This article presents a complete and detailed study of synthesis, structural characterization, and possible applications of a new family of azanaphthoquinones as antimicrobial agents. A series of (alkoxy) phenylamino-chloro-2-methylquinoline-5,8-dione derivatives (3a-j, 3a', 3e') was prepared by regioselective nucleophilic substitution of 6,7-dichloro2- methylquinoline-5,8-dione (1) with (alkoxy) arylamines (2) in the presence of CeCl3 center dot 7H(2)O. In vitro antimicrobial study of the newly synthesized compounds was evaluated in a panel of three fungi and seven bacterial strains (three Gram-positive and four Gram-negative bacteria). As a result, the compounds (3a, 3b, and 3h) were identified as the hits with the strong antibacterial efficiency against the human originated pathogens S. epidermidis and E. faecalis with some minimal inhibitory concentration values. The antibacterial activity of the compound (3h) was two times more active against S. epidermidis than the reference antimicrobial compound (Cefuroxime). Two compounds (3a and 3b) exhibited excellent antibacterial activity (four times more active than Cefuroxime) against S. epidermidis. In addition to S. epidermidis, these three compounds (3a, 3b, and 3h) were more active against E. faecalis than the reference antimicrobial compound (Amikacin). The antibacterial activity of the compounds (3a and 3h) was three times more active against E. faecalis. The compound (3b) was long dozen times more active against E. faecalis. For that reason, these three compounds (3a, 3b, and 3h) were thought to be considered as the promising antibacterial agents.