Design, Synthesis, and Evaluation of Thiol-Activated Sources of Sulfur Dioxide (SO₂) as Antimycobacterial Agents

Abstract

Here, 2,4-dinitrophenylsulfonamides with tunable cysteine-activated SO(2) release profiles with half-lives of SO(2) release varying from 2 to 63 min are reported. N-Benzyl-2,4-dinitrobenzenesulfonamide (6), which is prepared in one step from commercial sources, had a potency (MIC = 0.15 μM) of inhibiting Mycobacterium tuberculosis (Mtb) higher than the clinical agent isoniazid (MIC = 0.37 μM).

Thiol activated prodrugs of sulfur dioxide (SO2) as MRSA inhibitors

“…10,20 Our laboratory has recently developed thiol-activated sulfur dioxide (SO 2 ) donors which were found to inhibit Mycobacterium tuberculosis (Mtb) growth. 22,23 A mechanism based on attack of thiol on the aromatic ring to produce a Jackson-Meisenheimer complex, which decomposed to produce SO 2 , benzylamine and 2,4-dinitrophenylthioether was proposed (Scheme 1). 22,23 NBenzyl-2,4-dinitrosulfonamide (1a) was found to be the most potent in vitro inhibitor with a low micromolar minimum inhibitory concentration (MIC).…”

“…22 A library of 2,4-dinitrobenzenesulfonyl (DNs) derivatives were prepared using reported methods. 22,23 In addition, bis(2,4-dinitrophenylsulfonamides) 9a-9i which are expected to produce twice the number of moles of sulfur dioxide generated per mole of compound were synthesized from Mitsunobu reaction of 1d (Table 1). These compounds would be suitable for testing the effect of increasing the payload of SO 2 on inhibitory activity.…”

The Development and Application of Sulfur Dioxide Surrogates in Synthetic Organic Chemistry

“…Appreciating that current surrogates such as sulfites could not release SO 2 in the desired controlled manner inside a biological system and inspired by the antibiotic properties of SO 2 , well-known in the food industry, Chakrapani and co-workers investigated a potential novel class of antibacterials which can release SO 2 under physiological conditions. [33,34] These SO 2 prodrugs are based on a tuneable 2,4-dinitrosulfonamide structure and in the presence of thiol residues (e.g., from cysteine) release SO 2 via an S N Ar process (Scheme 7). The same group also examined 1-arylbenzosultine derivatives as sulfur dioxide surrogates.…”

A novel coumarin-based water-soluble fluorescent probe for endogenously generated SO2 in living cells

“…Furthermore, the capability of SS-1 for imaging of endogenously generated SO2 was demonstrated (Figure 4). It has been reported that SO2 can be generated from 2,4-dinitrophenylsulfonamides upon reaction with cellular thiols [44]. HeLa cells, initially incubated with a SO2 donor (250 μM) for 30 min, were incubated with SS-1 (5 μM) for a further 60 min and an fluorescence enhancement was observed in the green channel.…”