MedChemComm最新文献

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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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.

Alzheimer's disease (AD) is a prevalent degenerative disorder affecting the central nervous system of the elderly. Patients primarily manifest cognitive decline and non-cognitive neuro-psychiatric symptoms. Currently, western medications for AD primarily include cholinesterase inhibitors and glutamate receptor inhibitors, which have limited efficacy and accompanied by significant toxic side effects. Given the intricate pathogenesis of AD, the use of single-target inhibitors is limited. In recent years, as research on AD has progressed, traditional Chinese medicine (TCM) and its active ingredients have increasingly played a crucial role in clinical treatment. Numerous studies demonstrate that TCM and its active ingredients can exert anti-Alzheimer's effects by modulating pathological protein production and deposition, inhibiting tau protein hyperphosphorylation, apoptosis, inflammation, and oxidative stress, while enhancing the central cholinergic system, protecting neurons and synapses, and optimizing energy metabolism. This article summarizes extracts from TCM and briefly elucidates their pharmacological mechanisms against AD, aiming to provide a foundation for further research into the specific mechanisms of TCM in the prevention and treatment of the disease, as well as the identification of efficacious active ingredients.

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide, poses a formidable challenge due to its heterogeneity and the emergence of resistance to targeted therapies. While initially effective, first- and third-generation EGFR-tyrosine kinase inhibitors (TKIs) often fail to control disease progression, leaving patients with limited treatment options. To address this unmet medical need, we explored the therapeutic potential of multitargeting agents that simultaneously inhibit two key signalling pathways, the mesenchymal-epithelial transition factor (c-MET) and the G protein-coupled receptor Smoothened (SMO), frequently dysregulated in NSCLC. By employing a combination of in silico drug repurposing and structure-based structure–activity relationship (SAR) studies, we identified and developed novel c-MET/SMO-targeting agents with antiproliferative activity against first- as well as third-generation EGFR-TKI-resistant NSCLC cells suggesting a synergistic effect arising from the simultaneous inhibition of c-MET and SMO.

Enveloped viruses enter the host cells by endocytosis and subsequently fuse with the endosomal membranes, or fuse with the plasma membrane at the cell surface. The crucial stage of viral infection, regardless of the route taken to enter the host cell, is membrane fusion. The present work aims to develop a peptide-based fusion inhibitor that prevents membrane fusion by modifying the properties of the participating membranes, without targeting a protein. This would allow us to develop a fusion inhibitor that might work against a larger spectrum of enveloped viruses as it does not target any specific viral fusion protein. With this goal in mind, we have designed a novel peptide by modifying a native sequence derived from coronin 1, a phagosomal protein, that helps to avoid lysosomal degradation of mycobacterium-loaded phagosomes. The designed peptide, mTG-23, inhibits ∼30–40% fusion between small unilamellar vesicles containing varying amounts of cholesterol by modulating the biophysical properties of the participating bilayers. As a proof of principle, we have further demonstrated that the mTG-23 inhibits Influenza A virus infection in A549 and MDCK cells (with ∼EC₅₀ of 20.45 μM and 21.55 μM, respectively), where viral envelope and endosomal membrane fusion is a crucial step. Through a gamut of biophysical and biochemical methods, we surmise that mTG-23 inhibits viral infection by inhibiting viral envelope and endosomal membrane fusion. We envisage that the proposed antiviral strategy can be extended to other viruses that employ a similar modus operandi, providing a novel pan-antiviral approach.

Coronaviruses rely on the viral-encoded chymotrypsin-like main protease (M^pro or 3CL^pro) for replication and assembly. Our previous research on M^pro of SARS-CoV-2 identified cysteine 300 (Cys300) as a potential allosteric site of M^pro inhibition. Here, we identified tixocortol (TX) as a covalent modifier of Cys300 which inhibits M^pro activity in vitro as well as in a cell-based M^pro expression assay. Most importantly TX inhibited SARS-CoV-2 replication in ACE2 expressing HeLa cells. Biochemical analysis and kinetic assays were consistent with TX acting as a non-competitive inhibitor. By contrast, TX was a weaker inhibitor and modifier of C300S M^pro, confirming a role for Cys300 in inhibition of WT M^pro but also providing evidence for an additional Cys target. TX pivalate (TP), a prodrug for TX that was previously marketed as a nasal spray, also inhibited SARS-CoV-2 replication in HeLa–ACE2 cells at low micromolar IC₅₀s. These studies suggest that TX and/or TP could possibly be repurposed for the prevention and/or treatment of SARS-CoV-2 infection.

The regioselective synthesis of functionalized naphthoquinones via the formation and capture of naphthoquinonynes has been used to prepare trypanocidal compounds. The target compounds are functionalized on the aromatic ring, leaving the quinoidal ring intact. Using this technique, eighteen functionalized naphthoquinones were succesfull obtained, divided in two main groups: the first scope using N-nucleophiles, and the second scope using pyridine N-oxides, with yields up to 74%. Evaluation against bloodstream trypomastigotes of T. cruzi has identified fourteen compounds that are more potent than benznidazole (Bz); for instance, compounds 29b-I and 30b, with IC₅₀/24 h values of 10.5 and 10.1 μM, respectively, are approximately 10-fold more active than Bz. This study provides the first examples of the application of naphthoquinonyne chemistry for the synthesis of new compounds with potent trypanocidal activities.

The incorporation of saturated nitrogen-containing heterocycle 1,2,5-oxadiazinane into small molecules represents a compelling avenue in drug discovery due to its unexplored behavior within biological systems and incomplete protocols for synthesis. In this study, we present 1,2,5-oxadiazinane, an innovative heterocyclic bioisostere of piperizin-2-one and novel chemotype of the anti-schistosomal drug praziquantel (PZQ), which has been the only clinical drug available for three decades. PZQ is associated with significant drawbacks, including poor solubility, a bitter taste, and low metabolic stability. Therefore, the discovery of a new class of anti-schistosomal agents is imperative. To address this challenge, we introduce a pioneering method for the synthesis of 1,2,5-oxadiazinane derivatives through the cycloaddition of nitrones with N,N,N′,N′-tetraalkyldiaminomethane in the presence of an Ir^III complex photosensitizer. This transformative reaction offers a streamlined route to various kinds of 1,2,5-oxadiazinanes that is characterized by mild reaction conditions and broad substrate scope. Mechanistic investigations suggest that the photoredox pathway underlies the [3 + 3] photocycloaddition process. Thus, based on bioisosteric replacement, we identified a remarkable molecule as a new chemotype of a potent anti-schistosomal compound that not only exhibits superior solubility, but also retains the potent biological activity inherent to PZQ.