RSC medicinal chemistry最新文献

Computer-aided drug design (CADD), a cornerstone of modern drug discovery, can predict how a molecular structure relates to its activity and interacts with its target using structure-based and ligand-based methods. Fueled by ever-increasing data availability and continuous model optimization, artificial intelligence drug design (AIDD), as an enhanced iteration of CADD, has thrived in the past decade. AIDD demonstrates unprecedented opportunities in protein folding, property prediction, and molecular generation. It can also facilitate target identification, high-throughput screening (HTS), and synthetic route prediction. With AIDD involved, the process of drug discovery is greatly accelerated. Notably, AIDD offers the potential to explore uncharted territories of chemical space beyond current knowledge. In this perspective, we began by briefly outlining the main workflows and components of CADD. Then through showcasing exemplary cases driven by AIDD in recent years, we describe the evolving role of artificial intelligence (AI) in drug discovery from three distinct stages, that is, chemical library screening, linker generation, and de novo molecular generation. In this process, we attempted to draw comparisons between the features of CADD and AIDD.

Breast and colorectal cancers are the most common tumors, with high recurrence and low survival rates. We designed and synthesized a series of spirooxindole pyrrolidinyl derivatives, which were further evaluated for anti-proliferative activity using MDA-MB-468 and HCT 15 cell lines. The best inhibitor of this class, compound 6f, showed a very good inhibition potency, both on the MDA-MB-468 and HCT 15 cells as confirmed by molecular docking and molecular dynamic studies that predicted its binding mode into the active site of the targets. In summary, this study provided a new anti-proliferative derivative 6f which is worthy of further research.

DNA repair activity diminishes with age and genetic mutations, leading to a significantly increased risk of cancer and other diseases. Upregulating the DNA repair system has emerged as a potential strategy to mitigate disease susceptibility while minimizing cytotoxic side effects. However, enhancing DNA repair activity presents significant challenges due to the inherent inefficiency in activator screening processes. Additionally, pinpointing a critical target that can effectively upregulate overall repair processes is complicated as the available information is somewhat sporadic. In this review, we discuss potential therapeutic targets for upregulating DNA repair pathways, along with the chemical structures and properties of reported small-molecule activators. We also elaborate on the diverse mechanisms by which these targets modulate repair activity, highlighting the critical need for a comprehensive understanding to guide the development of more effective therapeutic strategies.

In pursuit of novel anti-plasmodial agents, a library of triclosan-based dimers both with and without a 1H-1,2,3 triazole core were designed and synthesized in order to achieve a multitargeted approach. In vitro assessment against chloroquine-susceptible (3D7) and resistant (W2) P. falciparum strains identified that two of the synthesized dimers containing triazole were the most potent in the series. The most potent of the synthesized compounds exhibited IC₅₀ values of 9.27 and 12.09 μM against the CQ-resistant (W2) and CQ-susceptible (3D7) strains of P. falciparum, with an RI of 0.77, suggesting little or no cross-resistance with CQ. Heme binding and molecular modelling studies revealed the most promising scaffold as a dual inhibitor for hemozoin formation and a P. falciparum chloroquine resistance transporter (PfCRT), respectively. In silico studies of the most potent compound revealed that it shows better binding affinity with PfACP and PfCRT compared to TCS. To the best of our knowledge, this is the first report of triclosan-based compounds demonstrating promising heme-inhibition behaviour, with binding values comparable to those of chloroquine (CQ).

Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014-2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.

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Helicobacter pylori (Hp) infection affects nearly half of the global population. Current therapeutic options include the administration of a combination of antibiotics and proton pump inhibitors, although antimicrobial resistance rise remains a big concern. Phenolic monoterpenes, e.g., eugenol, vanillin, carvacrol, and thymol, have always attracted researchers for their multifaced biological activities and the possibility to be easily derivatized. Thereby, herein we present the functionalization of such compounds through the conventional aryl diazotization reaction, generating a series of mono- and bis-azo derivatives (1-28). Also, to continue previous studies, we investigated the role of the free phenolic moiety of thymol with eight compounds (29-36). The compounds were tested against four Hp strains including three clinical isolates, finding some potent and selective inhibitors of bacterial growth. Thus, the representative compounds underwent in vitro cytotoxicity evaluation on two normal cell lines and putative target investigation by performing a structure-based approach based on docking calculations on some of the most studied pharmacological targets for Hp, e.g., urease, β-hydroxyacyl-acyl carrier protein dehydratase, glucose 6-phosphate dehydrogenase, and inosine 5'-monophosphate dehydrogenase.

Herein, we describe the continuous flow synthesis and in-line extraction of N,N-dimethyltryptamine (DMT) and several of its analogues using a Fischer indole reaction, along with a larger gram scale synthesis (4.75 g) of the model compound. These products could then be quickly transformed into their respective fumarate salts, making them easier to handle and stable for long time storage using a straightforward batch procedure. Additionally, the commercially available drug rizatriptan benzoate could be synthesised with high purity using this setup. The presented method employs relatively green solvents both for the synthesis and purification of the target products.

A series of sulfonamides incorporating a 1,2,3-triazolyloxime substituted 1,2,3-triazolyl moiety were conceptualized and synthesized as human carbonic anhydrase (hCA) inhibitors. The synthesized small structures, denoted 7a through 7o, exhibited moderate inhibitory effects against the tumor-associated isoforms hCA IX and hCA XII compared to the well-known hCA inhibitor acetazolamide. In contrast, these molecules demonstrated higher potency and a diverse range of selectivity against the cytosolic isoforms hCA I and hCA II. Notably, the 4-hydroxyphenyl derivative (compound 7dversus cytosolic isoforms), the 4-acetylphenyl derivative (compound 7o), and the phenyl derivative (compound 7a) emerged as the most potent and selective inhibitors in this series, with inhibition constants (K _I) of 47.1, 35.9, 170.0, and 149.9 nM, respectively, against hCA I, II, IX, and XII. Further cytotoxicity assays of compounds 7a-o against cancer cell lines Hep3B and A549, as well as normal cell line L929, were conducted to assess their selectivity towards malignant cells. Compounds 7d, 7g, and 7k exhibited selective cytotoxicity towards the Hep3B cell line, with reduced selectivity towards A549, whereas compound 7j demonstrated higher selectivity for the A549 cell line. Additionally, molecular docking studies were performed to elucidate the binding modes of these compounds within the active sites of hCAs, revealing crucial interactions that underpin their significant activity and selectivity for the tumor-specific isoforms.

Pimasertib, a potent antiproliferative drug, has been extensively studied for treating cancers characterized by dysregulation in the ERK/MAPK signaling pathway, such as melanoma. However, its therapeutic efficacy would greatly benefit from an increased selectivity for tumour cells and a longer half-life. Such improvements may be achieved by combining the rational design of a prodrug with its encapsulation in a potential nanodelivery system. For this reason, we synthesized a glutathione (GSH)-responsive putative prodrug of pimasertib (PROPIMA), which contains a redox-sensitive disulphide linker that can be processed by GSH to activate pimasertib. The synthesis of PROPIMA and its in vitro biological activity on a human melanoma cell line as a model are described. The results showed that PROPIMA, either free or embedded in liposomes, selectively inhibits cell proliferation and cell viability, reducing by about 5-fold the levels of pERK. Additionally, PROPIMA shows stronger inhibition of the cancer cell migration than the parent drug.