title: SAR studies on trisubstituted benzimidazoles as inhibitors of Mtb FtsZ for the development of novel antitubercular agents.
abstract: FtsZ, an essential protein for bacterial cell division, is a highly promising therapeutic target, especially for the discovery and development of new-generation anti-TB agents. Following up the identification of two lead 2,5,6-trisubstituted benzimidazoles, 1 and 2, targeting Mtb-FtsZ in our previous study, an extensive SAR study for optimization of these lead compounds was performed through systematic modification of the 5 and 6 positions. This study has successfully led to the discovery of a highly potent advanced lead 5f (MIC = 0.06 μg/mL) and several other compounds with comparable potencies. These advanced lead compounds possess a dimethylamino group at the 6 position. The functional groups at the 5 position exhibit substantial effects on the antibacterial activity as well. In vitro experiments such as the FtsZ polymerization inhibitory assay and TEM analysis of Mtb-FtsZ treated with 5f and others indicate that Mtb-FtsZ is the molecular target for their antibacterial activity.
authors.affiliation: Department of Chemistry and Institute of Chemical Biology and Drug Discovery, Stony Brook University , Stony Brook, New York 11794-3400, United States.
authors.forename: Divya
authors.initials: D
authors.lastname: Awasthi
authors.forename: Kunal
authors.initials: K
authors.lastname: Kumar
authors.forename: Susan E
authors.initials: SE
authors.lastname: Knudson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Slayden
authors.forename: Iwao
authors.initials: I
authors.lastname: Ojima
mesh_terms: D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects; D020128:Inhibitory Concentration 50; D046529:Microscopy, Electron, Transmission; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D001562:Benzimidazoles; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria