Activation of extrasynaptic δ-GABAARs represents a promising strategy for rapid-acting antidepressant therapy in major depressive disorder (MDD). Here, we report the discovery and pharmacological characterization of a novel series of thiazolo[4,5-d]pyrimidin-7(6H)-one derivatives as potent positive allosteric modulators selective for δ-GABAARs. Systematic SAR exploration identified compound 12i as a lead candidate, which demonstrated high potency on the extrasynaptic receptor subtype (α4β3δ: 950% current enhancement at 10 μM, EC50 = 0.8 μM) while maintaining favorable modulation of synaptic subtypes. In vivo, 12i exerted rapid-acting antidepressant effects in both the mouse tail suspension test and the chronic restraint stress-induced depression model, with no addictive behaviors observed. These effects were completely abolished in δ-subunit knockout mice, confirming target engagement. Furthermore, 12i significantly enhanced NREM sleep in a p-chlorophenylalanine-induced insomnia model, highlighting potential dual efficacy in MDD with comorbid sleep disturbance. Collectively, these findings position 12i as a promising clinical candidate for next-generation rapid-acting antidepressant therapy.

Despite their nanomolar potency against M. tuberculosis (MTB), benzothiazinone (BTZs) DprE1 inhibitors like PBTZ169 are ineffective against nontuberculous mycobacteria (NTM) due to a Cys387Ala mutation in the NTM DprE1 target. Here, 529 BTZs in our lab were screened againstM. abscessus, and two hits with the 2-benzyl-2,7-diazaspiro[3.5]nonane scaffold showed enhanced activity. Subsequent optimization led to the discovery of lead compound B2 with potent activity against MTB (MIC: < 0.01 μg/mL) and NTM strains (MIC: < 0.03125-2.5 μg/mL). Notably, B2 also has good safety and oral pharmacokinetic (PK) profiles. Further chiral resolution revealed its R-enantiomer (B2-1) as a more active form. Mechanistic investigations showed that B2-1 establishes a stable electrostatic interaction with Asp326 ofM. abscessusDprE1. As this residue is highly conserved among mycobacterial species, such an interaction likely underpins its broad-spectrum activity. Therefore, our findings provide a blueprint for developing next-generation BTZs with broad-spectrum activity against mycobacteria.

Status epilepticus (SE), a life-threatening neurological emergency, is primarily treated with benzodiazepines (BZDs), which act as positive allosteric modulators (PAMs) of γ2-containing GABAA receptors (GABAARs). However, their efficacy diminishes due to γ2 subunit internalization, leading to pharmaco-resistance. In this manuscript, a series of 2-(2-thienyl)-thiazolo[4,5-d]pyrimidin-7(6H)-one derivatives were designed and evaluated using two-electrode voltage clamp in Xenopus oocytes expressing α1β2 GABAARs. We identified (S)-9d as a potent α1β2γ2 subtype PAM, showing 13-fold potentiation at 10 μM (EC50: 0.9 μM in oocytes, 0.2 μM in CHO cells) as well as α1β2 (EC50 = 1.3 μM, 1700% enhancement, in oocytes). Molecular docking and mutagenesis revealed (S)-9d binds to a distinct β+/α- interface of α1β2 GABAARs. In SE mouse models, (S)-9d (5-30 mg/kg) significantly suppressed seizure progression and reduced delayed mortality, outperforming diazepam. This study establishes a promising strategy for refractory SE to overcome BZD limitations.

Acinetobacter baumannii bacteremia caused by pandrug-resistant strains poses a major challenge in intensive care units, necessitating novel therapeutic approaches. Phage-derived depolymerases offer a promising adjunct to conventional antibiotics. However, studies on A. baumannii phage depolymerases have been limited to non-mammalian models. This study investigates the therapeutic efficacy, safety, and potential mechanisms of action of DPO-HL, both as a monotherapy and in combination with polymyxin B, in a murine model of A. baumannii bacteremia. DPO-HL was expressed and purified via Ni-NTA affinity chromatography. Its bactericidal activity was assessed through dynamic killing and biofilm disruption assays. Interaction with human plasma was examined to determine its impact on plasma's bactericidal activity. Synergy with polymyxin B was evaluated by MIC reduction. Safety was assessed via cytotoxicity, haemolysis, and acute toxicity tests. A mouse bacteremia model was established to evaluate therapeutic efficacy via intraperitoneal and intravenous administration. DPO-HL, targeting KL160 capsular polysaccharide, exhibited stability in plasma and enhanced plasma's bactericidal effect. It showed strong synergy with polymyxin B, reducing its MIC by 16-fold, and efficiently eradicated mature biofilms. DPO-HL alone reduced bacterial load and endotoxin levels but rescued only 30% of bacteremia mice. Combination therapy (1.45 mg/kg DPO-HL + 0.5 mg/kg polymyxin B) significantly reduced endotoxin levels and achieved 100% survival, regardless of administration route. This study identifies a KL160-targeting depolymerase and demonstrates its potent synergy with polymyxin B in treating A. baumannii bacteremia, supporting its potential for clinical application.

Enhancing α7 nAChR function serves as a therapeutic strategy for cognitive disorders. Here, we report the synthesis and evaluation of 2-arylamino-thiazole-5-carboxylic acid amide derivatives 6–9 that as positive allosteric modulators (PAMs) activate human α7 nAChR current expressed in Xenopus ooctyes. Among the 4-amino derivatives, a representative atypical type I PAM 6p exhibits potent activation of α7 current with an EC50 of 1.3 μM and the maximum activation effect on the current over 48-fold in the presence of acetylcholine (100 μM). The structure–activity relationship (SAR) analysis reveals that the 4-amino group is crucial for the allosteric activation of α7 currents by compound 6p as the substitution of 4-methyl group results in its conversion to compound 7b (EC50 = 2.1 μM; max effect: 58-fold) characterized as a typical type I PAM. Furthermore, both 6p and 7b are able to rescue auditory gating deficits in mouse schizophrenia-like model of acoustic startle prepulse inhibition.

New hole transport materials (HTMs) with cross‐linkable units HT‐1 and HT‐2 are designed with suitable energy levels, good solubility, and good solvent resistance after film formation. Subsequently, the cross‐linkable HTMs based OLEDs with a green TADF emitter show significantly improved current efficiency (CE) of 52 cd/A and 68 cd/A, respectively, compared to the device without HTM of less than 23 cd/A. This study demonstrates a new HTM design strategy with controllable energetics for printable optoelectronic devices, including OLEDs and quantum‐dot LEDs.

Objective Isoflurane is an extensively used inhalational anesthesia, and its carcinogenic or anti-cancerous effect has been identified recently. However, the specific role of isoflurane in cervical cancer remains unclear. Aim This study aimed to investigate the function of isoflurane in cervical cancer as well as the underlying mechanism. Methods After isoflurane treatment, HeLa cell viability, percentage of apoptotic cells, expression of active caspase-3/9 were examined by CCK-8 assay, Annexin V-FITC/PI double staining, and Western blot analysis, respectively. ROS generation, ratio of NAD(+)/NADH, and ATP level after isoflurane stimulation were determined using commercial assay kits. Afterwards, activation of AMPK and autophagy was assessed through Western blot analysis and immunofluorescence. Whether AMPK mediated the isoflurane-induced apoptosis and autophagy was explored by adding an AMPK inhibitor (Compound C). Thein vivofunction of isoflurane was finally investigated on a HeLa cellxenograftmodel. Results Isoflurane inhibited cell viability and induced apoptosis evidenced by upregulation of active caspase-3/9 in HeLa cells. Oxidative stress was triggered by isoflurane, as isoflurane elevated ROS level, and lowered ratio of NAD(+)/NADH and ATP level. Further results showed isoflurane activated the AMPK/mTOR pathway and induced autophagy. In addition, inhibition of AMPK led to ameliorated effects of isoflurane on apoptosis and autophagy.In vivoexperiments proved isoflurane could repress tumorigenesis, activate AMPK, and induce autophagy inXenograftmouse. Conclusions Isoflurane activated AMPK to inhibit proliferation and promote apoptosis and autophagy bothin vitroandin vivo.

Enhancing neuronal α7 nicotinic acetylcholine receptor (α7 nAChR) function can alleviate cognitive deficits. Here, we report the design, synthesis, and evaluation of N-(4-(trifluoromethoxy)phenyl)-1,3,5-triazin-2-amine derivatives 8-10 as a series of novel α7 nAChR positive allosteric modulators (PAMs). The representative compound 10e functions as a type I PAM with an EC50 of 3.0 μM and approximately 38-fold enhancement of α7 current in the presence of agonist acetylcholine (100 μM). It specifically enhances α7 current with high selectivity. Compound 10e shows good pharmacokinetic property in mice. Intraperitoneal injection of 10e (3 mg/kg) exhibits sufficient blood-brain barrier penetration in mice. Furthermore, 10e can also rescue the auditory gating deficit in mice with schizophrenia-like behavior. Molecular docking of 10e with homopentameric α7 nAChR reveals a new mode of action. These results support the potential of 10e for treatment for schizophrenia and Alzheimer's disease.

An effective synthesis method for preparing 4,6-disubstituted pyridinones was reported.Ethyl 3-oxo-4-phenylbutyrate was an important intermediate,by which 6-substituted pyridinones could be prepared.The decarboxylation condition was optimized for compound 4.After protected with a methoxy group,the compound was reacted with BnBr to form the target compound 11.The structures were characterized by 1H NMR,13C NMR and HRMS,and its enzyme inhibition activity was also determined.

The synthesis of 2-amino-4-hydroxyl-6-hydroxymethyl-5,6,7,8-tetrahydropyrido[3,2-d]pyrimidine 3 is described from 2-amino-6-methyluracil 4 through the crucial step of 2-pivaloyl protecting and cyclization. The assignment of the structure of 3 was performed by its spectral data, the H-1 NMR, C-13 NMR, gHMQC, and HRMS spectra.

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A simple method for synthesis of tetracycline Mannich bases by C-2 reacting with primary and secondary amine was reported. Secondary Mannich base was obtained by primary amine reacting with tetracycline hydrochloride in methanol and water. Tertiary Mannich base was obtained by the reaction of secondary amine and tetracycline in t-butanol. The structures of synthesized ten of tetracyline analogs 4～13 had been identified.

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