Structure based design, synthesis, and biological evaluation of imidazole derivatives targeting dihydropteroate synthase enzyme

Bioorg Med Chem Lett. 2021 Mar 15:36:127819. doi: 10.1016/j.bmcl.2021.127819. Epub 2021 Jan 26.

Abstract

In this study, we have designed and synthesized 2-((5-acetyl-1-(phenyl)-4-methyl-1H-imidazol-2-yl)thio)-N-(4-((benzyl)oxy)phenyl) acetamide derivatives. Antimicrobial activities of all the imidazole derivatives have been examined against Gram-positive and Gram-negative bacteria and results showed that the conjugates have appreciable antibacterial activity. Besides, several analogous were evaluated for their in vitro antiresistant bacterial strains such as Extended-spectrum beta-lactamases (ESBL), Vancomycin-resistant Enterococcus (VRE), and Methicillin-resistant Staphylococcus aureus (MRSA). The SAR revealed that the 12l compound resulted in potency against all bacterial strains as well as ESBL, VRE, and MRSA strains. Lipinski's rule of five, and ADME studies were preformed for all the synthesized compounds with Staphylococcus aureus dihydropteroate synthase (saDHPS) protein (PDB ID: 6CLV) and were found standard drug-likeness properties of conjugates. Moreover, the binding mode of the ligands with the protein study has been examined by molecular docking and results are quite promising. Besides, all the analogous were tested for their in vitro antituberculosis, antimalarial, and antioxidant activity.

Keywords: ADME; Antiresistant bacterial strains; Imidazole; Molecular docking; saDHPS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Dihydropteroate Synthase / antagonists & inhibitors*
  • Dihydropteroate Synthase / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Ligands
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / enzymology
  • Structure-Activity Relationship
  • Vancomycin-Resistant Enterococci / drug effects*

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Ligands
  • imidazole
  • Dihydropteroate Synthase