Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1‐Activated Prodrugs as Antiviral Agents

Abstract

Recent studies indicate that tubulin can be a host factor for vector‐borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub‐micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.

The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19

“…A similar reduction in IL-6 but also in IL-8 or TNF-α levels can be observed in mucocutaneous Behcet's disease patients [205]. Moreover, colchicine has anti-viral properties against Flaviviridae and against the recombinant demyelinating strain of mouse hepatitis virus RSA59 as demonstrated reducing virus replication since microtubules are crucial in cell entry and blocking neuronal transport [206,207]. It inhibits RSV replication reducing IL-6 and TNF-α levels [208].…”

Colchicine in COVID-19: an Old Drug, New Use

“…The intracellular transport of viral particles in the host cell, including particle trafficking in later stages of the infection, is mediated by microtubules and associated proteins [ 30 , 31 ]. By inhibiting microtubule polymerization, colchicine has been reported to cause a significant decrease in virus replication in flaviviruses, such as dengue and Zika viruses [ 32 ]; blocks transport and reduces the replication of recombinant demyelinating strain of the mouse hepatitis virus [ 33 ]; inhibits respiratory syncytial virus (RSV) infection in neonatal rats through regulation of anti-oxidative factor production leading to inhibition of RSV replication, thus, leading to a significant reduction in the levels of IL-6 and TNF-α [ 34 ]. In addition, colchicine and colchicine derivatives may influence HIV viral load [ 35 ].…”

More Than Resveratrol: New Insights into Stilbene-Based Compounds

“…Interestingly, new prodrugs that contain the leucine cyclopentyl moiety were hydrolyzed by the hCE1, while phenylglycine cyclopentyl ester combretastatins were inert against hydrolysis. Overall, the antiviral activity of these analogues was similar or lower than that of CA-4 or colchicine [141].…”