Bactericidal Effect of Synthetic Phenylalkylamides Inspired by Gibbilimbol B Against Neisseria gonorrhoeae

Increasing multidrug resistance in <i>Neisseria gonorrhoeae</i> poses a serious and escalating public health crisis. The World Health Organization has classified <i>N. gonorrhoeae</i> as a high-priority pathogen for developing new antimicrobials. Natural products provide a promising avenue for antimicrobial discovery, serving as direct therapeutic agents or prototypes for novel drug development. Among these, gibbilimbol B, a compound isolated from <i>Piper malacophyllum</i>, is particularly attractive due to its biological potential and simple structure. In this study, eight synthetic phenylalkylamides (<b>1</b>-<b>8</b>) inspired by gibbilimbol B were synthesized and evaluated for their antibacterial activity against <i>N. gonorrhoeae</i>. The in vitro bacterial assays revealed that these compounds exhibit notable antibacterial activity, including against resistant strains selected from the CDC/FDA antimicrobial panel (strains AR-173, AR-174, AR-187, and AR-200). All synthesized compounds demonstrated superior efficacy in killing <i>N. gonorrhoeae</i> compared to gibbilimbol B. Notably, compound <b>8</b> [(<i>E</i>)-4-chloro-<i>N</i>-(oct-4-en-1-yl)benzamide] showed an MBC50 of 6.25 µM, representing a four-fold improvement in bactericidal activity over the natural compound. This study represents the first exploration of gibbilimbol analogs for antibacterial applications, highlighting the novelty of the work and paving the way for the development of new antibacterial agents.