Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME\u2013Tox and molecular docking studies of a series of imidazole derivatives

Btissam Bouchal,Mounia Elidrissi Errahhali,Manal Elidrissi Errahhali,Henri Doucet,Abdelilah Takfaoui,Rachid Touzani,Mohammed Bellaoui,Pierre H Dixneuf,Farid Abrigach

doi:10.1186/s13065-019-0623-6

Abstract

Thirty-four imidazole-based compounds synthesized by one-pot catalytic method were evaluated for their antifungal and antibacterial activities against several fungal and bacterial strains. None of the compounds had antibacterial activity. Interestingly, compounds 1, 2, 3, 10 and 15 displayed a strong antifungal activity against all the tested fungal species, while compounds 5, 7, 9, 11, 21 and 27 showed a moderate antifungal activity. To better understand the biological activity of the most active compounds ADME–Tox and molecular docking studies were carried out. Interestingly, compounds 1, 2, 3, 7, 10 and 15 showed excellent bioavailability. In addition, compounds 1, 2 and 3, exhibited good toxicity profiles. Docking studies of the two most active compounds 2 (IC50 of 95 ± 7.07 μM) and 10 (IC50 of 235 ± 7.07 μM) suggested that they might act by inhibiting the fungal lanosterol 14α-demethylase. Therefore, these novel antifungal agents merit further characterization for the development of new antifungal therapeutics.

Highlights

Human infectious diseases are among the top ten causes of death worldwide, according to the World Health Organization [1]
Antifungal and antibacterial activities of imidazole derivatives We first evaluated the antifungal activity of our imidazole derivatives against three fungal species (S. cerevisiae, C. albicans and C. krusei) as described in materials and methods
Further evaluation of the most active compounds of this series (10 and 15) has demonstrated that compound 10 was more potent than compound 15, with IC50’s against S. cerevisiae of 235 ± 7.07 μM and 305 ± 21.21 μM, respectively (Table 1). These findings suggest that the antifungal activity of these diarylated imidazole derivatives depends on the size, position and electronic effect of the substituent at the phenyl rings

Summary

Introduction

Human infectious diseases are among the top ten causes of death worldwide, according to the World Health Organization [1]. Increasing resistance of fungal pathogens to current antifungal drugs is one of the reasons for the difficulty to tackle fungal infections, in immune-compromised. In this view, many heterocyclic compounds have been studied in order to discover novel antimicrobial agents. Imidazole-based heterocyclic compounds occupy a prominent place in heterocyclic chemistry [12, 13]. Members of this family of compounds have diverse biological, pharmacological, environmental and industrial applications [14]. Several imidazole-based heterocyclic compounds have been clinically used to treat many diseases such as Bifonazole which is a clinically used antifungal

Methods

Results

Conclusion