RSC medicinal chemistry最新文献

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Taking a stand against obesity is an urgent priority, as it significantly impacts both the global economy and public health. Synthetic pancreatic lipase (PL) inhibitors represent one of the most effective therapeutics in the management of obesity. PL is a triacylglycerol acyl hydrolase from the family of serine hydrolases that play a key role in the hydrolysis of dietary fat into monoglycerides and fatty acids. Further, fatty acids get deposited in adipose tissue, which progressively results in weight gain. Over the last decade, various new drugs have been studied; however, orlistat still remains the first-line FDA-approved drug for obesity management. However, long-term use of orlistat can lead to serious health complications, including liver toxicity, osteoporosis, and gastrointestinal issues. Notably, the formation of an irreversible covalent bond of the β-lactone moiety of orlistat with the active serine site of HPL and PPL enzyme has been considered to be responsible for these complications. A deeper understanding of the crystal structure of HPL indicates that repositioning the hydrophobic lid domain, also known as the flap, opens access for designed inhibitors to interact with the active site residues: Ser152, His263, and Asp176. Additionally, predicting the mode of inhibition and the inhibition constant (K_i) value through enzyme kinetic study is helpful. This review presents a comprehensive overview of the in silico design, synthetic strategies, in vitro assays using human (HPL) and porcine (PPL) enzymes, in vivo activity, and structure–activity relationship (SAR) studies of synthetic PL inhibitors reported since 2014, aimed at the development of anti-obesity agents. Additionally, we propose the challenges to overcome and a potential path for future development in this field.

Cisplatin remains a cornerstone in the treatment of various solid tumors due to its exceptional antineoplastic efficacy. However, its clinical utility is significantly constrained by severe adverse effects, with ototoxicity emerging as particularly problematic due to its potential to cause permanent hearing impairment and substantially diminish patient quality of life. Recent investigations into mitigating cisplatin-induced ototoxicity have identified natural polyphenolic compounds as promising protective agents, attributable to their diverse biological activities and potent antioxidant properties. This review critically examines the molecular mechanisms underlying cisplatin-induced cochlear damage and systematically evaluates recent advances in employing polyphenolic compounds as otoprotective interventions. Evidence indicates these bioactive molecules attenuate cisplatin-mediated hearing loss through multiple complementary pathways, including modulation of oxidative stress, inflammatory responses, and apoptotic cascades within the cochlear architecture. However, significant challenges, such as low bioavailability and potential interference with cisplatin's antitumor efficacy, hinder their clinical translation. Based on evidence from studies published between 2010 and 2025, with a focus on advances from the last five years, this review systematically outlines protective mechanisms while critically addressing current research limitations. It further proposes future directions, highlighting advanced drug delivery systems and innovative therapeutic strategies. These insights provide a robust mechanistic framework for the rational design and development of novel otoprotective strategies that preserve cisplatin's antitumor efficacy while minimizing its ototoxic potential.

Melanin is essential for protecting human skin against harmful ultraviolet (UV) irradiation and environmental pollutants. However, excessive melanin accumulation in the epidermis can affect aesthetics, cause psychological distress, and reduce quality of life. Despite the development and utilization of several well-known tyrosinase (TYR) inhibitors as skin-whitening agents in cosmetics to address hyperpigmentation concerns, there remains a growing demand in the cosmetics market for safer, more efficient, and diverse skin-whitening agents. Guided by the binding model of thiamidol with TYR, this study synthesized and characterized 26 4-(2,4-dihydroxyphenyl)thiazole-2-carboxamide derivatives, evaluating their anti-TYR activities. Among these compounds, compound 4 exhibited the strongest anti-TYR activity (IC₅₀ = 1.51 μM) and effectively inhibited melanogenesis in the in vitro B16 cell model. Although its anti-TYR activity and anti-melanogenic effect in vitro were less than those of thiamidol (IC₅₀ = 0.72 μM), its depigmenting effect on the in vivo zebrafish embryo model was comparable to thiamidol. Additionally, compound 4 demonstrated excellent biocompatibility and exhibited lower toxicity compared to thiamidol. Overall, these results suggest that compound 4 holds potential as a promising candidate for application as a skin-whitening cosmetic ingredient.

The escalating prevalence of antibiotic resistance underscores the urgent need for innovative antimicrobial agents. Fusidic acid (FA), a fungal-derived tetracyclic triterpene clinically employed against methicillin-resistant Staphylococcus aureus (MRSA), is limited by rapid resistance development and elevated MIC values in resistant strains. While previous olefinic side chain (Δ^24,25) modifications yielded FA derivatives with retained anti-MRSA activity, most analogs exhibited compromised efficacy against Gram-positive bacteria. To address this limitation, we systematically engineered the olefinic side chain through Wittig and olefin metathesis reactions, synthesizing 26 novel FA derivatives. Compound 10a emerged as a standout candidate, demonstrating MIC value lower than FA against MRSA (0.125 μg mL⁻¹) as well as low resistance. It also exhibited biofilm disruption capability of reducing MRSA biofilm formation by 61.4% at 0.5 × MIC, along with downregulation of biofilm-related regulators (e.g. clfA, cna, agrA, agrC). In a murine skin infection model, compound 10a significantly inhibited bacterial growth and accelerated wound healing at 2 mg kg⁻¹. Given these advantages, compound 10a represents a promising candidate molecule for combating multidrug-resistant Gram-positive infections.

Conventional broad-spectrum antibiotics often disrupt gut microbiota, causing a range of health issues like inflammatory bowel disease (IBD), secondary infections, colorectal cancer, liver disease, cognitive impairment, diabetes, and obesity. While the ‘one drug treats all’ strategy offers convenience, the long-term consequences of microbiota imbalance caused by such antibiotics can no longer be ignored. Modern antibiotic discovery and development programs must consider the strategies that minimize microbiota disruption to prevent long-term dysbiosis. This article presents, for the first time, a critical analysis of emerging microbiota-sparing pharmacokinetic-pharmacodynamic (PK-PD) based innovative antibacterial therapeutic strategies, such as transporter (BmpD)-mediated selective uptake, selective accumulation driven by efflux deficiency, pathogen-specific and pH-dependent selective cellular absorption, adjuvant facilitated therapy, β-lactamase-directed selectivity, microbiota-conserving immunotherapy, and CRISPR-based phage therapy. It highlights target-specific antibacterial approaches aimed at distinct bacterial pathways, such as lipoprotein transport, fatty acid biosynthesis, protein biosynthesis via methionyl-tRNA synthetase (MetRS), and DNA replication through DNA polymerase IIIC, which can minimize microbiota disruption and antibiotic-associated dysbiosis. Additionally, the discovery of antibacterial clinical candidates, such as afabicin, lolamicin, hygromycin A, cadazolid, and ribaxamase, that exhibit pathogen-specific efficacy with limited gut exposure, has been discussed with an in-depth analysis of their mechanism of actions (MoAs) and specific bacterial targets, molecular structure-to-medicinal insights, and strategic innovations. Collectively, this article provides a perspective for next generation antibacterial drug design and discovery, focusing on innovative strategies, specific biological pathways, and key molecular features that spare gut microbiota while maximizing antibacterial treatment efficacy.

Twenty novel noscapinoid–triterpene conjugate derivatives were designed and synthesized. Four noscapine derivatives (as secondary amine) and five bile acids were applied for the synthesis of a diverse library. The synthetic compounds were evaluated for their antiproliferative activity against PC3, A549, HepG2, Caki-1, U138MG, and MRC5. This study identified eight potent cytotoxic agents (7e–7i, 7k, 7m, and 7o) possessing more than 80% cell viability. Compounds 7e and 7f exhibited the highest cytotoxic activity against Caki-1 with IC₅₀ values of 260 nM and 350 nM, respectively. Western blot analysis results indicated that the eight hit compounds decreased the α-tubulin and β-actin levels in A549 cells, and further cellular assays on A549 demonstrated that 7e and 7f significantly inhibited cell migration, induced pronounced G1 cell-cycle arrest (with 7f also showing a minor G2/M increase) and triggered marked apoptosis, with 7e showing the strongest pro-apoptotic effect.

Molecular hybridization, an emerging strategy for the discovery of new anticancer therapeutics, shows promise as a powerful tool for the development of new sialyltransferase (ST) inhibitors for cancer treatment. This concept inspired the design of novel ST inhibitors through the hybridization of lithocholic acid and diindolylmethane, leading to the discovery of LCA-DIM hybrids as potential chemical entities targeting STs. Preliminary screening revealed the significance of the DIM moiety and incorporation of Asp linker on enhancing the inhibitory activity and selectivity of the hybrids towards ST6GAL1, inhibiting up to 100% of ST6GAL1 activity at 25 μM with no ST3GAL1 inhibition even at 500 μM. Incorporation of various 5,5′-substituents enhanced the inherent antimigration properties of the hybrids, with IAN-5B (R = Cl) and IAN-15B (R = N₃) presenting the highest antimigration activity across several triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, BT549, Hs578T) and considerable antiangiogenetic effect by suppressing HUVEC tube formation. This could be attributed to the excellent ST6GAL1 inhibitory activities of the two hybrids with IC₅₀ values of 6.6 ± 0.2 μM and 3.3 ± 0.1 μM, respectively. Overall, this study highlights LCA-DIM hybrids as novel, potent, and N-glycan-selective ST inhibitors with promising antimigration properties against aggressive TNBC.

A strategy for targeting tumor-associated hypoxia utilizes reductase enzyme-mediated cleavage to convert biologically inert prodrugs to their corresponding biologically active parent therapeutic agents selectively in areas of pronounced hypoxia. Small-molecule inhibitors of tubulin polymerization represent unique therapeutic agents for this approach, with the most promising functioning as both antiproliferative agents (cytotoxins) and as vascular disrupting agents (VDAs). VDAs selectively and effectively disrupt tumor-associated microvessels, which are typically fragile and chaotic in nature. VDA treatment may augment existing tumor-associated hypoxia, thus enhancing the efficacy of hypoxia-selective prodrugs. Structure activity relationship-guided studies in our laboratories led to the discovery of promising lead molecules (OXi6196, KGP05, KGP18, and OXi8006) that bind to the colchicine site on the tubulin heterodimer. A series of bioreductively activatable prodrug conjugates (BAPCs) based on these molecules was synthesized utilizing ether-linked heteroaromatic hypoxia-selective triggers bearing a nitro group. Biological evaluation against the A549 human lung carcinoma cell line (under normoxic versus anoxic conditions) revealed several BAPCs with positive hypoxia cytotoxicity ratios. Preliminary in vivo evaluation of a representative BAPC (KGP291) demonstrated vascular shutdown in nude mice bearing orthotopic 4T1 breast tumors studied by bioluminescence imaging.

Natural products are an important source for developing anti-cancer agents. Previously, we identified the anti-cancer flavonoid protoapigenone from Thelypteris torresiana (Gaud.) and synthesized its derivative, WYC-0209, with improved anti-cancer properties. In this study, to further optimize this protoapigenone derivative for better therapeutic efficacy, various functional groups were introduced onto its naphthalene ring, and their anti-cancer properties were evaluated. A total of eighteen WYC-0209 derivatives were synthesized, among which the derivative containing two units of the isopentyl-substituted side chain exhibited superior cytotoxicity against cancer cells and was named WYC-241. Further investigation in A549 lung cancer cells showed that WYC-241 significantly inhibited colony formation (proliferation) and suppressed cell migration (mobility). Additionally, WYC-241 induced both necrosis and apoptosis, potentially through a substantial increase in intracellular reactive oxygen species (ROS) levels and inhibition of the PI3K/AKT pathway. In vivo studies showed that weekly intravenous (i.v.) injection of WYC-241 significantly suppressed tumor growth in mice. In silico ADMET analysis further indicated that WYC-241 possesses drug-like properties. Collectively, this study suggests that WYC-241 is a promising candidate for further development as a novel anti-cancer therapy and provides a foundation for future drug design and optimization.