Search Results (4)

RhoA-regulated gene transcription by serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factors (MRTFs) signaling pathway has emerged as a promising therapeutic target for pharmacological intervention in multiple diseases. Altered mitochondrial metabolism is one of the major hallmarks of cancer, therefore, this upregulation is a vulnerability that can be targeted with Rho/MRTF/SRF inhibitors. Recent advances identified a novel series of oxadiazole-thioether compounds that disrupt the SRF transcription, however, the direct molecular target of these compounds is unclear. Herein, we demonstrate the Rho/MRTF/SRF inhibition mechanism of CCG-203971 and CCG-232601 in normal cell lines of human lung fibroblasts and mouse myoblasts. Further studies investigated the role of these molecules in targeting mitochondrial function. We have shown that these molecules hyperacetylate histone H4K12 and H4K16 and regulate the genes involved in mitochondrial function and dynamics. These small molecule inhibitors regulate mitochondrial function as a compensatory mechanism by repressing oxidative phosphorylation and increasing glycolysis. Our data suggest that these CCG molecules are effective in inhibiting all the complexes of mitochondrial electron transport chains and further inducing oxidative stress. Therefore, our present findings highlight the therapeutic potential of CCG-203971 and CCG-232601, which may prove to be a promising approach to target aberrant bioenergetics. Full article

Plant diseases caused by phytopathogenic fungi are a serious threat in the process of crop production and cause large economic losses to global agriculture. To obtain high-antifungal-activity compounds with novel action mechanisms, a series of 4-substituted mandelic acid derivatives containing a 1,3,4-oxadiazole moiety were designed and synthesized. In vitro bioassay results revealed that some compounds exhibited excellent activity against the tested fungi. Among them, the EC₅₀ values of E₁₃ against Gibberella saubinetii (G. saubinetii), E₆ against Verticillium dahlia (V. dahlia), and E₁₈ against Sclerotinia sclerotiorum (S. sclerotiorum) were 20.4, 12.7, and 8.0 mg/L, respectively, which were highly superior to that of the commercialized fungicide mandipropamid. The morphological studies of G. saubinetii with a fluorescence microscope (FM) and scanning electron microscope (SEM) indicated that E₁₃ broke the surface of the hyphae and destroyed cell membrane integrity with increased concentration, thereby inhibiting fungal reproduction. Further cytoplasmic content leakage determination results showed a dramatic increase of the nucleic acid and protein concentrations in mycelia with E₁₃ treatment, which also indicated that the title compound E₁₃ could destroy cell membrane integrity and affect the growth of fungi. These results provide important information for further study of the mechanism of action of mandelic acid derivatives and their structural derivatization. Full article

A series of myricetin derivatives containing amide, thioether, and 1,3,4-thiadiazole moieties were designed and synthesized, and their antiviral and antibacterial activities were assessed. The bioassays showed that all the title compounds exhibited potent in vitro antibacterial activities against Xanthomonas citri (Xac), Ralstonia solanacearum (Rs), and Xanthomonas oryzae pv. Oryzae (Xoo). In particular, the compounds 5a, 5f, 5g, 5h, 5i, and 5l, with EC₅₀ values of 11.5–27.3 μg/mL, showed potent antibacterial activity against Xac that was better than the commercial bactericides Bismerthiazol (34.7 μg/mL) and Thiodiazole copper (41.1% μg/mL). Moreover, the in vivo antiviral activities against tobacco mosaic virus (TMV) of the target compounds were also tested. Among these compounds, the curative, protection, and inactivation activities of 5g were 49.9, 52.9, and 73.3%, respectively, which were better than that of the commercial antiviral Ribavirin (40.6, 51.1, and 71.1%, respectively). This study demonstrates that myricetin derivatives bearing amide, thioether, and 1,3,4-thiadiazole moieties can serve as potential alternative templates for the development of novel, highly efficient inhibitors against plant pathogenic bacteria and viruses. Full article

S-Alkylation of 5-(diphenylmethyl)-1,3,4-oxadiazole-2(3H)-thione (3) by 2-chloro-N-(pyrazin-2-yl)acetamide (2) affords the title compound, 2-{[5-(diphenylmethyl)-1,3,4-oxadiazol-2-yl]sulfanyl}-N-(pyrazin-2-yl)acetamide (4). The intermediate (2), in turn, was prepared by the acetylation of 2-aminopyrazine (1) with chloroacetyl chloride. The structure of the newly synthesized compound is characterized by IR, NMR and mass spectral data. Full article