Design, Synthesis,\nand Evaluation of the Antitubercular\nActivity of 5‑Phenyl Substituted-5, 6‑dihydropyrido[2,\n3‑<i>d</i>]pyrimidine-4, 7(<i>3H</i>, <i>8H</i>)‑dione Compounds

Tuberculosis (TB) remains a major public health challenge,\nwith\nresearch on new anti-TB drugs crucial for global TB elimination efforts.\nHere, we report a novel class of anti-TB agents. Especially, compounds <b>5b</b> and <b>5j</b> exhibited the highest activity [minimum\ninhibitory concentration (MIC) H37Rv: 0.16 and 0.12 μg/mL].\nChiral resolution was performed on compounds <b>5b</b> and <b>5j</b>; the isomers were evaluated for their activity and safety,\nconfirming that the <i>R</i>-isomer <b>5bb</b> and <b>5jb</b> displayed significant anti-TB activity (MIC H37Rv: 0.03–0.06\nμg/mL; MDR-<i>Mtb</i>: 0.125–0.06 μg/mL)\nand low hERG toxicity. Further evaluations on <b>5bb</b> and <b>5jb</b> demonstrated good metabolic stability, favorable kinetic\nparameters and oral bioavailability (F: 56.7 and 63.8%, respectively).\nThe results of <i>in vivo</i> activity assessment indicate\nthat <b>5bb</b> and <b>5jb</b> exhibit protective and\ntherapeutic effects on zebrafish larvae and adult zebrafish infected\nwith Mycobacterium marinum. Based on\nthese results, compounds <b>5bb</b> and <b>5jb</b> are\nconsidered promising candidates for further in-depth studies.