<p>Synthesis and Bioactivity of <em>N</em>-(4-Chlorophenyl)-4-Methoxy-3-(Methylamino) Benzamide as a Potential Anti-HBV Agent</p>

Abstract

Introduction Hepatitis B virus (HBV) is a global health concern that can cause acute and chronic liver diseases. Thus, there is an urgent need to research novel anti-HBV agents. Our previous reports show that N -phenylbenzamide derivatives exert broad-spectrum antiviral effects against HIV-1, HCV, and EV71 by increasing intracellular levels of APOBEC3G (A3G). As A3G is capable of inhibiting the replication of HBV, we screened the N -phenylbenzamide derivatives against HBV. Methods In this study, a new derivative, N -(4-chlorophenyl)-4-methoxy-3-(methylamino) benzamide (IMB-0523), was synthesized and its anti-HBV activity was evaluated in vitro and in vivo. The acute toxicity and pharmacokinetic profiles of IMB-0523 were also investigated. Results Our results show that IMB-0523 has higher anti-HBV activity in both wild-type HBV (IC 50 : 1.99 µM) and drug-resistant HBV (IC 50 : 3.30 µM) than lamivudine (3TC, IC 50 : 7.37 µM in wild-type HBV, IC 50 : >440 µM in drug-resistant HBV). The antiviral effect of IMB-0523 against HBV may be due to an increased level of intracellular A3G. IMB-0523 also showed low acute toxicity (LD 50 : 448 mg/kg) in mice and promising PK properties (AUC 0-t : 7535.10±2226.73 µg·h/L) in rats. Further, IMB-0523 showed potent anti-HBV activity in DHBV-infected ducks. Conclusion Thus, IMB-0523 may be a potential anti-HBV agent with different mechanisms than current anti-HBV treatment options.

IMB-0523 Inhibits Enterovirus 71 Replication by Activating Signal Transducer and Activator of Transcription 3 Signaling to Upregulate Interferon-Stimulated Genes Expression

“…As shown in Table 1, IMB-0523 has good inhibitory activities against all strains tested. In addition, IMB-0523 has an anti-HBV effect, [17] suggesting that IMB-0523 may be used as a lead compound in the development of broad-spectrum antiviral drugs.…”

“…IMB-0523 showed low acute toxicity (LD 50 , 448 mg/kg) in mice. [17] Therefore, although IMB-0523 has a similar effect of upregulating ISGs as IFNs, its toxic adverse effects may be far less than those of IFNs. Moreover, the short-term administration of acute viral diseases may not cause significant adverse effects.…”

“…Our previous study also confirmed that IMB-0523 has anti-HBV effect, indicating that IMB-0523 has broad-spectrum antiviral effects. [17] Considering the targeting of host proteins, long-term administration of host-targeting antiviral drugs may have toxic adverse effects. IMB-0523 showed low acute toxicity (LD 50 , 448 mg/kg) in mice.…”

“…[16] After further structural modification, IMB-0523 [Figure 1A], a chemical modification product of IMB-Z with better properties, developed good anti-hepatitis B virus (HBV) effects by upregulating the expression of A3G. [17] However, the mechanism by which IMB-0523 upregulates A3G expression remains unclear. Here, we mainly explored the effect and mechanism of IMB-0523 against EV71.…”

Comparing LD50/LC50 Machine Learning Models for Multiple Species

“…An external test set was curated by searching PubMed for papers from the last two years 2022–2020 describing “mouse and LD 50 .” These papers resulted in 53 molecules not in the training sets (Table ) that were ultimately used as a test set for the mouse toxicity models consisting of mouse data for oral (46), IV (4), and IP (2). − …”