Synthesis of N-benzyl-N-phenylthiophene-2-carboxamide analogues as a novel class of enterovirus 71 inhibitors

Abstract

A series of novel human enterovirus 71 inhibitors, N-benzyl-N-phenylthiophene-2-carboxamide analogues were 10 synthesized and their antiviral activities were evaluated in vitro. Most derivatives of this structure against EV71 with a low micromolar range in the RD (Rhabdomyosarcoma) cell lines. The most potent compound 5a, N-(4-bromobenzyl)-N-(4-fluorophenyl)thiophene-2-carboxamide, showed low 15 micromolar activity against EV71 (EC 50 = 1.42 µM) compared to the reference anti-EV71 drug Enviroxime (EC 50 = 0.15 µM). Preliminary SAR studies revealed that thiophene-2carboxamide core is crucial for maintaining antiviral activity, and N-substituent phenyl groups largely influenced anti-20 EV71 efficacy of this new class of potent antiviral agents.

A pyridinium/anilinium [2]catenane that operates as an acid–base driven optical switch

“…Overall, the synthesis of [2]catenane [ 8 DB24C8 ] 6+ required multiple steps and is outlined in Scheme 1 . Two literature preparations were used to construct each of the known compounds, terphenyl linker 6 [ 18 ] and bis(pyridinium)ethane axle [ 5 ][OTf] 2 [ 19 – 20 ], while the new benzylaniline axle 4 was prepared as shown from 3 [ 21 ] . Once the precursor components were synthesized, the [2]catenane was assembled in two steps.…”

“…Benzoyl peroxide was purchased from Acros and used as received. Compounds 3 [ 18 ], [ 5 ][OTf] 2 [ 19 – 20 ] and 6 [ 21 ] were prepared using literature methods. Solvents were dried using an Innovative Technologies solvent purification system.…”

Identification and Structure–Activity Relationships of Diarylhydrazides as Novel Potent and Selective Human Enterovirus Inhibitors

“…37 Very recently, we have developed thiophene-2carboxamides (6, Figure 1) as anti-EV71 agents, which show low micromolar activity against EV71 (EC 50 = 1.42 μM) compared with reference drug 1 (enviroxime). 38 As a part of our long-term interest in the development of antiviral agents, 39−41 as well as the further exploration of anti-EV71 drugs that might have superior efficacy and fewer side effects than existing therapeutic agents, diarylhydrazide derivatives with significant antiviral activity were identified based on the result of our previous work. Two hit compounds 10 and 11, based on a 2,6-dichlorosubstituted phenyl hydrazide scaffold, showed submicromolar potency against EV71 with EC 50 values of 0.47 and 0.94 μM, respectively, but suffer from poor selectivity indexes (Figure 2).…”

“…In 2015, itraconazole, a clinical drug for antifungal therapy, was found to be a broad spectrum inhibitor of enteroviruses by acting on the novel targets oxy-sterol-binding protein (OSBP) and OSBP-related protein 4 (ORP4) by Van Kuppeveld and co-workers . Very recently, we have developed thiophene-2-carboxamides ( 6 , Figure ) as anti-EV71 agents, which show low micromolar activity against EV71 (EC 50 = 1.42 μM) compared with reference drug 1 (enviroxime) …”

Design and synthesis of heteroaromatic-based benzenesulfonamide derivatives as potent inhibitors of H5N1 influenza A virus

“…A molecular docking investigation of this series of furan-carboxamide analogues indicated that they cannot efficiently interact with the M2 protein cavity due to the long linker. Our long-term aim is the development of antivirals with better inhibitory potency and fewer side effects than currently used drugs; [29][30][31][32][33] hence, to develop novel heteroaromatic-based benzenesulfonamide compounds as anti-influenza A/H5N1 agents, an attempt was made to modify the structural features of furan-carboxamide derivatives by shortening the linker length and transforming the heteroaromatic core structure (Scheme 1).…”