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

Abstract

Increasing multidrug resistance in Neisseria gonorrhoeae poses a serious and escalating public health crisis. The World Health Organization has classified N. gonorrhoeae 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 Piper malacophyllum, is particularly attractive due to its biological potential and simple structure. In this study, eight synthetic phenylalkylamides (1-8) inspired by gibbilimbol B were synthesized and evaluated for their antibacterial activity against N. gonorrhoeae. 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 N. gonorrhoeae compared to gibbilimbol B. Notably, compound 8 [(E)-4-chloro-N-(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.

Keywords: Neisseria gonorrhoeae; analogs; bactericidal; gibbilimbol B; natural products.

Figure 1

Chemical structure of gibbilimbol B.

Figure 2

Illustration of the schematic procedure employed in the synthesis of the amides 1–8. (a) Reaction with 1-octylamine; (b) reaction with (E)-oct-4-en-1-amine. Reaction conditions: CH₂Cl₂, 0 °C, N₂ atmosphere, Et₃N.

Figure 3

The bactericidal activity of gibbilimbol analogs 1–8 (blue) and ceftriaxone (CEF) (black) at 50 µM, assessed by viable counting in the bactericidal assay. The columns represent the mean % killing, and the error bars indicate the standard error of the mean (SEM) from four independent experiments (n = 4).

Figure 4

Heatmap showing the percentage of N. gonorrhoeae P9-17 killing at different concentrations (1.5625 to 50 µM) of gibbilimbol analogs 2–8. Data represent the mean of three independent experiments, each performed in triplicate.