Synthesis, characterization, molecular docking, pharmacokinetics, and molecular dynamics of new bis-thiazoles based on bis-thiosemicarbazone as anti-coxsackievirus

Abstract

Abstract It was known that the majority of viral infections start off as cutaneous eruptions, which heal on their own in most cases. The prognosis is dependent on the state of immunologic surveillance, just like in other infectious disorders. Therefore, those who are immunosuppressed are more in danger. But recently it’s becoming increasingly clear that eruptions that were once thought to be benign diseases can really cause problems and even death, even in immunocompetent patients. Hence, in this article, our goal was to identify possible potential antiviral candidates. We have synthesized a series of bis-thiazole derivatives via the reaction of bis-thiosemicarbazone derivative 3 with hydrazonoyl chlorides and haloketones in an effort to examine their potential antiviral properties and interactions with the main protease of Coxsackievirus B. Spectroscopic methods and elemental analysis were used to corroborate the structures of the novel bis-thiazole derivatives. The most potent derivative, bis-thiazole derivative 7a, was found to have the strongest antiviral activity against Coxsackievirus B (Cox B). Further investigation into its mode of action indicated that compound 7a has a dual activity that inhibits viral adsorption and replication. The efficacy of many compounds against Coxsackievirus adenovirus targets was assessed using molecular docking. The findings revealed that compounds 7a, 7c, 11b and 11c have high binding energies, efficiently engaging the active sites of essential Cox B virus proteins such as the Coxsackievirus adenovirus receptor (CAR), 3C-protease, and RNA-dependent RNA polymerase (RdRp). These interactions involved a variety of chemical bonding types, indicating that these substances can inhibit enzyme activity while also exhibiting substantial antiviral effects involving viral replication and adsorption. Furthermore, the computational ADMET study of these compounds indicated conformance to Lipinski’s criteria, implying positive physicochemical properties. Furthermore, MD simulations demonstrated stable complexes of 7a and 11b with Coxsackievirus adenovirus receptor (CAR), 3C-protease, and RNA dependent RNA polymerase (RdRp) with RMSD (0.1–0.30, 0.20–0.30, and 0.20–0.35 nm), RMSF (0.1–0.5 nm), and SASA (80–105, 140–150, and 220–235). These outcomes further reinforce the potential of these compounds in current antiviral drug development endeavors. The collective findings underscore the potential of these compounds as candidates for antiviral therapies against Coxsackievirus adenovirus.

Keywords

• Thiazoles
• Haloketones
• Molecular docking
• ADMET
• Dynamic simulations
• Coxsackievirus B