RSC medicinal chemistry最新文献

Vector control with insecticides is an important preventive measure against mosquito-borne infectious diseases, such as malaria and dengue. The intensive usage of few insecticides has resulted in emerging resistance in mosquitoes, and unwanted off-target toxic effects. Therefore, there is great interest in alternative active ingredients. Here, we explore indole-based compounds as selective inhibitors against acetylcholinesterase 1 (AChE1) from the disease-transmitting mosquitoes Anopheles gambiae (An. gambiae, AgAChE1) and Aedes aegypti (Ae. aegypti, AeAChE1) as potential candidates for future insecticides used in vector control. Three sets of compounds were designed to explore their structure-activity relationship, and investigate their potentials regarding potency and selectivity. 26 indole-based compounds were synthesized and biochemically evaluated for inhibition against AgAChE1, AeAChE1, and human AChE (hAChE). The compounds were shown to be potent inhibitors against AChE1, and selective for AChE1 over hAChE. N-Methylation of the indole moiety clearly increased the inhibition potency, and a bulkier benzyl moiety improved the selectivity. X-ray crystallography shows that the inhibitors bind at the bottom of the active site gorge of mouse AChE (mAChE), while molecular dynamics simulations revealed different binding poses in mAChE and AgAChE1. Four potent and selective inhibitors were subjected to in vivo mosquito testing. Topical application showed strong insecticidal effects on An. gambiae and Ae. aegypti, highlighting this compound class as an interesting alternative for future insecticide research.

Neglected tropical diseases (NTDs) encompass a broad spectrum of infectious diseases predominantly found in tropical and subtropical regions. The limitations of current therapies underscore the critical demand for novel antileishmanial agents. In this investigation, we designed, synthesized, and evaluated ten hybrid compounds (5, 8a–e, and 12a–d) integrating a 7-chloroquinoline scaffold with thiadiazole and thiazole moieties, assessing their in vitro efficacy against Leishmania major. These hybrids exhibited potent activity against the promastigote stage, displaying IC₅₀ values between 0.52 and 3.97 μM, outperforming miltefosine (IC₅₀ = 7.83 μM). Additionally, they demonstrated strong inhibition of the intracellular amastigote form, with IC₅₀ values ranging from 0.76 to 5.62 μM, compared to miltefosine's 8.07 μM. Notably, compound 5 emerged as a highly effective antileishmanial agent against both parasitic stages, while maintaining a favorable safety profile. Mechanistic studies revealed that compound 5 acts via an antifolate mechanism, selectively inhibiting key enzymes in the folate pathway: pteridine reductase 1 (PTR1) and dihydrofolate reductase-thymidylate synthase (DHFR-TS). Molecular docking and 100 ns molecular dynamics (MD) simulations demonstrated that the quinoline core occupies a hydrophobic pocket formed by residues Phe113, Leu188, Leu226, and Leu229, engaging in stable hydrophobic interactions and π–π stacking with Phe113. Furthermore, the quinoline scaffold and hydrazinecarbodithioate moiety formed hydrogen bonds with Tyr194, Gly225, and His241, reinforcing binding stability. Our findings introduce a promising new class of antileishmanial agents that disrupt the folate biosynthesis pathway, offering significant therapeutic potential for combating leishmaniasis.

Cancer remains the leading cause of mortality worldwide, driving the need for new and more effective therapeutics. Indole-based scaffolds have emerged as highly versatile structural frameworks in drug discovery in view of their structural diversity and ability to modulate multiple biological targets, including kinases, enzymes, and receptors. These compounds exhibit broad anticancer potential by inducing apoptosis, disrupting cell cycle progression, and inhibiting angiogenesis and metastasis. Recent studies have highlighted small-molecule indoles, bis-indoles, and oxindole-based scaffolds, including spirooxindoles, 3-alkenyl oxindoles, 3-iminooxindoles, 4, 5, 6, and 7-azaindole and isoindoline derivatives, as promising inhibitors of key cancer pathways, particularly through multi-kinase modulation. However, challenges such as drug resistance, off-target effects, and poor bioavailability must be addressed to fully realize their clinical potential. This review discusses recent progress in the development of indole-related compounds, focusing on their structural features, mechanisms of action, and therapeutic relevance in targeted cancer therapy.

Heat shock protein (HSP) 70 represents a clinically promising anti-tumor target, yet the development of effective inhibitors faces numerous technical challenges. To address this, we developed novel non-ATP site Proteolysis-targeting Chimeras (PROTACs) that selectively degrade HSP70 by engaging the E3 ubiquitin ligase CRBN. However, the PROTACs exhibited limited degradation activity, potentially due to heat shock response-mediated HSP70 upregulation. To circumvent this resistance mechanism, we explored combination therapy with the heat shock factor 1 (HSF1) inhibitor DTHIB to disrupt the heat shock feedback loop, markedly enhancing HSP70 degradation. The combination strategy showed synergistic and selective anti-tumor activity across a panel of cancer cell lines. This success relied on the distinct profile of C4, which preferentially targets cytosolic HSP70 and, unlike conventional inhibitors, effectively circumvents compensatory HSP70 upregulation.

Sonodynamic therapy (SDT) is an innovative, non-invasive, and effective method for cancer treatment. However, exploring sonosensitizers with high sonosensitivity and biosafety remains a significant challenge. Recent investigations have demonstrated that the excellent delocalized π-electron conjugation system and narrow HOMO–LUMO gap characteristic of acenes endow them with intrinsic sonoactivity, providing an opportunity for advancing novel sonosensitizers. Herein, two pentacene derivatives, 4Br-PEN and 4Br-CN-PEN, were successfully synthesized through site-specific peripheral tailoring of the pentacene backbone with bromine atoms and cyano groups. Both in vitro and in vivo therapeutic outcomes demonstrated that the synthesized compounds could generate singlet oxygen (¹O₂) under ultrasound irradiation, effectively eradicating cancer cells while exhibiting significant anti-proliferative effects and excellent biocompatibility. Notably, because of the synergistic inductive and conjugative effects of the cyano group, 4Br-CN-PEN exhibited superior sonodynamic activity to 4Br-PEN. These findings collectively suggest that pentacene derivatives hold promising potential as highly effective and safe sonosensitizers for SDT applications.

Bioisosterism, a fundamental concept in medicinal chemistry, involves the substitution of chemical groups with structural analogs that preserve similar physicochemical properties while potentially modulating potency or toxicity. To systematically investigate shifts in pChEMBL values upon such substitutions, we developed a KNIME workflow that extracts and analyzes compound pairs featuring literature-curated common bioisosteric exchanges. The workflow retrieves pChEMBL values across 88 off-targets from ChEMBL and supports decision-making through pair-level quality metrics such as the document consistency ratio and assay context consistency ratio, which assess the consistency of the source data. Our analysis revealed that ester-to-secondary-amide replacements at the muscarinic acetylcholine receptor M2 (CHMR2) result in a significant mean decrease in pChEMBL of 1.26 across 14 compound pairs (p < 0.01). In contrast, phenyl-to-furanyl substitutions at the adenosine A2A receptor (ADORA2A) led to a mean increase in pChEMBL of 0.58 across 88 compound pairs (p < 0.01). Furthermore, a second KNIME workflow was developed to assess selectivity profiles by analyzing pChEMBL shifts at secondary targets. Among 66 compound pairs active at both ADORA2A and ADORA1, the mean change at ADORA1 was only +0.14 ± 0.52, indicating a selective potency increase at ADORA2A. This exemplifies a potential case of increased potency at an off-target associated with adverse effects, while maintaining activity at a pharmacologically desirable target. Conversely, furanyl-to-phenyl replacements may selectively reduce undesired potency at ADORA2A while preserving potency at ADORA1. This framework enables systematic, data-driven evaluation of potency shifts induced by bioisosteric replacements, aiding in the identification of substitutions associated with off-target potency increases or decreases during lead optimization. The workflow offers a semi-automated, reproducible approach that integrates bioisostere generation, activity mapping, and statistical assessment in a single platform, making it readily adaptable to other compound series and target panels. In addition, it evaluates whether activity at other known targets remains unchanged, thereby providing an assessment of selectivity of the replacements. The workflow can be applied to prioritize replacement strategies that reduce off-target risks, evaluate selectivity profiles, and generate curated potency shift data to support predictive modeling efforts.

Alzheimer's disease (AD) is a neurodegenerative disorder characterised by cognitive impairment, memory loss, and decline in thinking and learning skills. The exact pathophysiology of the disease is still unknown; however, theories such as tau hyperphosphorylation, amyloid-β (Aβ) aggregation, and cholinergic dysfunction explain its pathogenesis. A few available drugs provide only symptomatic relief, while recently approved monoclonal antibody-based drugs target aggregated amyloid beta clearance. Extensive research is ongoing for drug development targeting various pathways, where one of the targets is glycogen synthase kinase (GSK-3β). GSK-3β plays diverse roles in physiological functions, and its dysregulation may lead to pathological conditions such as Alzheimer's disease (AD). GSK-3β comprises serine and threonine residues, is responsible for phosphorylation of the tau protein, and activates the amyloid precursor protein (APP) to synthesise Aβ. Consequently, the abnormal functioning of GSK-3β leads to hyperphosphorylation of the tau protein, and the formation of Aβ plaques eventually leads to neurofibrillary tangles. To develop GSK-3β inhibitors, one must know the requirements of crucial structural features in drug candidates to act at the active site for interaction. This review focuses on the latest pool of GSK-3β inhibitors and their design strategy, structure–activity relationship (SAR), molecular docking, and permeability across the brain layers. This broad review collection may benefit readers by providing the structural requirements to develop new GSK-3β inhibitors for treating AD.

Toxoplasma gondii infects approximately one-third of the human population, posing a severe and potentially fatal risk to individuals with compromised immune systems. Our previous studies demonstrated that modifying the arene in the herbicidal protoporphyrinogen oxidase (PPO) inhibitor, oxadiazon, yields analogs that potently inhibit T. gondii PPO, a key enzyme in the heme biosynthesis pathway. In this study, we further investigated the structure–activity relationship of oxadiazon analogs by introducing aliphatic chains with varying functionalities, resulting in 23 new derivatives. Some of these compounds exhibited significant intracellular inhibition of wild-type T. gondii, with IC₅₀ values ranging from 2 to 3 μM. Biochemical analysis confirmed that their mode of action is mediated by potent PPO inhibition, which further blocked heme production and damaged mitochondrial health status in the parasites. These findings enhance our understanding of oxadiazon's structural optimization and highlight its derivatives as promising early-stage candidates for developing effective therapies against toxoplasmosis in humans and other animals.

The biological properties of peptides are determined by their amino acid sequences, but the diversity of naturally occurring amino acids is limited. Accordingly, this study aimed to investigate the impact of sulfonation modification on the functional characteristics of peptide LALFVPR (LR-7), such as water solubility, stability, and antioxidant, anti-inflammatory, and angiotensin-converting enzyme (ACE) inhibitory activity. The results showed that the sulfonated peptide LC(SO₃)LFVPR (LR-7S) exhibited significantly improved water solubility (a 46-fold increase) and greater stability in gastric fluid compared to LR-7. In HK-2 cells exposed to 5 μM angiotensin II (Ang II) for 24 h, treatment with 100 μM LR-7S more effectively mitigated cellular damage, as indicated by enhanced mitochondrial membrane potential and increased cell viability. Notably, LR-7S treatment resulted in lower reactive oxygen species (ROS) levels and higher activities of catalase (CAT) and superoxide dismutase (SOD) relative to LR-7. This antioxidant effect may be associated with the promoted nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2). Both LR-7 and LR-7S significantly decreased the levels of monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and nuclear factor kappa-B (NF-κB). Furthermore, LR-7S exhibited a lower binding energy (−6.16 kcal mol⁻¹) with ACE and its ACE inhibitory activity was 162% higher than that of LR-7 at a concentration of 25 μM. These findings highlight sulfonation as an effective strategy for modulating the peptide structure and enhancing bioactivity. Despite the challenges in clarifying the metabolic pathways in vivo, the sulfonated peptide holds great promise for the development of the management of hypertensive nephropathy.

The natural product-based hybrid strategy is a promising approach for innovative drug discovery. Leveraging the privileged architecture of sulforaphane—a prominent anticancer natural product—we engineered a novel library of magnolol–sulforaphane molecular hybrids for antitumor evaluation through a concise synthetic strategy for the pharmacophore of sulforaphane (SFN), culminating in the identification of CTNPC8 as a promising anticancer compound. Notably, CTNPC8 not only displays exceptional broad-spectrum anticancer activity with potency surpassing both parent compounds and cisplatin, but also exhibits potent in vitro efficacy against the challenging nasopharyngeal carcinoma (NPC) cell model. Mechanistic studies in nasopharyngeal carcinoma models reveal that CTNPC8 triggers mitochondrial-mediated apoptosis through regulating ROS generation and induces G₂/M phase arrest. Transcriptomic profiling coupled with validation experiments reveals that CTNPC8 exerts its anti-NPC activity primarily by modulating the Akt/mTOR pathway. The present study provided a valuable strategy for discovering new antitumor agents through hybrid molecular design, nominating CTNPC8 as a promising hit compound for anti-NPC research.