AUTHOR=Khadke Sagar Kiran , Lee Jin-Hyung , Kim Yong-Guy , Raj Vinit , Lee Jintae 

TITLE=Appraisal of Cinnamaldehyde Analogs as Dual-Acting Antibiofilm and Anthelmintic Agents

JOURNAL=Frontiers in Microbiology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2022.818165

DOI=10.3389/fmicb.2022.818165

ISSN=1664-302X

ABSTRACT=<p>Cinnamaldehyde has a broad range of biological activities, which include antibiofilm and anthelmintic activities. The ever-growing problem of drug resistance and limited treatment options have created an urgent demand for natural molecules with antibiofilm and anthelmintic properties. Hence, we hypothesized that molecules with a scaffold structurally similar to that of cinnamaldehyde might act as dual inhibitors against fungal biofilms and helminths. In this regard, eleven cinnamaldehyde analogs were tested to determine their effects on fungal <italic>Candida albicans</italic> biofilm and nematode <italic>Caenorhabditis elegans</italic>. α-Methyl and <italic>trans</italic>-4-methyl cinnamaldehydes efficiently inhibited <italic>C. albicans</italic> biofilm formation (&gt;90% inhibition at 50 μg/mL) with minimum inhibitory concentrations (MICs) of ≥ 200 μg/mL and 4-bromo and 4-chloro cinnamaldehydes exhibited anthelmintic property at 20 μg/mL against <italic>C. elegans</italic>. α-Methyl and <italic>trans</italic>-4-methyl cinnamaldehydes inhibited hyphal growth and cell aggregation. Scanning electron microscopy was employed to determine the surface architecture of <italic>C. albicans</italic> biofilm and cuticle of <italic>C. elegans</italic>, and confocal laser scanning microscopy was used to determine biofilm characteristics. The perturbation in gene expression of <italic>C. albicans</italic> was investigated using qRT-PCR analysis and α-methyl and <italic>trans</italic>-4-methyl cinnamaldehydes exhibited down-regulation of <italic>ECE1</italic>, <italic>IFD6</italic>, <italic>RBT5</italic>, <italic>UCF1</italic>, and <italic>UME6</italic> and up-regulation of <italic>CHT4</italic> and <italic>YWP1</italic>. Additionally, molecular interaction of these two molecules with UCF1 and YWP1 were revealed by molecular docking simulation. Our observations collectively suggest α-methyl and <italic>trans</italic>-4-methyl cinnamaldehydes are potent biofilm inhibitors and that 4-bromo and 4-chloro cinnamaldehydes are anthelmintic agents. Efforts are required to determine the range of potential therapeutic applications of cinnamaldehyde analogs.</p>