Abstract
Foot-and-mouth disease (FMD) vaccine does not afford early effective protection until adaptive immune protection caused by the vaccination occurs. Therefore, an alternative prophylactic application of antiviral agents for inhibition of the FMD virus is needed, and this is the scope of this study. In this study, we tested nine adamantane-pyrazole derivatives that could exhibit antiviral activity against FMDV infection either in vitro through baby hamster kidney cells (BHK-21 cells) infected with FMD virus serotypes O pan Asia. Cytotoxicity Concentration 50 (CC50) activity of pyrazole derivatives (1, 2, 3, 4, 5a,b, 6a-c) were detected on BHK-21 cells and ranged between 500 to 3000µg/ml. Inhibitory Concentration 50 (IC50) on BHK-21 was achieved only for the most promising three derivatives 6a-c and exhibited an antiviral activity with a therapeutic index of 30, and that was reflected on the antiviral activity response in baby mice with different concentrations where a concentration of 50 µg/ml for pyrazole derivatives 6a and 6c compounds and 40 µg/ml for bis-tolyl pyrazole 6b that achieve 100% protection and this results was as effective as 50 µg/ml of amantadine. Specifically, diaryl pyrazole derivatives 6a-c that protected for six days following FMDV challenge. These results suggested that pyrazole derivatives 6a-c could be used as an effective antiviral agent against FMD virus infection. Molecular docking simulation of the target compounds 6a-c had good binding energy and the tested compounds recommended being an excellent 3C protease inhibitor compared to Amantadine and Ribavirin. These findings may explain the antiviral activity of the target compounds.
Highlights
Foot-and-mouth disease (FMD) is one of the most economically and publicly devastating diseases that affects cloven-hoof animals including cattle, sheep, swine and goats (Grubman and Baxt, 2004)
We examined the antiviral efficacy of nine adamantane pyrazole derivatives in vitro and in vivo in comparison with amantadine against foot and mouth disease virus
Before checking the antiviral activity of the compounds through observation of the cytopathic effect of FMDV on BHK-21, the compounds were screened for their cytotoxicity to BHK-21 cells which are characterized by a change in cell morphology like rounding, increased brightness, and detachment of the cells from the surface (Sarkar et al, 2019)
Summary
Foot-and-mouth disease (FMD) is one of the most economically and publicly devastating diseases that affects cloven-hoof animals including cattle, sheep, swine and goats (Grubman and Baxt, 2004). The release of virions from cells derivatives 5a, b displayed the difference in an azo-aryl infected with FMDV was inhibited by amantadine, a group (phenyl 5a, and p-methoxy phenyl 5b). We examined the antiviral efficacy of nine adamantane pyrazole derivatives in vitro and in vivo in comparison with amantadine against foot and mouth disease virus. Suckling mice were inoculated by intraperitoneal injection with a different safe concentrations of the di-aryl pyrazole derivatives 6a-c that ranged between 100, 50, 40, 30, 20 μg/ml while other compounds were not included as there is no antiviral activity evidence on tissue culture. After 48 hrs post-inoculation, the positive results showed spastic muscular paralysis of hindquarters leading to death due to activity of FMD virus but the action of different safe concentration of compounds were proved in life mice expressed as a percentage of several survivals. The pyrazole derivatives 6a-c as well as the standard drugs Amantadine and Ribavirin were drawn in chem-draw 14.0 and exported to MOE where protonated 3D, minimized energy and render hydrogen was achieved and docked inside the active site of the protein
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