Anti-Influenza Drug Discovery: Structure−Activity Relationship and Mechanistic Insight into Novel Angelicin Derivatives

Abstract

By using a cell-based high throughput screening campaign, a novel angelicin derivative 6a was identified to inhibit influenza A (H1N1) virus induced cytopathic effect in Madin-Darby canine kidney cell culture in low micromolar range. Detailed structure-activity relationship studies of 6a revealed that the angelicin scaffold is essential for activity in pharmacophore B, while meta-substituted phenyl/2-thiophene rings are optimal in pharmacophore A and C. The optimized lead 4-methyl-9-phenyl-8-(thiophene-2-carbonyl)-furo[2,3-h]chromen-2-one (8g, IC(50) = 70 nM) showed 64-fold enhanced activity compared to the high throughput screening (HTS) hit 6a. Also, 8g was found effective in case of influenza A (H3N2) and influenza B virus strains similar to approved anti-influenza drug zanamivir (4). Preliminary mechanistic studies suggest that these compounds act as anti-influenza agents by inhibiting ribonucleoprotein (RNP) complex associated activity and have the potential to be developed further, which could form the basis for developing additional defense against influenza pandemics.

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

“…The most potent compound, BPR3P0128, was identified biochemically as having potent anti-cap-snatching activity, and its chemical structure was distinct from that of two compounds identified previously in this screening ( Fig. 1) (52,53,62) and two other viral polymerase inhibitors, T-705 (favipiravir) and compound A3 (19,27). Here, we characterized BPR3P0128 and identified its underlying antiviral mechanism.…”

“…We conducted a drugscreening study using a large-scale anti-influenza virus cell-based assay based on the inhibition of the virally induced cytopathic effect (CPE) (52,53,62). An initial hit, CSV0C019002, with a 50% effective (inhibitory) concentration (EC 50 ) of 4.27 M toward A/WSN/33 was identified after screening 20,800 randomly selected small compounds (molecular masses, Ͻ500 Da) from a library.…”

Microwave-Assisted Synthesis of Bioactive Six-Membered Heterocycles and Their Fused Analogues

“…It also found in fruits (e.g., bilberry, cloudberry), green tea and other foods such as chicory. Coumarin derivatives possess a remarkable range of biological properties including antioxidant [109,110], vasorelaxant [111], antiviral (92, 93) [112,113], anti-cancer (94, 95), and anti-inflammatory activities [114,115]. Lastly, suksdorfin (96), another natural compound isolated from the fruit of Lomatium suksdorfii, exhibits a significant anti-HIV activity as it inhibits the viral replication in the T-cell line with an EC 50 in the 2.5 µM range [116] (Figure 8).…”

Design, synthesis and evaluation of 2,4-diarylpyrano[3,2-c]chromen-5(4H)-one as a new class of non-purine xanthine oxidase inhibitors

“…The presence of coumarin architecture in naturally occurring phytoconstituents with anticancer 15,16 , anti-HIV 17 , antituberculosis 18 , anti-influenza 19 , antialzheimer 20,21 , anti-inflammatory 22 , antiviral 23 , antimicrobial 13 and xanthine oxidase inhibitory activities [24][25][26] makes it a privileged structure. Among the diverse array of biological activities possessed by coumarins, we are particularly interested towards their xanthine oxidase inhibitory potential which has also been extensively explored [24][25][26] .…”