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Mycobacterium tuberculosis thymidylate kinase (Mt TMPK) has emerged as an attractive target for rational drug design. We recently investigated new families of non-nucleoside Mt TMPK inhibitors in an effort to diversify Mt TMPK inhibitor chemical space. We here report a new series of Mt TMPK inhibitors by combining the Topliss scheme with rational drug design approaches, fueled by two co-crystal structures of Mt TMPK in complex with developed inhibitors. These efforts furnished the most potent Mt TMPK inhibitors in our assay, with two analogues displaying low micromolar MIC values against H37Rv Mtb. Prepared inhibitors address new sub-sites in the Mt TMPK nucleotide binding pocket, thereby offering new insights into its druggability. We studied the role of efflux pumps as well as the impact of cell wall permeabilizers for selected compounds to potentially provide an explanation for the lack of correlation between potent enzyme inhibition and whole-cell activity. [Display omitted] • Structure-based design and synthesis of new Mt TMPK inhibitors, e.g. featuring a pyridine C-ring. • D-ring substitution afforded potent Mt TMPK inhibitors with submicromolar IC 50 -values. • A co-crystal structure indicates that inhibitor 3 addresses a new subsite in the Mt TMPK nucleotide binding pocket. [ABSTRACT FROM AUTHOR]