2. Academic Validation
  3. The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase

The rational design, synthesis, and antimicrobial investigation of 2-Amino-4-Methylthiazole analogues inhibitors of GlcN-6-P synthase

  • Bioorg Chem. 2020 Jun;99:103781. doi: 10.1016/j.bioorg.2020.103781.
Abdelsattar M Omar 1,  Saleh Ihmaid 2,  El-Sayed E Habib 3,  Sultan S Althagfan 4,  Sahar Ahmed 5,  Hamada S Abulkhair 6,  Hany E A Ahmed 7
Affiliations

Affiliations

  • 1 Pharmaceutical Chemistry Department, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address: [email protected].
  • 2 Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.
  • 3 Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 344, Saudi Arabia; Department of Microbiology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
  • 4 Clinical and Hospital Pharmacy Department, Taibah University, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia.
  • 5 Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
  • 6 Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt.
  • 7 Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address: [email protected].
PMID: 32222620 DOI: 10.1016/j.bioorg.2020.103781
Abstract

A series of novel 2-Amino-4-Methylthiazole analogs were developed via three-step reaction encompassing hydrazine-1-carboximidamide motif to combat Gram-positive and Gram-negative Bacterial and Fungal infections. Noticeably, the thiazole-carboximidamide derivatives 4a-d displayed excellent antimicrobial activity and the most efficacious analogue 4d with MIC/MBC values of 0.5 and 4 μg/mL, compared to reference drugs with very low toxicity to mammalian cells, resulting in a prominent selectivity more than 100 folds. Microscopic investigation of 4d biphenyl analogue showed cell wall lysis and promote rapid bactericidal activity though disrupting the Bacterial membrane. In addition, an interesting in vitro investigation against GlcN-6-P Synthase Inhibition was done which showed potency in the nanomolar range. Meanwhile, this is the first study deploying a biomimicking strategy to design potent thiazole-carboximidamides that targeting GlcN-6-P Synthase as antimicrobial agents. Importantly, Molecular modeling simulation was done for the most active 4d analogue to study the interaction of this analogue which showed good binding propensity to glucosamine binding site which support the in vitro data.

Keywords

Aminoguanidine; Antimicrobial activity; GlcN-6-P synthase inhibition; Thiazole.

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