Guang-Fu Yang
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, Wuhan 430079, P.R.China
Cytochrome bc1 complex (EC 1.10.2.2, bc1) is an essential component of cellular respiratory chain and plays a pivotal role in the life cycle. The function of the bc1 complex is to catalyze the electron transfer (ET) from ubiquinol (hydroxyquinones, QH2) to a water-soluble cytochrome c (cyt c) and couples this electron transfer to the translocation of protons across the membrane to generate a proton gradient and membrane potential for ATP synthesis. If the electron transport process of cyt bc1 was disturbed or disrupted, the cellular respiration will be blocked and resulted in cell death, thus the bc1 complex has been demonstrated as one of the most attractive targets for the development of pharmaceuticals and agrochemicals. Over the past years, great attention has been poured into the development of novel cytochrome bc1 complex (complex III) inhibitors. Although numerous inhibitors have been discovered, discovery of novel inhibitors with entirely new structures should still be a key area of focus.
Natural products invariably show a broad range of interesting and useful biological activities. More significantly, they demonstrate favorable environment-compatibility and could be readily biodegradable. However, synthesis of natural products could still be a formidable challenge due to their inherent structural complexity, which requires tedious synthetic procedures with low overall yields. In addition, they may suffer from limited activities and adverse photo-stability. Accordingly, instead of natural products themselves, their analogs usually serve as ideal candidates for development of medicines and pesticides. These analogs are valuable since they could give rise to novel and simplified structures with improved biological activities, new modes of action, and increased safety towards humans, plants, animals and the environment. Consequently, natural product-like compounds are ideal for identification of new lead molecules with useful functionalities.
Bacillamide C, a class of natural products bearing a bisamide thiazole motif, has captured our attention for its diverse bioactivities including algicidal and antibacterial activities. Our tested results showed that racemic Bacilliamide C showed inhibition activity against porcine bc1 with IC50 value of 72μM. In this presentation, we will introduce the structural optimization of Bacilliamide C with the guide of computational simulations and eventually yields a series of novel thiazole-3-amides as nanomolar bc1 inhibitors. In addition, multi-component reaction (MCR)-based synthesis strategy and stereochemistry-biological activity relationships will also be discussed.
