ChemMedChem最新文献

Inspired by marine compounds isolated from sponges and the increased need for new effective antimicrobials, novel quaternary ammonium compounds with long alkyl chains (C8-C12) were designed and synthesized. Antibacterial and antibiofilm activity of new compounds was evaluated against six microbial strains (S. aureus, E. coli, and P. aeruginosa). All synthesized ammonium salts displayed antibacterial activity with MIC values ranging from 5.0 to 25.0 μg/mL. In addition, most compounds showed strong inhibition of biofilm formation of S. aureus ATCC 25923, P. aeruginosa PA01, and colistin-resistant P. aeruginosa (CRPA) at a concentration of 5.0 μg/mL. Ammonium salt 3 showed 100% inhibitory activity against all tested bacterial biofilms except that of colistin-resistant S. aureus (CRSA).

7-methyl-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM1) and 6-methoxy-2-phenylimidazo[1,2-b]pyridazin-3-carboxylic acid (DM2) have been shown to act as human (h) Cav3.1 voltage-gated calcium channel blockers with promising in vivo anti-absence activity, positioning them as potential antiepileptic drugs. The primary aim of this work was to develop cost-effective and environmentally friendly synthetic procedures for preparing 2-phenylimidazo[1,2-b]pyridazine derivatives. After optimizing the synthesis of this compound class using efficient and green techniques such as microwaves and ultrasound irradiation, we further evaluated the antiepileptic effects of DM1 and DM2 in two animal models: CD-1 ICR mice after pentylenetetrazol administration and DBA/2 mice with seizures induced by audiogenic stimuli. Their neuroprotective effect against oxidative stress were assessed using C6 rat brain glioma cells. DM1 and DM2 exhibited potent anti-seizure effects in both animal models and demonstrated significant in vitro neuroprotective activity by reducing reactive oxygen species release. To lay the groundwork for the future rational optimization of this promising class of compounds, the molecular bases of DM1 and DM2 activity were investigated by modelling their interaction with hCav3.1 channels. The calculated binding modes of DM1 and DM2 to hCav3.1 channels partially mirrored that of the selective Cav3.1 blocker Z944, paving the way for future lead optimization.

An efficient approach has been developed for the trapping in situ generated benzopyrone-based ortho-quinone methide intermediates by 3- and 5-amino pyrazoles or isoxazoles. In cases of naturally occurring phenolic Mannich bases, hybrid compounds between the azole and flavonoid, namely, coumarin, chromone, isoflavone, and aurone were synthesized in moderate to good yields. It is remarkable that depending on 3- or 5-position of the amino group, the reaction led to the formation of C-4 or 3-NH substituted azole derivatives, respectively. In vitro studies showed that some of the obtained compounds bearing 5-aminoisoxazole part exhibit inhibitory activity towards α-glucosidase with IC50 values in the micromolar range.

Dipeptidyl peptidase 8 (DPP8) and 9 (DPP9) are proteases gaining significant attention for their role in health and disease. Distinctive studies of these proteases are hampered by their close homology. Furthermore, designing selective compounds is a major challenge due to the highly conserved catalytic site. Here, we provide mechanistic insights underlying the DPP9-over-DPP8 selectivity of the semi-selective inhibitor "Compound 42". We performed enhanced sampling molecular dynamics simulations to investigate the binding pose of "Compound 42", which enabled the design of various DPP9 mutants that were characterized through a combination of biochemical (Ki determinations) and in silico approaches. Our findings show that DPP9 residue F253 is an important selectivity-determining factor. This work marks the discovery and validation of a structural feature that can be exploited for the design of DPP8 or DPP9 selective inhibitors.

Here, we present a pleiotropic nanomedicine-a smart, functionalized redox buffering nanoparticle-that may be used to treat hematological diseases, associated splenic hyperplasia, and issues related to restricted erythropoiesis. With a diameter of 5-7 nm, the spherical nanomaterial is made of manganese oxide and citrate. Here, we have produced the novel nanomaterial and, using cutting-edge electron microscopic and spectroscopic techniques, extensively assessed its redox buffering potential in vitrowith its structural integrity. Using an appropriate animal model (phenyl hydrazine, PHz, intoxicated C57BL/6J mice), we assessed the therapeutic efficacy of the redox buffering nanomedicine in the treatment of anemia and related consequences. We have further investigated the intricate molecular mechanism of the nanomedicine and its therapeutic impact, which includes increased erythropoiesis and G6PDH production, decreased inflammatory responses, mitigation of splenic hyperplasia, and synergistic intracellular redox-buffering. To the best of our knowledge, our studies would find relevance in the innovative management of anemia, decreased erythropoiesis, and splenic hyperplasia.

We describe the identification of a candidate positron emission tomography (PET) imaging agent for the NLRP3 protein. NLRP3 plays a critical role in the immune system and has proven a difficult target for the development of imaging agents due to its low and cell-specific expression profile. A recently described series of pyridazine-based inhibitors, with improved permeability and brain-penetration properties, was used as a starting point for the development of a suitable PET imaging agent. Optimization of affinity, non-specific binding and pharmacokinetic properties led to the identification of aminopyridazine (R)-2-(6-((1-cyclopropylpiperidin-3-yl)amino)pyridazin-3-yl)-5-fluoro-3-methylphenol (17b), which meets the preclinical profile of a successful imaging agent, and whose tritiated version demonstrated excellent specificity in a radioligand saturation binding assay, confirming its imaging potential.18F labeling led to [18F]NP3-627, the proposed PET imaging agent.

The success of new therapeutic modalities relies on advancements in synthetic chemistry to produce compounds for evaluation throughout the drug discovery process. The use of non-canonical amino acids (ncAAs) allows the properties of peptide drugs to be modified and optimised beyond the defined characteristics of the 20 proteogenic amino acids. Synthesis of ncAAs can be either through a bespoke chemical synthesis, or directly from the parent compound - using either traditional chemical reagents or using enzymes - to achieve the desired modification. This review will highlight recent advancements in the enzymatic functionalisation of amino acids to produce a variety of ncAAs.

The biological properties of pentathiepins have been intensively studied in recent years. Although the proposed mechanism of action requires activation by intracellular thiols, the dependence of activity on the stability of pentathiepins towards glutathione (GSH) has not been directly investigated. Here, we determined the structure-related stability of six different pentathiepins with four different scaffolds in the presence of GSH by using reversed-phase high-performance liquid chromatography (RP-HPLC) and UV-vis spectroscopy over a wide range of GSH concentrations. We found significant differences in compound stability depending on the pentathiepin scaffold; these differences were reflected in their cytotoxic activities. However, we found no substantial differences in their inhibition of glutathione peroxidase 1 (GPx-1). While the intact pentathiepin ring is necessary for the antiproliferative activity of pentathiepins, the depletion of intracellular GSH content with dl-buthionine-(S,R)-sulfoximine (BSO) led to a significant increase in cytotoxicity of the tested substances. In view of the increased cytotoxicity following artificial GSH depletion, this calls into question the sole role of GSH in the intracellular activation mechanism.

A facile multicomponent synthesis of new indole-based phenylthiazolyl-dihydropyrazolone hybrids, their structural characterization, biological evaluation, and in silico investigations as anticancer agents are reported. Lead molecule 5 i of the series showed potent activity against MCF-7 breast cancer cells with an IC₅₀ of 3.92±0.01 μM while showing minimal toxicity to normal human lung cells (IC₅₀=69.85±3.95 μM). Further studies show that the compound exhibits antiproliferative activity by inducing apoptosis in MCF-7 cancer cells. The wound healing assay indicated impaired cell migration under the concentration-dependent dosage. The lead molecule 5 i also successfully inhibited the tubulin polymerase enzyme with an IC₅₀ of 4.16±0.18 μM. A flow cytometric assay indicated compound 5 i induced apoptosis through G0 phase cell cycle arrest. The binding mode and interactions of the compound with the tubulin were predicted by molecular modelling and calculating binding free energies. These findings explain the current series as a new class of microtubule polymerization inhibitors with anticancer activity suitable for developing anticancer agents targeting tubulin.

Diclofenac has a relatively low oral bioavailability (50-60 %) and is quickly metabolized with a half-life of less than 1 h. Therefore, the oral therapeutic effect of diclofenac is not optimal. This research developed polyvinylpyrrolidone K30-functionalized silk fibroin nanoparticles as an effective delivery system for diclofenac (FNPs-PVP-DC). The FNPs-DC and FNPs-PVP-DC were formulated by two methods of adsorption and solvent exchange. Depending on the formulation factors, the obtained particles exhibited different properties of nano-scale sizes (400-800 nm), narrow size distribution, negatively charged surfaces (-17 to -19 mV), high PVP K30 incorporation (23 %-50 %), pHpzc of ~6.6, and appropriate chemical interactions. Interestingly, particles formulated by the adsorption method showed low drug encapsulation efficiencies of <15 %, whereas the solvent exchange method yielded moderate results of ~40 %. The FNPs-DC possessed aggregated patterns, while the FNPs-PVP-DC were more uniformly distributed. All formulations limited diclofenac release (<20 %) under gastric conditions and sustained its release in the intestinal environment. In in-vivo carrageenan-induced paw edema mice model, the FNPs-PVP-DC demonstrated a 20-30 % higher anti-inflammatory effect and a faster onset of action (within 1 h) compared to pure diclofenac at the same dose (5 mg/kg). These findings suggest that FNPs-PVP-DC have promising potential as novel oral anti-inflammatory products.