Mannich base limits Candida albicans virulence by inactivating Ras-cAMP-PKA pathway

Sci Rep. 2018 Oct 8;8(1):14972. doi: 10.1038/s41598-018-32935-9.

Abstract

Mannich bases and its derivatives are regarded as supreme pharmacophores in therapeutics. The study investigates the antimycotic potential of Mannich bases, 1-((1H-benzimidazol-1-yl) methyl) urea (C1) and 1-((3-hydroxynapthalen-2-yl) methyl) thiourea (C2), against Candida albicans. Biofilm and hyphal inhibitory activities of the Mannich bases were tested by crystal violet quantification, fluorescence imaging cAMP rescue, qRT PCR, and by molecular docking analysis. The compounds inhibited the biofilms of C. albicans and restrained the filamentation abilities of the pathogen. Structure-activity relationship studies revealed that the presence of urea or thiourea moiety in the tail section is essential for interacting with adenylate cyclase (AC). The Mannich bases seemed to block Ras-cAMP-PKA pathway by inhibiting second messenger activity required for hyphal induction and biofilm formation. In conclusion, the study warrants point-of-care testing of C1/C2 and provides a starting point for deriving several structurally modified Mannich bases which might plausibly replace the prevailing antimycotic drugs in future.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antifungal Agents / chemistry*
  • Antifungal Agents / pharmacology*
  • Biofilms / drug effects
  • Biofilms / growth & development
  • Candida albicans / drug effects*
  • Candida albicans / pathogenicity
  • Candida albicans / physiology
  • Candidiasis / drug therapy
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Fungal Proteins / metabolism
  • Humans
  • Mannich Bases / chemistry*
  • Mannich Bases / pharmacology*
  • Molecular Docking Simulation
  • Signal Transduction / drug effects
  • Thiourea / analogs & derivatives*
  • Thiourea / pharmacology*
  • ras Proteins / metabolism

Substances

  • Antifungal Agents
  • Fungal Proteins
  • Mannich Bases
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • ras Proteins
  • Thiourea