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 and exhibited the highest activity [minimum inhibitory concentration (MIC) H37Rv: 0.16 and 0.12 μg/mL]. Chiral resolution was performed on compounds and ; the isomers were evaluated for their activity and safety, confirming that the -isomer and displayed significant anti-TB activity (MIC H37Rv: 0.03-0.06 μg/mL; MDR- : 0.125-0.06 μg/mL) and low hERG toxicity. Further evaluations on and demonstrated good metabolic stability, favorable kinetic parameters and oral bioavailability (F: 56.7 and 63.8%, respectively). The results of activity assessment indicate that and exhibit protective and therapeutic effects on zebrafish larvae and adult zebrafish infected with . Based on these results, compounds and are considered promising candidates for further in-depth studies.