Future medicinal chemistry最新文献

Human mitochondrial ClpP (hClpP), a pivotal protease regulating mitochondrial protein homeostasis, has emerged as an important target for anticancer drug development. In recent years, significant progress has been made in designing small molecules targeting hClpP, primarily classified into activators and inhibitors. Activators specifically stimulate ClpP proteolytic activity by mimicking the mechanism of its chaperone protein ClpX, with representative compounds, such as imipridone derivatives (ONC201/206/212) and their optimized products (ZK53, 7k, etc.) demonstrating excellent antitumor efficacy. Investigation of their structural design and pharmacological properties provides theoretical insights for subsequent drug development. Significant progress has been made in agonist research, and although there are still issues that need to be addressed, hClpP-targeted drugs hold promise as new therapies for the treatment of cancer.

Aims: This study explored the synthesis and evaluation of novel neuraminidase (NA) inhibitors, focusing on thiazolidine-4-carboxylic acid derivatives to combat influenza.

Materials and methods: The synthesized compounds were evaluated for their NA inhibitory activity and assessed against Influenza A (H7N3) using hemagglutination inhibition (HAI) assays. Molecular docking studies were also conducted to support the experimental findings.

Results: Compounds 4a, 4b, and 6a demonstrated potent NA inhibitory activity. While all compounds showed moderate HAI activity compared to Oseltamivir, 4a and 8a exhibited strong potency with low Mean MIC values against the H7N3 strain.

Conclusions: These findings suggest that the thiazolidine derivatives hold potential as novel inhibitory agents against influenza. Future research will focus on assessing their toxicity and safety profiles, paving the way for the development of effective and safer NA inhibitors.

Aims: This study aimed to design, synthesize, and evaluate a novel meclofenamic acid derivative (7) for its potential as a dual-target therapeutic agent with anti-inflammatory, antidiabetic, antioxidant, and anticancer activities.

Materials & methods: Compound 7 was synthesized and subjected to in vitro, in vivo, and in silico evaluations. Anti-inflammatory activity was assessed using acute and chronic models, including IL-6 and NF-κB quantification and histopathology. Antidiabetic potential was evaluated through α-glucosidase inhibition, glucose tolerance, and alloxan-induced diabetic models. Antioxidant activity was tested against ascorbic acid, while cytotoxicity was assessed on MCF-7, T24, and A-549 cell lines. Molecular docking, ADME profiling, and pathway analyses were performed to predict drug-likeness and target interactions.

Results: Compound 7 exhibited potent anti-inflammatory activity (IC₅₀ = 0.07 µM), reducing IL-6 and NF-κB by 62.99% and 59.13%, respectively. It demonstrated strong α-glucosidase inhibition (IC₅₀ = 12.78 µM) and improved insulin regulation. Antioxidant activity was comparable to ascorbic acid. Cytotoxicity studies revealed moderate anticancer activity with synergistic enhancement when combined with cisplatin.

Conclusions: Computational and experimental findings suggest that compound 7 exhibits favorable drug-like properties and holds promise as a multi-target therapeutic candidate.

The Perspective presents the strategy of double chiral switches of drugs, illustrating the scenario of consecutive double chiral switches of methylphenidate. The two chirality centers of methylphenidate hydrochloride give rise to four stereoisomers grouped into two racemates, two enantiomer pairs: [(αR,2S)/(αS,2R)] (racemate a) and [(αR,2R)/(αS,2S)] (racemate b). A detailed analysis of the development, drug-regulatory approvals and the corresponding patents and trademarks of methylphenidate drugs indicated the following double chiral switches: (±)-[(αR,2R)/(αS,2S)]-methylphenidate HCl + (±)-[(αR,2S)/(αS,2R)]-methylphenidate HCl (Centedrin)→(±)-[(αR,2R)/(αS,2S)]-methylphenidate HCl (Ritalin)→(+)-(αR,2R)-methylphenidate HCl (Focalin). The analysis showed that the Food and Drug Administration approval of Ritalin in 1955 represented the first chiral switch of the mixture of two racemates to the single racemate b. In 2001, Ritalin underwent a second chiral switch to the single-enantiomer Focalin. Ritalin and Focalin developed into successful Attention-Deficit/Hyperactivity Disorder (ADHD) drugs. Notably, the single-enantiomer drug Focalin has not driven away the racemate Ritalin from ADHD markets. The notations of the active ingredients of Ritalin (methylphenidate hydrochloride) and of Focalin (dexmethylphenidate hydrochloride) are stereochemically flawed and the designations of the stereodescriptors of relative configurations erythro and threo are obsolete. The Perspective calls for correct notations of methylphenidate drugs and for future applications of the double chiral-switches strategy.

In this review, the primary aim is to examine non-azole ring systems that have analgesic activity and, where applicable, to establish structure - activity relationships (SARs) with the nine major pathways, prostaglandin synthesis inhibition, opioid receptor modulation, sodium channel blockade, enhancement of serotonin and norepinephrine levels, cannabinoid receptor (CBR) binding, N-methyl-D-aspartate (NMDA) receptor antagonism, transient receptor potential cation channel subfamily V member 1 (TRPV1) antagonism, and P2X purinergic receptor blockade, have been described for pain relief. Analgesic effects have been observed in compounds containing ring systems such as piperidine, piperazine, pyridine, pyridazine, pyrazine, morpholine, thiomorpholine, pyran, thiopyran, indane, benzofuran, benzothiophene, quinoline, quinazoline, and chromene. These ring systems were classified in the whole study, first according to their molecular weights and then by bioisosteric similarity as same as first part. Differing from the initial study of this work, the advantages of newly developed and approved drug formulations were evaluated, and recent advances in analgesic drug development were discussed. Accordingly, this review also provides a framework for the formulation of compounds incorporating these core structures in the design of novel molecules with potential analgesic properties. In conclusion, these works highlight the current progress and emerging strategies in analgesic drug discovery and development.

Aims: Aza-peptide aldehydes and ketones were developed as a new class of peptidyl analogues to inhibit the human constitutive (c)20S proteasome as alternative therapeutics to treat multiple myeloma (MM).

Material and methods: Eleven new aza-peptide aldehydes and ketones were designed based on their preference to bind at the ß5 catalytic subunit of c20S proteasome with benzyloxycarbonyl(Cbz)-Leu-Leu-Leu (MG132-like) and morpholinyl(Mp)-Homophenylalanyl(HPh)-Leu-Phe-Leu (Carfilzomib-like) sequences, synthesized, structurally characterized and evaluated for their inhibitory potency in competitive kinetic assays in vitro. Additionally, cell viability assays and molecular modeling experiments were designed and performed in support.

Results: Aza-peptide aldehydes and ketones generated inhibitory activity with IC₅₀ values in the µM range when tested at the ß5 catalytic subunit of the human c20S proteasome. Compound 1 was the most potent compound with an IC₅₀ value of 2.3 ± 1.5 µM. When tested for concentration-dependent killing of three multiple myeloma, one leukemic and two normal natural killer (NK) cell lines, two compounds generated mid-µM EC₅₀ values only for the cancer cells after 48 h.

Conclusions: Overall, aza-peptide aldehydes and ketones are a new class of selective human c20S proteasome inhibitors with the potential for further development as alternative therapeutics for multiple myeloma.

Aim: To identify and validate novel small-molecule inhibitors targeting KRAS G12C, G12D, and G12V mutants through a structure-based drug design and experimental approach.

Methods: We employed molecular docking, molecular dynamics (MD) simulations, MM-PBSA binding free energy calculations, and principal component analysis (PCA) to screen and evaluate potential inhibitors targeting the Switch-II pocket of KRAS mutants. Top-ranking compounds were experimentally validated using Bio-Layer Interferometry (BLI) for binding affinity and MTT assays to assess anticancer activity in breast and lung cancer cell lines.

Results: Compound C797-1505 showed strong binding to KRAS G12V (Dissociation constant (KD) = 141 µM), outperforming the reference Sotorasib (KD = 345 µM). C190-0346 displayed weak affinity toward KRAS G12C. MTT assays revealed that C797-1505 reduced breast cancer cell viability (Half-maximal Inhibitory Concentration (IC50) = 43.51 µM), while both compounds demonstrated significant cytotoxicity against lung cancer cells (IC50 = 18.78 µM and 22.93 µM, respectively).

Conclusion: Our integrated computational and experimental strategies successfully identified selective KRAS mutant inhibitors with promising anticancer activity, particularly against G12V and G12C driven tumors. These findings support further development and preclinical evaluation of these compounds as targeted therapeutics.

Aims: This study aims to evaluate the antibacterial and antibiofilm activity of Lys-a1, particularly in combination with oxacillin (OXA), against foodborne E. coli and Klebsiella spp.

Materials and methods: The antibacterial activity was determined by minimum inhibitory/bactericidal concentration (MIC/MBC) and time-kill curves. Additionally, the potential synergistic effects between Lys-a1 and OXA were assessed using a checkerboard assay, and the ability of this combination to disrupt pre-formed biofilms was also investigated.

Results: All tested strains were sensitive to Lys-a1, exhibiting MIC values ranging from 25 to 100 µg/mL and MBC typically one or twice the MIC values. The time-kill curve indicated the bactericidal effect within 180-240 minutes, achieving a 99.99% reduction in viable cells. Despite the detectable additive action, a notable synergistic effect was observed when Lys-a1 was combined with OXA for most strains (5/8), with an FIC index between 0.31 and 0.50. The Lys-a1/OXA combination significantly reduced biomass by around 50% and 90% of pre-formed biofilms compared with control and OXA-treated and untreated cells, respectively.

Conclusions: The results suggest that Lys-a1/OXA combination could be a promising approach for sensitizing Gram-negative bacteria and expanding treatment options using OXA.