Identificationof Novel Antimicrobial 2‑(Pyrimidin-2-yl)-5-alkyl-pyridazin-3(2<i>H</i>)‑one Scaffolds against Klebsiellapneumoniae, Inspired by Luffariellolide

Luffariellolide (<b>1</b>) was previously isolated in useful quantities (>200 mg) from the marine sponge <i>Suberea</i> sp., collected from the Philippines. The intrinsic antibacterial activity of <b>1</b> was insignificant; however, 2-(pyridinyl)pyridazinone <b>2</b>, derived from <b>1</b>, exhibited considerable activity against Klebsiella pneumoniae. In this study, 12 natural-product-like pyridazinones <b>3</b>–<b>14</b> were synthesized by modifying the γ-hydroxylbutyrolactone core of <b>1</b>. Among them, 2-(5-fluoropyrimidinyl)pyridazinone <b>11</b> was 64-fold more potent than <b>1</b> against K. pneumoniae, with a MIC of 2 μg/mL. Using a convergent five-step synthesis, the diterpene side chain of <b>11</b> was simplified to a C₁₂ lipid chain and 2-methyl-2-pentene to obtain <b>20</b> and <b>22</b>, respectively, both of which retained the same MIC value as <b>11</b>. The <i>N</i>-phenylnaphthalen-1-amine (NPN) uptake assays of <b>20</b> and <b>22</b> revealed their effective permeability to the outer membrane of K. pneumoniae, 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<i>H</i>)-one scaffold targeting K. pneumoniae.