Design, Synthesis, and Evaluation of the Antitubercular Activity of 5-Phenyl Substituted-5, 6-dihydropyrido[2, 3- d ]pyrimidine-4, 7( 3H , 8H )-dione Compounds.

Tuberculosis (TB) remains a major public health challenge, with research on new anti-TB drugs crucial for global TB elimination efforts. Here, we report a novel class of anti-TB agents. Especially, compounds 5b and 5j exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 μg/mL]. Chiral resolution was performed on compounds 5b and 5j ; the isomers were evaluated for their activity and safety, confirming that the R -isomer 5bb and 5jb displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 μg/mL; MDR- Mtb : 0.125-0.06 μg/mL) and low hERG toxicity. Further evaluations on 5bb and 5jb demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of in vivo activity assessment indicate that 5bb and 5jb exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with Mycobacterium marinum . Based on these results, compounds 5bb and 5jb are considered promising candidates for further in-depth studies.