Identification of a 3-(5-methyl-2-thiazolylamino)phthalide as a new minor groove agent

Abstract

A new 3-(5-methyl-2-thiazolylamino)phthalide molecule, 3-((5-methylthiazol-2-yl)amino)isobenzofuran-1(3H)-one, was synthesized and characterized experimentally by FT-IR, NMR, UV-Vis, and single-crystal X-ray analysis and theoretically by quantum chemical calculations. The single-crystal X-ray studies revealed that the compound crystallizes in the monoclinic space group P-2_1/c with unit-cell parameters a = 8.0550(6) Å, b = 6.1386(3) Å, c = 23.3228(18) Å, β = 97.724(6)° and Z = 4. Optimized geometries and the vibrational frequencies were studied at the density functional theory (DFT) level by using the hybrid functional B3LYP with a 6-311 G (d,p) basis set. The title compound was evaluated for its anti-quorum sensing (anti-QS) activity on Chromobacterium violaceum 12472 and additionally for its antibacterial activity against Staphylococcus aureus 29213, Staphylococcus epidermidis 12228, Pseudomonas aeruginosa 27853, Escherichia coli 25922, and Proteus mirabilis 14153. The lowest MIC value was 0.24 μg/mL for S. aureus 29213 and the highest MIC value was 30.75 μg/mL for E. coli 25922. While anti-bacterial activity was observed in those other than the S. epidermidis and P. Mirabilis, anti-QS activity wasn’t detected. Investigations on dsDNA binding affinity indicate that the title compound binds to dsDNA via the groove binding mode. Molecular docking calculations and molecular dynamics simulations results showed also that the title compound prefers binding to the minor groove of dsDNA and remains stable in the minor groove throughout the molecular dynamics simulation.

Communicated by Ramaswamy H. Sarma

Keywords:

• Phthalide
• 2-aminothiazole
• DNA binding
• quorum sensing
• antibacterial
• molecular docking

Acknowledgments

The authors wish to thank to Istanbul Technical University, Faculty of Sciences and Letters, Department of Chemistry for the experimental conditions (Lab L-105 belonging to Prof. Gölcü) and Dr. Kübra Erkan Türkmen (Hacettepe University) for kindly providing us bacterial strain CV12472. The computational studies reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources) and Kocaeli University.

Disclosure statement

No potential conflict of interest was reported by the authors.