ChemMedChem最新文献

The treatment of acute myeloid leukemia (AML) presents a challenge to current therapies because of the development of drug resistance. Genetic mutation of FMS-like tyrosine kinase-3 (FLT3) is a target of interest for AML treatment, but the use of FLT3-targeting agents on AML patients has so far resulted in poor overall clinical outcomes.^[1] The incorporation of the boronic group in a drug scaffold could enhance the bioavailability and pharmacokinetic profile of conventional anticancer chemotypes. Boronic acids represent an intriguing and unexplored class of compounds in the context of AML, and they are only scantly reported as inhibitors of protein kinases. We identified α-triazolylboronic acids as a novel chemotype for targeting FLT3 by screening a library of structurally heterogeneous in-house boronic acids. Selected compounds show low micromolar activities on enzymatic and cellular assays, selectivity against control cell lines and a recurring binding mode in in-silico studies. Furthermore, control analogues synthesized ad hoc and lacking the boronic acid are inactive, confirming that this group is essential for the activity of the series. All together, these results suggest α-triazolylboronic acids could be a promising novel chemotype for FLT3 inhibition, laying the ground for the design of further compounds.

Hyperuricemia is characterised by high blood levels of uric acid, and it can degenerate into gout when monosodium urate crystals precipitate in joints and other tissues. Uric acid is produced during the catabolism of xanthine by the enzyme xanthine oxidase (XO), which is the primary therapeutic target in gout treatment. Current XO inhibitors approved to treat gout, such as allopurinol and febuxostat, suffer from serious adverse effects, creating the need for new drug molecules. Three libraries comprising 75 purine analogues were designed using a 1,2,4-triazolo[1,5-a]pyrimidine scaffold, synthesised and tested in vitro as potential XO inhibitors. The screening identified that 23 compounds exhibited better inhibitory activity than allopurinol, with 2-(4-isopropoxyphenyl)-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-a]pyrimidine-6-carboxylic acid being 23 times more potent. Enzyme kinetics studies and molecular docking simulations were performed on the most active compounds to identify the mechanism of action and intermolecular interactions between the active site of XO and the inhibitors. The most potent compounds exhibited a mix-type inhibition mechanism and were predicted to interact with the same amino acid residues as allopurinol. These novel purine analogues are promising hits for further new lead development among purine-like drug XO inhibitors with therapeutic potential in the treatment of hyperuricemia and associated diseases.

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC₅₀ values of the active compounds were determined using the rapid assay and six compounds displayed an IC₅₀ value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC₅₀ value <5 μM against one or more pancreatic cancer cell lines.

The Frontiers in Medicinal Chemistry (FiMC) is the largest international Medicinal Chemistry conference in Germany and took place from March 17^th to 20^th 2024 in Munich. Co-organized by the Division of Medicinal Chemistry of the German Chemical Society (Gesellschaft Deutscher Chemiker; GDCh) and the Division of Pharmaceutical and Medicinal Chemistry of the German Pharmaceutical Society (Deutsche Pharmazeutische Gesellschaft; DPhG), and supported by a local organizing committee from the Ludwigs-Maximilians-University Munich headed by Daniel Merk, the meeting brought together approximately 225 participants from 20 countries. The outstanding program of the four-day conference included 40 lectures by leading scientists from industry and academia as well as early career investigators. Moreover, 100 posters were presented in two highly interactive poster sessions.