A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5-dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization.