Synthesis and Biological Evaluation of Honokiol Derivatives Bearing 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones as Potential Viral Entry Inhibitors against SARS-CoV-2

Abstract

The 2019 coronavirus disease (COVID-19) caused by SARS-CoV-2 virus infection has posed a serious danger to global health and the economy. However, SARS-CoV-2 medications that are specific and effective are still being developed. Honokiol is a bioactive component from Magnoliae officinalis Cortex with damp-drying effect. To develop new potent antiviral molecules, a series of novel honokiol analogues were synthesized by introducing various 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)oxazol-2(3H)-ones to its molecule. In a SARS-CoV-2 pseudovirus model, all honokiol derivatives were examined for their antiviral entry activities. As a result, 6a and 6p demonstrated antiviral entry effect with IC50 values of 29.23 and 9.82 µM, respectively. However, the parental honokiol had a very weak antiviral activity with an IC50 value more than 50 µM. A biolayer interfero-metry (BLI) binding assay and molecular docking study revealed that 6p binds to human ACE2 protein with higher binding affinity and lower binding energy than the parental honokiol. A competitive ELISA assay confirmed the inhibitory effect of 6p on SARS-CoV-2 spike RBD’s binding with ACE2. Importantly, 6a and 6p (TC50 > 100 μM) also had higher biological safety for host cells than honokiol (TC50 of 48.23 μM). This research may contribute to the discovery of potential viral entrance inhibitors for the SARS-CoV-2 virus, although 6p’s antiviral efficacy needs to be validated on SARS-CoV-2 viral strains in a biosafety level 3 facility.

Jiedu Huoxue Decoction for Cytokine Storm and Thrombosis in Severe COVID-19: A Combined Bioinformatics and Computational Chemistry Approach

“…In this study, puerarin, as an ACE2 inhibitor, was docked with the high-resolution crystal of ACE2 (PBD ID: 1R42). 26,27 We set up the docking box of puerarin and ACE2 at the binding pocket of ACE2 inhibitors, reported in our previous research 28 and other literature. 26 This box centered just on the geometrical centers of the ACE2 crystal and was big enough to accommodate the active sites, including residues Tyr510, Arg514, Asn394, and Glu398 in the pocket mentioned above.…”

“…Puerarin also interacted with ACE2 via Asn394, Asp350, and His378, the same binding sites as a reported ACE2 inhibitor. 28 On EGFR, quercetin formed hydrogen bonds with AGR841, ASN842, and MET793, and hydrophobic interaction with VAL726, ALA743, LEU844, and LEU718 (Figure 8B). Figure 8C shows that Arg841, Met790, and Met793 of EGFR form hydrogen bonds with luteolin.…”

I2-Catalyzed Carbonylation of α-Methylene Ketones to Synthesize 1,2-Diaryl Diketones and Antiviral Quinoxalines in One Pot

“…SARS-CoV-2 antibody was used as a positive inhibitor. 5′,7-Diallyl-3,3′-bis((5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl)methyl)-[5,7′-bibenzo[ d ]oxazole]-2,2′(3 H ,3′ H )-dione ( 6p ), a recently reported ACE2 blocker, 63 was employed as a positive antiviral entrance reference. As a result ( Table 2 and Figure 1 ), 4ca , 4ha , and 4ad exhibited antiviral entry effect on SARS-CoV-2 spike pseudoviruses with IC 50 values of 19.70, 142.50, and 21.28 μM, respectively.…”

“…All synthesized quinoxalines 4aa – 4ca , 4ha , 4ia – 4ka , 4pa , 4ra , and 4ab – 4ag were evaluated for their potential to inhibit viral entry of a SARS-CoV-2 spike pseudotyped virus bearing luciferase reporter into HEK-293T-ACE2 h host cell that highly expresses human ACE2 (angiotensin-converting enzyme 2) receptor (Table ). Initially, the maximum nontoxic concentration (CC 0 ) values of all quinoxalines were examined on the host cells of HEK-293T-ACE2 h by MTT, , and their antiviral entry activities were subsequently evaluated under the compounds’ concentrations no more than the CC 0 values. SARS-CoV-2 antibody was used as a positive inhibitor.…”

“…In HEK-293T cells, pNL4-3.Luc.R-E- plasmid (from the NIH AIDS repository) and pcDNA3.1-SARS-CoV-2-Spike-Myc plasmid (from Beyotime, Shanghai, China) were utilized to produce SARS-CoV-2 spike pseudotyped viruses according to the published protocol. 63 The infectious competency of 30 μL generated pseudovirus was quantified in hexaplicate to be equivalent to that of 8.05 ± 0.39 × 10 7 copies of SARS-CoV-2 pseudovirus (10 10 copies/mL, PSV001) from Sino Biological by a viral infection equation: Y = 197.06 X – 87.679, R 2 = 0.9997. HEK-293T-ACE2 h cells (1 × 10 4 in 100 μL DMEM) were seeded in 96-well plates and cultured for 24 h. The culture medium was then replaced with 100 μL of compound-containing DMEM for a 2 h incubation at 37 °C.…”