Luffariellolide () was previously isolated in useful quantities (>200 mg) from the marine sponge sp., collected from the Philippines. The intrinsic antibacterial activity of was insignificant; however, 2-(pyridinyl)-pyridazinone , derived from , exhibited considerable activity against . In this study, 12 natural-product-like pyridazinones - were synthesized by modifying the γ-hydroxylbutyrolactone core of . Among them, 2-(5-fluoropyrimidinyl)-pyridazinone was 64-fold more potent than against , with a MIC of 2 μg/mL. Using a convergent five-step synthesis, the diterpene side chain of was simplified to a C lipid chain and 2-methyl-2-pentene to obtain and , respectively, both of which retained the same MIC value as . The -phenylnaphthalen-1-amine (NPN) uptake assays of and revealed their effective permeability to the outer membrane of , comparable to that of the positive control, polymyxin B. This study provides a foundation for future structural optimization of the novel antibacterial 2-(pyrimidin-2-yl)-5-alkyl-pyridazin-3-(2)-one scaffold targeting .