Overview of DprE1 Inhibitors and Development of Macozinone and Other Drugs

DprE1 is an indispensable enzyme responsible for the development and synthesis of Mycobacterium tuberculosis (Mtb) cell wall. A range of compounds has been reported to inhibit this essential enzyme, including a wealth of covalent and non-covalent inhibitors. Both covalent and non-covalent inhibitors have reached the clinical stages, such as Macozinone (MCZ) or PBTZ169 (Phase II), BTZ043 (Phase II), Quabodepistat (OPC-167832) (Phase II), and TBA-7371 (Phase II), along with many other small molecules. All of these compounds have diverse chemical scaffolds and possess drug-like properties. Herein, we will discuss the medicinal chemistry efforts for the development of these inhibitors, their clinical profiling, and other pharmacological properties. This topic will mainly cover the medicinal chemistry perspective of DprE1 inhibitors and their importance in anti-tubercular drug discovery.