Novel 5'-Norcarbocyclic Pyrimidine Derivatives as Antibacterial Agents

Abstract

A series of novel 5'-norcarbocyclic derivatives of 5-alkoxymethyl or 5-alkyltriazolyl-methyl uracil were synthesized and the activity of the compounds evaluated against both Gram-positive and Gram-negative bacteria. The growth of Mycobacterium smegmatis was completely inhibited by the most active compounds at a MIC₉₉ of 67 μg/mL (mc²155) and a MIC₉₉ of 6.7⁻67 μg/mL (VKPM Ac 1339). Several compounds also showed the ability to inhibit the growth of attenuated strains of Mycobacterium tuberculosis ATCC 25177 (MIC₉₉ 28⁻61 μg/mL) and Mycobacterium bovis ATCC 35737 (MIC₉₉ 50⁻60 μg/mL), as well as two virulent strains of M. tuberculosis; a laboratory strain H37Rv (MIC₉₉ 20⁻50 μg/mL) and a clinical strain with multiple drug resistance MS-115 (MIC₉₉ 20⁻50 μg/mL). Transmission electron microscopy (TEM) evaluation of M. tuberculosis H37Rv bacterial cells treated with one of the compounds demonstrated destruction of the bacterial cell wall, suggesting that the mechanism of action for these compounds may be related to their interactions with bacteria cell walls.

Keywords: 5′-norcarbocyclic nucleosides; Mycobacterium tuberculosis; antibacterial activity; uracil derivatives.

Figure 1

Previously reported anti-M. tuberculosis nucleosides.

Figure 2

Examples of anti-Mtb 5′-norcarbocyclic nucleosides.

Figure 3

Target compounds.

Scheme 1

(i) Pd/C, H₂, MeOH; (ii) Ac₂O, Py; (iii) Br₂, DCE, hv, 83 °C.

Scheme 2

(i) ROH; (ii) K₂CO₃, MeOH; (iii) NaN₃, DMF, 40 °C; (iv) RC≡CH, CuSO₄·5H₂O, sodium ascorbate, CH₂Cl₂/H₂O (1:1).

Figure 4

Transmission electron microscopy of M. tuberculosis H37Rv bacterial cells. Control bacterial cells were grown for 4 days in enriched Dubois medium (A) or in enriched Dubois medium containing DMSO/Twin-80/H₂O solution without compound 3 (B). Bacterial cells after treatment with compound 3 (50 µg/mL) for 4 days (C and D). Scale bar = 1 µm.