Ring substituent effects on biological activity of vinyl sulfones as inhibitors of HIV-1

Abstract

In a previous study, we prepared a small library of chicoric acid analogs that possessed both potent anti-integrase and antiviral activity. It was also shown that active compounds fell into one of two groups: those that inhibited an early stage in viral replication and those that inhibited at a later stage. In this study, a series of vinyl geminal disulfone-containing compounds possessing a range of ring substituents has been synthesized to probe the impact of structure on inhibitory mechanisms. Four active compounds were identified using HIV drug susceptibility assays. Three of the inhibitors possessing either no substituents or electron-withdrawing substituents on the aromatic rings led to high levels of cytotoxicity and antiviral activity. Intrigued by the potential implications of electronic effects on activity, we probed whether the active compounds could be nonspecifically reacting via 1,4-addition. To investigate this hypothesis, the compounds were incubated with glutathione and upon LC/MS analysis, molecular ion peaks corresponding to both mono and double addition adducts were identified. Second, we synthesized analogs lacking the ability to participate in 1,4-addition and tested them for antiviral activity and cytotoxicity, and found the compounds inactive for both activities. Taken together, the studies reported herein suggest that compounds lacking electron-donating substituents on the aromatic ring are promiscuous acceptors of biological nucleophiles, whereas compounds possessing electron-donating substituents seem to resist addition or at least be more selective and significantly less toxic.

Vinyl sulfones

“…The noncharged nature of the sulfone improves cellular penetration over ionizable mimics such as l-chicoric acid (Hadd et al, 2001;Meadows et al, 2005;Meadows & Gervay-Hague, 2006a). The vinyl sulfone groups in the compounds reported in this study, (I)-(IV), have been shown to be an important class of antivirals, with the possibility for covalent attachment (Meadows & Gervay-Hague, 2006b;Meadows et al, 2007). As part of these ongoing inhibition studies, we previously reported the structures of the saturated phosphonate monosulfone diisopropyl (diisopropoxyphosphorylmethylsulfonylmethyl)phosphonate and the disulfone diisopropyl (diisopropoxyphosphorylmethylsulfonylmethylsulfonylmethyl)phosphonate (Wong, Olmstead, Fettinger & Gervay-Hague, 2007) reagents, which are the starting materials for the title compounds.…”

Untitled

“…Dapsone (4, 4'diaminodiphenylsulphone), an antileprotic drug which is a sulfone analog, has been proved to be a powerful antimicrobial agent 16 . Sulfone derivatives provide an example of a vital class of bioactive compounds with a wide spectrum of activities, as the sulfone group is a fundamental found in diverse biologically active compounds with a vast range of biological activity including antifungal 17 , herbicidal 18 , anti-hepatitis 19 , antitumor 20 , antileprotic 21 , anti-inflammatory 22 , anticancer 23 , anti-HIV-1 24 and anti-tubercular 25 properties. So, our present study is aimed at studying the interaction details between Enoyl-ACP reductase and sulfone class of compounds.…”

A diisopropoxyphosphonate monosulfone

“…As part of our research into enzymes that are involved in the metastatic potential of tumor cells, a number of potential disulfone inhibitors for HIV-integrase have been identified (Meadows et al, 2005, Meadows & Gervay-Hague, 2006, Meadows et al, 2007. The monosulfone reagent reported here was envisioned and synthesized by a modification of the disulfone reaction (Hadd, et al, 2001).…”