Tuberculosis (TB) is a transmissible infectious disease caused by the intracellular bacteria, Mycobacterium tuberculosis (MtB), (1) which is currently one of the top 10 leading causes of death in low and middle-income countries (2). During 2020, 5.8 million patients were diagnosed with TB, 1.5 million of them died. In that year, 150 thousand patients were infected with drug-resistant TB strain.1 M. tuberculosis can quickly develop resistance against anti-TB regimens, and if not cured adequately, it can evolve into MDR-TB (multidrug resistant TB) and XDR-TB (extensive-drug resistant TB) (1). Therefore, there is a critical need to develop new chemotherapeutic agents with new mechanism of action to fight against a growing public health menace caused by cross-resistant TB strains (3).

We screened our in-house library of small molecules for their potential antimycobacterial properties identifying compound K1827 with excellent antimycobacterial in vitro activity against M. Kansasii (MIC₉₉ = 0.25 μM, which is more than 100 times more efficient that INH) and moderate activity against M. tuberculosis H37Rv (MIC99 = 32 - 64 μM, for comparison MIC99 of INH = 0.5 μM). This core scaffold of K1827 is pyrimidine that was functionalized to develop derivatives with higher activity against M. tuberculosis, better safety profile, and to determine the structure-activity relationships in the series. The effect of individual structural fragments on in vitro antimycobacterial activity, toxicity and selectivity of action have been evaluated and will be discussed within our contribution.

Keywords: Tuberculosis; pyrimidine; resistance