ChemMedChem最新文献

A diverse set of 4,7-dihydro-[1,2,3]thiadiazolo[5,4-b]pyridine-6-carboxamides 4(a-o) were synthesized via a one-pot reaction of 5-amino[1,2,3]thiadiazole, various aromatic aldehydes, and different acetoacetanilides, using glacial acetic acid as the solvent and without the need for any catalysts. The resulting compounds were obtained in moderate to good yields. All the newly synthesized compounds were evaluated for their antimicrobial activity. Among them, compound 4e demonstrated superior efficacy against Salinivibrio proteolyticus strain of Gram-(-Ve)-bacteria compared to ciprofloxacin. Compound 4d exhibited the highest potency against the fungal strain Candida albicans surpassing Amphotericin B. 4d and 4e's physicochemical characteristics were assessed. According to docking analysis, DHTDAPy 4e shows the higher binding affinity of -7.2 kcal moL-1 in the binding cavity of the receptor. These findings illustrate the safety and tolerability as well as the potency of newly syntehsized DHTDAPy against the fungal and bacterial infections.

Obesity is a critical risk factor for the development of metabolic diseases and is often associated with dysfunctional adipocytes. Prevalent treatments such as lifestyle intervention, pharmacotherapy, and bariatric surgery are often accompanied by adverse side effects and poor patient compliance. Nanotechnology and cell-based therapy offer innovative approaches for targeted obesity treatments, as they can directly target adipocytes, regulate lipid metabolism, and minimize off-target effects. Here, we provide an overview of the intricate relationship between adipocytes and obesity, highlighting the potential of nanotechnology and cell-based therapy in obesity treatment. Additionally, we discuss the advancements of adipose-derived mesenchymal stem cells (ADMSCs) in obesity progression, including the latest challenges and considerations for developing adipose-targeted treatments for obesity. The objective is to provide a perspective on the design and development of nanotechnology and cell-based therapy for treating obesity and related comorbidities.

The Spanish Society of Medicinal Chemistry (Sociedad Española de Química Terapéutica SEQT), founded in 1977, aims to advance pharmaceutical research and education in Spain, collaborating with academia, industry, and public entities. It was initially linked with the Institute of Medicinal Chemistry from Spanish National Research Council (IQM-CSIC), emphasizing the independence of medicinal chemistry as a discipline. SEQT's presidency rotates between representatives from universities, research institutes, and industry, ensuring diverse perspectives. With around 500 members, SEQT represents sectors including universities, CSIC, and industry, with a notable presence of early-career researchers. The Society actively participates in the European Federation for Medicinal chemistry and Chemical biology (EFMC). SEQT organizes conferences, summer schools, and mini symposia to facilitate networking and knowledge exchange among professionals. To support early-career scientists, SEQT organizes symposia and awards, recognizing achievements in drug discovery. It fosters mentorship opportunities and engages with international networks like EFMC-YSN. In 2023, SEQT established its Early Career Scientist (SEQT-ECS) group to provide tailored support and resources. With over 40 years of experience, SEQT continues to evolve, embracing social media and adapting to changes in medicinal chemistry and chemical biology. It remains committed to supporting its members and advancing research to address human health challenges.

Platinum(IV) prodrugs are highly promising anticancer agents because they can selectively target tumors and minimize the adverse effects associated with their Pt^II congeners. In this study, we synthesized dual action Pt^IV complexes by linking oxoplatin with lithocholic acid. The synthesized compounds, designated as PL-I, PL-II, and PL-III, can spontaneously self-assemble in water, resulting in the formation of spherical shape nanoparticles. Among the developed complexes, PL-III appeared to be the most potent compound against all the tested cancer cell lines, with 10 fold higher cytotoxicity compared to cisplatin in PC3 cells. The complex arrests the cell cycle in the S and G2 phases and induces DNA damage. Additional mechanistic investigations demonstrate that PL-III predominantly localizes within the mitochondria and cytoplasm. Consequently, PL-III disrupts mitochondrial membrane potential, increases ROS production, and perturbs mitochondrial bioenergetics in PC3 cells. The complex induces apoptosis through the mitochondrial pathway by upregulating pro-apoptotic protein expression and downregulating anti-apoptotic protein expression from the BCl-2 protein family. These results demonstrate that higher cellular uptake and reduction of PL-III by biological reductants in PC3 cells resulted in a synergistic effect of lithocholic acid and cisplatin, which can be easily observed due to its unique cytotoxic mechanism. This further underscores the significance of dual-action Pt^IV complexes in enhancing the efficacy of cancer therapy.

With the rapid advancement of DNA technology, intelligent DNA nanoreactors (iDNRs) have emerged as sophisticated tools that harness the structural versatility and programmability of DNA. Due to their structural and functional programmability, iDNRs play an important and unique role in in vivo tumor diagnosis and therapy. This review provides an overview of the structural design methods for iDNRs based on advanced DNA technology, including enzymatic reaction-mediated and enzyme-free strategies. This review also focuses on how iDNRs achieve intelligence through functional design, as well as the applications of iDNRs for in vivo tumor diagnosis and therapy. In summary, this review summarizes current advances in iDNRs technology, discusses existing challenges, and proposes future directions for expanding their applications, which are expected to provide insights into the development of the field of in vivo tumor diagnostics and targeted therapies.

The devastating impact of malaria includes significant mortality and illness worldwide. Increasing resistance of the causative parasite, Plasmodium, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide-drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell-penetrating peptides. This approach aims to enhance selective uptake into Plasmodium-infected red blood cells and impart additional cytotoxic actions on the intraerythrocytic parasite, thereby enabling targeted drug delivery and dual modes of action. We describe the development of PDCs featuring four compounds with antimalarial activity - primaquine, artesunate, tafenoquine and methotrexate - conjugated to three cell-penetrating peptide scaffolds with varied antiplasmodial activity, including active and inactive analogs of platelet factor 4 derived internalization peptide (PDIP), and a cyclic polyarginine peptide. Development of this diverse set of PDCs featured distinct and adaptable conjugation strategies, to produce conjugates with in vitro antiplasmodial activities ranging from low nanomolar to low micromolar potencies according to the drug cargo and bioactivity of the partner peptide. Overall, this study establishes a strategic and methodological framework for the further development of dual mode of action peptide-drug antimalarial therapeutics.

The evolution of chemotherapy, especially the dawn of metal-based drugs, represents a transformative era in cancer treatment. From the serendipitous discovery of mustard gas's cytotoxic effects to the sophisticated development of targeted therapies, chemotherapy has significantly refined. Central to this progression is the incorporation of metal-based compounds, such as platinum (Pt), ruthenium (Ru), and gold (Au), which offer unique mechanisms of action, distinguishing them from organic therapeutics. Among these, Ru complexes, exemplified by BOLD-100 and TLD1433, have shown exceptional promise due to their selective activity, lower propensity for resistance, and the ability to target spescific cellular pathways. This paper explores the journey of such Ru candidates, focusing on the mechanisms, efficacy, and clinical potential of these Ru-based drugs, which stand at the forefront of current research, aiming to provide more targeted, less toxic, and highly effective cancer treatments.

Signal Amplification by Reversible Exchange (SABRE) is a relatively simple and fast hyperpolarization technique that has been used to hyperpolarize the α-ketocarboxylate pyruvate, a central metabolite and the leading hyperpolarized MRI contrast agent. In this work, we show that SABRE can readily be extended to hyperpolarize 13C nuclei at natural abundance on many other α-ketocarboxylates. Hyperpolarization is observed and optimized on pyruvate (P13C=17%) and 2-oxobutyrate (P13C=25%) with alkyl chains in the R-group, oxaloacetate (P13C=11%) and alpha-ketoglutarate (P13C=13%) with carboxylate moieties in the R group, and phenylpyruvate (P13C=2%) and phenylglyoxylate (P13C=2%) with phenyl rings in the R-group. New catalytically active SABRE binding motifs of the substrates to the hyperpolarization transfer catalyst-particularly for oxaloacetate-are observed. We experimentally explore the connection between temperature and exchange rates for all of these SABRE systems and develop a theoretical kinetic model, which is used to fit the hyperpolarization build-up and decay during SABRE activity.

The X-chromosome-linked inhibitor of apoptosis protein (XIAP) plays a crucial role in controlling cell survival across multiple regulated cell death pathways and coordinating a range of inflammatory signalling events. The discovery of selective inhibitors for XIAP-BIR2, able to disrupt the direct physical interaction between XIAP and RIPK2, offer promising therapeutic options for NOD2-mediated diseases like Crohn's disease, sarcoidosis, and Blau syndrome. The objective of this study was to design, synthesize, and evaluate small synthetic molecules with binding selectivity to XIAP-BIR2 domain. To achieve this, we applied an interdisciplinary drug design approach and firstly we have synthesized an initial fragment library to achieve a first XIAP inhibition activity. Then using a growing strategy, larger compounds were synthesized and one of them presents a good selectivity for XIAP-BIR2 versus XIAP-BIR3 domain, compound 20c. The ability of compound 20c to block the NOD1/2 pathway was confirmed in cell models. These data show that we have synthesized molecules capable of blocking NOD1/2 signalling pathways in cellulo, and ultimately leading to new anti-inflammatory compounds.

The Front Cover shows the identification of the new natural product aniquinazoline B from the marine fungus Aspergillus nidulans by virtual drug screening of a chemical library with 40000 compounds. Aniquinazoline B binds to the μ-opioid receptor. The amino acid sequence of the human μ opioid receptor in the background represents the basis for the 3D structure enabling virtual drug screening. Biochemical and cell culture experiments confirmed the μ-opioid receptor agonizing effect. This compound may be a promising candidate in pain-management to fight the opioid crisis. More details can be found in article 10.1002/cmdc.202400213 by Thomas Efferth and co-workers. The figure was created with biorender.com and parts of the figure were retrieved from smart servier medical art (smart.servier.com).