Antibacterial resistance is a global problem, where pathogenic microorganisms develop resistance to many active substances, mainly due to improper use and overuse of antibacterial agents, increasing the need for new antibacterials. Enzymes involved in the synthesis of peptidoglycan, a key element of the bacterial cell wall, represent promising targets for development of new antibacterial agents. MurA enzyme (UDP-N-acetylglucosamine enolpyruvyl transferase) is an intracellular bacterial enzyme that plays an essential role in the first stage of peptidoglycan synthesis and is a good target, as its activity is essential for the survival of both Gram-negative and Gram-positive bacteria, and it is not found in humans.
We started with 2-chlorobenzo-1,3-thiazole (compound 1b), which in previous studies showed a good inhibition of MurA enzymes from Escherichia coli (IC50 = 120 ± 12 µM) and Staphylococcus aureus (IC50 = 123 ± 12 µM). Differently substituted derivatives of compound 1b were synthesized and biochemical testing was performed to determine how substitution on the aromatic ring effects the inhibitory potency of the compounds. Two-step synthesis of the final compounds yielded intermediates (benzo-1,3-thiazol-2-amines), for which inhibitory potencies were also determined.
The inhibitory activity of the compounds was significantly improved by introduction of substituents on the meta position (relative to nitrogen) on aromatic ring. Of all the synthesized compounds, compounds 6 (2-amino analogue) and 24 (2-chloro analogue) were the most potent inhibitors with meta and para substituents (IC50: 6 = 1,2 μM; 24 = 3,62 µM), followed by meta substituted compounds – 2-chloro products (IC50: 25 = 12,7 µM; 27 = 50 µM; 29 = 7,6 µM) and 2-amino analogues (IC50: 7 = 3,1 µM; 9 = 23 µM). Additionally, para substituted 2-amino analogues showed improved inhibition of MurA (IC50: 2 = 82 μM; 5 and 8 = 43 µM) in comparison to compound 1b. Derivatives 19, 20, 21, 22, 26, 35, 36 (IC50: 92–615 μM) with substituents at para position and the disubstituted compound 30 (IC50 = 116 µM), did not improve the inhibitory activity significantly in comparison to compound 1b. Interestingly, 2-amino derivatives also showed promising inhibition of MurA enzymes, which suggests that chlorine in benzothiazoles is not essential for the inhibition.