Chemical Biology & Drug Design最新文献

Inhibitors of the tubulin-microtubule system are part of an effective strategy to treat different kinds of cancer, whose research has allowed scientists to discover and develop new and more selective molecules. Cacalol (1) is a natural product with anti-cancer activity and documented selectivity in breast cells, but with an undescribed molecular mechanism associated with these properties. The main objective of this work is to provide evidence that helps to explain the inhibitory and selective activity reported for cacalol (1) against cancer cell lines and to expand the knowledge about the mechanism of action involved in it. Cacalol derivatives were studied using reactivity approaches, tubulin polymerization assays, mass spectrometry, and molecular modeling techniques to decode the inhibitory binding mechanism. This work demonstrates that an oxidated form of cacalol, the methylenecyclohexadienone 2, is generated in highly oxidant conditions, thus emulating the environment present in cancer cells. This species (2) is responsible for the inhibition of tubulin polymerization by promoting an irreversible binding interaction with the Cys347 in α-tubulin.

Molecular hybridization of isoniazid with hydrophobic aromatic moieties represents a promising strategy for the development of novel anti-tubercular therapeutics. In this study, a series of hybrid molecules (5a–i) was synthesized by linking isoniazid with aromatic sulfonate esters via a hydrazone bridge. Molecular docking studies revealed that these compounds interact effectively with the catalytic triad of the InhA enzyme (Y158, F149, and K165), suggesting their potential as InhA inhibitors. To enhance molecular flexibility and improve binding interactions with both NADH and the catalytic residues, a second generation of derivatives (8a–k) was designed and synthesized. All synthesized compounds were structurally characterized using spectroscopic techniques, including nuclear magnetic resonance (NMR), Fourier transform infrared spectroscopy (IR), and high-resolution mass spectrometry. As anticipated, these new compounds exhibited enhanced anti-tubercular activity compared to their precursors. Notably, compound 8b demonstrated significant potency with an MIC of 0.078 μg/mL, approximately twofold more active than its precursor 5b (MIC = 0.156 μg/mL) against Mycobacterium tuberculosis (Mtb). However, both generations of compounds (e.g., 5a, 5b, 8a, 8b, 8c, and 8 k) lost activity against INH-resistant Mtb strains harboring katG mutations. Importantly, no cytotoxicity was observed for these compounds in THP-1 human monocytic cells at a concentration of 10 μg/mL. The structural integrity of the lead compound 8b was confirmed via ¹H NMR stability studies. The ADME/T parameters (absorption, distribution, metabolism, excretion, and toxicity) were also explored to determine their drug likeness and safety profile. Collectively, these hybrid molecules present valuable scaffolds for further optimization in the pursuit of new anti-tubercular agents.

Leishmaniasis, a disease caused by Leishmania parasites, poses a significant health threat globally, particularly in Latin America and Brazil. Leishmania amazonensis is an important species because it is associated with both cutaneous leishmaniasis and an atypical visceral form. Current treatments are hindered by toxicity, resistance, and high cost, driving the need for new therapeutic targets and drugs. N-myristoyltransferase (NMT) is an important anti-leishmanial target. N-myristoyltransferase (NMT) is an important target in Leishmania parasites, as it plays a crucial role in the process of myristoylation, a lipid modification that involves the attachment of myristate, a 14-carbon saturated fatty acid, to the N-terminus of specific proteins. In this work, a shape-based modeling approach was employed to identify potential NMT inhibitors in Leishmania amazonensis. Using a pyrazole sulphonamide as a reference ligand, a five-feature shape-based model was developed and validated. Virtual screening of the DIVERSet EXP and CL libraries (~1 million compounds) prioritized the top 500 ranked molecules per subset based on the TanimotoCombo score. Molecular docking studies identified the three highest-ranking compounds from each subset based on ChemPLP scores and docking pose consistency. Among the selected ligands, CL 54016012, EXP 6689657, and EXP 9226834 exhibited the most favorable binding interactions, with CL 54016012 forming stable hydrogen bonds with Tyr80, Tyr217, and Tyr345. Molecular dynamics (MD) simulations indicated that ligand binding did not significantly alter NMT structural stability, although variations in binding energy and hydrogen bond were observed. CL 54016012 demonstrated the highest docking score, optimal RMSD stability, and the lowest predicted IC50 value (19.81 μM), suggesting its potential as a lead compound. In vitro cytotoxicity assays revealed that CL 54016012, CL 74995016, and EXP 6689657 reduced L. amazonensis viability in a dose-dependent manner, placing them as promising candidates for further investigation in anti-leishmanial drug development.

Leishmaniasis is one of the most important neglected tropical diseases, prevalent in underdeveloped or developing countries, and new pharmacological agents for this disease are urgently needed. In this study, thiophene derivatives based on the natural product 5′-methyl-(5-[4-acetoxy-1-butynyl])-2,2′-bithiophene were synthesized and evaluated against promastigote forms of Leishmania amazonensis. The bithiophene BT-1 was the most potent and selective synthetic compound toward the parasites, exhibiting IC₅₀ of 23.2 μM against promastigotes and CC₅₀ of 216.5 μM against macrophages, and its mechanism of action was determined through biochemical and ultrastructural analyses. An accumulation of lipid bodies, loss of cellular content, increased reactive oxygen species production and lipid peroxidation, damage to the plasma membrane, and mitochondrial depolarization were observed in BT-1-treated parasites. The results indicated that the death of L. amazonensis induced by BT-1 occurred via destabilizing the parasite's redox homeostasis. Our results also showed that the synthesis based on the natural compound scaffold consisted of useful strategies to obtain new synthetic antileishmanial compounds.

Carbohydrates are well known to be one of the most abundant and structurally diverse natural organic compounds, and they are of great importance as an energy source and as structural components of cell walls in different organisms. They are involved in various biological and pathological processes, including homeostasis, cell–cell interaction, cell migration, cell development, bacterial and viral infection, inflammation, immunology, and cancer metastasis. The variety of these properties is a result of the structural diversity found in carbohydrates. The chemistry of carbohydrates involved in the diagnosis and treatment of diseases has attracted increasing attention from researchers, which is why they should be one of the main focuses in new drug discovery. This study focuses on the synthesis of new glycotriazole–metronidazole compounds as antifungal agents and antifungal biofilm agents, from the glycosylation of metronidazole with various carbohydrates (d-glucose, d-galactose, d-N-acetylglucosamine, and d-lactose). Our hypothesis is that the glycosides could be taken into fungal biofilms through recognition by glycoreceptors and transporters, carrying the active residue with them. In a low-oxygen environment, the nitro group would then undergo bioreduction leading to the formation of toxic radicals potentially resulting in the destruction or paralysis of biofilm formation—essentially functioning as a bioactive “Trojan horse.” The compounds were obtained via a click chemistry reaction using a triazole connector, and the subsequent antifungal tests showed good results for a number of compounds. In silico studies demonstrated positive data for all synthesized compounds, and, in general, they present low toxicological risks.