Novel pyrimidine derivatives as promising antimycobacterial agents.

Tuberculosis (TB) remains a major global health challenge, particularly due to the rise of multidrug-resistance and extensively drug-resistant Mycobacterium tuberculosis (Mtb) strains. In addition to Mtb, many non-tuberculous mycobacterial (NTM) strains are associated with opportunistic infections in animals and humans. In this study, we report the design, synthesis, and evaluation of novel pyrimidine derivatives as potential antimycobacterial agents. A systematic structure-activity relationship study was conducted, leading to the identification of several promising compounds. Among them, derivative 55a demonstrated the highest efficacy, exhibiting minimum inhibitory concentration (MIC) of 8 μM against drug-susceptible Mtb, while retaining significant potency against multidrug-resistant and extensively drug-resistant clinical isolates. Additionally, compound 55a displayed excellent metabolic stability, with a half-life of 187 min and an intrinsic clearance rate of 7.41 μL/min/mg protein in human liver microsomes. Several compounds also revealed promising efficacy against M. kansasii as a representative from NTM strains. The most promising antimycobacterial agents showed no activity against Gram-positive or Gram-negative bacterial strains, indicating their selectivity towards mycobacteria. These finding highlight 55a as a promising structural motif for further optimization in the development of novel anti-TB therapeutics.