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In 2002, a new class of thymidylate synthase (TS) involved in the de novo synthesis of dTMP named <i>Flavin-Dependent Thymidylate Synthase</i> (<i>FDTS</i>) encoded by the <i>thyX</i> gene was discovered; <i>FDTS</i> is present only in 30% of prokaryote pathogens and not in human pathogens, which makes it an attractive target for the development of new antibacterial agents, especially against multi-resistant pathogens. We report herein the synthesis and structure-activity relationship of a novel series of hitherto unknown <i>pyrido[1,2-e]purine-2,4(1H,3H)</i>-dione analogues. Several synthetics efforts were done to optimize regioselective <i>N¹</i>-alkylation through organopalladium cross-coupling. Modelling of potential hits were performed to generate a model of interaction into the active pocket of <i>FDTS</i> to understand and guide further synthetic modification. All those compounds were evaluated on an in-house in vitro <i>NADPH oxidase</i> assays screening as well as against <i>Mycobacterium</i> <i>tuberculosis ThyX</i>. The highest inhibition was obtained for compound <b>23a</b> with 84.3% at 200 µM without significant cytotoxicity (CC₅₀ > 100 μM) on PBM cells.