Exploring Novel Compounds Targeting Mycobacterium tuberculosis Dihydroorotate Dehydrogenase: SAR Analysis and Biological Activity

Tuberculosis (TB), caused by the bacillus Mycobacterium Tuberculosis (MTB), persists as one of the oldest diseases despite being curable. However, it remains the world’s second leading cause of death from a single infectious agent, with 7.5 million new cases diagnosed globally in 20221, underscoring the urgent need for novel treatments, especially in the face of emerging drug-resistant MTB strains. Inhibition of crucial enzymes and pathways in MTB has been a focal point in the development of new drugs. Enzymes involved in nucleotide biosynthesis have emerged as promising targets due to their vital role in providing building blocks for DNA and RNA. Perturbations in cell metabolism can profoundly affect the proliferation of both infected cells and pathogens, rendering these enzymes pivotal targets for therapeutic interventions. In the tuberculosis mycobacterium, dihydroorotate dehydrogenase (mtDHODH), a crucial enzyme of the de novo pyrimidine biosynthesis pathway, is indispensable for its replication. Our recent efforts have focused on characterizing the full-length mtDHODH, resulting in the successful determination of the crystal structure of the protein2. Through screening our in-house compound library, we have identified MEDS322 as the first inhibitor of mtDHODH known so far. Here, we present the synthesis and biological evaluation of MEDS322 and its analogues based on a thiazolidinone ring scaffold as the first mtDHODH inhbitors.