Dual Acting Small-Molecule Inhibitors Targeting Mycobacterial DNA Replication

Abstract Mycobacterium tuberculosis (Mtb) is a pathogenic bacterium and a causative agent of tuberculosis (TB), a disease that kills more than 1.5 million people worldwide annually. One of the main reasons for this high mortality rate is the evolution of new Mtb strains that are resistant to available antibiotics. Therefore, new therapeutics for TB are in constant demand. Here we report the development of such inhibitors that target two DNA replication enzymes of Mtb, namely DnaG primase and DNA gyrase, which share a conserved TOPRIM fold near the inhibitors’ binding site. The molecules were developed on the basis of previously reported inhibitors for T7 DNA primase that bind near the TOPRIM fold. In order to improve the physicochemical properties of the molecules as well as their inhibitory effect on primase and gyrase, 49 novel compounds were synthesized as potential drug candidates in three stages of optimization. The last stage of chemical optimization yielded two novel inhibitors for the fast-growing nonpathogenic model Mycobacterium smegmatis (Msmg).