Preparation, Docking, Antimicrobial and Cytotoxic Activities of 2-arylquinazolinones

Aims: Recently the use of antifungal drugs in human medicine has been increased, especially with the advent of AIDS epidemic. The extensive use of antifungal drugs and their resistance against fungal infections have led to the discovery of new antimicrobial compounds. Despite the growing list of azole drugs, their clinical value has been limited by their relatively high risk of toxicity and the emergence of drug resistance. Also, chemotherapy for cancer is frequently limited by organ toxicities and emergence of drug resistance in tumor cells. So efforts have focused on the development of new, less toxic, and more effective antifungal and cytotoxic agents.

Study Design: Preparation of several 2-arylquinazolinones with both antifungal and cytotoxic activities.

Place and Duration of Study: Department of Medicinal Chemistry, Department of Medical Mycology and Institute for Cancer Research, Shiraz University of Medical Sciences, Shiraz, Iran, from October 2016 to September 2017.

Methodology: Several synthetic analogues of 2-arylquinazolinones have been developed aiming at drugs with high potency and diminished toxicity. Thus, 2-arylquinazolinones (1b-12b) are prepared according to literature. The antimicrobial activities of these compounds against different species of microorganisms including fungi, gram positive and gram negative bacteria are evaluated. Broth micro-dilution method as recommended by clinical and laboratory standard institute (CLSI) was used for this purpose. We also evaluated the cytotoxic activities of the compounds against three human cancer cell lines (MCF-7, A549 and SKOV3) using colorimetric MTT cytotoxic assay. The specific binding mode of synthetic 2-arylquinazolinones have been also indicated by molecular modelling studies to show the interactions and binding orientation of compounds to CYP51 active site.

Results: Compound 1b showed desirable activities against bacteria as well as yeasts and filaments fungi. Compounds 2b, 7b, 8b and 9b can inhibit the growth of different yeasts with acceptable MIC. The cytotoxic results showed compounds 7b, 8b, 9b and 10b had partial inhibitory effects on cancer cell lines in particular lung adenocarcinoma.

Conclusion: 2-arylquinazolinones are respectable candidate for further studies in biological research.