Recent Advances in Antiviral Activity of Benzo/Heterothiadiazine Dioxide Derivatives

Abstract

Benzo/heterothiadiazine dioxides have been identified as important fused heterocyclic systems possessing a broad spectrum of biological activities and potential pharmacological applications. Recently, a large number of structurally novel compounds derived from these heterocycle scaffolds were identified as antiviral agents. Especially, substituted benzo/heterothiadiazine dioxide derivatives have been shown to inhibit the replication of HCMV, VZV, HCV and HIV. Of particular interest, some potent HCV polymerase inhibitors possess a benzothiadiazine dioxide scaffold, which is critical for the anti-HCV potency through strong hydrogen bond formation of the SO(2)NH group with the active site of the enzyme, as shown by X-ray crystallography. Also, some compounds belonging to the benzothiadiazine dioxide class have been found to be potent antiviral agents against HCMV and VZV. Moreover, some novel heterothiadiazine dioxide derivatives have been synthesized and evaluated as potential HIV inhibitors with lower toxicity and/or increased activity against drug-resistant virus strains. No systematic review is available in the literature on these thiadiazine derivatives in the design of potent antiviral inhibitors. In this article, we review the recent advances in the antiviral profile of this kind of compounds, as well as the impact of structural modifications and the structure-activity relationship (SAR).

Recent advances in drug discovery of benzothiadiazine and related analogs as HCV NS5B polymerase inhibitors

“…Discovery of the benzothiadiazine core as an NS5B inhibitor 1,2,4-Benzothiadiazine-1,1-dioxide analogs were known as diuretics 61 for many years. Benzothiadiazine analogs are increasingly used in different therapeutic areas including as antiviral agents, 62 ATP-sensitive potassium channel inhibitors, [63][64][65] anti-tumor agents, 66 and allosteric modulators of AMPA receptors. 67 High throughput screening (HTS) of the GlaxoSmithKline (GSK) proprietary compound collection using an RdRp assay with oligo(rG)-primed poly(rC) substrate 68 allowed identification of several structurally distinct, putative polymerase inhibitors.…”

Novel Convenient Approach to 6-, 7-, and 8-Numbered Nitrogen Heterocycles Incorporating Endocyclic Sulfonamide Fragment

“…In particular, heterocyclic compounds of different size bearing an endocyclic pharmacophore sulfonamide fragment reveal a wide range of biological effects, including enzymes inhibition, antihypertensive [ 1 , 2 , 3 , 4 ], antimicrobial [ 5 ], and antiviral activity [ 6 ]. Benzothiadiazine- S , S -dioxides were used in the design of phosphodiesterase 7 inhibitors [ 7 ], HIV protease inhibitors [ 8 ], ATP-sensitive potassium channel openers exhibiting different tissue selectivity profiles [ 9 ], potent antiviral agents against HCMV, antagonists of the human CCR5 receptor [ 6 ], nonnucleoside human cytomegalovirus selective inhibitors [ 10 ], α 1 -adrenoceptor antagonists [ 11 ], drugs for treatment of cancer and the early stages of Alzheimer disease [ 12 ], human herpes virus (HHV-6) and Varicella-Zoster virus [ 10 ], and ligands for complexation TACe inhibitors [ 13 ] and others. Bridged sultams (bridged sulfonamides) besides applications in medicinal chemistry have been used as a template in stereoselective synthesis enabled by the rapid scission of the N-SO 2 bond [ 14 , 15 ].…”

Iodine-mediated synthesis of 3-acylbenzothiadiazine 1,1-dioxides

“…Benzothiadiazine 1,1-dioxide moieties have attracted remarkable attention in the pharmacological area because of their broad spectrum of activities [1–4], such as antihypertensive [5–6] or antiviral [7–8] and they are also used as cardiovascular agents [9–11] (Scheme 1). In this context, several synthetic methods have been developed to synthesize benzothiadiazine 1,1-dioxides and their analogues.…”