Forty-four benzofuroxan derivatives were designed and prepared as antifungal agents. Their structures were characterized by 1H NMR, 13C NMR, and HRMS. Their antifungal activities were tested in vitro ...with four important phytopathogenic fungi, namely, Rhizoctonia solani, Sclerotinia sclerotiorum, Fusarium graminearum and Phytophthora capsici, using the mycelium growth inhibition method. Compound A5 displayed the maximum antifungal activity against F. graminearum (IC50 = 1.1 μg/mL, which is about 2-fold higher than that of the well-known positive control carbendazim (IC50 = 0.5 μg/mL). A14 exhibited high antifungal effect against both S. sclerotiorum and F. graminearum Sehw., with IC50 values of 2.52 and 3.42 μg/mL, respectively. Among 14 benzofuroxan derivatives with substitutions at the R2 and R3 positions of the phenyl ring (B series), 7 compounds displayed strong growth inhibition against R. solani (IC50 ≤ 3.0 μg/mL). Analysis of the structure–activity relationship data of these compounds revealed that (1) introduction of an electron-donating amino group to the R2 position of the phenyl ring favors antifungal activity against R. solani and (2) the presence of a nitro group at the R4 position and substituent variation at the R1 position of the phenyl ring can result in good antifungal candidates against F. graminearum Sehw. Overall, the benzofuroxan was discovered as a novel scaffold for the development of fungicides. Significantly, A14 was demonstrated to successfully suppress disease development in S. sclerotiorum infected cole in vivo.
Gastric cancer is a highly metastatic malignant tumor with high morbidity and mortality globally. Recent studies reported that sulfonamide derivatives such as indisulam exhibited inhibitory effects ...on the viability and migration of cancer cells. However, multiple clinical trials revealed that indisulam did not significantly prevent cancer progression due to metastasis and drug resistance. Therefore, it is necessary to discover new potent derivatives to explore alternative therapeutic strategies. Here, we synthesize multiple indisulam derivatives and examine their inhibitory effects on the viability and migration of gastric cancer cells. Among them, compounds SR‐3‐65 and WXM‐1‐170 exhibit better inhibitory effects on the migration of gastric cancer cells than indisulam. Mechanistically, we discover that they could attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway and lead to the suppression of epithelial-to-mesenchymal transition (EMT)-related transcription factors. The influence of SR‐3‐65 on the migration of gastric cancer cells is blocked by the PI3K inhibitor LY294002 while SR‐3‐65 and WXM‐1‐170 reverse the effect of PI3K activator 740 Y-P on the migration of gastric cancer cells. Molecular docking and molecular dynamics simulation further confirm that PI3K is the target of SR‐3‐65. Our study unveils a novel mechanism by which SR‐3‐65 and WXM‐1‐170 inhibit the migration of gastric cancer cells. Together with the previous discovery, we reveal that subtle structural change in indisulam results in a striking switch on the molecular targets and their associated signaling pathways for the inhibition of the migration of gastric cancer cells. These findings might provide informative insights for the development of targeted therapy for gastric cancer.
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•SR‐3‐65 and WXM‐1‐170 exhibit better inhibition on gastric cancer cell migration.•SR‐3‐65 and WXM‐1‐170 attenuate the PI3K/AKT/GSK-3β/β-catenin signaling pathway.•The influence of SR‐3‐65 on the migration is blocked by the PI3K inhibitor LY294002.•SR‐3‐65 and WXM‐1‐170 reverse the effect of PI3K activator 740 Y-P on migration.•Subtle structural change results in a striking switch in the molecular targets.
The IC50s of seven potent N,N′-arylurea compounds against juvenile and adult S. japonicum. Compounds 16 and 38 showed higher activities than the positive control MMV665852. Display omitted
Although ...the antischistosomal activities of N,N′-arylurea analogs were reported, systematic structure–activity relationships have not been conducted. In this Letter, we reported the design, synthesis and evaluation of 45 N,N′-arylurea analogs. Among these prepared compounds, 13 compounds were urea linker modified and 32 were N,N′-arylurea derivatives. The activity evaluation revealed 12 analogs exhibited IC50 values lower than 22.6μM, and 7 of them had IC50 less than 10μM against the juvenile Schistosoma japonicum in vitro. Their worm killing potency was even higher against adult worm. Unfortunately, low to moderate worm burden reduction of 0–33.4% was recorded after administration of a single oral dose of 200mg/kg or 400mg/kg to mice harboring S. japonicum.
A rationally designed nucleoside inhibitor of Mycobacterium tuberculosis growth (MIC(99) = 0.19 microM) that disrupts siderophore biosynthesis was identified. The activity is due to inhibition of the ...adenylate-forming enzyme MbtA which is involved in biosynthesis of the mycobactins.
Rhodanine-based sulfonamides were developed as antagonists of anti-apoptotic Bcl-2 protein.
A series of novel rhodanine-based acylsulfonamide derivatives were designed, synthesized, and evaluated as ...small-molecule inhibitors of anti-apoptotic Bcl-2 protein. These compounds exhibit potent antiproliferative activity in three human tumor cell lines (Hep G2, PC-3 and B16-F10). Among them, the most potent compounds 10 and 11 bind to Bcl-2 with a Ki of 20 and 25nM, respectively. Docking studies demonstrated that these two compounds orient similarly at the binding site of Bcl-2, and the calculated binding affinities (Glide XP score) of compound 10 is more negative than that of compound 11. The binding interactions of compounds with high binding affinity to Bcl-2 protein were analyzed.
The antiparasitic clioquinol (CQ) represents a class of novel anticancer drugs by interfering with proteasome activity. In the present study, we found that CQ induced blood cancer cell apoptosis by ...inhibiting histone deacetylases (HDACs). CQ accumulated the acetylation levels of several key proteins including histone H3 (H3), p53, HSP90, and α-tubulin. In the mechanistic study, CQ was found to down-regulate HDAC1, -3, -4, and -5 in both myeloma and leukemia cells. Computer modeling analysis revealed that CQ was well docked into the active pocket of the enzyme, where the oxygen and nitrogen atoms in CQ formed stable coordinate bonds with the zinc ion, and the hydroxyl group from CQ formed an effective hydrogen bond with Asp-267. Moreover, co-treatment with CQ and zinc/copper chloride led to decreased Ac-H3. Furthermore, CQ inhibited the activity of Class I and IIa HDACs in the cell-free assays, demonstrating that CQ interfered with HDAC activity. By inhibiting HDAC activity, CQ induced expression of p21, p27, and p53, cell cycle arrest at G1 phase, and cell apoptosis. This study suggested that the HDAC enzymes are targets of CQ, which provided a novel insight into the molecular mechanism of CQ in the treatment of hematological malignancies.
Background: Clioquinol is a potent chelator of divalent metal ions including zinc.
Results: Clioquinol fits the zinc-centered active pocket of HDACs and inhibits HDAC activity, which results in cell cycle arrest and cancer cell apoptosis.
Conclusion: Clioquinol inhibits HDAC activity and induces blood cancer cell death.
Significance: This is the first report to demonstrate that clioquinol inhibits HDAC activity.
Schistosomiasis is a major health problem in tropical and sub-tropical areas caused by species of trematode belonging to the genus Schistosoma. The treatment and control of this disease has been ...relying on the use of a single drug praziquantel. However, the drug resistance concern urged the development of new drugs against schistosoma. Here, we report our systematic biological evaluation of DW-3-15, a new lead compound developed based on our conjugation design rationale as an effective anti-schistosomal agent.
The antischistosomal activity of DW-3-15 was systematically evaluated in S. japonicum infected mouse model for its stage-sensitivity and dose response. The results revealed that DW-3-15 exhibited 60-85% worm reduction rate against different development stage of worm. Scanning electron microscopy (SEM) observation indicated that DW-3-15 may damage to the tegument of male schistosomes.
Our results demonstrated that DW-3-15 showed potent anti-schistosomal activities in vivo. The results strongly support our conjugation design strategy of artemisinin analogs and further development of DW-3-15 as a new lead compound as anti-schistosomal agent.
4-anilinoquinazoline-containing inhibitors of the epidermal growth factor receptor (EGFR) are widely used in non-small cell lung cancer patients with mutated EGFR, but they are less effective in ...multiple myeloma (MM), a fatal malignancy derived from plasma cells. The present study designed a series of novel compounds by conjugating a peroxide bridge to the 4-anilinoquinazoline pharmacophore. Further studies showed that these agents such as 4061 and 4065B displayed potent activity to induce MM cell apoptosis by upregulating pro-apoptotic p53 and Bax while downregulating pro-survival Bcl-2. The mechanistic analysis revealed that both 4061 and 4065B inhibited IGF1-R, AKT and mTOR activation in a concentration dependent manner but had no effects on the expression of their total proteins, suggesting the conjugates of endoperoxide and 4-anilinoquinazoline may exert its anti-myeloma activity by targeting the IGF1-R/AKT/mTOR pathway.
Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills
(Mtb) through the inhibition of the essential cell wall enzyme ...decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound
displays improved solubility and bioavailability compared to the lead compound. Additionally, compound
shows Mtb-killing ability in an acute infection mouse model.
The design, synthesis, and biochemical characterization of a mechanism-based aryl carrier protein (ArCP) affinity probe that selectively modifies the terminal thiol of the aryl carrier protein ...phosphopantetheine (Ppant) prosthetic group is described. Labeling of the aryl carrier protein was shown to require the cognate adenylating enzyme to channel the affinity probe onto the Ppant cofactor. The selective labeling was established by observation of the phosphopantetheinyl ejection ion via MS/MS, and the probe was also found to stabilize an interaction between an aryl carrier protein and adenylating enzyme by an electrophoretic mobility shift assay.
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