Sulfonyl-polyol N,N-dichloroamines with rapid, broad-spectrum antimicrobial activity.

The discovery and development of antimicrobial agents that do not give rise to resistance remains an ongoing challenge. Our efforts in this regard continue to reveal new potential therapeutic agents with differing physicochemical properties while retaining the effective N,N-dichloroamine pharmacophore as the key antimicrobial warhead. In this Letter, we disclose agents containing polyol units as a water solubilizing group. These sulfonyl-polyol agents show broad spectrum bactericidal and virucidal activity. These compounds show 1 h MBC's of 16-512 µg/mL against Escherichia coli and 4-256 µg/mL against Staphylococcus aureus at neutral pH, and 1-h IC50's of 4.5-32 µM against Adenovirus 5 and 0.7-3.0 µM against Herpes simplex virus 1. The lead compounds were tested in a tissue culture irritancy assay and showed only minimal irritation at the highest concentrations tested.

Structure stability/activity relationships of sulfone stabilized N,N-dichloroamines.

Structure stability/activity relationships (SXR) of a new class of N,N-dichloroamine compounds were explored to improve antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans while maintaining aqueous solution stability. This study identified a new class of solution-stable and topical antimicrobial agents. These agents are sulfone-stabilized and possess either a quaternary ammonium or sulfonate appendages as a water solubilizing group. Several unique challenges were confronted in the synthesis of these novel compounds which are highlighted in the discussion.

Novel 3-chlorooxazolidin-2-ones as antimicrobial agents.

Antimicrobial resistance against many known therapeutics is on the rise. We examined derivatives of 3-chlorooxazolidin-2-one 1a (X=H) as antibacterial and antifungal agents. The key findings were that the activity and apparent in vitro cytotoxicity could be controlled by the substitution of charged solubilizers at the 4- and 5- positions. These changes both significantly increase the antifungal potency and decrease cytotoxicity. Particularly effective were trialkylammonium groups which led to 400- to 600-fold increases in the antifungal therapeutic index when compared to their unsubstituted counterparts.

Novel N-chloroheterocyclic antimicrobials.

Antimicrobial compounds with broad-spectrum activity and minimal potential for antibiotic resistance are urgently needed. Toward this end, we prepared and investigated a novel series of N-chloroheterocycles. Of the compounds examined, the N-chloroamine series were found superior over N-chloroamide series in regards to exhibiting high antimicrobial activity, low cytotoxicity, and long-term aqueous stability.

Chemical characterization and biological properties of NVC-422, a novel, stable N-chlorotaurine analog.

During oxidative burst, neutrophils selectively generate HOCl to destroy invading microbial pathogens. Excess HOCl reacts with taurine, a semi-essential amino acid, resulting in the formation of the longer-lived biogenerated broad-spectrum antimicrobial agent, N-chlorotaurine (NCT). In the presence of an excess of HOCl or under moderately acidic conditions, NCT can be further chlorinated, or it can disproportionate to produce N,N-dichlorotaurine (NNDCT). In the present study, 2,2-dimethyltaurine was used to prepare a more stable N-chlorotaurine, namely, N,N-dichloro-2,2-dimethyltaurine (NVC-422). In addition, we report on the chemical characterization, in vitro antimicrobial properties, and cytotoxicity of this compound. NVC-422 was shown effectively to kill all 17 microbial strains tested, including antibiotic-resistant Staphylococcus aureus and Enterococcus faecium. The minimum bactericidal concentration of NVC-422 against Gram-negative and Gram-positive bacteria ranged from 0.12 to 4 µg/ml. The minimum fungicidal concentrations against Candida albicans and Candida glabrata were 32 and 16 µg/ml, respectively. NVC-422 has an in vitro cytotoxicity (50% cytotoxicity = 1,440 µg/ml) similar to that of NNDCT. Moreover, our data showed that this agent possesses rapid, pH-dependent antimicrobial activity. At pH 4, NVC-422 completely killed both Escherichia coli and S. aureus within 5 min at a concentration of 32 µg/ml. Finally, the effect of NVC-422 in the treatment of an E. coli-infected granulating wound rat model was evaluated. Treatment of the infected granulating wound with NVC-422 resulted in significant reduction of the bacterial tissue burden and faster wound healing compared to a saline-treated control. These findings suggest that NVC-422 could have potential application as a topical antimicrobial.

Quaternary ammonium N,N-dichloroamines as topical, antimicrobial agents.

A series of backbone modified and sulfonic acid replacement analogs of our topical, clinical candidate (iii) were synthesized. Their antimicrobial activities and aqueous stabilities at pH 4 and pH 7 were determined, and has led us to identify quaternary ammonium N,N-dichloroamines as a new class of topical antimicrobial agents.