We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
In Silico Studies, Design and Synthesis of Novel Fused Pyrimidine Derivatives as a DNA Gyrase Inhibitor and Antibacterial Activity Against Quinolone Resistant Escherichia Coli.
- Authors
Bhandare, Richie R.; Helina, N.; Subramani, Arun kumar; Natarajan, Ramalakshmi; Mali, Suraj N.; Shaik, Afzal B.
- Abstract
In recent years, antimicrobial agents have been crucial in improving public health worldwide. However, due to improper usage, bacteria have developed resistance to these agents. This has led researchers to explore the use of heterocyclic compounds as alternative antimicrobial agents to combat resistance. Considering the success of heterocyclic derivatives in developing effective antimicrobial drugs, we conducted a 2D-QSAR (QSAR models using 2D-descriptors) study on novel pyrimidine derivatives and performed in silico simulations to evaluate their potential antibacterial activity against quinolone-resistant Escherichia coli. We used QSARINS V.2.2 (Insubria) software for the 2D-QSAR analysis and performed in silico absorption, distribution, metabolism, and excretion (ADME) and docking studies on 16 newly designed compounds. The best QSAR model had a high correlation coefficient ( R 2 = 0. 9 6 3 3 , Q LOO 2 = 0. 9 5 3 8 , Q LMO 2 = 0. 9 5 1 3) and showed no outliers. Based on these favorable results, we designed 16 new compounds and predicted their antibacterial activity using the best equation. Amongst the top six designed compounds, which had the best docking scores were subjected to practical synthesis. Compound 3cd was found to be good candidature from in-vitro anti-E. Coli activity. This compound may be targeting the DNA gyrases and thus, have inhibitory activity against E. Coli. This observation was also supported by 100 ns molecular dynamics and normal mode analysis results. The most promising compounds identified through these computational studies may be synthesized and tested as potential new drug candidates for treating bacterial infections. To summarize, we have developed a statistically robust and valid 2D-QSAR model with a set of 51 compounds of antibacterial pyrimidines using QSARINS V.2.2. The model is tested on newly designed fused pyrimidine derivatives for predicting bioactivity. Based on the QSAR model, binding affinity and ADMET prediction results, six designed compounds 3ae, 3af, 3be, 3bf, 3ca, and 3cd can act as a potent DNA gyrase inhibitor. These 4 compounds were synthesized with good yield and screened for antibacterial activity against E. coli.
- Subjects
DNA topoisomerase II; ANTIBACTERIAL agents; PYRIMIDINE derivatives; PYRIMIDINES; ESCHERICHIA coli; QSAR models
- Publication
Journal of Computational Biophysics & Chemistry, 2023, Vol 22, Issue 6, p687
- ISSN
2737-4165
- Publication type
Article
- DOI
10.1142/S2737416523500357