Synthesis, in silico Study, Theoretical Stereochemistry Elucidation and Antifungal Activity of New Imides Derived from Safrole

Raquel Vilela,Petronio De Athayde-Filho,Luiz Cruz,Edeltrudes Lima,Helivaldo Souza,José Barbosa-Filho,Laísa Cordeiro,Normando Costa,Gerd Rocha,Kelyonara De Assis,Bruno Lira

doi:10.21577/0103-5053.20200110

Raquel Vilela, Petronio De Athayde-Filho + Show 9 more

Open Access

https://doi.org/10.21577/0103-5053.20200110

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Abstract

Ten imides derived from safrole, 4a-4j, were synthesized and their structures were fully characterized by infrared (IR) spectroscopy, 1H and 13C nuclear magnetic resonance (NMR) spectroscopy and high resolution mass spectrometry (HRMS) analysis. Among the ten imides studied, eight are new. The compounds were evaluated in an in silico study and showed strong to moderate antifungal activity against various strains of Candida and Cryptococcus. In particular, compounds 4b, 4c and 4h exhibited strong antifungal activity, with minimum inhibitory concentration (MICs) between 0.17-0.73 µmol mL-1. The compound 4j exhibited antifungal activity with MIC 1.28 µmol mL-1 for all strains tested. In silico studies of the parameters of Lipinski’s rule of five indicated that these compounds are potential new drug candidates. The predict oral bioavailability can be evaluated through these parameters. In addition, a computational study helped assigning the stereochemistry of compound 4j, where the synthesized mixture is composed by two stereoisomers, 4j(1) (SRR) and 4j(2) (RSS).

Highlights

There is a need for more research on the development of new antifungal drugs as indicated by worrisome increase in the frequency of opportunistic fungal infections, those caused by Candida spp. and Cryptococcus spp.[1]
In the 1H nuclear magnetic resonance (NMR) spectrum for the anhydride (3), there were characteristic signals of a singlet assigned to the two hydrogens of the CH2 of the methylenedioxy group at dH 5.87, multiple signals for two hydrogens, one at dH 2.54 and one at dH 2.46 of the methylene hydrogens, CH2, a doublet at dH 1.02 referring to three hydrogens of the CH3 group
Compound 4e showed 100% inhibition and good activity against C. neoformans LM-260 and C. neoformans FCF-119 with a minimum inhibitory concentration (MIC) of 1.40 μmol mL‐1, and it exhibited activity against C. gattii INCQS-40113, C. parapsilosis ATCC-22019 and C. krusei LM-656 with a MIC of 2.80 μmol mL-1

Summary

Introduction

There is a need for more research on the development of new antifungal drugs as indicated by worrisome increase in the frequency of opportunistic fungal infections, those caused by Candida spp. and Cryptococcus spp.[1]. We tested these compounds for antifungal activity against strains of the genera Candida and Cryptococcus and theoretically assessed the potential of these compounds to become new drug candidates on the basis of an in silico study according to the Lipinski’s rule of five using freely available programs.

Results

Conclusion