2. Academic Validation
  3. Design, synthesis, and molecular dynamic simulations of some novel benzo[d]thiazoles with anti-virulence activity against Pseudomonas aeruginosa

Design, synthesis, and molecular dynamic simulations of some novel benzo[d]thiazoles with anti-virulence activity against Pseudomonas aeruginosa

  • Eur J Med Chem. 2024 Sep 14:279:116880. doi: 10.1016/j.ejmech.2024.116880.
Esraa Z Mohammed 1,  Nehad M El-Dydamony 2,  Enas A Taha 3,  Mostafa N Taha 4,  Ahmed B M Mehany 5,  Hatem A Abdel Aziz 6,  Rehab H Abd El-Aleam 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt. Electronic address: dr.esraazakaria@o6u.edu.eg.
  • 2 Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.
  • 3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, October 6 University, Giza, 12585, Egypt.
  • 4 Microbiology and Immunology Department, Faculty of Pharmacy, Nahda University, Beni-Suef, Egypt.
  • 5 Zoology Department, Faculty of Science, Al-Azhar University, Cairo, Egypt.
  • 6 Applied Organic Chemistry Department, National Research Centre, Dokki, Giza, P.O.Box 12622, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Pharos University in Alexandria, Canal El Mahmoudia St., Alexandria, 21648, Egypt. Electronic address: ha.abdel-aziz@nrc.sci.eg.
  • 7 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Modern University for Technology and Information MTI, Cairo, 11571, Egypt.
PMID: 39303517 DOI: 10.1016/j.ejmech.2024.116880
Abstract

Inhibition of quorum sensing (QS) is an impending approach for targeting Bacterial infection. Fourteen benzo[d]thiazole and 2-pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazoles analogues were designed and synthesized as promising LasR antagonists with QS inhibition activity. Among the investigated compounds, compounds 3c, 3e, and 8d exhibited the highest percentage inhibition in biofilm formation (77 %, 63.9 %, 69.4 %), pyocyanin production (74.6 %, 64.9, 69.4 %), and rhamnolipids production (58.5 %, 51 %, 54.3 %) in P. aeruginosa, respectively. Additionally, compounds 3c, 3e and 8d achieved IC50 values against Las R equal 1.37 ± 0.35, 1.55 ± 0.24, 1.1 ± 0.15 μM respectively. Also, molecular docking of the target compounds into the LasR binding site co-crystalized "odDHL" revealed their binding with the essential residues for protein inhibition. Additionally, molecular dynamics simulation (MDS) experiments over 200 ns of compound 3c showed its ability to interact with the LasR binding site with dissociation of the protein's dimer confirming its action as a LasR antagonist. The obtained findings inspire further investigation for benzo[d]thiazole and 2-pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazoles aiming to design and synthesize more potential QS inhibitors.

Keywords

Antivirulence; Benzo[d]thiazoles; LasR; MD simulation; P. aeruginosa; QSI.

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