Design, synthesis and investigation of activities of interleukin-1 inhibitor drug candidate new 5-(trifluoromethoxy)-1h-indole-2,3-dione 3-(4-phenylthiosemicarbazone) derivatives

In this work, 5-(trifluoromethoxy)-1H-indole-2,3-dione (1) was reacted with methyl/ ethyl/ benzyl halide to get 1-substituted 5-(trifluoromethoxy)-1H-indole-2,3-diones (2a-c). 4-(Substituted phenyl)thiosemicarbazide derivatives (4a-o) have been synthesized by reaction of substituted phenyl isothiocyanate derivatives (3a-o) with hydrazine hydrate and novel 1-substituted 5-(trifluoromethoxy)-1H-indole-2,3-dione 3-[4-(substituted phenyl)thiosemicarbazone] derivatives (5-7) have been obtained by condensation of compounds 2a-c with 4a-o. The structures of the compounds 5-7 were proved by analytical and spectral data. The molecular and isomeric structure of compound 5f was determined by X-ray single crystal diffraction analysis and it was found that the compound had the Z- configuration. Molecular modelling studies were carried out and physicochemical parameters were calculated for interleukin-1 receptor (IL-1R) and herpes simplex virus (HSV) species. The amounts of embryonic alkaline phosphatase was measured by stimulation with interleukin-1 (IL-1) in cell lines expressing IL-1R and by stimulation with lipopolysaccharide (LPS) in cell lines expressing toll-like receptor 2 (TLR2) and efficiency and selectivity of compounds 5-7 have been identified. A tetrazolium proliferation assay was used for cell viability. It was determined that compounds 5d, 5f, 5h, 6m and 7h were selectively effective and non-toxic IL-1R antagonists in in vitro conditions. Compound 5h was selected as the lead molecule and its antipyretic effect was defined on increased body temperature induced with LPS in thermoregulation experiments in rats and mice. No damage was observed at micro level to kidney and liver tissues in histopathological examinations. Inhibiting effect on IL-1 mediated inflammation of 5h has been investigated using the collagen-induced arthritis model. Parenteral form with polyvinyl pyrrolidone (PVP) and nanoparticular drug delivery systems with polylactic-co-glycolic acid (PLGA) and Pluronic 123 of compound 5h were designed and prepared. Compounds 5c, 6e, 6j, 6k and 6m were effective against HSV-1 (KOS), HSV-2 (G), HSV-1 TK- KOS ACVr and VV (229E), while compound 6c was effective against AV-2 and HCV (229E) in in vitro antiviral activity tests.