title: Synthesis and antibacterial activity of some novel 4-oxopyrido[2,3-a]phenothiazines.
abstract: A series of substituted 4-oxopyrido[2,3-a]phenothiazine-3-carboxylic acids (6a-d) were prepared via cyclization of the corresponding ethyl 7-(arylthioxy)-8-nitro(or azido)-4-oxoquinoline-3-carboxylates (3a-d/4a-d), followed by hydrolysis of the resultant esters (5a-d). Among these tetracyclics, compound 6a with unsubstituted terminal benzo-ring D was the most active against representative Gram-positive and Gram-negative bacterial strains. These compounds were also active against methicillin-resistant Staphylococcus aureus (MRSA), with very low toxicity to normal cells. Virtual screening using ligand-protein docking modeling predicted that the compounds 6a-d are potential inhibitors of the topoisomerase IV enzyme and that hydrophobic interactions and hydrogen bonds are the major molecular interactions between these compounds and the residues of the active site of topoisomerase IV.
authors.affiliation: Faculty of Science, Chemistry Department, The University of Jordan, Amman, Jordan.
authors.forename: Hadeel T
authors.initials: HT
authors.lastname: Al-Sinjilawi
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: El-Abadelah
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Mubarak
authors.forename: Amal
authors.initials: A
authors.lastname: Al-Aboudi
authors.forename: Mohammed M
authors.initials: MM
authors.lastname: Abadleh
authors.forename: Adel M
authors.initials: AM
authors.lastname: Mahasneh
authors.forename: Asaad K M A
authors.initials: AK
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000254:growth & development; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000254:growth & development; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D059003:Topoisomerase Inhibitors; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D010640:Phenothiazines; D059003:Topoisomerase Inhibitors; D027101:DNA Topoisomerase IV
keywords: Antibacterial activity; Chemical synthesis; Oxopyrido[2,3-a]phenothiazines; Topoisomerase IV/Ligand-protein docking