Synthesis and antiviral activity of thiazolyl hydrazones against dengue virus

Our group has previously reported on (E)-4-(1-(2-(5-(4-chlorophenyl)thiazol-2-yl)hydrazono)ethyl)phenol (3a) as an antiviral agent against DENV with an EC₅₀ of 1.32 μM. In this study, we present the X-ray crystallographic structure and in vitro ADME profile of compound 3a. Additionally, to optimize 3a, we synthesized four derivatives (3b-3e) using an active analogue approach. The newly synthesized and characterized compounds were screened for antiviral activity against DENV via a virus reduction assay (RT-qPCR). Among them, compound 3c emerged as the most potent, with an EC₅₀ of 0.01 μM and a selectivity index (SI) of 200. This compound was found to be 132 times more potent than 3a, although its toxicity was 63 times higher than that of 3a. Despite this, its selectivity index was twofold higher than that of compound 3a. In vitro permeability and metabolic stability studies showed that compound 3a exhibited permeability issues but demonstrated metabolic stability in both rat and human liver microsomes. In vivo pharmacokinetic studies in male rats revealed a bioavailability (F) of 6 % and a half-life (T_1/2) of 1.75 h for compound 3a. The in vivo pharmacokinetic results for compound 3c suggest that it may require an appropriate formulation strategy to enhance its pharmacokinetic parameters.