction conditions, employing readily accessible ortho-amino/hydroxy chalcones to facilitate annulation with in situ generated isocyanates from dioxazolones. The reaction proceeds through a cascade sequence of decarboxylation, Lossen rearrangement and formal [4 + 2] annulation, forming three new C-X bonds in a single operation. Moreover, this domino strategy exhibits broad substrate scope and outstanding functional group tolerance.

Three libraries containing pyrrolo[2,3-d]pyrimidine moiety linked to diazospiro[3.5]nonane, diazospiro[5.5]undecane and piperazine - piperidine hybrid derivatives were synthesized involving various N-deprotection and acid amine coupling reactions. They were tested for their invitro cytotoxicity against triple negative human breast cancer cells MDA-MB-231 and BT-549. Promising results were obtained by pyrrolo[2,3-d]pyrimidine linked diazospiro[3.3]nonane compounds (7a and 7c) containing ortho-trifluoro and meta-bromo functional groups against MDA-MB-231 cells. Their dose response curves were plotted and their IC50 value found to be 11.66 µM (7a) and 10.37 µM (7b). Additionally, performed acridine orange and rhodamine 123 straining tests to study the cell deformation at various dosages, which garnered promising results.