In this work, we report on possible isomerization and cyclization pathways in 3-styrylpyridine (3-STPY) and 4-styrylpyridine (4-STPY) isomers. A thorough comparative analysis based on the computational results obtained using the second-order Møller-Plesset (MP2) and algebraic diagrammatic construction to the second-order (ADC(2)) methodologies is presented. The positional variation of the nitrogen atom in the pyridine ring relative to the styryl group alters electronic distribution in the system and influences molecular conformational diversity. While there are two distinct rotamers for each of the trans, cis, and cyclized conformers in 3-STPY, symmetry in 4-STPY limits conformational flexibility, yielding only a single isomer per configuration. To elucidate the non-radiative decay channels operative upon photoexcitation, minimum energy conical intersection structures (MECIs) between the ground and first excited states were calculated using the complete active space self-consistent field (CASSCF) method. We analyzed cis and trans isomerization as well as cyclization mechanisms along image-dependent pair potential (IDPP) pathways. Our results reveal that isomerization through twisted-pyramidalized MECIs originating from the cis side involves lower energy barriers than from the trans side, with 3-C2 → 3-CI1 and 4-C1 → 4-CI1 identified as the most favorable pathways for 3-STPY and 4-STPY, respectively. Additionally, relaxation toward the cyclized MECIs proceeds with little to no energy barriers in both systems. The findings offer mechanistic insight into the excited-state processes in styrylpyridine derivatives and suggest isomer-specific pathways for photoinduced isomerization and cyclization of the two molecules.

Inclusion of a fused pyridine ring onto the core motif of an azaphosphinine heterocycle, as well as functionalization with an N-acetamide group, furnishes a chiral, quadruple hydrogen bonding face that is capable of strong homodimerization. Eleven different azaphosphinine derivatives were prepared with variable electron donor and acceptor functionalization. Contrary to simple DA azaphosphinine dimers, trends from substituent effects showed that the hydrogen bond acceptors (A) were more sensitive to the substituents than the hydrogen bond donors (D). With electron donating groups appended onto the azaphosphinine scaffold, dimerization constants rose to as high as 209 M-1 in 10% DMSO-d6 in water-saturated CDCl3. X-ray crystallographic data unexpectedly showed that the quadruply hydrogen bonding system preferred the theoretically less stable donor-acceptor-donor-acceptor (DADA) H-bond orientation despite having the capability to tautomerize to the potentially more stable DDAA structure. Computational analysis revealed that maintaining pyridine aromaticity was more stabilizing than the secondary interactions that would be created from a DDAA dimer. Additionally, these molecules associate as the first examples of R,R- and S,S-azaphosphinine homodimers, compared to the R,S-heterodimers typically found for simple azaphosphinines. This observation was explained by computational analysis, which found a geometric difference between the nitrogen atoms adjacent to the phosphorus chiral center of the Homo and Hetero dimer, leading to a stronger hydrogen bonding interaction in the Homo dimer. Further understanding of this quadruply hydrogen bonding core will allow us to explore further applications that integrate this strongly hydrogen bonding system into larger and more complex supramolecular frameworks such as supramolecular polymers or capsules.

ABSTRACT According to the different application scenarios in the field of electronic packaging, it is of great research significance to screen out the suitable PSPI with low coefficient of thermal expansion (CTE). The introduction of a rigid structure into the backbone structure can effectively reduce the CTE. In this paper, polyamine esters (PAEs) were prepared by acyl chlorination method using diamine 2,5‐bis(4‐aminophenyl)pyridine (PRD) containing pyridine structure and four different dianhydrides, and then a series of films were finally obtained by heat curing treatment at different temperatures and heat curing treatment at different temperatures after light curing. The CTE value of all films decreased with the increase of heat treatment temperature. The CTE value of the films of PSPI and PSPI‐p series is higher than that of PI series films, and the PP series has the lowest CTE value in PI, PSPI, and PSPI‐p due to the stronger rigidity of PMDA. The photoresists formed by the four different backbone structures can achieve an optical resolution of 10 μm. The research results and laws of this paper can screen different spindle structures and heat treatment temperatures according to the required different CTE values for the field of electronic packaging.

Three unprecedented nitrogenated azaphilone hybrids, talamangins A-C (1-3), were isolated from the endophytic fungus Talaromyces mangshanicus SB17. Their structures, along with their absolute configurations, were determined by extensive spectroscopic data analysis and single-crystal X-ray diffraction. Compounds 1-3 represent the first examples of nitrogenated azaphilone hybrids, distinguished by a novel fused scaffold formed through the angular fusion of nitrogenated azaphilone and a benzophenone unit, with the azaphilone fragment featuring a pyridine ring. Plausible biosynthetic pathways for 1-3 are proposed. Compounds 1-3 exhibit potent immunosuppressive activities against concanavalin A (ConA)-induced T cell proliferation, with IC50 values of 13.0, 14.3, and 24.1 μM, respectively, as well as against lipopolysaccharide (LPS)-induced B cell proliferation, with IC50 values of 14.5, 18.5, and 19.2 μM, respectively. Additionally, compounds 1-3 inhibit nitric oxide production in LPS-induced RAW264.7 cells, with IC50 values of 6.2, 9.4, and 10.5 μM, respectively.

This work presents a comprehensive theoretical investigation of magnesium-to-nitrogen (Mg···N) noncovalent interactions in substituted pyridine-MgH2 (X-Pyr.MgH2) complexes and their implications for single-molecule electron transport. Geometry optimization, binding-energy analysis, AIM, NBO, and SAPT calculations reveal electrostatically dominated Mg···N interactions with strengths ranging from -100.03 to -77.29 kJ/mol, modulated systematically by the substituent-dependent basicity of the pyridine ring. Complex formation induces measurable structural perturbations and a pronounced reduction (1-2.5 eV) in the HOMO-LUMO energy gap. DFT-NEGF simulations of Au-molecule-Au junctions show that Mg···N bonding significantly alters transmission characteristics, producing distinct quantum interference features and a substituent-dependent suppression of current near the Fermi level. The resulting I-V responses exhibit stepwise "Coulomb staircase'' behaviour, indicating quantized charge transport across the junction. These results establish Mg···N noncovalent interactions as tunable electronic perturbations that can modulate conductance in pyridine-based single-molecule junctions, providing a feasible molecular framework for exploring single-electron transistor-like behaviour.

ABSTRACT The management of bacterial plant diseases is impeded by biofilm fortifications and the poor foliar affinity of conventional antimicrobials. Supramolecular assemblies have recently emerged as promising biofilm‐eradicating agents with enhanced surface adhesion. Yet, supramolecular polymers, although endowed with comparable or even greater potential, remain largely untapped in this arena. Herein, we introduce NOP@CB[8], a flower‐like supramolecular polymer self‐assembled in water from a de novo designed cationic pyridinium salt (NOP) and cucurbit[8]uril (CB[8]). Acting as a multifunctional agent, NOP@CB[8] disrupts bacterial membranes, perturbs redox equilibrium, disintegrates biofilms, and concurrently enhances foliar affinity. These combined attributes endow NOP@CB[8] with potent in vivo efficacy, exhibiting protective and curative efficacies of 56.1% and 51.2%, respectively, at 200 µg mL −1 against rice bacterial leaf blight, thereby surpassing both free NOP (47.9%/43.1%) and thiodiazole copper (TC, 36.2%/33.7%). Remarkably, NOP@CB[8] delivers high control efficacy with uncompromised safety toward both target and non‑target organisms, even demonstrates enhanced safety in zebrafish relative to free NOP. Extending its scope to citrus and kiwifruit cankers, NOP@CB[8] achieves approximately 80% protective and over 60% curative efficacy, consistently outperforming NOP and TC. Together, this study delineates a green alternative for crop protection and a conceptual framework for next‐generation functional supramolecular polymers.

The sucking pests such as aphids, planthoppers, and whiteflies pose a significant threat to global crop productivity, causing estimated losses of up to 40% in affected areas. Reports indicate that resistance to traditional agents such as imidacloprid has increased by more than 50% over the last decade, underscoring the urgency for innovative solutions. Neonicotinoids, which target insect nicotinic acetylcholine receptors (nAChRs), remain a vital component of pest management, offering an important alternative. Flupyrimin, a pyridylamide-type neonicotinoid with a unique mode of action on insect nAChRs, exhibits strong efficacy against resistant pest populations. In this study, a synthetic route to Flupyrimin was established, and the design and preparation of ten structural analogs were carried out. In these analogs, the trifluoroacetyl group was replaced by pyridylcarbamoyl moieties, and the pyridine ring was further derivatized. The synthetic strategy utilizes mild, non-hazardous solvents and high-efficiency reaction conditions, thus providing a practical and scalable approach for the generation of this novel class of compounds. Bioassays against Lipaphis erysimi (200mg/L) demonstrated that compounds IIIa and IIIc exhibited mortality rates in excess of 45%, while IIIb exhibited a mortality rate that exceeded 65% mortality. Molecular docking simulation indicated that IIIb exhibited the strongest binding to insect nAChRs, supported by favorable hydrogen-bonding and π-π interactions. Conversely, fluorine substitution at the 3-position in IIIc resulted in a slight deviation in binding orientation and a reduction in affinity. Furthermore, the larger chlorine atom in IIId introduced steric hindrance that prevented optimal binding. Single-crystal X-ray analysis of IIIe confirmed its structure and conformation. These results suggest that pyridylamide-based neonicotinoids may serve as a valuable scaffold for the development of next-generation insecticidal agents. The distinct structural features of these receptors are distinct, and their predicted binding modes suggest the potential for different receptor interactions. This has the potential to provide avenues for future resistance-management strategies.

Protecting hierarchical data via multi-level encryption and authenticating high-contrast touch traces represents an emerging frontier demanding technological innovation in molecular materials. Herein, via precise molecular interventions, three D-A-A' (donor-acceptor-acceptor) type aggregation induced emission (AIE)-active positional isomers (p-TPy, m-TPy, and o-TPy) are designed by varying the pyridine ring position in the acceptor. Their systematic investigation reveals key photophysical and structure-property insights, revealing their potential in advanced security and encryption. Positional modulation regulates electron-accepting strength and molecular packing, leading to red-shifted solid-state emission and influencing PLQY, transient PL, solvatochromism, and thermal stability as supported by crystal analysis and theoretical calculations. These stimuli-adaptive isomers address two critical challenges in advanced security systems. First, thermochromic luminescent materials (TLMs) exhibiting multiple temperature-dependent luminescent states are formulated as security inks by doping the para-isomer into phase-change matrices, enabling a multi-level security system. Second, a red-emissive, water-soluble amphiphilic fluorescent probe is obtained by functionalizing the para-isomer into a pyridinium emitter (p-TPyMe), capable of detecting latent fingerprints on diverse substrates and revealing level-3 ridge details with an exceptional contrast value of 5.39. These results demonstrate how molecular design in single chromophores translates into strategic AIE-active stimuli-adaptive positional isomers with intricate structure-property relationships, highlighting their potential for next-generation anti-counterfeiting, data encryption, and forensic technologies.

The management of bacterial plant diseases is impeded by biofilm fortifications and the poor foliar affinity of conventional antimicrobials. Supramolecular assemblies have recently emerged as promising biofilm-eradicating agents with enhanced surface adhesion. Yet, supramolecular polymers, although endowed with comparable or even greater potential, remain largely untapped in this arena. Herein, we introduce NOP@CB[8], a flower-like supramolecular polymer self-assembled in water from a de novo designed cationic pyridinium salt (NOP) and cucurbit[8]uril (CB[8]). Acting as a multifunctional agent, NOP@CB[8] disrupts bacterial membranes, perturbs redox equilibrium, disintegrates biofilms, and concurrently enhances foliar affinity. These combined attributes endow NOP@CB[8] with potent in vivo efficacy, exhibiting protective and curative efficacies of 56.1% and 51.2%, respectively, at 200µg mL-1 against rice bacterial leaf blight, thereby surpassing both free NOP (47.9%/43.1%) and thiodiazole copper (TC, 36.2%/33.7%). Remarkably, NOP@CB[8] delivers high control efficacy with uncompromised safety toward both target and non‑target organisms, even demonstrates enhanced safety in zebrafish relative to free NOP. Extending its scope to citrus and kiwifruit cankers, NOP@CB[8] achieves approximately 80% protective and over 60% curative efficacy, consistently outperforming NOP and TC. Together, this study delineates a green alternative for crop protection and a conceptual framework for next-generation functional supramolecular polymers.

Dokdothiocin, a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the thiopeptide family, was isolated from Streptomyces sp. 20A130. Its structure was elucidated by extensive NMR analyses, high-resolution mass spectrometry, and chemical derivatization, revealing a 29-membered macrocyclic scaffold bearing oxazole, thiazole, and a central pyridine ring. Dokdothiocin differs from previously reported thiopeptides in macrocycle size, heterocycle arrangement, and residue-specific modifications, including the incorporation of a 3-hydroxyproline residue within the macrocyclic framework. Bioinformatic analysis of the corresponding biosynthetic gene cluster is consistent with a maturation pathway involving heterocycle formation and pyridine aromatization. Functionally, dokdothiocin attenuated lipopolysaccharide-induced activation of BV2 microglial cells by reducing nitric oxide production and suppressing NF-κB signaling, highlighting it as a structurally distinctive thiopeptide scaffold with antineuroinflammatory potential.

Monocyclic N-heterocyclic radicals are the elementary reactive intermediates in synthetic chemistry and biochemical processes, but their isolation remains a central challenge due to extremely high reactivity. Here we report the first structurally characterized example of monocyclic pyridine radical supported by metal ions, [K(crypt-222)][Cp*2RE(PyS2-•)] (2-RE, PyS2-• = radical anion of pyridine-2-thiolate), and the first stable monocyclic triazine radical for any species, [K(crypt-222)][(Cp*2RE)3(TrizS4-•)] (4-RE, TrizS4-• = radical anion of 1,3,5-triazine-2,4,6-tris(thiolate)), based on rare earth thiolate systems. Detailed structural, computational, UV-vis, and EPR data support the presence of heterocyclic radicals, which show a complicated, uneven spin density distribution at both pyridine and triazine rings. Remarkably, the unusual bonding characters between the lanthanide centers and the SOMO π*-orbital of the radical promote strong ferromagnetic coupling from radical to lanthanide ions and achieve the largest gadolinium-radical ferromagnetic coupling observed to date, JGd-rad = +28.55(57) cm-1 (Ĥ = -2JGd-Rad ŜGd·ŜRad) in 2-Gd, while compound 4-Dy exhibits slow magnetic relaxation. Furthermore, the initial exploration on reactivity revealed the potential ability of the pyridine radical to activate inert bonds. Those results contribute to a better understanding of highly reactive species involving monocyclic heterocyclic radicals.

Abstract Three novel phosphor/thiophosphor-amides, [(5-CH 3 )- 2 Py-NH] 2 [C 6 H 11 (CH 3 )N]P(X) (X = O ( 1 ) and S ( 2 )) and [(5-CH 3 )- 2 Py-NH]P(O)[OCH 2 C(CH 3 ) 2 CH 2 O] ( 3 ), were synthesized and characterized by FT-IR and 1 H/ 13 C/ 31 P-NMR spectroscopy. The structures of 1 and 3 were determined by using single-crystal X-ray diffraction (SC-XRD) crystallography which reveals both compounds to crystallize in monoclinic space groups ( P 2 1 / c and P 2 1 / n , respectively). A crystal packing analysis shows that neighbouring molecules are connected together via N–H⋯O═P hydrogen bonds forming one-dimensional chains. A Hirshfeld surface analysis indicates that crystal packing is dominated by H⋯H, H⋯O/O⋯H, H⋯C/C⋯H, and H⋯N/N⋯H contacts, with O⋯H/H⋯O interactions including the classical N–H⋯O═P hydrogen bonds being particularly favored. Phosphor/thiophosphor-amide derivatives are emerging as promising scaffolds for targeting key enzymes of acetylcholinesterase (1EEA, 5FPP) and urease (2UBP, 4GY7). Molecular docking revealed favorable binding affinities (up to −10.3 kcal/mol for 1 with 1EEA), with compounds 1 and 2 generally exhibiting stronger predicted interactions than compound 3 . Key stabilizing interactions involve phosphoryl/thiophosphoryl groups and pyridine rings. Redocking of co-crystallized ligands with RMSD assessment confirmed the reliability of the docking protocol. While these results do not provide definitive evidence of inhibitory potency, they support further computational refinement and experimental evaluation, highlighting the potential of these derivatives as enzyme-interacting agents with biomedical relevance.

Development of molecular catalysts compatible with water is essential for achieving sustainable ammonia synthesis. In this context, metal-oxo species have rarely been recognized as catalysts for nitrogen fixation but, rather, regarded as dead-end species formed through the reaction of low-valent metal complexes with water. Herein, we report a series of cationic molybdenum-oxo complexes bearing NHC-based PCP-type pincer ligands and their utility as catalyst precursors for ammonia formation under ambient reaction conditions. The molybdenum-oxo complexes were prepared from reactions of the corresponding triiodide complexes with water. Reactions of an atmospheric pressure of N2 with SmI2 as a reductant and water as a proton source in the presence of the molybdenum-oxo complexes as catalysts at room temperature afforded up to 22,000 equiv of ammonia based on the molybdenum atom. The oxo complexes also served as effective catalysts for ammonia formation employing metallocenes and pyridinium salts. Stoichiometric reactions, electrochemical measurements, and DFT calculations revealed that the oxo complexes are readily converted into the corresponding nitride complexes as catalytically active species. The oxo-to-nitride conversion is triggered by oxygen abstraction with SmI2 or by protonation/reduction steps to form aqua complexes, followed by N≡N bond cleavage of the coordinated N2. We also revealed the reverse reaction from the nitride complex to the oxo complex in the presence of H2O under reductive conditions. Our study demonstrates that molybdenum-oxo complexes should not be merely regarded as dead-end species but as viable catalyst precursors, offering new options for catalyst design toward sustainable nitrogen fixation.

Piperidines are prominent scaffolds in medicinal chemistry. However, methods that incorporate chiral N-alkyl substituents on piperidine remain limited. Here, we report a platform for the synthesis of enantioenriched N-(α-chiral)alkylpyridinium salts from commercially available pyridines and enantiopure primary amines; the resulting pyridinium salts serve as versatile precursors to stereoenriched N-(α-chiral)alkylpiperidines via established reduction protocols. We discovered potassium metabisulfite as a reaction additive that significantly enhanced the robustness of the pyridinium formation reaction. Mechanistic and computational studies reveal that potassium metabisulfite deconjugates Zincke imines, enabling a lower-energy polar cyclization pathway to pyridinium formation compared to a pericyclic one. We performed high-throughput experimentation that demonstrated a broad scope for both coupling partners, providing a robust, general platform for generating libraries of piperidine precursors relevant to medicinal chemistry.

We report here a photosensitized strategy for protein labeling in which N-substituted pyridinium salts are activated using a 2,4-diaryl-N-methyl quinolinium scaffold. Structure-reactivity relationships were performed to optimize the sensitizer structure and ultimately generated a system that gives protein labeling in minutes at micromolar reagent concentrations. Mechanistic studies suggest a photoinduced electron transfer-based sensitization mechanism. The mildness of this system enabled us to assay sensitization both on individual biomolecules and in complex proteomes and demonstrated excellent compatibility with lysate- and live-cell-based systems. Imaging of photolabeled HeLa cells was performed and revealed that catalysis occurs in multiple cellular compartments. Chemical proteomics performed at the lysate level resulted in the enrichment of 319 proteins with 93% selectivity to Tryptophan residues. Live cell labeling resulted in 101 enriched proteins, primarily from the nucleus.

Stable luminescent multiradicals are photophysically very attractive materials as well as stable luminescent monoradicals due to their complex spin‐multiplicity states or intramolecular electronic and magnetic interactions. This concept article highlights synthetic advances in triarylmethyl‐type stable luminescent radicals, emphasizing methods to construct diradical, triradical, and multiradical systems. These radicals are prepared from triarylmethane precursors via deprotonation, followed by oxidation. The initial synthesis of perchlorinated triphenylmethanes through the BMC methodology (S 2 Cl 2 and AlCl 3 in SO 2 Cl 2 ) chlorination led to perchlorinated Chichibabin diradical. Friedel–Crafts reactions have been widely employed to produce various halogenated triphenylmethanes, which serve as versatile platforms for further functionalization. Incorporation of pyridine rings into the triarylmethyl core enables the formation of coordination systems with multiple radical ligands. Coupling reactions play an important role in expanding these radical frameworks. Direct substitution to the tris(2,4,6‐trichlorophenyl)methyl radical allows for the introduction of N ‐donor groups, creating donor–acceptor luminescent radicals and acceptor–donor–acceptor luminescent diradicals. Pd‐catalyzed couplings enable the functionalization of halogenated triarylmethanes, facilitating their dimerization, trimerization, and other complex architectures. The development of triarylmethane‐based boronic acids and esters has further expanded the synthetic scope, overcoming previous limitations and opening new pathways to stable luminescent diradicals.

Pyrethroids continue to play a vital role as pesticides for the management of agricultural and public health pests. Despite decades of application, their benefits still highlight substantial potential for further development, although addressing key concerns remains a complex challenge. This article presents a straightforward synthesis of four novel series of pyrethroids that incorporate pyridine heterocycles. These compounds leverage aryloxypyridinyl ethanone scaffolds, which were previously developed by our research group and serve as plug-in molecules. Notably, compound 4-1 exhibited remarkable activity against both mosquitoes and aphids, designating it as a promising lead compound for further exploration of species selectivity. Our findings indicate that substituting the α-cyano group in the benzyl alcohol moiety with a methyl group significantly influences pyrethroid activity. While this substitution typically results in reduced activity, the introduction of a pyridyl group effectively mitigates this decline. Interestingly, this structural modification appears to be essential for enhancing species selectivity. Additionally, optimizing the synergistic interaction between chrysanthemic acid and chrysanthemic alcohol moieties represents another critical strategy for advancing novel pyrethroid development. Our research also reinforces two established principles of structure-activity relationships: (1) a phenoxy group positioned at the meta-position on the pyridine ring enhances activity, and (2) substituents on the benzene ring exert no significant effect on activity. Molecular docking studies provide detailed structural insights that corroborate these conclusions at the receptor level.

The updated guidelines from the World Health Organization highlight that treatment options for multidrug-resistant tuberculosis (MDR-TB) remain limited due to the scarcity of effective drugs. As a result, there is an urgent necessity to develop novel or repurposed drugs that demonstrate efficacy against multidrug-resistant (MDR) strains. In this study, a new series of thiazole-pyridine hybrids were thoughtfully designed and synthesized to assess their potential as antitubercular agents. These compounds were specifically created to target enoyl acyl carrier protein reductase (InhA), a crucial enzyme in the pathogenesis of Mycobacterium tuberculosis. The majority of the compounds evaluated demonstrated substantial antitubercular activity, with minimum inhibitory concentrations (MIC) ranging from 0.5 to 3.9 μg mL-1 against Mycobacterium tuberculosis H37Rv. Among them, compound 5a was the most effective, with an MIC of 0.5 μg mL-1. Further evaluations of compound 5a demonstrated its ability to disrupt bacterial biofilms and its strong inhibition of InhA, with an IC50 of 0.19 ± 0.008 μg ml-1, demonstrating superior efficacy compared to triclosan, which was employed as the reference drug. Molecular docking and dynamics analyses demonstrated that the pyridine ring and thiazole group are essential for binding affinity, and the pyridine-thiazole framework in compound 5a formed stable interactions within the active site of InhA.

A simple pseudofour-component reaction catalyzed by CuBr2 has been developed to deliver C3-imidazoylquinoxalinones with decent yields from quinoxalin-2(1H)-ones, acetophenones, and ammonium persulfate in DMSO. This process follows a sequence of cross-dehydrogenative coupling/Kornblum oxidation/aza-cyclization, creating selectively four new C-C, two C-N, and C═N bonds. Interestingly, the Kornblum oxidation step can be skipped by simply replacing CuBr2 with Cu(OAc)2. This alteration leads to high-value C3-pyridylquinoxalinones. Notably, DMSO serves both as a C-H source for pyridine ring synthesis and an effective solvent for this conversion. In addition, the acquired 3-imidazolyl- and pyridylquinoxalinones were transmuted into value-added 3-(imidazo[1,2-a]pyrazin-3-yl)quinoxalinone and 2-sulfonylquinoxalines, showcasing the synthetic utility of our method.

Extrasynaptic δ-containing γ-aminobutyric acid type A receptors (GABAARs) are potential drug targets in the treatment of several neurological disorders with altered tonic inhibition. Only a few compounds exhibit δ-GABAAR selectivity, among which the imidazo[1,2-a]pyridine compound DS2 constitutes a valuable tool compound. Guided by the recently identified molecular determinants responsible for the positive allosteric modulation by DS2 in the TMD α(+)β(-) interface of the α4β1δ GABAAR, a series of DS2 analogues were synthesized. Replacement of a thienyl moiety with an N-methylated pyrrolyl ring (1e) converted the pharmacological profile from positive to negative allosteric modulation. Compound 1e exhibited no activity at selected γ2-containing GABAAR subtypes, indicating δ-GABAAR selectivity. The ability of 1e to reduce the GABA currents of recombinant receptors carrying α4- and δ-subunit gain-of-function mutations found in patients with neurodevelopmental disorders and epilepsy, as well as being brain-permeable, identifies 1e as a lead compound for reducing pathophysiologically excessive tonic inhibition.