5-(3\'-Indolyl)oxazole moiety is a privileged heterocyclic scaffold, embedded in many biologically interesting natural products and potential therapeutic agents. Compounds containing this scaffold, whether from natural sources or synthesized, have demonstrated a wide array of biological activities. This has piqued the interest of synthetic chemists, leading to a large number of reported synthetic approaches to 5-(3\'-indolyl)oxazole scaffold in recent years. In this review, we comprehensively overviewed the different biological activities and chemical synthetic methods for the 5-(3\'-indolyl)oxazole scaffold reported in the literatures from 1963 to 2024. The focus of this study is to highlight the significance of 5-(3\'-indolyl)oxazole derivatives as the lead compounds for the lead discovery of anticancer, pesticidal, antimicrobial, antiviral, antioxidant and anti-inflammatory agents, to summarize the synthetic methods for the 5-(3\'-indolyl)oxazole scaffold. In addition, the reported mechanism of action of 5-(3\'-indolyl)oxazoles and advanced molecules studied in animal models are also reviewed. Furthermore, this review offers perspectives on how 5-(3\'-indolyl)oxazole scaffold as a privileged structure might be exploited in the future.

UNASSIGNED: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound.
UNASSIGNED: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry.
UNASSIGNED: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype.
UNASSIGNED: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.

The increasing resistance of Candida albicans against the currently available antifungal drugs has exerted enormous damage to human health. To develop novel and efficient antifungal agents with unique structure, a series of derivatives containing 5-nitrofuran scaffold (33 examples) were designed, synthesized, and screened the in vitro antifungal activities. Bioassay results disclosed that 5-nitrofuran derivatives could dramatically inhibit the growth of six strains of Candida albicans, particularly the drug-resistant clinical ones. There were ten kinds of compounds exhibited stronger inhibitory activities against tested fungi than those of fluconazole. For all tested fungi, B5 showed the highest activity with the MIC80 values of 0.25-8 µg/mL. The results of cytotoxicity assay displayed that B5 hardly influenced the growth of HL-7702 cell lines, consequently, it was safe for people and animals. The preliminary exploration of antifungal mechanism documented that B5 could destroy the morphology of tested fungi, facilitate the formation of reactive oxygen species, ultimately inhibited the proliferation of the tested fungi. In conclusion, a new and safe lead compound was successfully developed for the treatment of Candida albicans infection.

Global burden of hepatocellular carcinoma (HCC) is increasing. Chemotherapy and immunotherapy are the prevailing options for therapy. Developing new therapeutic strategies for HCC patients is still highly desirable. Recent studies demonstrate that cryptotanshinone is capable of inhibiting tumor growth in HCC and induces antitumor immunity in vitro. In our previous research, we discovered a new cryptotanshinone derivative 11 as an effective immunoregulatory enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor. This study aims to evaluate its in vitro and in vivo antitumor activity against hepatocellular carcinoma. 11 displayed robust anti-proliferative activity against HCC cell lines and promoted apoptosis of HCC cell line through the mitochondrial-mediated apoptotic pathway. In H22 tumor-bearing mice models, 11 exhibited significant in vivo anti-tumor activity with different administration routes. And no obvious toxicity was observed. RNA-seq analysis demonstrated the differential expressed genes and alteration of key pathways associated with immune responses after administration of 11. Up-regulation of anti-tumor cytokines and down-regulation of cytokines that promote tumor growth were indicated and further validated. Our study demonstrates that 11 exhibits promising anti-tumor activity both in vitro and in vivo against hepatocellular carcinoma cancer. It is a lead compound for HCC immunotherapy and is worthy for further development.

One of the main challenges in small molecule drug discovery is finding novel chemical compounds with desirable activity. Traditional drug development typically begins with target selection, but the correlation between targets and disease remains to be further investigated, and drugs designed based on targets may not always have the desired drug efficacy. The emergence of machine learning provides a powerful tool to overcome the challenge. Herein, a machine learning-based strategy is developed for de novo generation of novel compounds with drug efficacy termed DTLS (Deep Transfer Learning-based Strategy) by using dataset of disease-direct-related activity as input. DTLS is applied in two kinds of disease: colorectal cancer (CRC) and Alzheimer\'s disease (AD). In each case, novel compound is discovered and identified in in vitro and in vivo disease models. Their mechanism of actionis further explored. The experimental results reveal that DTLS can not only realize the generation and identification of novel compounds with drug efficacy but also has the advantage of identifying compounds by focusing on protein targets to facilitate the mechanism study. This work highlights the significant impact of machine learning on the design of novel compounds with drug efficacy, which provides a powerful new approach to drug discovery.

Chagas\' disease affects approximately eight million people throughout the world, especially the poorest individuals. The protozoan that causes this disease-Trypanosoma cruzi-has the enzyme cruzipain, which is the main therapeutic target. As no available medications have satisfactory effectiveness and safety, it is of fundamental importance to design and synthesize novel analogues that are more active and selective. In the present study, molecular docking and the in silico prediction of ADMET properties were used as strategies to optimize the trypanocidal activity of the pyrimidine compound ZN3F based on interactions with the target site in cruzipain. From the computational results, eight 4-amino-5-carbonitrile-pyrimidine analogues were proposed, synthesized (5a-f and 7g-h) and, tested in vitro on the trypomastigote form of the Tulahuen strain of T. cruzi. The in silico study showed that the designed analogues bond favorably to important amino acid residues of the active site in cruzipain. An in vitro evaluation of cytotoxicity was performed on L929 mammal cell lines. All derivatives inhibited the Tulahuen strain of T. cruzi and also exhibited lower toxicity to L929 cells. The 5e product, in particular, proved to be a potent, selective (IC50  = 2.79 ± 0.00 μM, selectivity index = 31.3) inhibitor of T. cruzi. The present results indicated the effectiveness of drugs based on the structure of the receptor, revealing the potential trypanocidal of pyrimidines. This study also provides information on molecular aspects for the inhibition of cruzipain.

Pseudomonas aeruginosa-induced biofilm infection is difficult to treat and poses a significant threat to public health. Our previous study found a new coumarin derivative LP4C which exerted potent in vitro and in vivo anti-biofilm activity against Pseudomonas aeruginosa; however, the underlying molecular mechanism and drug-likeness of LP4C is unclear. In this study, we confirmed that LP4C could inhibit the biofilm in dose-dependent manner without bactericidal activity. The transcriptomic profiling and RT-PCR result revealed that bacterial pyrimidine mediated the inhibitory activity of LP4C. The cell viability was not affected in LP4C treatment groups with the concentration under 200 μg/mL, and no death or toxicity sign was observed in mice treated by 20, 40 and 80 mg/kg LP4C during the three-week test period. Ames test presented that LP4C had no effect on the bacterial reverse mutation. In additional, pharmacokinetic results showed that LP4C was likely to have the orally bioavailable properties. Our data indicate that LP4C is a possible lead compound for the development of new anti-biofilm infection agents against Pseudomonas aeruginosa.

Src homology 2 domain-containing phosphatase 2 (SHP2) is a cytoplasmic protein tyrosine phosphatase (PTP) that regulates signal transduction of receptor tyrosine kinases (RTKs). Abnormal SHP2 activity is associated with tumorigenesis and metastasis. Because SHP2 contains multiple allosteric sites, identifying inhibitors at specific allosteric binding sites remains challenging. Here, we used structure-based virtual screening to directly search for the SHP2 \"tunnel site\" allosteric inhibitor. A novel hit (70) was identified as the SHP2 allosteric inhibitor with an IC50 of 10.2 μM against full-length SHP2. Derivatization of hit compound 70 using molecular modeling-guided structure-based modification allowed the discovery of an effective and selective SHP2 inhibitor, compound 129, with 122-fold improved potency compared to the hit. Further studies revealed that 129 effectively inhibited signaling in multiple RTK-driven cancers and RTK inhibitor-resistant cancer cells. Remarkably, 129 was orally bioavailable (F = 55%) and significantly inhibited tumor growth in haematological malignancy. Taken together, compound 129 developed in this study may serve as a promising lead or candidate for cancers bearing RTK oncogenic drivers and SHP2-related diseases.

The ocean has always been one of the important sources of natural products. In recent years, many natural products with different structures and biological activities have been obtained, and their value has been clearly recognized. Researchers have been deeply engaged in the field of separation and extraction, derivative synthesis, structural studies, biological evaluation, and other fields of research for marine natural products. Thus, a series of marine indole natural products which have structural and biological prospect have caught our eyes. In this review, we summarize some of these marine indole natural products with relatively good pharmacological activity and research value, and discuss issues concerning chemistry, pharmacological activity, biological evaluation, and synthesis, including monomeric indoles, indole peptides, bis-indoles, and annelated indoles. Most of the compounds have cytotoxic, antiviral, antifungal, or anti-inflammatory activities.

A series of alkynyl-containing maleimides with potent anti-tuberculosis (TB) activity was developed through a rigid group substitution strategy based on our previous study. Systematic optimization of the two side chains flanking the maleimide core led to new compounds with potent activity against Mycobacterium tuberculosis (MIC < 1 μg/mL) and low cytotoxicity (IC50 > 64 μg/mL). Among them, compound 29 not only possessed good activity against extensively drug-resistant TB and favorable hepatocyte stability, but also displayed good intracellular antimycobacterial activity in macrophages. This study lays a good foundation for identifying new alkynyl-containing maleimides as promising leads for treating drug-resistant TB.