Thiazolides as Novel Antiviral Agents. 1. Inhibition of Hepatitis B Virus Replication

Abstract

We report the syntheses and activities of a wide range of thiazolides [viz. 2-hydroxyaroyl-N-(thiazol-2-yl)amides] against hepatitis B virus replication, with QSAR analysis of our results. The prototypical thiazolide, nitazoxanide [2-hydroxybenzoyl-N-(5-nitrothiazol-2-yl)amide; NTZ] 1 is a broad spectrum antiinfective agent, effective against anaerobic bacteria, viruses and parasites. By contrast, 2-hydroxybenzoyl-N-(5-chlorothiazol-2-yl)amide 3 is a novel, potent and selective inhibitor of hepatitis B replication (EC50 = 0.33 μm) but is inactive against anaerobes. Several 4′- and 5′-substituted thiazolides show good activity against HBV; by contrast, some related salicyloylanilides show a narrower spectrum of activity. The ADME properties of 3 are similar to 1, viz. the O-acetate is an effective prodrug and the O-aryl glucuronide is a major metabolite. The QSAR study shows a good correlation of observed EC90 s for intracellular virions with thiazolide structural parameters. Finally we discuss the mechanism of action of thiazolides in relation to the present results.

Second-Generation Nitazoxanide Derivatives: Thiazolides are Effective Inhibitors of the Influenza a Virus

“…The syntheses of the 4 -and 5 -substituted analogs used in the IAV assays, compounds 3-5 and 8-19 (Table 1), were described in earlier papers [12,13]. The 4 -(alkylsulfonyl)thiazolides are particularly active against IAV in this screen, and we now give an improved synthesis, exemplified for compound 13, Figure 3.…”

“…Preparations of compounds 3-5 and 8-19 were given previously [12,13]; an improved preparation of compound 13 follows. …”

“…It was immediately acylated with O-acetylsalicyloyl chloride in THF, and in this series (as opposed to the 2-amino-5-substituted thiazoles) [12,13] the weaker base N-ethylmorpholine was superior to triethylamine, affording the thioether intermediate 24 in 81% yield. Finally this compound was oxidized with MCPBA (2 equivalents) to afford the desired sulfone 13 in excellent yield.…”

“…Earlier [12,13] we prepared the 2-amino-4-(trifluoromethyl)thiazole and 2-amino-5-(trifluoromethyl)thiazole precursors 25 and 26, Figure 4, required for analogs 17 and 18 by multistep routes using sulfone chemistry. One-step preparations are in fact available for both, using respectively a Hantzsch synthesis [28] for 25 and a radical trifluoromethylation procedure [29] for 26. , there is in general little difference between free phenols and acetates in this screen, typically a factor of two at most, in contrast to the behavior of the thiazolides against hepatitis C virus [13].…”

“…We have disclosed the broad-spectrum antiviral activity of the thiazolides, typified by the prototype nitazoxanide 1 (Scheme 1) and described the structure-activity relationships of a wide range of thiazolides against hepatitis B and C viruses in particular [12,13]. In the case of influenza A virus (IAV), we have shown that a few thiazolide analogs such as 3, 4 and 5 (Scheme 1), were also active in vitro against an H1N1 subtype and that a novel mechanism of action was involved [2].…”