Structure–Activity Relationship of Novel Pyrimidine Derivatives with Potent Inhibitory Activities against Mycobacterium tuberculosis

Discovery
of novel antitubercular drugs is an effective strategy
against drug-resistant tuberculosis (TB). Our previous study has identified LPX-16j as a novel antitubercular compound. Herein, we perform
a comprehensive structure–activity relationship (SAR) based
on LPX-16j, indicating that the central pyrimidine ring
moiety was crucial for the antitubercular activities of its derivatives,
and replacing the naphthyl group with hydrophobic substitutes was
well tolerated. The representative derivative 5a exhibited
potent activity against H37Ra, H37Rv, and clinical drug-resistant
TB with minimum inhibitory concentration (MIC) values of 0.5–1.0
μg/mL. Meanwhile, 5a showed an acceptable safety in vivo and displayed a favorable oral bioavailability with
a value of 40.7%. The differential scanning fluorescence, isothermal
titration calorimetry, and molecular docking assays indicated that
PknB could be one of the targets of compound 5a. Overall,
this study identified 5a as a novel promising lead compound
with the potential to develop candidates for the treatment of drug-resistant
TB.