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Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T 1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and C max values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent. [Display omitted] • Tetrahydroisoquinolineindoles were screened as PRMT5 inhibitors/hnRNP E1 promoters. • Some compounds exhibited significant antitumor activities. • Compounds 3m and 3s4 significant up-regulate hnRNP E1 protein level. • The study firstly indicates the regulatory relationship between PRMT5 and hnRNP E1. • Compound 3m was observed a 31.4% F and quite satisfying T 1/2 , AUC and Cmax values. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were identified. • Some of derivatives significantly increased α-glucosidase inhibition. • The non-competitive inhibitors 15o and 22d did not have cytotoxicity towards LO2 cells. • Compound 15o showed significant in vivo anti-hyperglycaemic activity. In the present study, a series of 2-phenyl-1 H -benzo[ d ]imidazole-based α-glucosidase inhibitors were synthesized and evaluated for their in vitro and in vivo anti-diabetic potential. Screening of an in-house library revealed a moderated α-glucosidase inhibitor, 6a with 3-(1 H -benzo[ d ]imidazol-2-yl)aniline core, and then the structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased activity than 6a , and the most promising inhibitors were found to be compounds 15o and 22d with IC 50 values of 2.09 ± 0.04 and 0.71 ± 0.02 µM, respectively. Fluorescence quenching experiment confirmed the direct binding of compounds 15o and 22d with α-glucosidase. Kinetic study revealed that both compounds were non-competitive inhibitors, that was consistent with the result of molecular docking studies where they located at the allosteric site of the enzyme. Cell viability evaluation demonstrated the non-cytotoxicity of 15o and 22d against LO2 cells. Furthermore, the in vivo pharmacodynamic study revealed that compound 15o showed significant hypoglycemic activity and improved oral sucrose tolerance, comparable to the positive control acarbose. [ABSTRACT FROM AUTHOR]

[Display omitted] In this present study, a series of novel (E)-2-benzylidene- N -(3-cyano-4,5,6,7-tetrahydrobenzo[ b ]thiophen-2-yl)hydrazine-1-carboxamide derivatives against α-glucosidase were designed and synthesized, and their biological activities were evaluated in vitro and in vivo. Most of the designed analogues exhibited better inhibitory activity than the marketed acarbose, especially the most potent compound 7 with an IC 50 value of 9.26 ± 1.84 μM. The direct binding of 7 and 8 with α-glucosidase was confirmed by fluorescence quenching experiments, and the kinetic and molecular docking studies revealed that 7 and 8 inhibited α-glucosidase in a non-competitive manner. Cytotoxicity bioassay indicated compounds 7 and 8 were non-toxic towards LO2 and HepG2 at 100 μM. Furthermore, both compounds were demonstrated to have in vivo hypoglycemic activity by reducing the blood glucose levels in sucrose-treated rats. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives were designed and synthesized. • Tetrahydrobenzo[ b ]thiophen-2-yl)urea derivatives significantly increased α-glucosidase inhibition. • The most potent compounds 8r and 8s showed non-toxicity towards LO2 and HepG2 cells. • Compound 8r showed promising in vivo anti-hyperglycaemic activity. α-Glucosidase inhibitors, which can inhibit the digestion of carbohydrates into glucose, are one of important groups of anti-type 2 diabetic drugs. In the present study, we report our effort on the discovery and optimization of α-glucosidase inhibitors with tetrahydrobenzo[ b ]thiophen-2-yl)urea core. Screening of an in-house library revealed a moderated α-glucosidase inhibitors, 5a , and then the following structural optimization was performed to obtain more efficient derivatives. Most of these derivatives showed increased inhibitory activity against α-glucosidase than the parental compound 5a (IC 50 of 26.71 ± 1.80 μM) and the positive control acarbose (IC 50 of 258.53 ± 1.27 μM). Among them, compounds 8r (IC 50 = 0.59 ± 0.02 μM) and 8s (IC 50 = 0.65 ± 0.03 μM) were the most potent inhibitors, and showed selectivity over α-amylase. The direct binding of both compounds with α-glucosidase was confirmed by fluorescence quenching experiments. Kinetics study revealed that these compounds were non-competitive inhibitors, which was consistent with the molecular docking results that compounds 8r and 8s showed high preference to bind to the allosteric site instead of the active site of α-glucosidase. In addition, compounds 8r and 8s were not toxic (IC 50 > 100 μM) towards LO2 and HepG2 cells. Finally, the in vivo anti-hyperglycaemic activity assay results indicated that compounds 8r could significantly decrease the level of plasma glucose and improve glucose tolerance in SD rats treated with sucrose. The present study provided the tetrahydrobenzo[ b ]thiophen-2-yl)urea chemotype for developing novel α-glucosidase inhibitors against type 2 diabetes. [ABSTRACT FROM AUTHOR]