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Abstract Tuberculosis (TB) remains a significant public health concern in the 21st century, especially due to drug resistance, coinfection with diseases like immunodeficiency syndrome (AIDS) and coronavirus disease 2019, and the lengthy and costly treatment protocols. In this review, we summarize the pathogenesis of TB infection, therapeutic targets, and corresponding modulators, including first‐line medications, current clinical trial drugs and molecules in preclinical assessment. Understanding the mechanisms of Mycobacterium tuberculosis (Mtb) infection and important biological targets can lead to innovative treatments. While most antitubercular agents target pathogen‐related processes, host‐directed therapy (HDT) modalities addressing immune defense, survival mechanisms, and immunopathology also hold promise. Mtb’s adaptation to the human host involves manipulating host cellular mechanisms, and HDT aims to disrupt this manipulation to enhance treatment effectiveness. Our review provides valuable insights for future anti‐TB drug development efforts.

Abstract Dihydroorotate dehydrogenase (DHODH) is a quite attractive target in cancer therapy. Nevertheless, the antitumor effects of DHODH inhibitors against colorectal cancer (CRC) and the underlying mechanism have seldom been studied. Here, we explored the anti‐CRC efficacy of M62, a novel and potent DHODH inhibitor. In the study, M62 significantly inhibited the proliferation of CRC cells and induced S phase arrest. The antiproliferative effects caused by M62 were rescued by uridine supplementation. Mechanistically, messenger RNA sequencing results showed that M62‐triggered gene changes related to mitochondrial dysfunction, DNA damage, and DNA damage repair. Further validation showed that M62 treatment induced the generation of reactive oxygen species and decreased ΔΨm and ATP production. Meanwhile, M62 induced the accumulation of γ‐H2AX and longer comet tail moment, which were both markers of DNA damage. The downregulated DNA repair proteins and PI3K/ATK pathway were observed after M62 treatment. Furthermore, M62 significantly inhibited CRC xenograft tumor growth without detectable toxicity. Therefore, we conclude that M62 inhibits CRC growth both in vitro and in vivo by causing mitochondrial dysfunction and DNA damage, suggesting that DHODH inhibitors are potential therapeutic strategies for treating CRC.

Abstract Ovarian cancer (OC) is currently one of the most life‐threatening types of gynecological malignancy with limited treatment options and poor clinical outcomes. Human caseinolytic protease P (HsClpP) is located in the mitochondria and plays an important role in several tumors. Moreover, HsClpP is overexpressed in OC and several other tumor cells. Thus, HsClpP modulation is regarded as a potential approach for OC treatment. In this study, we identified and validated a novel boron peptide Compound 43‐8F as a potent HsClpP inhibitor. Upon 43‐8F treatment, mitochondrial damage was observed to be closely correlated with upregulated intracellular reactive oxygen species production, decreasement of membrane potential, and ATP content suppression. Meanwhile, the expression level of SDHB and the ATF4 was increased after 43‐8F treatment, suggesting that 43‐8F treatment induces mitochondrial respiratory disorders and activates the integrated stress response pathway to inhibit tumor cell growth. Further, 43‐8F exhibited a good therapeutic and safety profile in OC xenograft model in nude mice. Together, these results suggest that 43‐8F exerts an anti‐ovarian cancer effect by inhibiting HsClpP pathway.

Human dihydroorotate dehydrogenase (DHODH), the enzyme that catalyzes the rate‐limiting step in de novo pyrimidine biosynthesis, is considered to be an attractive target for potential treatment of autoimmune disease and cancer. Here, we present a novel class of human DHODH inhibitors with high inhibitory potency. The high‐resolution crystal structures of human DHODH complexed with various agents reveal the details of their interactions. Comparisons with the binding modes of teriflunomide and brequinar provide insights that may facilitate the development of new inhibitors targeting human DHODH.

Dental caries is a chronic oral infectious disease caused by cariogenic biofilm adhered on the tooth surface. Our previous study demonstrated that a repurposed natural compound napabucasin (NAP) showed good antimicrobial activity against oral streptococcal biofilms. The current study designed a novel small molecule, namely LCG-N25, using NAP as a lead compound, and aimed to investigate its potential as an antimicrobial agent in the control of dental caries. LCG-N25 was designed and synthesized with reference to the structure of NAP. The minimal inhibitory concentrations and the minimal bactericidal concentrations of LCG-N25 against Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii were evaluated by microdilution method. The antimicrobial activity of LCG-N25 was further evaluated by crystal violet staining, colony forming units counting, biofilm metabolism assay, dead/live fluorescent staining, and scanning electron microscopy. The effect of LCG-N25 on the extracellular polysaccharides of biofilms was determined by both anthrone-sulfuric acid method and fluorescent staining. The microbial composition of streptococcal biofilms after LCG-N25 treatment was further visualized and quantified by fluorescence in situ hybridization. Besides, the cytotoxicity of LCG-N25 was evaluated by Cell Counting Kit-8 assay, and repeated exposure of S. mutans to LCG-N25 treatment was performed to assess if this novel compound could induce drug resistance of this cariogenic bacterium. We found that LCG-N25 exhibited a good antibacterial activity, low-cytotoxicity, and did not induce drug resistance of cariogenic S. mutans. These findings suggest that LCG-N25 may represent a promising antimicrobial agent that can be used as an adjuvant to the management of dental caries.

Background Limitations of current intracanal irrigants such as sodium hypochlorite (NaOCl) and chlorhexidine (CHX) necessitate the development of novel antimicrobial agents to control endodontic infection. Aim This study investigated the antimicrobial activities of a small molecule II-6s against Enterococcus faecalis associated with endodontic diseases. Methods The susceptibility of E. faecalis to II-6s was evaluated by the microdilution method and time-kill assay. Microbial resistance was assessed by repeated exposure of E. faecalis to II-6s. Cytotoxicity of II-6s was evaluated by CCK-8 assay. Virulence gene expression of the II-6s-treated E. faecalis cells was measured by RT-qPCR. Bacterial reductions in the dentinal tubules were further assessed by confocal laser scanning microscopy. Results II-6s exhibited potent antimicrobial activity against E. faecalis and down-regulated virulence-associated genes in E. faecalis. II-6s induced no drug resistance in E. faecalis with lower cytotoxicity as compared to NaOCl and CHX. More importantly, 0.003125% II-6s exhibited significant bactericidal effect against E. faecalis residing in the dentinal tubules, which was comparable to 5.25% NaOCl and 2% CHX. Conclusions II-6s has excellent antimicrobial activity, moderate cytotoxicity and induces no drug resistance, and thus is a promising agent for the treatment of endodontic infection.

Background: The side effects of present antimicrobials like chlorhexidine (CHX) and the emergence of drug resistance necessitate the development of alternative agents to control dental caries. Aim: This study developed a novel small molecule, namely II-6s, and investigated its antimicrobial activities against common oral streptococci associated with dental caries. Methods: The susceptibility of streptococci to II-6s was evaluated by the microdilution method, time-kill assay and scanning electron microscopy. The exopolysaccharides, dead/live bacteria and bacterial composition of the II-6s-treated Streptococcus mutans/Streptococcus gordonii/Streptococcus sanguinis 3-species biofilms were analyzed by confocal laser scanning microscopy, fluorescent in situ hybridization and quantitative PCR. The anti-demineralization effect and cytotoxicity of II-6s were evaluated by transverse microradiography and CCK-8 assay, respectively. Repeated exposure of S. mutans to II-6s was performed to assess if II-6s could induce drug resistance. Results: II-6s exhibited antimicrobial activity similar to CHX against S. mutans, S. gordonii and S. sanguinis and significantly inhibited exopolysaccharides production, live bacteria and the demineralizing capability of the 3-species streptococcal biofilms. Besides, II-6s showed reduced cytotoxicity relative to CHX and did not induce drug resistance in S. mutans after 15 passages. Conclusion: - II-6s may serve as a promising part of a successful caries management plan.

In the title compound, C13H13FN2O3, the fused piperidine ring is in a chair conformation. The fused pyrrolidine ring shows an envelope conformation with the N atom displaced by 0.661 (3) Å out of the plane formed by the four C atoms of the pyrrolidine ring. The dihedral angle between this plane and the plane formed by the four attached C atoms of the piperidine ring (not including the carbonyl C atom) is 67.63 (10)°. The F atom is disordered and was refined using a split model with an occupancy ratio of 0.910 (3): 0.080 (3).

In the molecule of the title compound, C13H13BrN2O2S, the dihedral angle formed by the pyridine and benzene rings is 66.87 (3)°. An intramolecular N—H...Br hydrogen bond is observed. In the crystal structure, N—H...O hydrogen bonds, C—H...π interactions and aromatic π–π stacking interactions [centroid–centroid distance = 3.757 (14) Å] link the molecules into a three-dimensional network.

A series of ( E)-3-(aryl(arylamino)methylene)indolin-2-one derivatives were synthesised using an efficient synthetic approach. The method involved reaction of 3-bromo-3-(bromo(aryl)methyl)indolin-2-one with substituted anilines through nucleophilic substitution and a simultaneous elimination using NaHCO3 in DMF. The anticancer activity of the products against four cell lines, HCT-116, A549, SKOV3 and MDA-MB-231, was also evaluated, and several compounds showed moderate inhibitory activity. [ABSTRACT FROM AUTHOR]

A series of 1H-thieno[2,3-c]chromen-4(2H)-one derivatives were synthesised through Knoevenagel condensation of substituted flavanones with thiazolidine-2,4-dione in ethanol in the presence of piperidine. The mechanism of the reaction was proposed. All synthesised compounds were characterised by IR, 1H NMR, 13C NMR, HRMS, and elemental analysis. The structure of 2-(3-chlorophenyl)-1H-thieno[2,3-c]chromen-4(2H)-one was confirmed by a single crystal X-ray diffraction analysis. A preliminary antitumour screening showed that 2-(2-fluorophenyl)-1H-thieno [2,3-c]chromen-4(2H)-one had moderate to good activity against A549, BGC-823, HCT116 and MDA-MB-453 cancer cell lines, and 2-(3,4-dimethoxyphenyl)-1H-thieno[2,3-c]chromen-4(2H)-one displayed similar activity against these four kinds of cancer cells compared with the reference drug. [ABSTRACT FROM AUTHOR]

DB-6, with an IUPAC name of (Z)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5′-methyl-7,7′-dimethoxy-[4,4′-bibenzo[d][1,3]dioxole]-5,5′-dicarboxylate, is an investigational agent for acute liver failure. The focus of this study is the identification and characterization of major unknown impurities in DB-6 bulk drug samples. Four major impurities of DB-6 were detected by a high-performance liquid chromatography (HPLC) method and designated as IMP-I, IMP-II, IMP-III and IMP-IV. Accurate masses of these impurities were determined by using a Q-TOF mass spectrometer. Based on chromatographic, spectrometric data and plausible chemical transformation mechanism, the structures of IMP-I, IMP-II, IMP-III and IMP-IV were identified, respectively, as bifendate, (E)-5-(2,4-di-tert-butyl-6-((2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-5′-methyl-7,7′-dimethoxy-[4,4′-bibenzo[d][1,3]dioxole]-5,5′-dicarboxylate, (Z)-5-(3,5-di-tert-butyl-2-hydroxybenzylidene) thiazolidine-2,4-dione and bis(2,4-di-tert-butyl-6-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)phenyl)-7,7′-dimethoxy-[4,4′-bibenzo[d][1,3]dioxole]-5,5′-icarboxylate. The impurities were isolated by preparative-HPLC or preparative high-speed counter-current chromatography and their structures were confirmed by NMR spectroscopy. [ABSTRACT FROM AUTHOR]

An increasing number of studies have suggested that phosphoinositide 3-kinase-γ (PI3Kγ) and PI3Kδ are involved in the pathogenesis of autoimmune and inflammatory diseases, such as asthma and atherosclerosis. However, the underlying mechanism of acute hepatitis remains unknown. The present study aimed to determine the effect of PI3Kδ/γ inhibition on hepatic injury in a murine model of hepatitis induced by concanavalin A (ConA). It was demonstrated that the pharmacological inhibition of PI3Kδ/γ by TG100-115 did not prevent liver damage following ConA challenge. Furthermore, the PI3Kδ/γ inhibition resulted in elevated transaminase activity in the serum, aggravated hepatic lesions characterized by hepatic necrosis, increased inflammatory cell infiltration and apoptosis of hepatocytes. Survival tests demonstrated that TG100-115 significantly increased the death rate of mice following ConA challenge. In addition, TG100-115 increased the serum levels of the proinflammatory cytokine IL-2 following ConA injection. These results may oppose the development of PI3Kδ/γ inhibitors as therapeutic agents, particularly for the treatment of human hepatitis. [ABSTRACT FROM AUTHOR]

Reversible or phenotypic tolerance to antibiotics within microbial populations has been implicated in treatment failure of chronic infections and development of persister cells. However, the molecular mechanisms regulating phenotypic drug tolerance are largely unknown. In this study, we identified a four-gene operon in Streptococcus pneumoniae that contributes to phenotypic tolerance to vancomycin (ptv). RNA sequencing, quantiative reverse transcriptase PCR, and transcriptional luciferase reporter experiments revealed that transcription of the ptv operon (consisting of ptvR, ptvA, ptvB, and ptvC) is induced by exposure to vancomycin. Further investigation showed that transcription of the ptv operon is repressed by PtvR, a PadR family repressor. Transcriptional induction of the ptv operon by vancomycin was achieved by transcriptional derepression of this locus, which was mediated by PtvR. Importantly, fully derepressing ptvABC by deleting ptvR or overexpressing the ptv operon with an exogenous promoter significantly enhanced vancomycin tolerance. Gene deletion analysis revealed that PtvA, PtvB, and PtvC are all required for the PtvR-regulated phenotypic tolerance to vancomycin. Finally, the results of an electrophoretic mobility shift assay with recombinant PtvR showed that PtvR represses the transcription of the ptv operon by binding to two palindromic sequences within the ptv promoter. Together, the ptv locus represents an inducible system in S. pneumoniae in response to stressful conditions, including those caused by antibiotics. [ABSTRACT FROM AUTHOR]