The isatin group is widespread in nature and is considered to be a privileged building block for drug discovery. In order to develop novel SHP1 inhibitors with fluorescent properties as tools for SHP1 biology research, this work designed and synthesized a series of isatin derivatives. The presentive compound 5a showed good inhibitory activity against SHP1PTP with IC50 of 11 ± 3 μM, displayed about 92% inhibitory rate against MV-4-11 cell proliferation at the concentration of 20 μM, exhibited suitable fluorescent properties with a long emission wavelength and a large Stokes shift, and presented blue fluorescent imaging in HeLa cells with low cytotoxicity. This study could offer chemical tool to further understand SHP1 biology and develop novel SHP1 inhibitors in therapy.

New chiral ligands could be obtained by introducing proline moieties and imidazoline moieties to binaphthyl skeletons. The chiral ligands exhibited balanced rigidity and flexibility which could allow the change of the conformations during the reactions on one hand, and could provide sufficient asymmetric induction on the other. The proline moiety could act as a linker connecting the binaphthyl skeletons and the imidazoline moieties as well as a coordinating group for the central metal, and the electronic and steric properties of the imidazoline groups could be carefully fine-tuned by the use of different substituents. In the presence of Cu(II) catalyst bearing such chiral ligands, aza-Friedel-Crafts reaction of 1-naphthols and electron-rich phenols with isatin-derived ketimines provided the desired products with good to excellent yields and up to 99 % ee. The reactions showed good scalability, and excellent ee could still be obtained when the reaction was carried out in gram-scale.

UNASSIGNED: Postoperative cognitive dysfunction (POCD) is a central nervous system complication that occurs after anesthesia, particularly among the elderly. However, the neurological pathogenesis of postoperative cognitive dysfunction remains unclear. The aim of this study was to evaluate the effects of sevoflurane exposure on serum metabolites and hippocampal gene expression in elderly patients and aging mice by metabolomics and transcriptomic analysis and to explore the pathogenesis of sevoflurane induced POCD.
UNASSIGNED: Human serum samples from five patients over 60 years old were collected before sevoflurane anesthesia and 1 hour after anesthesia. Besides, mice aged at 12 months (n=6 per group) were anesthetized with sevoflurane for 2 hours or with sham procedure. Subsequently, serum and hippocampal tissues were harvested for analysis. Further investigation into the relationship between isatin and neuroinflammation was conducted using BV2 microglial cells.
UNASSIGNED: Sevoflurane anesthesia led to the activation of inflammatory pathways, an increased presence of hippocampal astrocytes and microglia, and elevated expression of neuroinflammatory cytokines. Comparative analysis identified 12 differential metabolites that exhibited changes in both human and mouse serum post-sevoflurane anesthesia. Notably, isatin levels were significantly decreased after anesthesia. Notably, isatin levels significantly decreased after anesthesia, a factor known to stimulate proliferation and proinflammatory gene expression in microglia-the pivotal cell type in inflammatory responses.
UNASSIGNED: Sevoflurane-induced alterations in serum metabolites in both elderly patients and aging mice, subsequently contributing to increased inflammation in the hippocampus.

A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 μM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.

Eleven two-carbon tethered artemisinin-isatin hybrids (4a-k) were designed, synthesized, and evaluated for their antiproliferative activity against MCF-7, MDA-MB-231, and MDA-MB-231/ADR breast cancer cell lines, as well as cytotoxicity toward MCF-10A cells in this paper. Among them, the representative hybrid 4a (IC50: 2.49-12.6 µM) was superior to artemisinin (IC50: 72.4->100 µM), dihydroartemisinin (IC50: 69.6-89.8 µM), and Adriamycin (IC50: 4.46->100 µM) against the three tested breast cancer cell lines. The structure-activity relationship revealed that the length of the alkyl linker between artemisinin and isatin was critical for the activity, so further structural modification could focus on evaluation of the linker. The in silico studies were used to investigate the mechanism of the most promising hybrid 4a. Target prediction, bioinformatics, molecular docking, and molecular dynamics revealed that the most promising hybrid 4a may exert anti-breast cancer activity by acting on multiple targets such as EGFR, PIK3CA, and MAPK8 and thus participating in multiple tumor-related signaling pathways.

Skin is the most important defense shield which touched external environment directly. Effectively clearing microbes in infected wound via non-antibiotic therapy is crucial for the promotion of recovery in complex biological environments, and the wound healing is a crucial process after sterilization to avoid superinfection. Herein, a kind of Prussian blue-based photothermal responsive gel, Bletilla striata polysaccharide-mingled, isatin-functionalized Prussian blue gel (PB-ISA/BSP gel) was reported for effective treatment of bacterial infection and wound healing. The introduction of effective components of traditional Chinese medicine (TCM), isatin (ISA), enhanced the efficiency of sterilization synergistically. Furthermore, the process of wound healing was promoted by Bletilla striata polysaccharides (BSP). PB-ISA@BSP had a considerable antibacterial rate with 98.5 % under an 808 nm laser for 10 min in vitro. Besides, PB-ISA/BSP gel showed an effective antibacterial efficacy in vivo and a fast wound healing rate as well. The as-prepared functional particles can invade and destroy bacteria membrane to kill microbes. This work highlights that PB-ISA/BSP gel is a promising antibacterial agent based on synergistically enhanced photothermal effect and wound healing promotion ability and provides inspiration for future therapy based on the synergy between photothermal agent and active components in TCM.

Multicomponent reactions (MCRs) have undoubtedly emerged as the most indispensable tool for organic chemists worldwide, finding extensive utility in the synthesis of intricate natural products, heterocyclic molecules with significant bioactivity, and pharmaceutical agents. The multicomponent one-pot 1,3-dipolar cycloaddition reactions, which were initially conceptualized by Rolf Huisgen in 1960, find extensive application in contemporary heterocyclic chemistry. In terms of green synthesis, the multicomponent 1,3-dipolar cycloaddition is highly favored owing to its numerous advantages, including high step- and atom-economies, remarkable product diversity, as well as excellent efficiency and diastereoselectivity. Among the numerous pieces of research, the most fascinating reaction involves the utilization of azomethine ylides generated from isatins and amino acids that can be captured by various dipolarophiles. This approach offers a highly efficient and convenient method for constructing spiro-pyrrolidine oxindole scaffolds, which are crucial building blocks in biologically active molecules. Consequently, this review delves deeper into the dipolarophiles utilized in the 1,3-dipolar cycloaddition of isatins and amino acids over the past six years.

A convenient synthetic procedure for the construction of novel dispirooxindole motifs was successfully developed by base-promoted three-component reaction of ammonium acetate, isatins and in situ-generated 3-isatyl-1,4-dicarbonyl compounds. The piperidine-promoted three-component reaction of ammonium acetate, isatins and the in situ-generated dimedone adducts of 3-ethoxycarbonylmethyleneoxindoles afforded mutlifunctionalized dispiro[indoline-3,2\'-quinoline-3\',3\'\'-indoline] derivatives in good yields and with high diastereoselectivity. On the other hand, a similar reaction of the dimedone adducts of 3-phenacylideneoxindoles afforded unique dispiro[indoline-3,2\'-pyrrole-3\',3\'\'-indoline] derivatives with a cyclohexanedione substituent. A plausible reaction mechanism is proposed to explain the formation of the different spirooxindoles.

New Delhi metallo-β-lactamase-1 (NDM-1) poses a threat to public health due to its capability to hydrolyze nearly all β-lactam antibiotics, leaving limited treatment options for NDM-1 positive pathogens. Regrettably, there are presently no effective NDM-1 inhibitors in clinical use. This compels us to seek new compounds to combat multi-drug resistant bacterial infections (MDR). In our study, Zndm19 was identified as a new NDM-1 inhibitor through virtual screening and an NDM-1 enzyme activity inhibition assay. Subsequently, we employed the checkerboard method, time-killing assay, and combined disk test to investigate the synergistic bactericidal efficacy of Zndm19 in combination with meropenem (MEM). Meanwhile, molecular docking and site-directed mutagenesis were conducted to uncover the crucial amino acid residues engaged in Zndm19 binding. Finally, we established a mice peritonitis infection model to assess the synergistic effect of Zndm19 and MEM in vivo. Our findings demonstrated that 16 µg/mL of Zndm19 inhibited NDM-1 activity without affecting NDM-1 expression, restoring the bactericidal activity of MEM against NDM-1-positive Escherichia coli in vitro. Furthermore, MET-67, ASP-124, HIS-189, and HIS-250 amino acid residues constituted the active site of Zndm19 in NDM-1. Importantly, this combination therapy exhibited synergistic anti-infection activity in the mice peritonitis infection model, leading to an approximate 60% increase in survival rates and reduction of tissue bacterial load, effectively combating bacterial infection in vivo. In summary, our research validates that the synthetic novel NDM-1 inhibitor Zndm19 holds promise as a drug to treat drug-resistant bacterial infections, especially those harboring NDM-1.

Breast cancer (BC) is one of the most prevalent malignancies and the major contributor to cancer mortality in women globally, with a high degree of heterogeneity and a dismal prognosis. As drug resistance is responsible for most BC fatalities and advanced BC is currently considered incurable, finding innovative anti-BC chemotherapeutics is urgently required. Indole and its analog isatin (indole-1H-2,3-dione) are prominent pharmacophores in the development of novel medications, and their derivatives exhibit strong anticancer activities, also against BC. In particular, indole/isatin hybrids exhibit significant potency against BC including multidrug-resistant forms and excellent selectivity by influencing a variety of biological targets associated with the disease, supplying helpful building blocks for the identification of potential new BC treatment options. This review includes articles from 2020 to the present and provides insights into the in vitro and in vivo anti-BC potential, molecular mechanisms, and structure-activity relationships (SARs) of indole/isatin hybrids that may be helpful in the development of innovative anti-BC chemotherapeutics.