Design, synthesis and antitubercular evaluation of benzothiazinones containing a piperidine moiety

We herein report the design and synthesis of benzothiazinones containing a piperidine moiety as new antitubercular agents based on the structure feature of IMB-ZR-1 discovered in our lab. Some of them were found to have good in vitro activity (MIC < 1 μg/mL) against drug-susceptible Mycobacterium tuberculosis H37RV strain. After two set of modifications, compound 2i were found to display comparable in vitro anti-TB activity (MIC < 0.016 μg/mL) to PBTZ169 against drug-sensitive and resistant mycobacterium tuberculosis strains. Compound 2i also showed acceptable PK profiles. Studies to determine PK profiles in lung and in vivo efficacy of 2i are currently under way

Design, synthesis and in vitro anti-Zika virus evaluation of novel Sinefungin derivatives

We report herein the design and synthesis of a series of novel Sinefungin (SIN) derivatives, based on the structures of SIN and its analogue EPZ004777. Our results reveal that target compounds 1ad-af, 1ba-bb and 1bf-bh show better activity (IC50 = 4.56–20.16 μM) than EPZ004777 (IC50 = 35.19 μM). Surprisingly, SIN was founded to be not as active (IC50 > 50 μM) as we and other research groups predicted. Interestingly, the intermediates 9a-b and 11b display potent anti-ZIKV potency (IC50 = 6.33–29.98 μM), and compound 9a also exhibits acceptable cytotoxicity (CC50 > 200 μM), suggesting their promising potential to be leads for further development

Prognostic genes related to mitochondrial dynamics and mitophagy in diffuse large B-cell lymphoma are identified and validated using an integrated analysis of bulk and single-cell RNA sequencing

BackgroundWhile the link between mitochondrial homeostasis, specifically dynamics and mitophagy, and the progression of diffuse large B-cell lymphoma (DLBCL) has been suggested, their prognostic significance and functional networks remain unclear. This study aimed to investigate the role of mitochondrial dynamics-related genes (MDRGs) in DLBCL patient outcomes.MethodsCandidate MDGRs were identified via Weighted Gene Co-expression Network Analysis (WGCNA) and differential expression analysis using public RNA-seq data. A prognostic signature was established via LASSO-Cox regression, followed by proportional hazards assumption validation. Functional pathways, regulatory networks (including miR-1252-5p/NEAT1), and a risk-scoring model were analyzed. Model assessment included nomograms, immune cell infiltration, m6A regulator, and pharmacogenomics. Single-cell mapping was employed to characterize B-cell differentiation and spatial gene expression. Finally, the findings were validated using RT-qPCR on clinical samples.ResultsSix lysosomal-enriched genes (TCF7, CEBPA, BBC3, GALR3, BMP8B, and BAALC) were identified as independent prognostic indicators. A composite model integrating our risk score and clinical parameters showed superior predictive accuracy (AUC &gt; 0.8). High-risk DLBCL was characterized by altered M0 macrophage infiltration, YTHDC1-mediated m6A dysregulation, and dihydrotestosterone sensitivity. Single-cell analysis revealed an association between stage-specific B-cell differentiation and gene expression gradients. RT-qPCR confirmed the upregulation of CEBPA, BBC3, GALR3, BMP8B, and BAALC in DLBCL clinical samples.ConclusionTCF7, CEBPA, BBC3, GALR3, BMP8B, and BAALC were identified as novel lysosomal pathway-enriched prognostic genes in DLBCL. Our validated composite model demonstrated strong predictive power. These findings establish an association between high-risk disease and specific tumor microenvironment alterations (M0 macrophages), epitranscriptomic dysregulation (m6A), and therapeutic vulnerabilities, providing valuable insights for refining prognosis and advancing targeted therapies for DLBCL