ABSTRACT
Aztreonam, first discovered in 1980, is an FDA approved, intravenous, monocyclic beta-lactam antibiotic. Aztreonam is active against Gram-negative bacteria and is still used today. The oral bioavailability of aztreonam in humans is less than 1%. Herein we describe the design and synthesis of potential oral prodrugs of aztreonam.
ABSTRACT
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.
Subject(s)
Amines/chemistry , Anti-Infective Agents/chemistry , Polymers/chemistry , Adenoviridae/metabolism , Amines/chemical synthesis , Amines/pharmacology , Animals , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Cell Line, Tumor , Chlorocebus aethiops , Cytopathogenic Effect, Viral/drug effects , Escherichia coli/drug effects , Herpesvirus 1, Human/metabolism , Humans , Hydrogen-Ion Concentration , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Vero CellsABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemical synthesis , Chloramines/chemical synthesis , Sulfones/chemical synthesis , Water/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Infective Agents/pharmacology , Chloramines/chemistry , Chloramines/pharmacology , Drug Stability , Escherichia coli/drug effects , Molecular Structure , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
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.
Subject(s)
Anti-Infective Agents/pharmacology , Bacteria/drug effects , Chlorine/chemistry , Fungi/drug effects , Oxazolidinones/pharmacology , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/chemistry , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistryABSTRACT
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.
Subject(s)
Anti-Infective Agents/chemistry , Anti-Infective Agents/pharmacology , Bacteria/drug effects , Fungi/drug effects , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Anti-Infective Agents/chemical synthesis , Chlorine/chemistry , Heterocyclic Compounds/chemical synthesis , Microbial Sensitivity Tests , Molecular StructureABSTRACT
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.
Subject(s)
Anti-Infective Agents, Local/chemical synthesis , Chloramines/chemistry , Quaternary Ammonium Compounds/chemistry , Sulfhydryl Compounds/chemical synthesis , Anti-Infective Agents, Local/chemistry , Anti-Infective Agents, Local/pharmacology , Chloramines/chemical synthesis , Microbial Sensitivity Tests , Quaternary Ammonium Compounds/chemical synthesis , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacology , Sulfonic Acids/chemical synthesis , Sulfonic Acids/chemistryABSTRACT
New topical anti-infectives comprised of N,N-dichloro-beta,beta-disubstituted taurines [Tetrahedron Lett.2008, 49, 2193; Biorg. Med. Chem. Lett. 2009, 19, 196] have been examined for structure-stability relationships (SSR) based upon various alkyl, heteroalkyl and cycloalkyl beta-substitutions. These substitutions affect order-of-magnitude changes in the aqueous stability of these N,N-dichloroamines which can undergo Stieglitz rearrangement of alkyl groups under extremely mild conditions (H(2)O, pH 4-7, 0-20 mM acetate or phosphate buffer, 20-40 degrees C). This process produces beta-ketosulfonic acids which function as substrates for chlorination by the N-chlorotaurines which leads to their further degradation.
Subject(s)
Hydrocarbons, Chlorinated/chemical synthesis , Taurine/analogs & derivatives , Taurine/chemical synthesis , Combinatorial Chemistry Techniques , Hydrocarbons, Chlorinated/chemistry , Hydrocarbons, Chlorinated/pharmacology , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Taurine/chemistry , Taurine/pharmacology , Water/chemistryABSTRACT
2-Dichloroamino-2-methyl-propane-1-sulfonic acid sodium salt (2a), a stable derivative of endogenous N,N-dichlorotaurine (1), has been identified and is under development as a topical antimicrobial agent. Structure-activity relationships of analogs were explored to achieve optimal antimicrobial activity with minimal mammalian toxicity while maintaining the desired stability. All the analogs synthesized showed antimicrobial activity against Staphylococcus aureus, Escherichia coli, and Candida albicans in the range of 1-128 microg/mL and cytotoxicity against mammalian L929 cells in the range 80-1900 microg/mL.
Subject(s)
Anti-Infective Agents/chemical synthesis , Sulfonic Acids/chemical synthesis , Animals , Anti-Infective Agents/pharmacology , Anti-Infective Agents, Local , Candida albicans/drug effects , Cell Line , Cell Survival/drug effects , Escherichia coli/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Structure-Activity Relationship , Sulfonic Acids/pharmacologyABSTRACT
The solution conformation of N-methyl-2-(tributylstannyl)piperidines has been determined through the use of vicinal 119Sn-13C coupling constants, revealing a conformational distortion caused by an unexpected stereoelectronic effect in some cases. Specifically, the "equatorial" conformer is distorted into a half-chair, in which the nitrogen lone pair eclipses the C-Sn bond. This distortion, which "costs" approximately 1 kcal/mol, correlates with a conformational dependence of geminal 119Sn-15N couplings and a possible correlation with reactivity in the tin-lithium exchange reaction.