N-Myristoyl Transferase Inhibitors with Antifungal Activity in Quinolinequinone Series: Synthesis, In-silico Evaluation and Biological Assay

Abstract

A series of anilino and aryl derivatives of quinolinequinone and naphthoquinone were synthesized via Pd catalysed cross-couplings. The results of docking the compound series towards the binding site of fungal N-myristoyl transferase (NMT) indicated that the quinones favourably interacted with the protein at binding free energy ranges of -5.14 to -8.01 kcal/mol. In addition, Candida albican and Candida anthra were susceptible to many of synthesized molecules in vitro, at MIC range of 1.60 -25 μg/ml. However, some of the compounds which had binding interaction with NMT in docking calculations fails to demonstrated measurable antifungal effect; and that highlights the importance of target-ligand complex stability dynamic situations that characterize biological system. Analysis of predicted binding modes revealed interesting structure-activity-relationship that can provide information on activity optimization process