ABSTRACT
A new class of benzoxaborole ß-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K(i) values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C ß-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzoxazoles/chemistry , Boron Compounds/chemistry , Enzyme Inhibitors/chemical synthesis , Pyrazines/chemical synthesis , beta-Lactamase Inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Boron Compounds/chemical synthesis , Boron Compounds/pharmacology , Enterobacter cloacae/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Microbial Sensitivity Tests , Pyrazines/chemistry , Pyrazines/pharmacology , Structure-Activity Relationship , beta-Lactamases/metabolismABSTRACT
A series of dicationic diaryl ethers have been synthesized and evaluated for in vitro antibacterial activities, including drug resistant bacterial strains. Most of these compounds have shown potent antibacterial activities. Several compounds, such as piperidinyl and thiomorpholinyl compounds 9e and 9l, improved the antimicrobial selectivity and kept potent anti-MRSA and anti-VRE activity. The most potent bis-indole diphenyl ether 19 exhibited anti-MRSA MIC value of 0.06 microg/mL and enhanced antimicrobial selectivity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzimidazoles/chemical synthesis , Enterococcus/drug effects , Ethers/chemical synthesis , Indoles/chemical synthesis , Methicillin-Resistant Staphylococcus aureus/drug effects , Pentamidine/chemical synthesis , Phenyl Ethers/chemical synthesis , Vancomycin Resistance , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Ethers/chemistry , Ethers/pharmacology , Indoles/chemistry , Indoles/pharmacology , Microbial Sensitivity Tests , Pentamidine/chemistry , Pentamidine/pharmacology , Phenyl Ethers/chemistry , Phenyl Ethers/pharmacology , Structure-Activity RelationshipABSTRACT
A series of bis-benzimidazole diamidine compounds containing different central linkers has been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Seven compounds have shown potent antibacterial activities. The anti-MRSA and anti-VRE activities of compound 1h were more potent than that of the lead compound 1a and vancomycin.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Benzimidazoles/chemistry , Benzimidazoles/chemical synthesis , Methicillin-Resistant Staphylococcus aureus/drug effects , Pentamidine/analogs & derivatives , Vancomycin Resistance/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Benzimidazoles/pharmacology , Cations/chemistry , Microbial Sensitivity Tests , Pentamidine/chemical synthesis , Pentamidine/chemistry , Pentamidine/pharmacology , Structure-Activity RelationshipABSTRACT
A new class of novel bis-benzimidazole diamidine compounds have been synthesized and evaluated for in vitro antibacterial activities, including drug-resistant bacterial strains. Anti-MRSA and anti-VRE activities of the most potent compound 1 were more active than Vancomycin. The mechanism of action for this class of compounds appears to be different from existing antibiotics. Bis-benzimidazole diamidine compounds have potential for further investigation as a new class of potent anti-MRSA and anti-VRE agents.
Subject(s)
Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacology , Enterococcus faecium/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/classification , Anti-Bacterial Agents/pharmacology , Benzimidazoles/classification , Drug Resistance, Multiple, Bacterial/drug effects , Methicillin Resistance/drug effects , Structure-Activity Relationship , Vancomycin Resistance/drug effectsABSTRACT
Derivatives of chlorogenic acid or its analogues were synthesized by coupling protected chlorogenic acid or its analogues with p-octyloxyaniline and selected amino acids. Most of the compounds exhibited significant potency against Cryptococcus neoformans and Candida species with low toxicity to brine shrimps. The 4,5-dihydroxyl groups in the quinic acid moiety were necessary for the activity and introduction of a free amino group increased the inhibitory activity against Aspergillus fumigatus.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Candida/drug effects , Chlorogenic Acid/analogs & derivatives , Cryptococcus neoformans/drug effects , Antifungal Agents/chemical synthesisABSTRACT
A series of borinic acid picolinate esters were synthesized and screened for their minimum inhibitory concentration (MIC) against Gram-positive and -negative bacteria. Our lead compounds were then screened for anti-inflammatory activity. From these studies, we identified 3-hydroxypyridine-2-carbonyloxy-bis(3-chloro-4-methylphenyl)borane (2g, AN0128) as having the best combination of anti-bacterial and anti-inflammatory activities. This compound is now in clinical development for dermatological conditions.
