ChemMedChem最新文献

In the recent two decades, the multidisciplinary field of medicinal chemistry has undergone several conceptual and technology-driven paradigm changes with significant impact on the skill set medicinal chemists need to acquire during their education. Considering the need for academic medicinal chemistry teaching, this article aims at identifying important skills, competences, and basic knowledge as general learning outcomes based on an analysis of the relevant stakeholders and concludes effective teaching strategies preparing students for a future career as medicinal chemists and drug designers.

In recent years, selenocompounds have gained increasing attention as potential anticancer and antibacterial agents. Several selenoderivatives have been confirmed to act as MDR efflux pump inhibitors, based on their in vitro results against the bacterial AcrAB-TolC system and the cancer MDR efflux pump P-glycoprotein. Efflux pumps can contribute directly or indirectly to the virulence of bacteria, as they can reduce the intracellular concentration of antibacterial substances by expelling them out of the cell. The present work aims to study the antibacterial and efflux pump inhibiting properties of four families of selenoesters, namely aspirin-selenoesters, phenone-selenoesters, hydroxy-selenoesters, and benzyl-selenoesters. The real-time ethidium bromide accumulation assay confirmed that these derivatives inhibited the efflux systems of methicillin-resistant Staphylococcus aureus (MRSA) without exerting any antibacterial effect. The relative expression of efflux pump gene of NorA transporter was also monitored in the presence of the most potent derivatives on reference S. aureus, finding that these derivatives could change the expression of the tested efflux pump gene. Regarding the anti-biofilm activity, aspirin-selenoesters, benzyl-selenoesters, and hydroxy-selenoesters could efficiently inhibit the biofilm production of the MRSA strain. It can be concluded that selenocompounds could act as efflux pump inhibitors, thus reducing the virulence of biofilm-producing bacteria.

The Alanine, Serine, and Cysteine Transporter 2 (ASCT2) transports glutamine into cells and is upregulated in many cancers. Attachment to glutamine to enable ASCT2 to transport anticancer agents into cells has been proposed, but the impact of such modifications is a critical determinant of the potential of this strategy. Transport via ASCT2 of two glutamine analogues modified in ways that reflect possible mechanisms for attaching anticancer agents was studied. The aim was to determine if the modification of glutamine interferes with its transport via ASCT2 and thereby establish whether the conjugation of drugs to glutamine can facilitate the accumulation of anticancer drugs in cancer cells. L-theanine and a glutamine derivative modified at the carboxylate (7) were applied to Xenopus laevis oocytes expressing ASCT2. Two-electrode voltage clamp electrophysiology was used to measure substrate-elicited currents over a range of membrane potentials. Compound 7 was identified as neither a substrate nor an inhibitor while L-theanine was identified as an inhibitor of ASCT2. Thus, modification of glutamine in these ways prevents it from acting as a substrate and suggests that ASCT2 may not be a suitable target for delivery of anticancer drugs attached via either the carboxylate or side chain positions.

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.