351980-73-9Relevant academic research and scientific papers
5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives as inhibitors of full-length RORγt
Lao, Chuyu,Zhou, Xiaoqing,Chen, Huanpeng,Wei, Fengjiao,Huang, Zhaofeng,Bai, Chuan
, (2019/07/18)
Retinoid-related orphan receptor gamma-t (RORγt) belongs to the nuclear receptor superfamily that takes vital roles in the development and maturation of T-helper 17 cell (Th17) and lymph-node genesis. Because Th17 cells have been proved to be major effectors in human autoimmune and inflammatory diseases, the agonists and antagonists of RORγt have been discovered as promising leads for the therapeutics of these diseases. Most of the current studies of RORγt inhibitors have been focused on ligand binding domain (LBD) of RORγt because the structure and binding pockets of LBD have been elucidated and studied in detail. Recent research elucidated that the hinge domain (HD) of RORγt was significantly involved in the SUMOylation of RORγt and thus specifically affecting T cell development but not lymph-node genesis. These discoveries highlighted the potential of HD of RORγt as the target of RORγt inhibitors that could specifically inhibit Th17-related activities without affecting lymph-node genesis. In this study, we utilized a screening system with full-length RORγt including DBD, HD and LBD to evaluate the activities of a synthesized library of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. We identified a potent lead compound (28) that effectively inhibited Th17 cell differentiation. Docking and structure–activity relationship (SAR) studies showed that compound 28 may not bind in the binding pocket as most of the known inhibitors, but may bind in the pocket closed to Gln223 and Leu244 in HD. Our studies showed evidence that the HD of RORγt could afford a binding pocket for Th17 specific inhibitors and this domain should be further studied to discover potent and specific RORγt inhibitors.
Structure-Based Virtual Screening, Compound Synthesis, and Bioassay for the Design of Chitinase Inhibitors
Dong, Yawen,Jiang, Xi,Liu, Tian,Ling, Yun,Yang, Qing,Zhang, Li,He, Xiongkui
, p. 3351 - 3357 (2018/04/11)
Chitinases play a vital part in the molting phase of insect pests. Inhibiting their activities by the use of drug-like small chemical molecules is thought to be an efficient strategy in pesticide design and development. On the basis of the crystal structure of OfChtI, a chitinase indispensable for the molting of the insect pest Ostrinia furnacalis (Asian corn borer), here we report a chemical fragment and five variant compounds as inhibitors of OfChtI obtained from a library of over 200?000 chemicals by a structure-based-virtual-screening approach. The compounds were synthesized with high atom economy and tested for their OfChtI-inhibitory activities in a bioassay. Compound 3 showed preferential inhibitory activity with a Ki value of 1.5 μΜ against OfChtI. Analysis of the structure-activity relationships of the compounds provided insight into their interactions with the enzyme active site, which may inform future work in improving the potencies of their inhibitory activities.
Enterovirus inhibitory activity of C-8-tert-butyl substituted 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones
Kumar Biswas, Bishyajit,Malpani, Yashwardhan R.,Ha, Neul,Kwon, Do-Hyun,Soo Shin, Jin,Kim, Hae-Soo,Kim, Chonsaeng,Bong Han, Soo,Lee, Chong-Kyo,Jung, Young-Sik
supporting information, p. 3582 - 3585 (2017/07/07)
Members of a series of 4-aryl-6,7,8,9-tetrahydrobenzo[4,5]thieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidin-5(4H)-ones (1, Fig. 2) were prepared and tested against representative enteroviruses including Human Coxsackievirus B1 (Cox B1), Human Coxsackievirus B3 (Cox B3), human Poliovirus 3 (PV3), human Rhinovirus 14 (HRV14), human Rhinovirus 21 (HRV 21) and human Rhinovirus 71 (HRV 71). The C-8-tert-butyl group on the tetrahydrobenzene ring in these substances was found to be crucial for their enterovirus activity. One member of this group, 1e, showed single digit micromolar activities (1.6–8.85?μM) against a spectrum of viruses screened, and the highest selectivity index (SI) values for Cox B1 (>11.2), for Cox B3 (>11.5), and for PV3 (>51.2), respectively. In contrast, 1p, was the most active analog against the selected HRVs (1.8–2.6?μM), and showed the highest selectivity indices among the group of compounds tested. The SI values for 1p were 11.5 for HRV14, 8.4 for HRV21, and 12.1 for HRV71, respectively.
Syntheses and biological evaluation of 2-amino-3-acyl- tetrahydrobenzothiophene derivatives; Antibacterial agents with antivirulence activity
The Dang, Hung,Chorell, Erik,Uvell, Hanna,Pinkner, Jerome S.,Hultgren, Scott J.,Almqvist, Fredrik
, p. 1942 - 1956 (2014/03/21)
Developing new compounds targeting virulence factors (e.g., inhibition of pilus assembly by pilicides) is a promising approach to combating bacterial infection. A high-throughput screening campaign of a library of 17500 small molecules identified 2-amino-3-acyl-tetrahydrobenzothiophene derivatives (hits 2 and 3) as novel inhibitors of pili-dependent biofilm formation in a uropathogenic Escherichia coli strain UTI89. Based on compounds 2 and 3 as the starting point, we designed and synthesized a series of structurally related analogs and investigated their activity against biofilm formation of E. coli UTI89. Systematic structural modification of the initial hits provided valuable information on their SARs for further optimization. In addition, small structural changes to the parent molecules resulted in low micromolar inhibitors (20-23) of E. coli biofilm development without an effect on bacterial growth. The hit compound 3 and its analog 20 were confirmed to prevent pili formation in a hemagglutination (HA) titer assay and electron microscopy (EM) measurements. These findings suggest that 2-amino-3-acyl-tetrahydrobenzothiophenes may serve as a new class of compounds for further elaboration as antibacterial agents with antivirulence activity.
