It is estimated that one-third of the world's population has been exposed to the tuberculosis bacterium; killing eight million every year. Since the 1960s there have been no new drugs marketed, which is primarily due to the Mycobacterium tuberculosis bacilli having a complex cell wall structure, intracellular existence in the host and its ability to stay dormant for extended periods. The continual increase in drug resistance and the lack of new chemotherapeutic agents means the search for a new antimycobacterial agent is of great importance. Our molecular modelling studies identified a thiazole-based scaffold as a potential candidate for optimization, which has a feasible synthetic route and is amenable to library generation to effectively explore local chemical space. Biological screening of the prepared compounds resulted in the identification of some compounds expressing excellent activity against M. tuberculosis with no observed toxicity. The most active compounds will be tested in vivo in mouse models infected with the pathogenic bacilli in order to perform further lead optimization to more drug-like compounds.