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.

3-a]phenothiazines. -Compounds (I) are prepared and evaluated towards their antibacterial activity with (Ia) showing the highest activity. Molecular docking simulations reveal that all compounds are docking in the binding site of topoisomerase IV enzyme. -(AL-SINJILAWI, H. T.; EL-ABADELAH*, M. M.; MUBARAK, M. S.; AL-ABOUDI, A.; ABADLEH, M. M.; MAHASNEH, A. M.; AHMAD, A. K. M. A.; Arch. Pharm. (Weinheim, Ger.) 347 (2014) 11, 861-872, http://dx.