doiSerbia

Synthesis and biological profiling of novel isocoumarin derivatives and related compounds

Simić Milena R. (University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Belgrade, Serbia), [email protected]
Erić Slavica (University of Belgrade, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Belgrade, Serbia)
Borić Ivan (IQVIA, Clinical Department, Belgrade, Serbia)
Lubelska Annamaria (Jagiellonian University, Medical College, Department of Technology and Biotechnology of Drugs, Kraków, Poland)
Latacz Gniewomir (Jagiellonian University, Medical College, Department of Technology and Biotechnology of Drugs, Kraków, Poland)
Kiec-Kononowicz Katarzyna (Jagiellonian University, Medical College, Department of Technology and Biotechnology of Drugs, Kraków, Poland)
Vojnović Sandra (University of Belgrade, Institute for Molecular Genetics and Genetic Engineering, Laboratory for Microbial Molecular Genetics and Ecology, Belgrade, Serbia)
Nikodinović-Runić Jasmina (University of Belgrade, Institute for Molecular Genetics and Genetic Engineering, Laboratory for Microbial Molecular Genetics and Ecology, Belgrade, Serbia)
Savić Vladimir M. (University of Belgrade, Faculty of Pharmacy, Department of Organic Chemistry, Belgrade, Serbia)

In the continuation of our study of substituted isocoumarins a series of novel 3-azolyl isocoumarin and their thio derivatives, including some related lactone compounds was prepared and biologically profiled against C. albicans showing moderate activity with MIC values in range of 4–60 g mL-1, in general. The additional characterisation of selected compounds was carried out by exploring their activity on CYP3A4 and CYP2D6 enzymes, while experiments on mutagenicity were performed by AMES test. The representative isocoumarins 3b, 4a and 4b showed lower inhibitory activity on CYP enzymes, when compared to the reference inhibitors, ketoconazole and quinidine. Compound 4a showed a higher mutagenic potential than the other two compounds. Further characterization included cytotoxicity profiling against normal MRC5 cells.

Keywords: antifungal compounds, isocoumarins, Candida albicans, CYP enzymes, AMES

Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 451-03-68/2020-14/200161 and Grant no. 451-03-68/2020-14/200042