Diastereomeric pure pyrazolyl-indolyl dihydrofurans: Unveiling isomeric selectivity in antibacterial action via in vitro and in silico insights

Bioorg Med Chem Lett. 2024 Dec 1:114:130005. doi: 10.1016/j.bmcl.2024.130005. Epub 2024 Oct 24.

Abstract

Developing pure diastereoisomeric molecular hybrids for the selective inhibition of bacterial growth opened new avenues for combating the ever-increasing microbial resistance. Considering this, a series of diastereoisomeric pure pyrazolyl-dihydrofurans (7a-7y) were synthesized and characterized using NMR, LCMS, and X-ray crystallography. DFT based method was used to explore the configurational stability of cis over trans isomeric form. Considering 7a and 8a as representative isomeric forms with same structural framework, the difference in their bio-efficacy against bacterial and fungal strains was assessed using serial dilution method. The relatively high inhibition of bacterial growth by the cis isomeric form (7a) (MIC = 1.562 µg/mL), amoxicillin (MIC = 3.125 µg/mL) inspired us to broaden the substrate scope for synthesizing a series of pure diastereoisomeric cis forms as selective anti-bacterial agents. However, both the isomers displayed antifungal activity less than the standard drug (Fluconazole) employed in the study. All the reactions proceeded smoothly and yielded a diverse array of dihydrofuran derivatives. The developed synthetics were found to be non-cytotoxic against mouse fibroblast cells and didn't affect the seed germination of Brassica nigra seeds when treated at 1 mg/mL concentration. The experimentally determined in vitro results were further validated using in silico molecular docking and dynamics studies.

Keywords: Anti-microbial; DFT and in silico study; Diastereoisomeric forms; Dihydrofuran; Indole; Pyrazole.

MeSH terms

  • Animals
  • Anti-Bacterial Agents* / chemical synthesis
  • Anti-Bacterial Agents* / chemistry
  • Anti-Bacterial Agents* / pharmacology
  • Antifungal Agents* / chemical synthesis
  • Antifungal Agents* / chemistry
  • Antifungal Agents* / pharmacology
  • Dose-Response Relationship, Drug
  • Furans* / chemical synthesis
  • Furans* / chemistry
  • Furans* / pharmacology
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology
  • Mice
  • Microbial Sensitivity Tests*
  • Molecular Docking Simulation
  • Molecular Structure
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Furans
  • Antifungal Agents
  • Pyrazoles
  • Indoles