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  2. Design and synthesis of novel benzimidazole derivatives as potential Pseudomonas aeruginosa anti-biofilm agents inhibiting LasR: Evidence from comprehensive molecular dynamics simulation and in vitro investigation

Design and synthesis of novel benzimidazole derivatives as potential Pseudomonas aeruginosa anti-biofilm agents inhibiting LasR: Evidence from comprehensive molecular dynamics simulation and in vitro investigation

  • Eur J Med Chem. 2022 Nov 5;241:114629. doi: 10.1016/j.ejmech.2022.114629.
Rehab H Abd El-Aleam 1 Ahmed M Sayed 2 Mostafa N Taha 3 Riham F George 4 Hanan H Georgey 5 Hamdy M Abdel-Rahman 6
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information MTI, Cairo, 11571, Egypt.
  • 2 Pharmacognosy Department, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt; Department of Pharmacognosy, Faculty of Pharmacy, Almaaqal University, 61014, Basra, Iraq.
  • 3 Microbiology and Immunology Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
  • 4 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. Electronic address: riham.eskandar@pharma.cu.edu.eg.
  • 5 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt.
  • 6 Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University, Beni Suef, Egypt.
Abstract

Quorum sensing (QS) inhibition is one of the potential methods to target Bacterial infection. In this study, comprehensive molecular dynamics simulation (MDS) experiments were conducted on the LasR structure to understand its structural dynamic behavior either in its ligand-free form or in its ligand-bound form (i.e. agonist or antagonist). The results revealed that LasR structure is significantly unstable in its ligand-free and antagonist-bound forms and such structural instability led eventually to complete dissociation of the functioning LasR dimeric form. Accordingly, twenty-eight benzimidazole derivatives were designed, synthesized as potential LasR antagonists, and characterized in vitro as QS inhibitors. Compounds 3d and 7f disclosed the highest percentage inhibition in biofilm formation, pyocyanin, and rhamnolipids production in Pseudomonas aeruginosa (71.70%, 68.70%, 54.00%) and (68.90%, 68.00%, 51.80%), respectively. MDS experiments revealed that these compounds as inhibitors, particularly, 3d, 7f, 8a, and 9g induce LasR structure instability and complete dissociation of its functioning dimeric form similarly to the previously reported inhibitor bromophenethyl-2-nitrobenzamide (BPNB). Furthermore, gene expression assays as another mechanism targeting quorum sensing genes to prove the inhibitory activity of these compounds on virulence factors, revealed that a number of the synthesized compounds were able to downregulate lasR (e.g. 3d and 7f by 61.70% and 26.00%, respectively) and rhlR (e.g. 7f by 16.30%) expressions. The results presented here provide a functional model for LasR that could guide future design of LasR inhibitors.

Keywords

Anti-virulence; Benzimidazoles; Biofilm; LasR; Molecular dynamics simulation; Molecular modeling; P. aeruginosa; QSI.

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