The effect of microtubule destabilizing compounds on the infection of Vero cells with the SARS-CoV-2 coronavirus

Abstract

Microtubules, cytoskeleton components, are essential for viruses for their transportation to the replication site as well as for the subsequent release from the cell, so affecting the structure and function of microtubules could be considered as a promising approach to suppress viral infection. In this regard, 50 chemical compounds of various structures with microtubule destabilizing mechanism of action were tested on Vero cells infected with the SARS-CoV-2 coronavirus (Wuhan line). Combretastatin analogs, polyalkoxy-substituted 4,5- and 3,4-diarylpyridazines (24 compounds), were synthesized in 73–99% yields by the Diels—Alder reaction of tetrazines with aryl- and diarylacetylenes. The previously described antitubulin agents were also studied, including various derivatives of combretastatin, podophyllotoxin, and indibulin, as well as isoflavonoid glaziovianin, etc. Nine compounds with a selectivity index >10 were found within the analogs of combretastatins A-2 and A-4, namely, 5 diarylpyridazines, diarylpyrazole, two diarylisoxazoles, and chalcone. In general, the ability of the compounds to suppress viral infection did not depend on the value of their antimitotic antitubulin activity. However, the most effective inhibitor of viral infection, bromo-substituted diarylpyrazole 9 with a selectivity index of 241, exhibited a pronounced antimitotic effect as well, causing sea urchin embryo cleavage alteration at a concentration of 5 nmol L⁻¹.