Chemical Biology & Drug Design

Hyperoxia‐induced acute lung injury (ALI) in neonates is driven by oxidative stress and inflammation. This study aims to evaluate the efficacy and underlying mechanisms of Relaxin‐2 (RLX‐2) in a neonatal rat model of hyperoxia‐induced ALI. Neonatal Wistar rats were exposed to 90% O2 for one week and treated with RLX‐2 (0.5 mg/kg/day) via an osmotic pump. Methods included histopathology (hematoxylin–eosin staining), bronchoalveolar lavage fluid (BALF) analysis, Enzyme‐Linked Immunosorbent Assay (ELISA) for interleukin‐1β (IL‐1β), monocyte chemoattractant protein‐1 (MCP‐1), and tumor necrosis factor‐α (TNF‐α), oxidative stress markers [malondialdehyde (MDA) and superoxide dismutase (SOD)], and Western blotting for Toll‐like Receptor 4 (TLR4), Nuclear Factor‐kappa B (NF‐κB), and Sirtuin 1 (SIRT1). Human alveolar epithelial cells (HPAEpiCs) underwent assays using Cell Counting Kit‐8 (CCK‐8), 2′,7′‐Dichlorofluorescin diacetate (DCFH‐DA), and quantitative real‐time polymerase chain reaction (qRT‐PCR). RLX‐2 mitigated alveolar damage and inflammatory infiltration in neonatal rats with hyperoxia‐induced acute lung injury. It decreased cytokine levels, reduced MDA levels, and enhanced SOD activity, thereby alleviating oxidative stress. RLX‐2 suppressed TLR4/NF‐κB signaling by reducing p65 and Myeloid Differentiation Primary Response 88 (MyD88) expression and upregulated SIRT1. SIRT1 silencing abolished RLX‐2's effects, confirming its role in attenuating OS and inflammation. These findings demonstrated RLX‐2's efficacy in neonatal ALI via SIRT1‐dependent TLR4/NF‐κB inhibition, highlighting therapeutic potential.

Fused pyrimidine scaffolds serve as a flexible and versatile foundational heterocycle in the field of pharmaceutical development. Thienopyrimidines are a diverse family of molecules characterized by the fusion of a thieno ring with a pyrimidine moiety, resulting in a unique scaffold with promising chemical and pharmacological properties. Thienopyrimidines exhibit multifarious features, mainly, this is due to their structural resemblance with purine bases, such as guanine and adenine. The diverse range of biological effects displayed by thienopyrimidines, such as their ability to combat bacteria, fungi, parasites, cancer and viruses, has inspired us to explore and organize their structure–activity relationship (SAR). Their intricate molecular structures enable them to interact with specific molecular targets, such as enzymes, receptors, and cellular signaling pathways, leading to their therapeutic efficacy. The presence of thienopyrimidine derivatives in several FDA‐approved drugs and clinical trial candidates underscores their therapeutic potential and safety profile. The review elaborates on the primary approach for synthesis of thienopyrimidines, using thiophene derivatives or pyrimidine analogues. As our understanding of their structure–function relationships deepens, we can expect further advancements in the development of thienopyrimidine‐based therapies.

Last few decades, extensive research efforts have been dedicated to uncovering novel cancer treatments. Among the most vital targets in this pursuit are matrix metalloproteinases (MMPs), enzymes integral to the progression and spread of cancer. Their role in tumor development and metastasis positions MMPs as key players in cancer pathogenesis, offering promising avenues for therapeutic intervention. Specifically, MMP‐2 and MMP‐9 have emerged as promising targets in cancer treatment based on their critical roles in cell invasion, angiogenesis, immune evasion, and metastasis. Studies indicate the potential of plant‐derived natural products as anticancer agents through the regulation of MMP activity. Among various phytochemicals, flavonoids are reported to exhibit inhibitory activities against MMPs and antioxidant properties that present them as candidates for anticancer molecules. In this study, the potential of flavonoids as anticancer agents was explored by investigating the effects of flavonoids on (i) cancer cell viability and migration, (ii) enzymatic activity and cellular expression of MMP‐2/9, and (iii) the MAPK signaling pathway. Docking simulation data regarding the interactions between MMP‐2/9 and selected flavonoids provide an in‐depth look at the potential mechanisms through which these molecules suppress the enzymatic activities of MMPs. Select flavonoids exhibited notable efficacy in suppressing cell proliferation and migration in A549 cells, which may be a consequence of their ability to attenuate MMP activity and expression through the suppression of the MAPK signaling pathway. These observations demonstrate the prospect of flavonoids as a naturally occurring molecular framework for the development of novel anticancer therapeutics.

Vitamin E can exert either a cancer preventive effect or improve the therapeutic efficacy of chemotherapeutic drugs against multiple types of cancer. Ample evidence suggests that the cancer preventive activity of vitamin E is form‐dependent; however, it is not clear whether its chemosensitization effect is also influenced by its forms. The objectives of this study were to investigate whether the eight natural forms of vitamin E produced differential sensitization effects on cancer chemotherapeutic drugs and to address whether the chemosensitization effect of vitamin E was associated with its inhibitory effect on programmed cell death ligand 1 (PD‐L1) signaling. We carried out a comparative evaluation of the chemosensitization effect of eight vitamin E forms using paclitaxel as a representative therapeutic drug and breast/prostate cancer as the representative types of cancer. Results showed that the sensitization effect of vitamin E on chemotherapeutic drugs was also form‐dependent, with δ‐tocotrienol (δ‐T3) as the most effective one for sensitizing breast and prostate cancer cells to paclitaxel, mechanistically associated with its ability to suppress PD‐L1‐mediated tumor‐promoting signaling. The findings provided novel insights into understanding the sensitization effect of vitamin E and its related mechanisms and support that δ‐T3 is the best candidate as an enhancer of taxanes among the eight forms.

Osteoporosis is a widespread metabolic bone disorder. Lycopene (LYC), a potent antioxidant in tomatoes, has been shown to exhibit anti‐osteoporosis effects. Here, we elucidated its molecular determinants in treating osteoporosis. Network pharmacology and molecular docking were utilized to screen target proteins of LYC in osteoporosis treatment. KEGG pathway and GO enrichment analyses were used to observe biological functions of these target proteins. The osteoblastic differentiation of human marrow‐derived mesenchymal stem cells (hBMSCs) was induced and evaluated by ALP staining and activity assay, Alizarin Red S (ARS) staining, and related protein expression analysis. An osteoporotic mouse model was induced by ovariectomy (OVX). For the anti‐osteoporosis effect of LYC, network pharmacology and molecular docking showed estrogen receptor 1 (ESR1) as a potential therapeutic target, and KEGG pathway enrichment analysis suggested the involvement of the PI3K/AKT pathway. LYC promoted osteogenic differentiation of hBMSCs and increased ESR1 expression in the hBMSC osteogenic differentiation process in vitro. LYC diminished bone loss and increased ESR1 expression in OVX mice. Reduction of ESR1 attenuated LYC‐induced osteogenic differentiation of hBMSCs. Moreover, LYC activated the PI3K/AKT pathway in the hBMSC osteogenic differentiation process by upregulating ESR1. Our findings suggest that LYC induces osteogenic differentiation of hBMSCs by the ESR1/PI3K/AKT pathway, thereby contributing to its anti‐osteoporosis effect. Our study provides a molecular basis for the potential application of LYC as a therapeutic agent in osteoporosis.

A series of aminated quinolinequinones linked to piperazine analogs (QQ1‐7) were synthesized and screened against the full panel of National Cancer Institute (NCI) cancer cell lines for their potential as cytotoxic agents. The Developmental Therapeutics Program of the NCI analyzed the NCI‐60 screening results and revealed that seven QQs were potent inhibitors of cancer cell growth across several cell lines, advancing them to the five‐dose assay. Encouraged by the NCI five‐dose assay results, the cytotoxicity of the selected QQs (QQ1 and QQ4) was further studied in three cancer cell lines—HCT‐116 (colon cancer), ACHN (renal cancer), MCF7, and T‐47D (breast cancer)—as well as in a normal cell line (HUVEC) for a deeper understanding. QQ1 was the hit compound for ACHN cells with an IC50 value of 1.55 μM. QQ1 could inhibit ACHN cell proliferation, induce oxidative stress, and cause cell cycle arrest in ACHN cells. QQ1 did not affect the apoptotic value in ACHN cells. Oral bioavailability was poor for both QQ1 and QQ4 in vivo in rats due to faster intrinsic hepatic clearance in comparison with humans, as evidenced by in vitro metabolic studies with rat and human liver microsomes. Molecular docking simulation with putative target CDC25A revealed the interaction of QQ1 and QQ4 with active site residues responsible for substrate recognition.

This research extracted and purified polysaccharides from Corydalis yanhusuo residue. The structure of purified polysaccharides of Corydalis yanhusuo (CYP‐1) was characterized by methods such as infrared spectroscopy, nuclear magnetic resonance, and monosaccharide composition analysis. In addition, the purified polysaccharides were subjected to preliminary studies in vitro for antioxidant and antitumor activities. The average molecular weight of CYP‐1 was 1.427 × 10³ kDa. FT‐IR analysis revealed that CYP‐1 displayed characteristic absorption bands typical of polysaccharides. Furthermore, NMR spectroscopy suggested that the sugar residue units of CYP‐1 consisted of →1)‐α‐D‐Glcp‐(4→, →6)‐α‐D‐Galp‐(1→, and α‐D‐Arap‐(1→. In vitro bioactivity experiments revealed that CYP‐1 exhibits antioxidant activity and effectively inhibits HepG2 cell proliferation with an IC50 value of 1.381 mg/mL, suggesting its potential as a natural antioxidant and antitumor agent.

Oxidized low‐density lipoprotein (ox‐LDL)‐induced endothelial cell damage plays an important role in the pathogenesis of atherosclerosis (AS). This study aimed to investigate the ability of Erianin to protect human umbilical vein endothelial cells (HUVECs) against ox‐LDL‐induced oxidative stress and its underlying mechanisms. HUVECs were treated with Erianin (0, 5, 10, and 20 μM) for 2 h and then stimulated with ox‐LDL (100 μg/mL) for 24 h. Flow cytometry and MTT assay determined cell apoptosis and viability, respectively. The protein levels of caspase‐9, caspase‐3, cleaved poly (ADP‐ribose) polymerase‐1 (PARP‐1), nuclear factor E2‐related factor 2 (Nrf2), histone H3, NAD(P)H: quinone oxidoreductase‐1 (NQO‐1), heme oxygenase‐1 (HO‐1), cytochrome c, and cytochrome c oxidase subunit IV (COX IV) were evaluated by Western blot. Matrix metalloproteinase (MMP) membrane potential was measured. The impact of Erianin on ox‐LDL‐induced injury in HUVECs was confirmed by using small interfering RNA si‐Nrf‐2. Erianin pretreatment notably rescued the impaired ox‐LDL‐treated HUVEC viability and apoptosis and inhibited ox‐LDL‐induced mitochondrial dysfunction in HUVECs. Furthermore, Erianin reduced ox‐LDL‐induced oxidative stress by enhancing Nrf2 signaling activation, and Nrf2 knockdown by siRNAs diminished the anti‐oxidative role of Erianin in HUVECs. These suggest that Erianin suppresses ox‐LDL‐induced apoptosis and oxidative stress by regulating Nrf2 signaling in HUVECs.

Despite extensive research, the topic of anti‐PD‐L1 small‐molecule inhibitors remains elusive. Herein, we report the design, synthesis, and bioevaluation of a series of small molecule PD‐L1 inhibitors via optimization of the solvent‐interaction region. Among them, compound GJ19 showed the most potent anti‐PD‐L1 effects with an IC50 of 32.06 nM in the HTRF (homogenous time‐resolved fluorescence) assay, better than BMS‐202 (IC50 = 62.1 nM). In addition, the SPR (surface plasmon resonance) assay revealed that GJ19 can effectively bind to human/murine PD‐L1 protein with KD values of 171 and 290 nM, respectively. Furthermore, GJ19 concentration‐dependently promoted HepG2 cell mortality in a co‐culture model of HepG2/hPD‐L1 and Jurkat T/hPD‐1 cells. In the in vivo efficacy studies, GJ19 (intraperitoneal injection, 15 mg/kg) effectively suppressed tumor growth with a TGI of 56.8% in a B16‐F10 melanoma mouse model by activating antitumor immunity. In conclusion, GJ19 represents a potential small molecule inhibitor of PD‐L1, deserving further investigation for tumor immunotherapy.

Ferulic acid (FA), a natural phenolic compound, shows potential therapeutic effects on renal interstitial fibrosis, although its antifibrotic mechanism remains unclear. This study investigated the molecular mechanisms of FA by focusing on epithelial‐mesenchymal transition (EMT) and related signaling pathways. By using a hypoxia‐induced HK2 cell model, the optimal FA concentration was determined by CCK‐8 assay, and the cells were assigned to low‐, medium‐, and high‐FA groups. Renal fibrosis‐associated protein and mRNA levels were evaluated by western blotting (WB) and reverse transcription‐quantitative polymerase chain reaction. In a 5/6 nephrectomy‐induced chronic renal failure rat model, renal oxygen consumption, serum creatinine, and blood urea nitrogen levels were measured, while ultrastructural and morphological changes in renal tissues were examined by transmission electron microscopy (TEM), hematoxylin–eosin (HE) staining, and Masson's trichrome staining. Renal fibrosis‐related indicators were further assessed by Western Blot (WB) and immunofluorescence assay. The results showed that FA treatment significantly reduced fibronectin, HIF‐1α, and α‐SMA expression; inhibited partial EMT in vivo and in vitro; improved renal function; and attenuated fibrosis in kidney tissues. Combining siTwist or oe‐HIF‐1α transfection with FA treatment revealed that FA targeted the HIF‐1α/Twist signaling pathway, impeding EMT and delaying renal fibrosis. In conclusion, FA inhibited partial EMT of tubular epithelial cells and suppressed the HIF‐1α/Twist pathway, thereby mitigating renal interstitial fibrosis and providing a foundation for FA‐based treatment of chronic kidney disease.

Ulcerative colitis (UC) is a chronic inflammatory condition. Glutamine (Gln) has shown an improved effect on UC. However, its molecular determinants are incompletely understood. NCM460 cells were stimulated with lipopolysaccharide (LPS) to generate an in vitro UC cell model, and dextran sulfate sodium (DSS)‐induced UC models were established in mice. Methylated RNA immunoprecipitation (MeRIP) and messenger RNA (mRNA) stability experiments were used to validate the influence of Wilms' tumor 1‐associating protein (WTAP) on nuclear receptor coactivator‐3 (NCOA3) mRNA. In LPS‐exposed NCM460 cells, Gln promoted NCOA3 expression and reduced WTAP expression. Gln relieved LPS‐triggered inflammation, oxidative stress, and apoptosis in NCM460 cells, which were abolished by NCOA3 downregulation or WTAP upregulation. Mechanistically, Gln suppressed WTAP‐mediated m6A modification of NCOA3 mRNA. WTAP reduction attenuated LPS‐evoked NCM460 cell phenotype alterations, which were reversed by NCOA3 downregulation. Furthermore, Gln reduced the DAI score and histopathological changes, increased colon length, and attenuated inflammation and oxidative stress in DSS‐induced UC mice, which were abrogated by WTAP increase. We showed that the WTAP/NCOA3 axis underlies the protective effect of Gln on UC, providing a rationale for Gln as a promising anti‐UC agent.

Protein arginine methyltransferase 5 (PRMT5) is an epigenetic‐related enzyme that has been shown to be a promising target for the treatment of human cancers. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the androgen receptor (AR), but this method has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. We hope to design and synthesize a new compound that can inhibit prostate cancer at different stages. A series of candidate PRMT5 inhibitor molecules were designed on the basis of virtual molecular docking screening, and the binding mode was predicted via molecular docking simulation. Prostate cancer cell proliferation was detected by CCK‐8, EdU, and flow assays, which verified the changes in the cancer cell cycle. Migration and invasion assays verified the effects of the compounds on the metastatic function of prostate cancer cells. Finally, Western blotting was used to detect the mechanism of action of the compounds in the treatment of prostate cancer. In prostate cancer, gene knockout has been shown to inhibit cancer cells by regulating the AR, but it has no effect on advanced prostate cancer without AR expression, and existing anticancer drugs are effective only in the current stage and promote the progression of cancer to advanced prostate cancer. SJL2‐1 may be a promising compound for novel therapies for early androgen‐sensitive prostate cancer and advanced castration‐resistant prostate cancer (CRPC).

This study investigates the molecular mechanism of action of F4B1, a novel oleanolic acid derivative in human lung adenocarcinoma cells. F4B1 is a naturally occurring oleanolic acid derivative that was isolated and purified from the leaves of Sesbania grandiflora. Structural analyses were carried out using 1D and 2D NMR, FT‐IR, and mass spectrometric analyses. MTT assay was employed to evaluate antiproliferative effects in A549 (a model for lung cancer), MCF‐7 (a model for breast cancer), HEP‐2 (a model for head and neck cancer) and in MRC‐5 (human lung fibroblast cells). Fluorescence staining, scanning electron microscopy, and flow cytometry were employed to study apoptosis and cell cycle. Western blotting, RT‐PCR, and immunofluorescence techniques were followed to study the mechanisms of cell death. Schrodinger software was employed for docking studies. While preliminary screening was conducted in multiple cell lines, A549 cells were chosen for further mechanistic exploration based on their higher sensitivity to F4B1 treatment. F4B1 blocks the proliferation and causes intrinsic mode of cell death in lung adenocarcinoma cells. In particular, the above anticancer effect was mediated through a mechanism that is associated with the inactivation of NF‐kappa B signaling and suppression of cyclin D1 expression leading to cell cycle arrest at the G1/S phase. Our study confirms that F4B1 induces apoptosis, as confirmed through Annexin V staining results. It is intrinsic apoptosis, as evidenced by upregulation of pro‐apoptotic markers (BAX), downregulation of anti‐apoptotic markers (BCL‐2), cytochrome C release, activation of caspase‐9, and caspase‐3. These results establish the involvement of the mitochondrial‐mediated apoptotic pathway. The pathway also involved the suppression of the proto‐oncogene c‐Myc both at the transcriptional and translational levels. Docking studies show that F4B1 has a high affinity binding towards CXCR4 and SRC kinase. Our findings specifically contribute to understanding the mechanism of F4B1, the isolated molecule from S. grandiflora, as an anticancer drug candidate and will hopefully pave the way toward further studies.

Emergence of life‐threatening fungal infections like systemic candidiasis concurrently with bacterial infections and limitations of current antifungal therapies warrant the discovery of novel inhibitors. We identified besifloxacin (BS), an FDA‐approved antibacterial, as a potent antifungal inhibitor. A combination of besifloxacin with fluconazole showed a positive synergy (δ = 29.58) resulting in 80% inhibition of microbial growth. BS was able to reduce the MIC of FLC from 2 mg/L to 0.5 mg/L when used in combination. Additionally, in murine systemic Candida infection, BS reduced fungal load by 83% in mice kidneys at a dose of 100 mg/kg/day. The findings demonstrated the antifungal potential of BS, proposing its use in combination therapy with fluconazole to combat resistance through alternative mechanisms.

Ischemic stroke damages the blood–brain barrier (BBB), worsening neuronal injury. Treatments to protect the BBB are limited. We evaluated the neurovascular protective capacity of Kisspeptin‐54 in ischemic stroke using in vivo and in vitro models. In vivo, mice underwent middle cerebral artery occlusion (MCAO), and cerebral infarct volume, neurological function, and blood–brain barrier (BBB) permeability were evaluated. In vitro, human brain microvascular endothelial cells (HBMVECs) were exposed to oxygen–glucose deprivation/reperfusion (OGD/R) to assess the effects of Kisspeptin‐54 on paracellular flux and transendothelial electrical resistance (TEER). Additionally, GATA‐4 was silenced to investigate its role in mediating protection. Our results showed that cortical ischemia downregulated KISS‐1 metastasis‐suppressor (KISS1, 59% mRNA; 55% protein) and G protein‐coupled receptor 54 (GPR54, 54% mRNA; 48% protein), with a 32% decline in circulating Kisspeptin‐54. Prophylactic Kisspeptin‐54 reduced cerebral infarct volume by 42%, enhanced neurological performance by 49%, and decreased BBB leakage by 26%, with near‐complete occludin recovery. In vitro: Kisspeptin‐54 treatment reduced paracellular flux by 48% and increased transendothelial resistance by 60%. GATA‐4 silencing abolished Kisspeptin‐54‐induced occludin restoration, increasing permeability by 65% and diminishing barrier resistance by 28%. This study reveals Kisspeptin‐54 modulates BBB stability via GATA‐4‐driven occludin expression, highlighting the KISS1/GPR54 pathway as a potential therapeutic target for ischemic stroke.

The prostaglandin E2 (PGE2) regulates several biological processes via interaction with 1 of 4 E‐type prostanoid receptors (EP1–EP4). The E‐type prostanoid receptor 4 (EP4) is expressed primarily on myeloid cells, T lymphocytes, and tumor cells, and has emerged as a major contributor to PGE2‐mediated enhancement of tumor survival pathways and as a suppressor of innate and adaptive antitumor immune responses. To date, significant work on the discovery of EP4 receptor antagonists has been carried out, but no compound has been approved for use in humans yet. Toward our aim of discovering potential EP4 antagonists, a pharmacophore‐based scaffold‐hopping approach combined with docking studies has been envisaged. As a result, compound 4 was found to be a non‐toxic, potent EP4 antagonist binding in the orthosteric site. This compound exhibited good aqueous solubility, with acceptable in vitro metabolic stability and permeability. Albeit high protein binding, it displayed sustained exposure and significant oral bioavailability in mice and can thus have the potential for further optimization to yield next‐generation EP4 antagonists.

Urolithin A (UA) is a dibenzo[b,d]pyran‐6‐one polyhydroxy derivative produced as intestinal microbe metabolize ellagitannin and ellagic acid. Because of its superior anti‐inflammatory and antioxidant effects, it can cure neuronal damage in a variety of ways and play a neuroprotective role. More and more research has revealed that UA is a potential medicine for the treatment of neurodegenerative diseases. Due to UA source limitations, it is insufficient to achieve disease treatment concentrations, and the activity of UA inhibiting PDE2 needs further enhancement. As a result, we used UA as the parent nucleus structure, independently designed and used Discovery Studio software to assist in the structural design and molecular docking screening of the compounds, and tested the in vitro enzyme activity of the synthesized compounds, hoping to obtain UA‐based PDE2 inhibitors. The IC50 of 6–18, 6–19, 6–20, 6–22, and 6–29 were 0.62, 0.85, 1.51, 1.09, and 1.58 μM, respectively. In this study, UA derivatives that can bind to the crystal structure of PDE2 protein 4HTX were proposed, which laid a groundwork for further structural modification, lead design, and development of small molecule inhibitors with inhibitory activity of PDE2.

The metabolic dependence of acute myeloid leukemia (AML) cells on mitochondrial oxidative phosphorylation (OXPHOS) has become a cutting‐edge area in cancer energy metabolism research, playing a pivotal role in cell survival and drug resistance. Consequently, targeted inhibition of human mitochondrial RNA polymerase (POLRMT) to block mitochondrial gene expression emerges as a novel potential strategy for treating AML through OXPHOS modulation. In this study, based on the previously reported crystal structure of the POLRMT inhibitor IMT1B, we employed a scaffold hopping strategy to design and synthesize a series of derivatives featuring additional hydrophobic occupying groups. A new potent POLRMT inhibitor (10a) was discovered, which displayed potent antiproliferative activity and could disrupt mitochondrial function and induce apoptosis in MOLM‐13 cells. Together, these results demonstrate that 10a is a new POLRMT inhibitor, which may provide a candidate lead for AML treatment.

Twenty azole‐fluoroquinolone hybrids were designed and synthesized by conjugating thiazole and thiadiazole structures to ciprofloxacin and norfloxacin via a 2‐oxoethyl bridge. The structures and purities of the synthesized compounds were proven by spectral techniques. The antimycobacterial effects of target compounds 21–40 were tested against Mycobacterium tuberculosis H37Rv strain. Among the 20 synthesized compounds, 12 exhibited minimal inhibition concentration (MIC) values in the range of 1.56–25 μg/mL. Among the molecules screened for antimycobacterial effects, the most effective was compound 35, a thiadiazole‐ciprofloxacin hybrid. The cytotoxic effect of this molecule was found to be lower than the reference drugs, and it was also determined to be a more effective inhibitor than ciprofloxacin and norfloxacin in the DNA‐gyrase supercoiling test. The antimicrobial effects of compounds 21–40 were screened by agar‐well diffusion and microdilution tests against Gram‐positive/negative bacteria, a fast‐growing mycobacterium, and two yeast strains. While most of the compounds tested showed antibacterial effects, the most effective fluoroquinolone derivative appeared to be compound 31 with an MIC value of < 0.63 μg/mL against all Gram‐negative bacteria tested. Azole‐fluoroquinolone hybrids 21–40 did not show any activity against non‐pathogenic Lactobacillus species and yeast‐like fungi, indicating that they have selective antibacterial and antimycobacterial activity, particularly against Gram‐negative bacteria. In silico molecular docking studies were conducted to uncover the interactions between lead compound 35 and the DNA gyrase proteins of M. tuberculosis and S. aureus. Additionally, a 100 ns molecular dynamics simulation was carried out to assess the stability of the complexes formed between compound 35 and both proteins.

Bacterial resistance represents one of the greatest challenges in modern medicine, requiring innovative strategies. This study presents the rational design of two synthetic analogue peptides, WK‐MAP1, and WG‐MAP2, inspired by the structure of the enzyme papain (PDB 9PAP), emphasizing the novelty of using an enzyme as a model for developing new antimicrobials. Initially, in silico studies, including molecular modeling and docking experiments, revealed a high affinity of the peptides for mimetic bacterial membranes. Subsequently, in vitro assays confirmed their antimicrobial efficacy. WK‐MAP1 demonstrated superior activity against carbapenem‐resistant Klebsiella pneumoniae (KPC+), with a minimum inhibitory concentration (MIC) of 25 μM, whereas WG‐MAP2 exhibited activity against both tested strains (KPC+ and ATCC), with MICs of 50 and 100 μM, respectively. Both peptides effectively inhibited biofilm formation and exhibited low cytotoxicity in murine cells. This research highlights the potential of WK‐MAP1 and WG‐MAP2 as promising candidates for novel antimicrobial therapies, offering an innovative approach to overcoming the limitations of conventional antibiotics.

A series of 3,4‐dimethoxybenzene‐based fibrate derivatives were designed and synthesized, which were screened for preliminary lipid‐lowering activity in a Triton WR‐1339‐induced hyperlipidemic mouse model. T5 had the strongest triglyceride (TG) and total cholesterol (TC) lowering effect among these target compounds. In a dose‐dependent study, the lowering effects of T5 on TG and TC were progressively enhanced with increasing doses administered. Further studies revealed that T5 had a hypolipidemic significant effect on high‐fat diet (HFD)‐induced hyperlipidemia mouse model, with substantial reductions in TG, TC, and low‐density lipoprotein cholesterol (LDL‐C) levels, and a significant reduction in aspartate transaminase (AST) and alanine aminotransferase (ALT) levels in the liver, which had a protective effect on the liver. The of liver pathology showed that T5 could effectively inhibit lipid accumulation as well as inflammatory infiltration in the liver, thus reducing the degree of liver tissue damage. The expression of peroxisome proliferator‐activated receptor‐α (PPAR‐α), which regulates lipid metabolism, was significantly upregulated in liver tissues. Molecular docking assays also confirmed the high binding affinity between T5 and PPAR‐α active sites. In addition, T5 exhibited significant anti‐inflammatory and antioxidant effects. These findings suggest that T5 has multiple activities and may be a potential novel hypolipidemic drug with hypolipidemic and hepatoprotective effects.

The PI3K‐Akt axis is abnormally activated in KRAS‐mutated colorectal cancer and is considered to be a potential therapeutic target. A novel series of phenoxyacetic acid (4‐aminophenoacetic acid) shikonin esters was designed by computer‐aided drug design (CADD) and synthesized as Akt allosteric inhibitors. Most compounds exhibited greater anti‐proliferative activity compared to the positive control MK2206, while also demonstrating lower cytotoxicity against normal cells than shikonin. One of the promising candidates, L8, was selected for further biological evaluation. Docking studies indicated that L8 effectively bound to the allosteric site of Akt through hydrophobic and hydrogen interactions. Enzyme activity and kinetics assessments revealed that L8 bound to Akt with a Kd of 2.07 × 10⁻⁶ M and inhibited its activity. Further intracellular assays, including western blotting, enzyme activity assay, flow cytometry, etc., verified that L8 mediated the death of two KRAS‐mutant colon cancer cell lines HCT116 (KRASG13D) and HCT‐8 (KRASG12A) cells by inactivating Akt, causing tumor cell apoptosis, cell cycle arrest, and interfering with tumor cell invasion and metabolism. A 3D‐QSAR model was constructed to understand the relationship between the structure of the shikonin derivatives and their anti‐proliferative activity. The in silico ADMET and toxicity prediction studies revealed a few undesired pharmacokinetic attributes of our compounds.

In response to the rising threat of antimicrobial resistance, a novel series of thiazole‐based heterocyclic compounds incorporating benzimidazole, benzoxazole, and benzothiazole via the reaction of 2‐chloro‐N‐(4‐(6‐methyl‐2,4‐dioxo‐3,4‐dihydro‐2H‐pyran‐3‐yl)thiazol‐2‐yl) acetamide (3) with some mercapto derivatives. Pyrazolo[1,5‐a]pyrimidine motifs were synthesized via the reaction of aminopyrazole derivative 9 with some electrophilic reagents and systematically characterized. The antimicrobial potential of these molecules was assessed against Staphylococcus aureus, Escherichia coli, and Candida albicans. Among the tested derivatives, compounds 6, 20, and 22 emerged as particularly effective, with minimum inhibitory concentrations (MICs) reaching as low as 3.125 μg/mL. Structure–activity relationship (SAR) analysis highlighted the role of electron‐withdrawing groups in enhancing bioactivity. Molecular docking studies further supported the experimental findings, showing favorable interactions with bacterial DNA gyrase (PDB ID: 1KZN). Additionally, SwissADME profiling revealed that the compounds possess promising drug‐like properties and oral bioavailability. These findings position the synthesized thiazole‐containing scaffolds as promising candidates for future antimicrobial drug development.

The WD Repeat‐Containing Protein 5 (WDR5) and MYC interaction is crucial for MYC‐mediated oncogenesis, yet effective therapeutic intervention remains challenging due to the limited efficacy of current treatments targeting WDR5. Herein, we report the discovery of novel WDR5‐MYC protein–protein interaction (PPI) inhibitors with improved potency and drug‐like properties by utilizing a generative chemistry platform along with a physics‐model‐based tool AlChemistry. Initially, three hits were identified with reasonable binding affinity for WDR5, and further refinement through detailed structural analysis led to the discovery of sub‐micromolar affinity compounds (compound 9c‐1), which are > 30‐fold better than reported inhibitors. These findings provide a promising starting point for targeting the WDR5‐MYC interaction in MYC‐driven cancers.

In this study, we synthesized and characterized novel brominated methoxyquinolines ( 7 and 11 ) and nitrated bromoquinoline ( 17 ) derivatives with potential antiproliferative activity against cancer cell lines. Starting from 1,2,3,4‐tetrahydroquinoline (THQ, 1 ), a series of brominated quinoline compounds was obtained via regioselective bromination and subsequent reactions. The structure of the key compound, 3,5,6,7‐tetrabromo‐8‐methoxyquinoline ( 7 ), was confirmed using 1D and 2D NMR techniques. Additionally, unexpected bromination of 3,6,8‐trimethoxyquinoline ( 5 ) yielded 5,7‐dibromo‐3,6‐dimethoxy‐8‐hydroxyquinoline ( 11 ), allowing functionalization of both rings in the quinoline. The direct nitration of 6,8‐dibromoquinoline ( 6 ) yielded the corresponding 5‐nitro derivative ( 17 ), a precursor to amino derivatives that activate the bromine group on the ring. Antiproliferative activities of these derivatives ( 7 , 11 , 17 ) were assessed against C6, HeLa, and HT29 cancer cell lines using the BCPE assay. Compounds 7 , 11 , and 17 exhibited significant inhibitory effects, with compound 11 showing the highest activity (IC 50 values of 5.45–9.6 μg/mL). Furthermore, the cytotoxicity of these compounds was evaluated using the LDH assay, indicating lower cytotoxic effects compared to the control drug 5‐FU. The ability of compounds 11 and 17 to induce apoptosis was confirmed through DNA laddering, while compound 7 showed no such effect. Compounds 7 and 11 inhibited human topoisomerase I, a critical enzyme for DNA replication and repair, with significant binding energies determined by MM‐PBSA studies. The wound healing assay demonstrated that compound 17 effectively inhibited the migration of HT29 cells. These findings highlight the potential of these novel quinoline derivatives as effective anticancer agents, warranting further investigation into their mechanisms of action and therapeutic applications.