MedChemComm最新文献

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Correction for ‘Computational design, synthesis, and assessment of 3-(4-(4-(1,3,4-oxadiazol-2-yl)-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole derivatives as effective epidermal growth factor receptor inhibitors: a prospective strategy for anticancer therapy’ by Nilesh Raghunath Khedkar et al., RSC Med. Chem., 2024, 15, 1626–1639, https://doi.org/10.1039/D4MD00055B.

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In light of the ongoing pandemic caused by SARS-CoV-2, effective and clinically translatable treatments are desperately needed for COVID-19 and its emerging variants. In this study, some derivatives, including 7β-aminocholestene compounds, and 3β-acetoxy-6-nitrocholesta-4,6-diene were synthesized, in quantitative yields from 7β-bromo-6-nitrocholest-5-enes (1–3) with a small library of amines. The synthesized steroidal products were then thoroughly characterized using a range of physicochemical techniques, including IR, NMR, UV, MS, and elemental analysis. Next, a virtual screening based on structures using docking studies was conducted to investigate the potential of these synthesized compounds as therapeutic candidates against SARS-CoV-2. Specifically, we evaluated the compounds' binding energy of the reactants and their products with three SARS-CoV-2 functional proteins: the papain-like protease, 3C-like protease or main protease, and RNA-dependent RNA polymerase. Our results indicate that the 7β-aminocholestene derivatives (4–8) display intermediate to excellent binding energy, suggesting that they interact strongly with the receptor's active amino acids and may be promising drug candidates for inhibiting SARS-CoV-2. Although the starting steroid derivatives; 7β-bromo-6-nitrocholest-5-enes (1–3) and one steroid product; 3β-acetoxy-6-nitrocholesta-4,6-diene (9) exhibited strong binding energies with various SARS-CoV-2 receptors, they did not meet the Lipinski Rule and ADMET properties required for drug development. These compounds showed either mutagenic or reproductive/developmental toxicity when assessed using toxicity prediction software. The findings based on structure-based virtual screening, suggest that 7β-aminocholestaines (4–8) may be useful for reducing the susceptibility to SARS-CoV-2 infection. The docking pose of compound 4, which has a high score of −7.4 kcal mol⁻¹, was subjected to AI-assisted deep learning to generate 60 AI-designed molecules for drug design. Molecular docking of these AI molecules was performed to select optimal candidates for further analysis and visualization. The cytotoxicity and antioxidant effects of 3β-acetoxy-6-nitrocholesta-4,6-diene were tested in vitro, showing marked cytotoxicity and antioxidant activity. To elucidate the molecular basis for these effects, steroidal compound 9 was subjected to molecular docking analysis to identify potential binding interactions. The stability of the top-ranked docking pose was subsequently assessed using molecular dynamics simulations.

We report the characterization of potent and selective ROCK inhibitors identified through a core-hopping strategy. A virtual screening workflow, combining ligand- and structure-based methods, was applied on a known series of ROCK inhibitors bearing an acetamido-thiazole scaffold. The most promising replacement of the central core was represented by a benzoazepinone ring, which was selected as a starting point for a subsequent chemical exploration. The overall design approach exploited previous SARs available for congeneric series and crystallographic information to optimize the hinge-binding group as well as the terminal aromatic moiety interacting with the glycine-rich loop. The introduction of elongated and flexible charged groups led to compound 15, which exhibited sub-nanomolar potencies in biochemical and cellular assays, as well as a remarkable selectivity over PKA. HDX studies not only supported the postulated binding mode of compound 15 but also confirmed the crucial role of specific ROCK peptide segments in driving ligand selectivity.

NAFLD/NASH has emerged as a global health concern with no FDA-approved treatment, necessitating the exploration of novel therapeutic elements for NASH. Probiotics are known as an important adjunct therapy in NASH. Zbiotics (ZB183) is the first commercially available genetically engineered probiotic. Herein, we aimed to evaluate the potential therapeutic effects of Zbiotics administration on NASH management by modulating the cGAS-STING-signaling pathway-related RNA network. In silico data analysis was performed and three DEGs (MAPK3/EDN1/TNF) were selected with their epigenetic modulators (miR-6888-5p miRNA, and lncRNA RABGAP1L-DT-206). The experimental design included NASH induction with an HSHF diet in Wistar rats and Zbiotics administration in NASH rats in comparison to statin treatment. Liver functions and lipid profile were assessed. Additionally, the expression levels of the constructed molecular network were assessed using RT-PCR. Moreover, the Zbiotics effects in NASH were further validated with histopathological examination of liver and colon samples. Also, immunohistochemistry staining of hepatic TNF-α and colonic occludin was assessed. Oral administration of Zbiotics for four weeks downregulated the expression of the cGAS-STING-related network (MAPK3/EDN1/TNF/miR-6888-5p miRNA/lncRNA RABGAP1L-DT-206) in NASH models. Zbiotics also ameliorated hepatic inflammation and steatosis, as evidenced by a notable improvement in NAS score and decreased hepatic TNF-α levels. Furthermore, Zbiotics exhibited favorable effects on colon health, including increased crypt length, reduced inflammatory cell infiltration, and restoration of colonic mucosa occludin expression. In conclusion, our findings suggest that Zbiotics has potential therapeutic effects on NASH via modulating the gut–liver axis and the cGAS-STING signaling pathway.

Despite Hsp90's well documented promise as a target for developing cancer chemotherapeutics, its inhibitors have struggled to progress through clinical trials. This is, in part, attributed to the cytoprotective compensatory heat shock response (HSR) stimulated through intracellular Hsp90 inhibition. Beyond its intracellular role, secreted extracellular Hsp90 (eHsp90) interacts with numerous pro-oncogenic extracellular clients. This includes fibronectin, which in the tumour microenvironment enhances cell invasiveness and metastasis. Through the rational modification of known Hsp90 inhibitors (SNX2112 and SNX25a) we developed four Hsp90 inhibitory compounds, whose alterations restricted their interaction with intracellular Hsp90 and did not stimulate the HSR. Two of the modified cohort (compounds 10 and 11) were able to disrupt the assembly of the extracellular fibronectin network at non-cytotoxic concentrations, and thus represent promising new tool compounds for studying the druggability of eHsp90 as a target for inhibition of tumour invasiveness and metastasis.

Microtubules are highly dynamic structures and constitute a crucial component of the cellular cytoskeleton. Besides, topoisomerases (Topo) play a fundamental role in maintaining the appropriate structure and organization of DNA. On the other hand, dual mechanism drug candidates for cancer treatment primarily aim to enhance the efficacy of cancer treatment and potentially overcome drug resistance. Hence, this work was tailored to design and synthesize new multi-target tetrabromophthalimide derivatives (2a–2k) that are capable of inhibiting the colchicine binding site (CBS) and topoisomerase II (Topo-II). The conducted in vitro studies showed that compound 2f showed the lowest IC₅₀ value (6.7 μg mL⁻¹) against the MDA-MB-468 cancer cell line. Additionally, compound 2f prompted upregulation of pro-apoptotic markers (caspases 3, 7, 8, and 9, Bax and p53). Moreover, some anti-apoptotic proteins (MMP2, MMP9, and BCL-2) were downregulated by compound 2f treatment. Besides, the colchicine binding assay showed that compounds 2f and 2k displayed promising inhibitory potential with IC₅₀ values of 1.92 and 4.84 μg mL⁻¹, respectively, in comparison with colchicine (1.55 μg mL⁻¹). Furthermore, the Topo-II inhibition assay displayed the prominent inhibitory potential of compound 2f with an IC₅₀ value of 15.75 μg mL⁻¹, surpassing the IC₅₀ of etoposide (20.82 μg mL⁻¹). Cell cycle analysis revealed that compound 2f induced cell cycle arrest at both the G0–G1 and G2–M phases. The new candidates were docked against both the CBS (PDB ID: 5XIW) and Topo-II (PDB ID: 5CDP) targets to investigate their binding interactions and affinities as well. Accordingly, the synthesized compounds could serve as promising multi-target anticancer candidates with eligible apoptotic activity.

We developed first-in-class antimitotic prodrugs phenyl 4-(2-oxo-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) bioactivated by cytochrome P450 (CYP) 1A1 that are highly selective toward several breast cancer cells. However, they show sparingly water solubility. Therefore, we replaced their phenyl ring B with a substituted pyridinyl group preparing novel pyridinyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PYRAIB-SOs) and their hydrochloride salts. Our results evidence that PYRAIB-SO hydrochloride salts show higher water solubility compared to their neutral and PAIB-SO counterparts by up to 625-fold. PYRAIB-SOs with a nitrogen atom at position 3 of the pyridinyl ring exhibited strong antiproliferative activity (IC₅₀: 0.03–3.3 μM) and high selectivity (8–>1250) toward sensitive CYP1A1-positive breast cancer cells and cells stably transfected with CYP1A1. They induce cell cycle arrest in the G2/M phase and disrupt microtubule dynamic assembly. Enzymatic assays confirmed that CYP1A1 metabolizes PYRAIB-SOs into their active form with in vitro hepatic half-lives (55–120 min) in rodent and human liver microsomes. Overall, this will allow to increase drug concentration for in vivo studies.

Metabolic syndrome is a multifaceted condition marked by interconnected risk factors, significantly increasing the risk of serious diseases like cardiovascular disease, type 2 diabetes, and stroke. Effective management often demands new medications due to complexity of the conditions and limitations of current treatments. Natural compounds are increasingly recognized in drug discovery due to their vast chemical diversity, commercial availability, low cost, and minimal side effects. One such compound is stachydrine (STA), also known as proline betaine or N-dimethyl proline. This simple pyrrole alkaloid is a major constituent of the genus Leonurus and the family Lamiaceae, and it shows promise due to its potential therapeutic properties. A comprehensive review of the literature, sourced from databases such as PubMed, Scopus, SciFinder, and Google Scholar, has provided extensive information on the sources, chemistry, biosynthesis, derivatives, molecular targets, biological activities, bioavailability, and toxicity of STA. This review highlights numerous in vitro and in vivo studies that demonstrate the effectiveness of STA in various therapeutic areas, including anti-obesity, neuroprotective, nephroprotective, and cardiovascular protection, among others. The wide range of biological activities of STA is attributed to its influence on multiple molecular targets and signaling pathways, such as ACE/AngII/AT1R-TGFβ1, NF-κB, JAK/STAT, AKT/ERK, AMPK/CAMKKβ/LKB1, CaMKII/PLN, etc. which are critical in the development and progression of metabolic syndrome. Additionally, this review addresses limitations related to the pharmacokinetics and bioavailability of STA. Overall, the findings underscore the potential of STA as a therapeutic agent for metabolic syndrome and related disorders, suggesting that further clinical investigation is warranted to fully understand and utilize its benefits.