RSC medicinal chemistry最新文献

[This corrects the article DOI: 10.1039/D4MD00599F.].

Exploring new inhibitors with good bioavailability and high selectivity for managing type 2 diabetes mellitus (T2DM) and its associated complications is a major challenge for research, academia, and the pharmaceutical industry. Protein tyrosine phosphatase-1B (PTP1B) arose as an important negative regulator in insulin signaling pathways associated with metabolic disorders, including T2DM and obesity. Novel neutral compounds with a benzene-sulfonamide scaffold were designed and synthesized based on structural- and ligand-based drug design strategies for fragment growth. Promising hits against PTP1B were identified through in vitro enzymology inhibition assay. Mechanistic aspects of the compound's different inhibition activities were rigorously investigated through molecular docking coupled with explicit dynamics simulations. Four identified hits, 3c, 8, 10a, and 11, with sub-micromolar PTP-1B IC₅₀ and significant predicted pharmacokinetic and pharmacodynamic parameters, were further biologically evaluated for their anti-diabetic, anti-obesity, anti-inflammatory, and anti-oxidant effects in a high-fat diet (HFD) + streptozotocin (STZ)-induced T2DM rat model. All these hit compounds exhibited a significant anti-diabetic and anti-obesity effect and a significant efficacy in reducing oxidative stress and increasing anti-oxidant enzymes while reducing inflammatory markers. Improving compound potency was further highlighted by improving the pharmacokinetic profile of the most active compound, 10a, through nano formulation. Compound 10a nano formulation showed the most promising anti-diabetic and anti-obesity effects and a remarkable histopathological improvement in all organs studied.

In our continued efforts to tackle antibiotic resistance, a new series of pyrazole-ciprofloxacin hybrids were designed, synthesized, and evaluated for their antibacterial activity against Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa), and Mycobacterium tuberculosis (Mtb). Most of the compounds exhibited good to excellent activities against S. aureus, and six compounds (7a, 7b, 7d, 7g, 7k, and 7p) exhibited higher or comparable activity (MIC = 0.125-0.5 μg mL^-1) to ciprofloxacin (0.125 μg mL^-1). Further, these selected compounds were non-toxic (CC₅₀ ≥ 1000 μg mL^-1) when evaluated for cell viability test against the Hep-G2 cell line. Three compounds (7a, 7d, and 7g) demonstrated excellent activity against ciprofloxacin-resistant S. aureus with MIC values ranging from 0.125-0.5 μg mL^-1 and good antibiofilm activity. Among them, 7g displayed remarkable antibiofilm activity with an MBIC₅₀ value of 0.02 μg mL^-1, which is 50 times lower than ciprofloxacin (MBIC₅₀ = 1.06 μg mL^-1). A time-kill kinetics study indicated that 7g showed both concentration and time-dependent bactericidal properties. In addition, 7g effectively inhibited DNA-gyrase supercoiling activity at 1 μg mL^-1 (8× MIC). Two compounds 7b and 7d exhibited the highest activity against Mtb with a MIC of 0.5 μg mL^-1, while 7c showed the highest activity against P. aeruginosa with a MIC value of 2 μg mL^-1. Molecular docking studies revealed that 7g formed stable interactions at the DNA active site.

The development of chemical scaffolds that target highly conserved MALAT1 RNA received attention due to its significance in splicing, nuclear organization, and gene expression in disease progression pathways. Here, we synthesized a series of N-fused quinazolino-quinazoline-diones via a PIDA-induced C-N coupling methodology to target MALAT1. Interestingly, compound 2z binds to the UUG pocket of a MALAT1 RNA triple-helix through intercalation, evidenced from molecular docking studies, fluorescence-based assay and CD experiments. 2z exhibited cytotoxicity towards MALAT1 overexpressing cancer cells (SKOV-3, IC₅₀ of 8.0 ± 0.4 μM). These findings demonstrated 2z as a MALAT1 RNA triple-helix intercalator with therapeutic potential, offering an important chemical scaffold to understand MALAT1 activity in disease development pathways.

The evolution of antimicrobial-resistant strains jeopardizes the existing clinical drugs and demands new therapeutic interventions. Herein, we report the synthesis of cationic thiazolidine bearing a quaternary pyridinium group, in which thiazolidine was N-acylated with fatty acid to establish a hydrophilic-lipophilic balance that disrupts bacterial membranes. The bacterial growth inhibition assays and hemolytic activity against human red blood cells indicate that the N-acylated cationic thiazolidine (QPyNATh) inhibits Gram-positive bacteria at lower minimum inhibitory concentrations (MIC) and is selective for bacteria over mammalian cells. N-Acylation modulates MIC, and it is found that the N-palmitoylated compound, QPyN16Th, had the lowest MIC (1.95 μM) against Gram-positive, Enterococcus faecalis, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). In contrast, the N-myristoylated compound, QPyN14Th, showed the lowest MIC (31.25 μM) against Gram-negative, Escherichia coli, uropathogenic Escherichia coli, and Pseudomonas aeruginosa. At 1× MIC, QPyNATh permeabilizes the bacterial membrane, depolarizes the cytoplasmic membranes, and produces excess reactive oxygen species to kill the bacteria, as evidenced by live and dead staining. Interestingly, only QPyNATh containing a palmitoyl acyl chain demonstrated membrane-damaging activity at 2 μM concentrations, suggesting that the optimal hydrophilic-lipophilic balance enables QPyN16Th to selectively kill Gram-positive bacteria at lower doses. S. aureus develops resistance to ciprofloxacin quickly; however, no resistance to QPyN16Th is observed after several passages. As a proof of concept, the animal study revealed that QPyN16Th treatment reduced the bacterial burden in MRSA-infected zebrafish, allowing them to recover from infection and resume normal life. The results imply that lipidation and derivatizing thiazolidine with cationic charge offer an antimicrobial that is selective to treat Gram-positive bacterial infections, biocompatible, and less prone to develop resistance.

Cyclic lipopeptides (CLiPs) are a highly diverse class of secondary metabolites produced by bacteria and fungi. Examples of CLiPs have been found that possess potent antimicrobial activity against multidrug-resistant Gram-negative bacteria. Globomycin is a 19-membered CLiP that kills both Gram-positive and Gram-negative bacteria through inhibition of lipoprotein signal peptidase II (Lsp). It can only be obtained in small quantities from its Streptomyces producer strain, so there has been much interest in development of synthetic methods to access globomycin and analogues. Globomycin contains an N-terminal anti-α-methyl-β-hydroxy nonanoyl lipid tail, whose hydroxyl group forms an ester with the C-terminal carboxylate. Constructing the anti-arrangement between the α-methyl and β-hydroxy is synthetically challenging and previous globomycin syntheses are not compatible with diversification of the lipid tail after the stereocenters have been installed. Herein, we describe a new approach for the synthesis of globomycin that allows for facile lipid diversification. Using an anti-Evans Aldol condensation, a common intermediate is obtained that allows different "lipid swapping" through Grubbs-catalyzed cross-metathesis. Upon auxiliary cleavage, the resulting lipid can then be utilized in solid-phase peptide synthesis. Given the plethora of lipopeptides that contain β-hydroxy lipids, this method offers a convenient approach for convergent generation of lipopeptide analogues.

The continuous mutational nature of SARS-CoV-2 and its inter-species' similarities emphasize the urgent need to design and develop more direct-acting antiviral agents against highly infectious variants. Herein, we report on the efficient discovery of potent non-covalent non-peptide-derived M^pro inhibitors using miniaturized click chemistry and direct screening. Based on the privileged piperazine scaffold, 68 triazole-containing derivatives were assembled and screened. Notably, representative compound C1N46 (IC₅₀ = 1.87 μM, EC₅₀ = 6.99 μM, CC₅₀ > 100 μM) displayed potent inhibition activity against M^pro and showed promising anti-SARS-CoV-2 properties in vitro. Additionally, C1N46 exhibited improved liver microsome stability compared to lead compound GC-14. Docking studies predicted a multi-site binding mode of the triazole-based compounds. In conclusion, our studies validate the efficacy and feasibility of click chemistry in rapidly discovering antiviral agents.

Antibody-drug conjugates (ADCs) have emerged as a powerful avenue in the therapeutic treatment of cancer. Site-specific antibody-drug conjugations represent the latest trend in the development of ADCs, addressing the limitations of traditional random conjugation technologies. This article summarizes the innovative development of Fc-glycan-specific ADCs (gsADCs), which utilize the conserved Fc N-glycan as the anchor point for site-specific conjugation. This approach offers significant strengths, including improved ADC homogeneity and overall hydrophilicity, enhanced pharmacokinetics and therapeutic index, and potentially reduced Fc receptor-mediated side effects. Currently dozens of gsADCs are in different preclinical and clinical development stages. Notably, JSKN003 and IBI343 have demonstrated promising results in phase 1 trials and are advancing into phase 3 studies. This review discusses the advantages of Fc-glycan-conjugation, various glycan-specific conjugation techniques, and the preclinical and clinical development of gsADCs. While challenges such as increased manufacturing cost for large-scale production need continuous innovation to overcome and there are different opinions regarding the pros and cons of reduced/diminished affinities to Fc gamma receptors, ongoing research and clinical progress underscore the potential of gsADCs to renovate ADC cancer therapy.

In this study, a series of 13 new D-ring fused steroidal N(2)-substituted-1,2,3-triazoles were synthesized, characterized and evaluated for their biological activities. The relative binding affinities of the synthesized compounds for the ligand-binding domains of estrogen receptors α and β, androgen receptor and glucocorticoid receptor demonstrated that androstane derivatives 3a and 3h and estratriene derivative 4e showed highly specific and strong binding affinity for estrogen receptor β, while 3b, 3e, 4a and 4b displayed high binding affinity for the glucocorticoid receptor. The synthesized compounds were tested for their ability to inhibit aldo-keto reductases 1C3 and 1C4 in vitro by monitoring NADPH consumption using fluorescence spectroscopy. The most potent aldo-keto reductase 1C3 inhibitors were compounds 3h (71.17%) and 3f (69.9%). Moreover, a molecular docking study was carried out for compounds 3f and 3h against aldo-keto reductase 1C3 and results showed that compounds 3h and 3f could bind in the same site and orientation as EM1404. However, polar atoms in the triazole group enable additional hydrogen bonding deeper in SP1 with Tyr319, Tyr216 and the NADP⁺ cofactor, which are not visible in the AKR1C3-EM1404 crystal structure. The synthesized compounds were screened for their anticancer activity against four cancer cell lines. Compound 3f demonstrated moderate toxic effects across various cancer types, while displaying lower toxicity towards the healthy cell line. In summary, our findings indicate that N(2)-substituted-1,2,3-triazoles are high-affinity ligands for estrogen receptor β and glucocorticoid receptor, inhibitors of aldo-keto reductase 1C3 enzyme, and exhibit antiproliferative effects against cancer cells, suggesting that they could serve as scaffolds for anticancer drug development.

Mycobacterium fortuitum is an emerging human pathogen, characterized by an increase in prevalence and antibacterial resistance over the years, highlighting the need for the development of new drugs against this rapidly growing nontuberculous mycobacterium (NTM). To support this crusade, this review summarizes findings from the past two decades concerning compounds with antimycobacterial activity against M. fortuitum. It identifies the most promising and effective chemical frameworks to inspire the development of new therapeutic alternatives for infections caused by this microorganism. Most compounds effective against M. fortuitum are synthetic, with macozinone, featuring a 2-piperazine-benzothiazinone framework, standing out as a notable drug candidate. Among natural products, the polyphenolic polyketide clostrubin and the sansanmycin peptide analogs have shown efficacy against this NTM. Some compounds' mechanisms of action on M. fortuitum have been studied, including NITD-916, which acts as an enoyl-acyl carrier protein reductase inhibitor, and TBAJ-5307, which inhibits F-ATP synthase. Moreover, this review discusses the pathogenic molecular mechanisms and potential therapeutic targets within this mycobacterium.