Synthesis and Structure–Activity Relationship (SAR) Studies of Novel Pyrazolopyridine Derivatives as Inhibitors of Enterovirus Replication

Abstract

A series of novel pyrazolopyridine compounds have been designed and prepared by a general synthetic route. Their activities against the replication of poliovirus-1, EV-A71, and CV-B3 enteroviruses were evaluated. The comprehensive understanding of the structure-activity relationship was obtained by utilizing the variation of four positions, namely, N1, C6, C4, and linker unit. From the screened analogues, the inhibitors with the highest selectivity indices at 50% inhibition of viral replication (SI) were those with isopropyl at the N1 position and thiophenyl-2-yl unit at C6 position. Furthermore, the C4 position offered the greatest potential for improvement because many different N-aryl groups had better antiviral activities and compatibilities than the lead compound JX001. For example, JX040 with a 2-pyridyl group was the analogue with the most potent activity against non-polio enteroviruses, and JX025, possessing a 3-sulfamoylphenyl moiety, had the best activity against polioviruses. In addition, analogue JX037, possessing a novel pyrazolopyridine heterocycle, was also shown to have good antienteroviral activity, which further enlarges the compound space for antienteroviral drug design.

A derivatization-directed three-component synthesis of fluorescent spiro [dihydropyridine-4,3ʹ-indoline]s

“…As a continuation of our ongoing program toward the development of multicomponent synthetic methods, 7–10 herein, we introduce an efficient route to the synthesis of several novel spiro[chromeno[4,3- b ]pyrazolo[4,3- e ]pyridine-7,3ʹ-indoline]s. The products consist of an oxindole moiety spiro-fused to a 1,4-dihydropyridine core, which itself is fused on two sides with 1 H -pyrazole and coumarin ring systems. Pyrazolopyridine is a privileged heterocyclic core existing in many synthetic compounds exhibiting inhibition of enterovirus replication 11 and angiogenesis, 12 and shows potential for the treatment of autoimmune diseases and leukocyte malignancies via PI3K inhibition. 13 Pyrazolopyridine-based compounds have also shown antileishmanial, 14 antimicrobial, antiquorum-sensing, and antitumor activities.…”

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei

“…Some hinged aromatic compounds show significant anti-EV71 activity. They include conjugates of aniline–oxazolopyridine [ 24 ], benzene–heterocycle [ 25 ], benzene–oxadiazole [ 26 ], pyridine–quinolone–arene [ 27 ], pyrazolopyridine–thiophene [ 28 ], etc. In 2019, Egorova et al [ 29 ] summarized recent developments of hinged capsid-binding inhibitors of EV71.…”

Inhibition of Glioma Cell Growth and Apoptosis Induction through Targeting Wnt10B Expression by Pyrazolo[4,3-c]pyridine-4-one

“…Celecoxib and lonazolac are used as anti-inflammatory drugs, fipronil acts as an insecticide, dipyrone is a promising analgesic and antipyretic molecule [ 8 ], and sildenafil is used for erectile dysfunction treatment, all of these drugs are pyrazole based compounds [ 9 ]. Fused-pyrazoles have been found to exhibit several biological properties like anti-inflammatory [ 10 ], anti-viral [ 11 ], anti-tumor [ 12 ], anti-microbial [ 13 ], and antiprotozoal [ 14 ]. In addition, many fused-pyrazoles have shown significant anti-human immunodeficiency virus (HIV) properties [ 15 ].…”