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Triple-negative breast cancer (TNBC) is characterized by a highly aggressive phenotype and limited therapeutic options. This study investigated whether the vitamin D receptor (VDR) modulates aggressiveness and chemotherapeutic response in TNBC and explored its interaction with paclitaxel (PTX) in the presence of a non-hypercalcemic vitamin D analogue (UVB1). Functional cellular assays, orthotopic murine models, and computational approaches were integrated using murine 4T1 and human MDA-MB-468 TNBC cells with differential VDR expression, including PTX-resistant models. The results show that VDR overexpression reduced invasive capacities in vitro and pulmonary metastatic dissemination in vivo, and sensitized cells to PTX alone or combined with UVB1. 4T1-PTX-resistant cells exhibited elevated VDR levels and less aggressive features compared with wild-type cells. Computational analyses revealed stable PTX binding to an allosteric site near the activation function-2 domain of VDR, further stabilized by UVB1. Functional assays demonstrated that the combination of PTX and UVB1 enhanced the transcriptional activity of VDR compared with UVB1 treatment alone. These findings identify VDR signaling as a modulator of tumor aggressiveness and PTX response in TNBC and support a model in which PTX contributes to nuclear receptor regulation, thus highlighting the relevance of non-canonical drug–receptor interactions in shaping cellular responses to chemotherapy.

Dipeptidyl peptidase IV (DPP IV) inhibition prolongs incretin activity and represents an established therapeutic strategy for the management of type 2 diabetes mellitus. To investigate the underexplored combination of benzyl groups at the N7 position and a piperazine-linked arylthiazole moiety at the C8 position of the xanthine scaffold, 15 novel compounds (6a–6o) were synthesised. The synthetic route involved bromination at the C8 position of theophylline, introduction of benzyl groups at the N7 position, replacement of the bromine atom at the C8 position with piperazine, and subsequent cyclocondensation with phenacyl thiocyanate derivatives. All final compounds were characterised by ¹H and ¹³C NMR spectroscopy, high-resolution accurate-mass mass spectrometry, and analytical HPLC. All derivatives inhibited DPP IV in the low-nanomolar range, with compounds 6c and 6b showing the highest activities, with IC₅₀ values of 3.95 ± 0.53 and 4.04 ± 0.65 nM, respectively. NIH3T3 cytotoxicity IC₅₀ values ranged from 28.52 to 397.63 µM, indicating substantial preliminary concentration margins relative to DPP IV inhibition. Molecular docking, 100 ns molecular dynamics simulations, interaction-fingerprint analyses and trajectory-based MM/PBSA calculations supported persistent interactions with key DPP IV active-site residues. These results identify the synthesised derivatives, particularly 6b and 6c, as promising lead structures for further optimisation.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease, largely driven by oxidative stress and inflammation. This study evaluated the protective role of carbocisteine, a mucolytic with antioxidant and anti-inflammatory properties, against streptozotocin (STZ)-induced DN in rats. Male Sprague–Dawley rats were divided into four groups: normal, diabetic, carbocisteine (250 mg/kg), and carbocisteine (500 mg/kg). After 8 weeks, diabetic rats showed significant hyperglycemia, weight loss, renal dysfunction (elevated serum creatinine, BUN, and urinary protein), oxidative stress (increased MDA, decreased GSH), and upregulation of inflammatory mediators; IL-1β, IL-6, and TNF-α, along with downregulation of Sirt-1 and Nrf-2 expression and upregulation of NLRP3 and caspase-1. Moreover, diabetic rats exhibited a pro-apoptotic shift, characterized by increased Bax and decreased Bcl-2 expression. Histopathology revealed mesangial expansion, tubular degeneration, and interstitial fibrosis. Carbocisteine treatment, particularly at the high dose, significantly improved renal function, attenuated oxidative and inflammatory responses, restored Sirt-1 and Nrf-2 levels, suppressed NLRP3/caspase-1 activation, and reversed the Bax/Bcl-2 imbalance, thereby ameliorating histopathological damage. These findings suggest that carbocisteine exerts nephroprotective effects in diabetic rats through modulation of the Sirt-1/Nrf-2/NLRP3/caspase-1 signaling axis and regulation of the Bax/Bcl-2 apoptotic pathway, highlighting its potential as a promising adjunct therapy for DN.

Cancer remains one of the leading causes of mortality worldwide, highlighting the need for novel anticancer agents with improved efficacy and selectivity. In this study, a series of chalcone derivatives bearing phenylpiperazine, 2-fluorophenylpiperazine, and morpholine moieties (1a–g, 2a–g, and 3a–g) were designed, synthesized, and evaluated for their anticancer potential. The target compounds were synthesized via Claisen–Schmidt condensation under basic conditions and characterized by ¹H NMR, ¹³C NMR, and elemental analysis. Their cytotoxic activities were assessed against PC-3, PANC-1, A549, and MCF-7 cancer cell lines using the MTT assay, with HEK-293 cells serving as a non-cancerous control. Most compounds exhibited notable antiproliferative activity and favorable selectivity compared with doxorubicin, cisplatin, and gemcitabine. Among the tested cell lines, A549 cells were the most sensitive. Compounds 2d, 2b, 2c, 2e, 2g, and 2a showed particularly potent activity against A549 cells, with IC₅₀ values of 5.35 ± 0.08, 5.71 ± 0.09, 5.95 ± 0.09, 5.83 ± 0.09, 5.94 ± 0.09, and 5.96 ± 0.09 µM, respectively. Notably, 2c exhibited the highest selectivity toward A549 cells (SI = 3.26). SAR analysis indicated that the 2-fluorophenylpiperazine moiety enhanced anticancer activity, while halogen substitution generally improved potency and selectivity. Induced Fit Docking and Glide XP simulations supported these findings, suggesting that 2d and 2c achieve their activity through key hinge-region anchoring and isoform-specific interactions with PI3K-α and PI3K-γ. Overall, these findings identify fluorinated chalcone derivatives, particularly 2d, as promising leads for further anticancer drug development.

The epidermal growth factor receptor (EGFR) family is a key biomarker and therapeutic target for cancer therapy. Although acridone scaffolds have previously inhibited other tyrosine kinases, their specific targeting of EGFR has not been reported. This study provides novel acridone-N-aceto/benzohydrazide derivatives with anti-EGFR activity. Cytotoxicity screening revealed AE4, AE11, and AF11 as highly effective against the A-431 cell line, with IC₅₀ values 3.22 µM, 2.43 µM, and 4.06 µM, respectively, keeping Erb as a standard with an IC₅₀ of 1.62 µM. In vitro EGFR kinase assays confirmed their inhibition, with IC₅₀ values of 3.95 µM (AE4), 3.49 µM (AE11), and 4.45 µM (AF11), selectively reduced p-EGFR Tyr¹⁰⁶⁸ and ERK1/2 levels in a dose-dependent manner, while inducing G₀/G₁ cell-cycle arrest and apoptosis. SAR indicates isopropyl substitutions on the phenyl ring and 2-methoxy on the acridone ring are important for anti-proliferative activity. Notably, AE4 exhibited a high DNA-binding affinity (K_b = 7.41 × 10³M⁻¹), suggesting that its efficacy might be due to DNA intercalation. In contrast, AE11 and AF11 demonstrated significant cytotoxicity, implying the involvement of the RAS/ERK downregulating pathway. Molecular docking indicated favorable EGFR active site interactions. In silico studies predicted oral bioavailability and low toxicity, supported by kinetic solubility and plasma stability assays, highlighting their potential as selective p-EGFR Tyr¹⁰⁶⁸ inhibitors for further development.

Emergence of drug-resistant Mycobacterium tuberculosis necessitates the development of new drugs. Here, we studied the activity of new piperazine nitrofuranylamides against a collection of clinical strains from an multidrug-resistant tuberculosis (MDR-TB) high-burden country. A series of nitrofuranylamides 9–15 was synthesized and evaluated using a collection of diverse clinical strains representing globally spread genotypes (Beijing, LAM, and Haarlem; susceptible, MDR, and pre-extensively drug resistant). Minimal inhibitory concentrations (MIC) were determined using a resazurin assay. Whole-genome sequencing was performed on an Illumina HiSeq platform. Although clinical isolates differed in their MICs, some tested compounds—namely 11 and 12—showed higher MICs regardless of the clinical strain. In contrast, compounds 13–15 exhibited promising activity (MIC < 0.1 µg/mL) against the majority of strains. Moreover, 13 and 14 were previously shown to have low toxicity in JCL:ICR mice and low cytotoxicity against human cell lines. A closer look at structural variation indicated that the presence of a pyridine- or quinoline-type aryl substituent leads to a broader spectrum of activity. The additional nitro group in 14 appears to contribute significantly to its activity. A nonsynonymous mutation in the efflux pump gene Rv3728 (372 A > V, GCC → GTC) in one of the Haarlem genotype strains may speculatively correlate with its high-level intrinsic resistance to nitrofurans. Further biological research is warranted to investigate the mechanism of action of the most promising compounds.

The epidermal growth factor receptor (EGFR) is a validated therapeutic target for EGFR-mutant non-small cell lung cancer (NSCLC) and colorectal cancer, yet secondary T790M/C797S mutations and mesenchymal–epithelial transition factor (MET) amplification confer profound resistance to first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs). Indole hybrids integrate indole cores (including azaindoles and fused indoles) with diverse pharmacophores to achieve multi-site binding within the EGFR ATP pocket, conferring higher selectivity toward mutant EGFR than mono-indole scaffolds. This review systematically summarizes indole-based EGFR hybrids reported from 2021 to date into three categories: Phase I/II clinical candidates (1, 10), C797S-resistant preclinical leads (11a, 14a, 34, 48a, and 50a), and structurally diversified analogs with favorable blood–brain barrier (BBB) permeability and low systemic toxicity. Optimized indole hybrids exhibit prominent advantages over commercial TKIs, including enhanced binding affinity toward mutant EGFR, optimized pharmacokinetic profiles, minimized off-target effects, and the capacity to suppress compensatory oncogenic signals. We comprehensively dissect their binding modes, structure–activity relationships (SARs), in vitro/in vivo anticancer activities, and pharmacological features, and summarize critical substituent optimization rules for overcoming resistance. This work establishes a systematic structural basis for rational development of next-generation indole EGFR inhibitors against refractory EGFR-driven malignancies.