ABSTRACT
The design and synthesis of a new class of minor groove binder (MGBs) in which, the cationic tail group has been replaced by a neutral, polar variant including cyanoguanidine, nitroalkene, and trifluoroacetamide groups. Antibacterial activity (against Gram positive bacteria) was found for both the nitroalkene and trifluoroacetamide groups. For the case of the nitroalkene tail group, strong binding of a minor groove binder containing this tail group was demonstrated by both DNA footprinting and melting temperature measurements, showing a correlation between DNA binding and antibacterial activity. The compounds have also been evaluated for binding to the hERG ion channel to determine whether non-cationic but polar substituents might have an advantage compared with conventional cationic tail groups in avoiding hERG binding. In this series of compounds, it was found that whilst non-cationic compounds generally had lower affinity to the hERG ion channel, all of the compounds studied bound weakly to the hERG ion channel, probably associated with the hydrophobic head groups.
Subject(s)
Acetamides/pharmacology , Alkenes/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Design , Fluoroacetates/pharmacology , Gram-Positive Bacteria/drug effects , Guanidines/pharmacology , Acetamides/chemical synthesis , Acetamides/chemistry , Alkenes/chemical synthesis , Alkenes/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Binding Sites/drug effects , Fluoroacetates/chemical synthesis , Fluoroacetates/chemistry , Guanidines/chemical synthesis , Guanidines/chemistry , Humans , Molecular Structure , Structure-Activity Relationship , Trans-Activators/antagonists & inhibitors , Trans-Activators/chemistry , Transcriptional Regulator ERGABSTRACT
Antibacterial minor groove binders related to the natural product, distamycin, are development candidates for novel antibiotics. Alkenes have been found to be effective substitutes for the isosteric amide links in some positions and alkyl groups larger than methyl have been found to increase binding to DNA in both selectivity and affinity. However the impact of other isosteres such as diazenes and the position of an alkyl group with respect to DNA binding and antibacterial activity are not known. The effects of some systematic variations in the structure of polyamide minor groove binders are investigated. Isosteres of the amide link (alkenes and diazenes) are compared: it is shown that all three are competent for binding to DNA but that alkene links give the tightest binding and highest antibacterial activity; no significant antibacterial activity was found for compounds with a diazene link. Within a series of alkene linked compounds, the effect of branched N-alkyl substituents on binding to DNA and antibacterial activity is investigated: it was found that C3 and C4 branched chains are acceptable at the central pyrrole residue but that at the pyrrole ring adjacent to the basic tail group, a C4 branched chain was too large both for DNA binding and for antibacterial activity. The active branched alkyl chain compounds were found to be especially active against Mycobacterium aurum, a bacterium related to the causative agent of tuberculosis.
Subject(s)
Amides/chemistry , Amides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , DNA/chemistry , DNA/metabolism , Nucleic Acid Conformation , Alkanes/chemistry , Amides/chemical synthesis , Amides/metabolism , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/metabolism , Bacteria/drug effects , Drug Design , Microbial Sensitivity Tests , Models, Molecular , Structure-Activity RelationshipABSTRACT
A practical synthesis of alkene-containing minor-groove binders for DNA, related to distamycin, with potential for wide structural diversity is described, based upon the Wittig chemistry of N-alkylpyrrole aldehydes. The compounds prepared have been evaluated for binding to DNA by physical methods (melting temperature and NMR) and for their antibacterial activity. Significantly, it was found that alkenes linking the aryl head group of the minor-groove binder promote strong binding to DNA and high antibacterial activity against Gram-positive bacteria. Conversely, a minor-groove binder containing an alkene located towards the alkylamino tail group has a low affinity for DNA and does not show antibacterial activity. These observations suggest an important role for specific hydrogen bonds in the binding of compounds of this type to DNA, and in their antibacterial activity.
Subject(s)
Alkenes/chemistry , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , DNA/chemistry , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/isolation & purification , Chromatography, High Pressure Liquid , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Staphylococcus/drug effectsABSTRACT
The synthesis and properties of 80 short minor groove binders related to distamycin and the thiazotropsins are described. The design of the compounds was principally predicated upon increased affinity arising from hydrophobic interactions between minor groove binders and DNA. The introduction of hydrophobic aromatic head groups, including quinolyl and benzoyl derivatives, and of alkenes as linkers led to several strongly active antibacterial compounds with MIC for Staphylococcus aureus, both methicillin-sensitive and -resistant strains, in the range of 0.1-5 microg mL-1, which is comparable to many established antibacterial agents. Antifungal activity was also found in the range of 20-50 microg mL-1 MIC against Aspergillus niger and Candida albicans, again comparable with established antifungal drugs. A quinoline derivative was found to protect mice against S. aureus infection for a period of up to six days after a single intraperitoneal dose of 40 mg kg-1.
