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Correction for ‘Chiral hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: the search for selective p53-activating agents for colorectal cancer therapy’ by Mees M. Hendrikx et al., RSC Med. Chem., 2024, 15, 1652–1663, https://doi.org/10.1039/D4MD00076E.

Piglets afflicted with porcine epidemic diarrhea virus (PEDV) experience severe diarrhea and elevated death rates, leading to substantial financial losses in the pig farming sector. The objective of this study is to investigate the impact of saponins on PEDV within Vero cells by utilizing different methodologies to evaluate their anti-PEDV effect. By producing 40 saponins, we have discovered that No. 29, No. 31, No. 35, and No. 38 exhibit properties that make them effective against PEDV, serving as potential drugs. The findings showed that in a clear dose-dependent manner, the mRNA levels of PEDV were significantly inhibited in the high, middle, and low-dose groups of No. 29, No. 31, No. 35, and No. 38, when compared to the PEDV control. The four tested saponins significantly inhibited the levels of PEDV N contents and viral titers. Furthermore, concentration of cytotoxicity 50% (CC₅₀) values for No. 29, No. 31, No. 35, and No. 38 saponins were 37.13 μM, 52.86 μM, 44.98 μM, and 43.81 μM, respectively, demonstrating the safety of these medications in clinical environments. Collectively, these findings indicate that the four examined saponins could efficiently modulate the immune response against PEDV and hold promise for utilization in antiviral treatments.

In continuation of our efforts to develop new anticancer compounds, a new series of imidazo[1,5-a]pyridine-chalcone derivatives was designed, synthesized, characterized, and evaluated for its cytotoxicity against five human cancer cell lines, i.e., breast (MDA-MB-231), colon (RKO), bone (Mg-63), prostate (PC-3), and liver (HepG2) cell lines, as well as a normal cell line (HEK). Among the synthesized compounds, two exhibited promising cytotoxicity against the MDA-MB-231 cell line with IC₅₀ values of 4.23 ± 0.25 μM and 3.26 ± 0.56 μM. We also studied apoptotic induction of the compounds using annexin V-FITC/PI staining, and ROS-mediated mitochondrial damage was elucidated using DCFDA, followed by JC-1 staining. The potential activity of the compounds was further confirmed by immuno-fluorescence and molecular docking studies, which revealed the anticancer activity of active compounds through binding and microtubule disruption.

Aberrant protein misfolding and accumulation is considered to be a major pathological pillar of neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. Aggregation of amyloid-β (Aβ) peptide leads to the formation of toxic amyloid fibrils and is associated with cognitive dysfunction and memory loss in Alzheimer's disease (AD). Designing molecules that inhibit amyloid aggregation seems to be a rational approach to AD drug development. Over the years, researchers have utilized a variety of therapeutic strategies targeting different pathways, extensively studying peptide-based approaches to understand AD pathology and demonstrate their efficacy against Aβ aggregation. This review highlights rationally designed peptide/mimetics, including structure-based peptides, metal-peptide chelators, stapled peptides, and peptide-based nanomaterials as potential amyloid inhibitors.

High-throughput chemistry (HTC) and direct-to-biology (D2B) platforms allow for plate-based compound synthesis and biological evaluation of crude mixtures in cellular assays. The rise of these workflows has rapidly accelerated drug-discovery programs in the field of targeted protein degradation (TPD) in recent years by removing a key bottleneck of compound purification. However, the number of chemical transformations amenable to this methodology remain minimal, leading to limitations in the exploration of chemical space using existing library-based approaches. In this work, we expanded the toolbox by synthesising a library of degraders in D2B format. First, reaction conditions are established for performing key medicinal chemistry transformations, including reductive amination, S_NAr, palladium-mediated cross-coupling and alkylation, in D2B format. Second, the utility of these alternative reactions is demonstrated by rapidly identifying developable PROTACs for a range of protein targets.

Many cancers have displayed resistance to chemotherapeutic drugs over the past few decades. EGFR has emerged as a leading target for cancer therapy via inhibiting tumor angiogenesis. Besides, studies strongly suggest that blocking telomerase activity could be an effective way to control the growth of certain cancer cells. Based on the fact that multi-target design rationale can afford candidates with greater treatment effectiveness. Besides, it was evidenced that inhibition of human telomerase enhances the effect of some tyrosine kinase inhibitors. So, in the current work, we aimed to design and synthesize novel 1,2,3-triazole-tethered Schiff bases (5a–l) to act as dual EGFR and telomerase inhibitors. Growth inhibition (GI)% was conducted for the synthesized compounds using a panel of eleven cancer cell lines as well as two normal cell lines. Interestingly, compound 5e displayed the highest mean GI% (76.78%) among the investigated compounds surpassing the mean GI% of the reference drug doxorubicin (65.79%). In addition, compound 5g displayed notably the lowest IC₅₀ values (13.31, 13.31, 12.62, and 31.19 μM) for the four utilized cancer cell lines HNO97, HCT116, A375, and HEPG2, respectively. Interestingly, the investigated compounds exhibited significant inhibitory potential to EGFR and telomerase protein expression; in particular, compound 5g recorded inhibitory potentials of 3.45 and 1.31 ng mL⁻¹, respectively. Hence, protein expression of the apoptosis-related proteins was carried out for compound 5g. Pro-apoptotic proteins (caspases 3, 8, and 9) were upregulated by 1.35, 1.55, and 1.51-fold change, respectively. Meanwhile, the anti-apoptotic proteins (CDK-2, CDK-4, and CDK-6) were downregulated by 2.91, 2.01, and 9.15-fold change, respectively, ensuring the apoptotic potential of compound 5g. Accordingly, compound 5g was selected for further investigation of its effects on cell cycle progression in A375 cancer cells. Obviously, compound 5g prompted cell cycle arrest at the G0–G1 phase. Additionally, the investigated compounds showed eligible pharmacokinetic profiles with feasible oral bioavailability. Consequently, the synthesized compounds can be treated as lead multi-target anticancer ligands for future optimization.

A series of 2-(4-bromobenzyl) tethered 4-amino aryl/alkyl-5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines (7a–7u) were designed, synthesized, characterized and screened against a panel of cancer cell lines. Compound 7a, in particular, emerged as a potent antiproliferative agent against FaDu cells (HTB-43) with an IC₅₀ value of 1.73 μM. 7a induced morphological alterations in FaDu cells were observed via brightfield microscopy and DAPI staining, confirming cytotoxicity. Autophagy and apoptotic effects of 7a were confirmed by acridine orange staining, Rhodamine 123 staining, and western blot analysis, which revealed dose-dependent increases in LC3A/B and cleaved caspase-3 levels, respectively. Further, 7a impaired cell migration and colony formation, as demonstrated by scratch and clonogenic assays. Additionally, 7a reduced oxidative stress and induced G2/M phase cell cycle arrest in MCF-7 cells. 7a emerged as a dual topoisomerase I and II inhibitor, and results were supported by molecular docking and simulation studies. In anti-inflammatory studies, 7a exhibited selective inhibition of COX-2 over COX-1, supporting its dual anticancer and anti-inflammatory properties.

Melanoma, the most fatal form of skin cancer, often becomes resistant to the current therapeutic approaches in most patients. To explore new treatment options, fused thiazole derivatives were synthesized, and several of these compounds demonstrated potent anti-melanoma activity both in vitro and in vivo. These compounds exhibited significant cytotoxicity against melanoma cell lines at low concentrations. The lead molecules induced apoptosis and caused G2/M phase cell cycle arrest to a lesser extent. These compounds also displayed remarkable antimetastatic activities in several cell-based and molecular assays, significantly inhibiting key processes of metastasis, such as cell migration and adhesion. mRNA sequencing revealed significant downregulation of β-actin (ACTB) and γ-actin (ACTG1) at the transcriptional level, and a similar effect was observed at the protein level by western immunoblotting and proteomics assays. Actin-rich membrane protrusions formation is crucial for facilitating metastasis by promoting cell migration. Fluorescence microscopy demonstrated that compounds E28 and E47 inhibited the formation of these membrane protrusions and impaired actin cytoskeleton dynamics. Docking studies suggested the lead compounds may suppress tumor proliferation and metastasis by targeting the mechanistic target of Rapamycin complex 2 (mTORC2). All these findings unanimously indicated the translational perspective of ethisterone and androstenone fused thiazole derivatives as potent antimetastatic and antimelanoma agents. In a preclinical mouse melanoma model, compounds E2 and E47 significantly reduced tumor growth and greatly improved overall mice survival, while showing a favorable safety profile based on a comprehensive blood plasma metabolite profile. These lead molecules also displayed promising physicochemical properties, making them strong candidates for further drug development studies.

Alzheimer's disease (AD) is a complex, incurable neurological condition characterized by cognitive decline, cholinergic neuron reduction, and neuronal loss. Its exact pathology remains uncertain, but multiple treatment hypotheses have emerged. The current treatments, single or combined, alleviate only symptoms and struggle to manage AD due to its multifaceted pathology. The developmental drugs target pivotal disease factors involved in the envisaged hypotheses and include targets such as amyloid aggregation, hyperphosphorylated tau proteins, and receptors like cholinergic, adrenergic, etc. Present-day research focuses on multi-target directed ligands (MTDLs), which inhibit multiple factors simultaneously, helping slow the disease's progression. This review attempts to collate the recent information related to proposed hypotheses for AD etiology. It systematically organizes the advances in various therapeutic options for AD, with a particular emphasis on clinical candidates. Also, it is expected to help medicinal chemists design novel AD treatments based on available information, which could be helpful to AD patients.

The Wnt/β-catenin signaling pathway plays a critical role in various biological processes, including cell proliferation, differentiation, and tissue homeostasis. Aberrant activation of this pathway is strongly associated with the development of various cancers, including colorectal, pancreatic, and gastric cancers, making it a promising therapeutic target. In recent years, inhibitors targeting different components of the Wnt/β-catenin pathway, including small molecules, peptides, and nucleic acid-based therapies, have been developed to suppress cancer cell growth. These inhibitors work by disrupting key interactions within the pathway, thereby preventing tumor progression. Antibody-based therapies have also emerged as potential strategies to block ligand-receptor interactions within this pathway. Despite these advancements, challenges such as the complexity of the pathway and toxicity concerns remain. Innovative approaches, including allosteric inhibitors, proteolysis-targeting chimeras (PROTACs), and peptide-based inhibitors, offer new opportunities to address these challenges. This review provides an overview of the latest progress in the development of Wnt/β-catenin pathway inhibitors and explores future directions in cancer therapy.