Discovery of novel N4-alkylcytidines as promising antimicrobial agents

The emergence of drug-resistant strains of pathogenic microorganisms necessitates the creation of new drugs. In order to find new compounds that effectively inhibit the growth of pathogenic bacteria and fungi, we synthesized a set of N 4 -derivatives of cytidine, 2′-deoxycytidine and 5-metyl-2′-deoxycytidine bearing extended N 4 -alkyl and N 4 -phenylalkyl groups. The derivatives demonstrate activity against a number of Gram-positive bacteria, including Mycobacterium smegmatis (MIC = 24–200 μM) and Staphylococcus aureus (MIC = 50–200 μM), comparable with the activities of some antibiotics in medical use. The most promising compound appeared to be N 4 -dodecyl-5-metyl-2′-deoxycytidine 4h with activities of 24 and 48 μM against M. smegmatis and S. aureus, respectively, and high inhibitory activity of 0.5 mM against filamentous fungi that can, among other things, damage works of art, such as tempera painting. Noteworthy, some of other synthesized compounds are active against fungal growth with the inhibitory concentration in the range of 0.5–3 mM. • A set of N 4 -derivatives of (2′-deoxy)cytidine with extended N 4 -groups was obtained. • Activity vs. Gram-positive bacteria is comparable with antibiotics in medical use. • Сytotoxicity in A549 cells: 80–200 μM; in vivo toxicity of 4h in mice: 270 mg/kg. • N 4 -modified 2′-deoxy-5-metylcytidines inhibit the growth of biodestructive fungi. • This new series is promising for the protection of cultural heritage from biodamage.