Synthesis, Microbiological Activity and In Silico Investigation for Some Synthesized Coumarin Derivatives

Selma Špirtović-Halilović,Mirsada Salihović,Davorka Završnik,Dženita Softić,Aida Šapčanin,Sunčica Roca,Snežana Trifunović,Amar Osmanović,Elma Veljović,Aida Selmanagić,Nihada Škrijelj,Selma Škrbo

doi:10.5562/cca3637

Abstract

Four 4-hydroxycoumarin derivatives were synthesized and the structure was confirmed by NMR spectroscopy and Mass spectrometry. Tested compounds have shown significant antimicrobial activity against Bacillus subtilis subsp. spizizenii, Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis, and the effect of more halogens on the benzene nucleus, as well as the combination of halogen and alkyl groups, on the antimicrobial activity, was investigated. According to the docking study, these compounds can operate simultaneously on two enzymes, amylase and gyrase (1BAG and 1KZN), which are known to play an important role in bacterial life. Obtained docking study parameters for tested compounds showed an association with the in vitro results of the antimicrobial activity of these compounds. In silico tests of molecular properties of the tested compounds showed that the compounds met Lipinski's rule of five. In this paper, the ADME parameters of tested compounds were also calculated: Caco2 (in vitro Caco2 cell permeability), HIA (human intestinal absorption), MDCK (in vitro Mandin Darby Canine Kidney (MDCK) cell permeability), TPSA (topological polar surface area), etc.

Highlights

O NE of the reasons that drive researchers to synthesize new substances is the resistance of microbes to applied antibiotics
Four 4-hydroxycoumarin derivatives were synthesized and the structure was confirmed by NMR spectroscopy and Mass spectrometry
This study aims were to evaluate the affinity of the binding of selected synthesized 4-hydroxycoumarin derivatives to bacterial enzymes gyrase and amylase and to correlate obtained parameters in silico with obtained results of in vitro antimicrobial activity of compounds

Summary

Introduction

O NE of the reasons that drive researchers to synthesize new substances is the resistance of microbes to applied antibiotics. There has been a big interest in coumarin substances, in the synthesis of their derivatives with antimicrobial activity.[1,2] Antibacterial drugs that target only one enzyme often lead to bacterial resistance due to single-mutation. The presence of coumarin moiety has an important pharmacological and therapeutic role due to anti-inflammatory, anticoagulant, anticancer, antimicrobic, and antineurodegenerative properties, the scientific interest in these compounds is enormous. Numerous coumarin derivatives with biological activity have been synthesized.[4,5,6,7,8] On the other side, cinnamic acids are a group of aromatic carboxylic acids (C6–C3) appearing naturally in the plant kingdom.[9] Cinnamic acids are formed in the biosynthetic pathway leading to

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