1. Bioactivity Studies of β-Lactam Derived Polycyclic Fused Pyrroli-Dine/Pyrrolizidine Derivatives in Dentistry: In Vitro, In Vivo and In Silico Studies.
- Author
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Meiyazhagan G, Raju R, Winfred SB, Mannivanan B, Bhoopalan H, Shankar V, Sekar S, Venkatachalam DP, Pitani R, Nagendrababu V, Thaiman M, Devivanayagam K, Jayaraman J, Ragavachary R, and Venkatraman G
- Subjects
- Animals, Anti-Bacterial Agents chemistry, Bicuspid microbiology, Biofilms, Computer Simulation, Drosophila melanogaster, Drug Evaluation, Preclinical, Enterococcus faecalis drug effects, Female, Humans, Mice, Inbred BALB C, Microbial Sensitivity Tests, Models, Molecular, Penicillin-Binding Proteins chemistry, Protein Binding, Pyrrolidines chemistry, Reactive Oxygen Species metabolism, Root Canal Irrigants chemistry, Root Canal Therapy, Salmonella typhimurium drug effects, beta-Lactams chemistry, Anti-Bacterial Agents pharmacology, Pyrrolidines pharmacology, Root Canal Irrigants pharmacology, beta-Lactams pharmacology
- Abstract
The antibacterial activity of β-lactam derived polycyclic fused pyrrolidine/pyrrolizidine derivatives synthesized by 1, 3-dipolar cycloaddition reaction was evaluated against microbes involved in dental infection. Fifteen compounds were screened; among them compound 3 showed efficient antibacterial activity in an ex vivo dentinal tubule model and in vivo mice infectious model. In silico docking studies showed greater affinity to penicillin binding protein. Cell damage was observed under Scanning Electron Microscopy (SEM) which was further proved by Confocal Laser Scanning Microscope (CLSM) and quantified using Flow Cytometry by PI up-take. Compound 3 treated E. faecalis showed ROS generation and loss of membrane integrity was quantified by flow cytometry. Compound 3 was also found to be active against resistant E. faecalis strains isolated from failed root canal treatment cases. Further, compound 3 was found to be hemocompatible, not cytotoxic to normal mammalian NIH 3T3 cells and non mutagenic. It was concluded that β-lactam compound 3 exhibited promising antibacterial activity against E. faecalis involved in root canal infections and the mechanism of action was deciphered. The results of this research can be further implicated in the development of potent antibacterial medicaments with applications in dentistry.
- Published
- 2015
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