ABSTRACT
Novel 3-elongated arylalkoxybenzamide derivatives were designed, synthesized and evaluated for their cell division inhibitory activity and antibacterial activity. Among them, the subseries of 3-alkyloxybenzamide derivatives exhibited greatly improved on-target activity against Bacillus subtilis and Staphylococcus aureus, and remarkably increased antibacterial activity against B. subtilis ATCC9372, penicillin-susceptible S. aureus ATCC25923, methicillin-resistant S. aureus ATCC29213 (MRSA) and penicillin-resistant S. aureus PR compared with 3-methoxybenzamide. In contrast, the subseries of 3-phenoxyaklyloxybenzamide, 3-heteroarylalkyloxybenzamide and 3-heteroarylthioalkyloxybenzamide derivatives only showed a significant improvement in on-target activity and antibacterial activity against B. subtilis ATCC9372.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Benzamides/chemistry , Cytoskeletal Proteins/antagonists & inhibitors , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacterial Proteins/metabolism , Benzamides/chemical synthesis , Benzamides/pharmacology , Cytoskeletal Proteins/metabolism , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Staphylococcus aureus/drug effectsABSTRACT
A series of novel 11,4â³-disubstituted azithromycin analogs were synthesized and evaluated for their antibacterial activity. All the 11,4â³-disubstituted analogs exhibited excellent activity (0.03-0.12 µg/ml) against erythromycin-susceptible Streptococcus pneumoniae, and significantly improved activity against three phenotypes of erythromycin-resistant S. pneumoniae compared with erythromycin A, clarithromycin or azithromycin. Among them, compounds 26-28 showed the most potent activity (0.25, 0.03 and 2 µg/ml) against S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, respectively. In addition, compound 28 was the most effective (0.03 and 0.12 µg/ml) against erythromycin-susceptible S. pneumoniae and Staphylococcus aureus as well. It is noteworthy that the most active compounds described above possess the same terminal 3,5-dinitrophenyl groups on their C-4â³ bisamide side chains.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Azithromycin/chemical synthesis , Azithromycin/pharmacology , Drug Resistance, Bacterial/drug effects , Staphylococcus aureus/drug effects , Streptococcus pneumoniae/drug effects , Anti-Bacterial Agents/chemistry , Azithromycin/chemistry , Erythromycin/pharmacology , Microbial Sensitivity Tests , Molecular StructureABSTRACT
The emergence and prevalence of bacterial resistance has resulted in a clear demand for novel antibacterial drugs. As a tubulin homologue, FtsZ is an essential cell-division protein in prokaryotic organisms and is showing increasing promise as a target for antibacterial drug discovery. This review describes the role of FtsZ in bacterial cytokinesis and various FtsZ inhibitors, with particular focus on their discovery, antibacterial activities, mechanisms of action, synthetic methods, and representative analogues.
Subject(s)
Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Cytoskeletal Proteins/antagonists & inhibitors , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Bacterial Proteins/metabolism , Cytoskeletal Proteins/metabolism , High-Throughput Screening Assays , Humans , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Novel azithromycin (AZM) derivatives with the C-4â³ bisamide side chains were synthesized and evaluated for their in vitro antibacterial activities. The 4â³-O-(benzamido)alkyl carbamates showed excellent activity against the erythromycin-susceptible Streptococcus pneumoniae and exhibited greatly improved activity against erythromycin-resistant S. pneumoniae. Among them, compounds 5g and 6g, which had the same electron-withdrawing group, 3,5-dinitrophenyl, on the termination of their C-4â³ bisamide side chains, demonstrated the most potent activity against erythromycin-resistant S. pneumoniae expressing the erm gene, the mef gene and the erm and mef genes, showing 128-fold, 33-fold and 32-fold improved activity in comparison with the parent AZM.The Journal of Antibiotics advance online publication, 15 February 2012; doi:10.1038/ja.2012.3.
ABSTRACT
Novel 4â³-O-benzimidazolyl clarithromycin derivatives were designed, synthesized and evaluated for their in vitro antibacterial activities. These benzimidazolyl derivatives exhibited excellent activity against erythromycin-susceptible strains better than the references, and some of them showed greatly improved activity against erythromycin-resistant strains. Compounds 16 and 17, which have the terminal 2-(4-methylphenyl)benzimidazolyl and 2-(2-methoxyphenyl)benzimidazolyl groups on the C-4â³ bishydrazide side chains, were the most active against erythromycin-resistant Staphylococcus pneumoniae expressing the erm gene and the mef gene. In addition, compound 17 exhibited the highest activity against erythromycin-susceptible S. pneumoniae ATCC49619 and Staphylococcus aureus ATCC25923 as well. It is worth noting that the 4â³-O-(2-aryl)benzimidazolyl derivatives show higher activity against erythromycin-susceptible and erythromycin-resistant strains than the 4â³-O-(2-alkyl)benzimidazolyl derivatives.
