Safety Assessment and Evaluation of Novel Thiourea Derivatives as Antivirals

Abstract

DSA-00 and its two derivatives (DSA-02 & DSA-09) are new thiourea derivatives that exhibit strong antiviral activity against hepatitis B virus comparable to Entecavir. Here these compounds were evaluated for in-vitro cytotoxicity and genotoxicity, and in vivo acute toxicity for their potential therapeutic use. The cytotoxicity of thiourea derivatives was assessed in HepG2 and HepG2.2.15 cells by MTT assay whereas their genotoxicity was measured by Ames II test. The acute toxicity study was carried out in the Sprague-Dawley rats by observing the following parameters: mortality, clinical symptoms, hematological parameters, urine and changes in animal body & organs weight, gross necropsy and histopathology. DSA-00, DSA-02, and DSA-09 were non-cytotoxic even at the 320M concentration with respective CC50 values of 329.6, 323.5, and 349.7 M. The Ames II test revealed that these molecules were non-mutagenic at a [~]1M concentration. The acute toxicity studies revealed LD50 values belong from the moderate range of toxicity of DSA-00, DSA-02 and DSA-09. Importantly, there were no abnormal change in body weight and organs weight. Moreover, no abnormal clinical signs such as hematological parameter, urinalysis, gross necropsy and or histopathological in any of the animals after receiving oral doses of thiourea derivatives. Thiourea derivatives DSA-00, DSA-02, and DSA-09 appear to have a moderate range of acute toxicity at dosages used and thus, appear to be generally safe. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/546447v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@8c8abaorg.highwire.dtl.DTLVardef@e7bcb1org.highwire.dtl.DTLVardef@15446dorg.highwire.dtl.DTLVardef@3f5d7b_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Illustration of the study design and the findings for each aspect of the study: in-vitro cytotoxicity (1), genotoxicity by the Ames test (2), and oral toxicity in rats (3). C_FIG