MedChemComm最新文献

Herein, we report the synthesis and anticancer properties of 21 new 1,3,4-thiadiazole-2-yl-imino-thiazolidine-4-one containing binary heterocyclic molecules. Cytotoxicity of the synthesized molecules was evaluated on various in vitro cancer cell lines (MCF-7, PC3, 4T1, MDA-MB-231, and MOC2) and normal human embryonic cell lines (HEK-293) via MTT assay. The cytotoxicity data of developed compounds was compared with the reference anticancer molecule BG45, a selective inhibitor of the HDAC3 enzyme. All compounds showed a significant cytotoxic effect higher than BG45 on tested cancer cell lines. Moreover, the compounds exhibited better selectivity on cancer cells than on normal cells. Among the molecules, compound 6e is the most potent in cytotoxic activity on MCF-7 cell lines (IC₅₀ value of 3.85 μM). Additional mechanistic investigation revealed that compound 6e promotes apoptosis (25.3%) and G0/G1 phase cell cycle arrest of MCF-7 cells. Also, compound 6e induces intracellular ROS accumulation and subsequent nuclear fragmentation. Hence, this research finds new hybrid molecules active against in vitro cancer cells.

Bcr-Abl is successfully applied to drug discovery as a CML therapeutic target, but point mutation resistance has become a major challenge in the clinical treatment of CML. Our previous studies have shown that the introduction of amino acids as flexible linkers and heterocyclic structures as HBMs can achieve potent inhibition of Bcr-Abl^T315I. In continuation of these studies, we further enriched the linker types by developing a library of compounds with tert-leucine or serine as a linker. Biological results showed that these compounds exhibited enhanced inhibition against Bcr-Abl^WT and Bcr-Abl^T315I kinases as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL10, BS4, BS10, SR5 and SR11 exhibited potent inhibitory activities against Ba/F3 cells bearing a T315I mutant. Additionally, compounds TL8, BS4 and SR5 effectively induced K562 cell apoptosis, arrested the cell cycle at the S or G2/M phase, and inhibited the phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies verified the rationality of tert-leucine or serine as a flexible linker and indicated that phenylpyridine with an amide side chain favored the potency of these inhibitors. Moreover, ADME prediction suggested that the tested compounds had a favorable safety profile. Thus, tert-leucine or serine can be used as a promising class of flexible linkers for Bcr-Abl inhibitors with heterocyclic structures as HBMs, and compounds BS4, SR5, and especially TL8, can be used as starting points for further optimization.

Calculable physicochemical descriptors are a useful guide to assist compound design in medicinal chemistry. It is well established that controlling size, lipophilicity, hydrogen bonding, flexibility and shape, guided by descriptors that approximate to these properties, can greatly increase the chances of successful drug discovery. Many therapeutic targets and new modalities are incompatible with the optimal ranges of these properties and thus there is much interest in approaches to find oral drug candidates outside of this space. These considerations have been a focus for a while and hence we analysed the physicochemical properties of oral drugs approved by the FDA from 2000 to 2022 to assess if such concepts had influenced the output of the drug-discovery community. Our findings show that it is possible to find drug molecules that lie outside of the optimal descriptor ranges and that large molecules in particular (molecular weight >500 Da) can be oral drugs. The analysis suggests that this is more likely if lipophilicity, hydrogen bonding and flexibility are controlled. Crude physicochemical descriptors are useful in that regard but more accurate and robust means of understanding substructural classes, shape and conformation are likely to be required to improve the chances of success in this space.

Dihydroorotate dehydrogenase (DHODH), an enzyme that plays a critical role in the de novo pyrimidine biosynthesis, has been recognized as a promising target for the treatment of diseases that involve cellular proliferation, such as autoimmune diseases and cancers. Pharmacological inhibition of human DHODH (hDHODH) that offers a potential therapeutic strategy for the treatment in adult subjects with acute myeloid leukemia (AML) has recently been supported by phase I/II clinical trials for the treatment of patients with relapsed/refractory AML. To facilitate the development of optimized hDHODH inhibitors, the presence of an in vivo imaging probe that is able to demonstrate in vivo target engagement is critical and desirable. Brequinar is one of the most potent hDHODH inhibitors so far discovered. In this work, we use a copper-mediated radiofluorination (CMRF) strategy and compare the chemical design and radiosynthesis starting from either pinacole boronate p-nitrobenzyl ester (4) or tributylstannate (tin) p-nitrobenzyl ester (5), chosen for their suitability as a precursor to [¹⁸F]brequinar. We report here the design, synthesis, radiolabeling and characterization of [¹⁸F]brequinar, and a preliminary PET imaging study of DHODH in vivo. This study provides the strategies to create [¹⁸F]brequinar, the first hDHODH inhibitor PET radiotracer, which will facilitate its use as a tool (theranostics) for hDHODH drug development and for diagnosis and monitoring therapeutic efficacy in AML and cancers.

The synthesis, anticancer activity, and metabolic stability of di-arylated 1,2,4-triazole molecules have been reported. Utilizing an efficient programmed arylation technique which starts from commercially available 3-bromo-1H-1,2,4-triazole, a series of therapeutic agents have been synthesized and screened against three human breast cancer cell lines, MDA-MB-231, MCF-7, and ZR-75-1, via an in vitro growth inhibition assay. At 10 μM concentration, 4k, 4m, 4q, and 4t have displayed good anticancer potency in the MCF-7 cell line, among which 4q has shown the best efficacy (IC₅₀ = 4.8 μM). Mechanistic investigations of 4q have indicated the elevation of the pro-apoptotic BAX protein in the malignant cells along with mitochondrial outer membrane permeabilization which are hallmarks of apoptosis. Further metabolic stability studies in diverse liver microsomes have provided insights into the favorable pharmacokinetic properties of 4q in humans, establishing it as a promising lead compound of this series that deserves further investigation.

Cryopreservation is crucial to fields including immune and stem cell therapies, reproductive technology, blood banking, regenerative medicine and across all biotechnology. During cryopreservation, cryoprotectants are essential to protect cells from the damage caused by exposure to freezing temperatures. The most common penetrating cryoprotectants, such as DMSO and glycerol do not give full recovery and have a cytotoxicity limit on the concentration which can be applied. The non-reducing disaccharide trehalose has been widely explored and used to supplement these, inspired by its use in nature to aid survival at extreme temperatures and/or desiccation. However, trehalose has challenges to its use, particular its low membrane permeability, and how its protective role compares to other sugars. Here we review the application of trehalose and its reported benefit and seek to show where chemical tools can improve its function. In particular, we highlight emerging chemical methods to deliver (as cargo, or via selective permeation) into the intracellular space. This includes encapsulation, cell penetrating peptides or (selective) modification of hydroxyls on trehalose.

Huntington's disease (HD) is a devastating, incurable condition whose pathophysiological mechanism relies on mutant RNA CAG repeat expansions. Aberrant recruitment of RNA-binding proteins by mutant CAG hairpins contributes to the progress of neurodegeneration. In this work, we identified a novel binder based on an aurone scaffold that reduces the level of binding of HTT mRNA to the MID1 protein in vitro. The obtained results introduce aurones as a novel platform for the design of functional ligands for disease-related RNA sequences.

Tuberculosis is a worldwide health problem that warrants attention given that the current treatment options require a long-term chemotherapeutic period and have reported the development of Mycobacterium tuberculosis (M. tuberculosis) multidrug resistant strains. In this study, n-butyl and isobutyl quinoxaline-7-carboxylate 1,4-di-N-oxide were evaluated against replicating and non-replicating H37Rv M. tuberculosis strains. The results showed that seventeen of the twenty-eight derivatives have minimum inhibitory concentration (MIC) values lower than isoniazid (2.92 μM). The most active antimycobacterial agents were T-148, T-149, T-163, and T-164, which have the lowest MIC values (0.53, 0.57, 0.53, and 0.55 μM respectively). These results confirm the potential of quinoxaline-1,4-di-N-oxide against M. tuberculosis to develop and obtain new and more safety antituberculosis drugs.

The increasing threat of nuclear incidents and the widespread use of ionizing radiation (IR) in medical treatments underscore the urgent need for effective radiation countermeasures. Despite the availability of compounds such as amifostine, their clinical utility is significantly limited by adverse side effects and logistical challenges in administration. This study focuses on the synthesis and evaluation of novel piperazine derivatives as potential radioprotective agents, with the aim of overcoming the limitations associated with current countermeasures. We designed, synthesized, and evaluated a series of 1-(2-hydroxyethyl)piperazine derivatives. The compounds were assessed for cytotoxicity across a panel of human cell lines, and for their radioprotective effects in the MOLT-4 lymphoblastic leukemia cell line and in peripheral blood mononuclear cells (PBMCs) exposed to gamma radiation. The radioprotective efficacy was further quantified using the dicentric chromosome assay (DCA) to measure DNA damage mitigation. Among the synthesized derivatives, compound 6 demonstrated the most significant radioprotective effects in vitro, with minimal cytotoxicity across the tested cell lines. Compound 3 also showed notable efficacy, particularly in reducing dicentric chromosomes, thus indicating its potential to mitigate DNA damage from IR. Both compounds exhibited superior safety profiles and effectiveness compared to amifostine, suggesting their potential as more viable radioprotective agents. This study highlights the development of novel piperazine derivatives with promising radioprotective properties. Compound 6 emerged as the leading candidate, offering an optimal balance between efficacy and safety, with compound 3 also displaying significant potential. These findings support the further development and clinical evaluation of these compounds as safer, and more effective radiation countermeasures.

This study investigates the potential of click chemistry for the development of novel anti-tuberculosis agents. A targeted library of 1,4-dihydropyridine–1,2,3-triazole conjugates was synthesized and evaluated for their in vitro activity against Mycobacterium tuberculosis H₃₇Ra using the resazurin microtiter assay (REMA). Among the synthesized derivatives, compounds J10, J11, J14, J22 and J23 demonstrated significant antimycobacterial activity. These compounds exhibited low MIC values ranging from 6.24 to 6.64 μg mL⁻¹, highlighting their promising potential as lead compounds for further developing novel tuberculosis therapeutics. In addition to the promising in vitro activity, structure–activity relationship (SAR) analysis revealed that electron-withdrawing groups on the aryl-substituted ring of the dihydropyridines (J10–J24), a triazole with an unsubstituted aryl ring or with electron-donating groups (methyl or methoxy), and a geminal dimethyl group are essential structural features for the observed antitubercular activity. Furthermore, in silico ADME (absorption, distribution, metabolism, and excretion) parameters and pharmacokinetic studies supported the potential of these conjugates for oral bioavailability. These findings collectively highlight the 1,4-dihydropyridine–1,2,3-triazole scaffold as a promising platform for developing novel orally active anti-tuberculosis drugs.