Design of 4-Substituted Sulfonamidobenzoic Acid Derivatives Targeting Coxsackievirus B3

Simple Summary Enteroviruses are essential human pathogens worldwide which cause a wide variety of diseases with neurologic, respiratory, skin, and gastrointestinal findings. Despite the fact that most people who become infected with non-polio enteroviruses suffer only mild illness, the enteroviruses D68 and A71 (EV-D68 and EV-A71), as well as the coxsackie viruses, can cause severe pathological conditions, including viral meningitis and acute flaccid myelitis. For example, patients with asthma are at high risk of suffering severe effects from an EV-D68 or rhinovirus infection. A vaccination option for non-polio enteroviruses is available only for EV-A71 in China. Currently, there is no specific antiviral treatment for non-polio enterovirus infections, but it is known that targeting viral capsids (capsid binders) offers a promising antiviral therapeutic approach. Recently, 4-(4-(1,3-dioxoisoindolin-2-yl)phenylsulfonamido)benzoic acid (compound 2a in this study) was identified as a new capsid binder. In the present study, we synthesized 15 novel derivatives of 2a and compared their antiviral properties in vitro. Two compounds were found to have higher antiviral activity against coxsackievirus than the reference capsid binder molecule. The current results indicate that our new capsid-binding molecules for targeting enteroviruses are of great importance for the development of antiviral therapy. A series of novel 4-substituted sulfonamidobenzoic acid derivatives was synthesized as the structural evolution of 4-(4-(1,3-dioxoisoindolin-2-yl)phenylsulfonamido)benzoic acid, which is the known inhibitor of the enterovirus life cycle. Antiviral properties of prepared compounds were evaluated in vitro using phenotypic screening and viral yield reduction assay. Their capsid binding properties were verified in thermostability assay. We identified two new hit-compounds (4 and 7a) with high activity against the coxsackievirus B3 (Nancy, CVB3) strain with potencies (IC50 values of 4.29 and 4.22 mu M, respectively) which are slightly superior to the reference compound 2a (IC50 5.54 mu M). Both hits changed the heat inactivation of CVB3 in vitro to higher temperatures, suggesting that they are capsid binders, as 2a is. The results obtained can serve as a basis for further development of the lead compounds for novel drug design to combat enterovirus infection.

Automated summary

Enteroviruses are important human pathogens worldwide, causing a wide range of diseases, with some leading to severe conditions. A vaccine is available only for EV-A71 in China, and there is still a lack of specific antiviral treatment for non-poliovirus enterovirus infections.