Synthesis, antimicrobial properties and in silico evaluation of coumarin derivatives mediated by 1,4-dibromobutane

Abstract

In this study, monobrominated coumarins (5–6) and bis-coumarins (7–9) were synthesized from 3-carboxylic coumarin and 7-hydroxy-4-methyl coumarin using 1,4-dibromobutane as a binding agent, according to the synthesis procedures described in the literature. Amongst these coumarins, three are new compounds: monobrominated coumarin 5 and bis-coumarins 7 and 9. The structures of the synthesized coumarins were confirmed by FTIR, NMR and HRMS-ESI. In vitro antimicrobial evaluation of these coumarins against strains of twelve bacteria and four fungi revealed their bactericidal and fungicidal properties, with increased antibacterial activity for monocoumarins and improved antifungal activity for bis-coumarins. It was also found that the antibacterial activity was enhanced by the etheric bond, Br atom and alkyl chain and reduced by the ester bonds at position 3 of the pyrone ring or an additional coumarin unit, while the antifungal activity was reinforced by ester bonds and deactivated by the Br atom. For the first time, the in silico investigations of such coumarins were carried out and it was observed that they are less toxic, suitable for oral administration with good permeability through cell membrane, are able to circulate freely in the bloodstream and cross Blood-Brain-Barriers. Moreover, their molecular docking in DNA indicated stable coumarin-DNA complexes with good scores. The results of molecular dynamics simulations performed for 200 ns revealed the rigidity and stability of bis-coumarins (7–9) in the DNA binding pocket and predict that they are potent binders.

Communicated by Ramaswamy H. Sarma

Keywords:

• Coumarins
• lipophilicity
• antimicrobial activity
• pharmacokinetic
• molecular docking and dynamics

Acknowledgments

Our thanks to Mr. Ngueko Lionel and Mr. Onana Edmond Loic, respectively MSc student and laboratory technician in organic synthesis at the University of Douala, for their involvement in this work. Authors are grateful to the Consortium des Équipements de Calcul Intensif (CÉCI, http://www.ceci-hpc.be) and particularly the Technological Platform of High-Performance Computing for all calculations through financial support from the FNRS-FRFC, of the Walloon Region, and of the University of Namur (Conventions No. 2.5020.11, GEQ U.G006.15,1610468, and RW/GEQ2016).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by UNESCO-TWAS and the Swedish International Development Cooperation Agency (Sida) under Grant (21-327 RG/CHE/AF/AC_G-FR32403). The views expressed herein do not necessarily represent those of UNESCO-TWAS, Sida or its Board of Governors.