New 5-Modified Pyrimidine Nucleoside Inhibitors of Mycobacterial Growth

Abstract

The WHO has declared tuberculosis (TB) a global health emergency. Therefore, there is an urgent need to discover and develop new anti–TB drugs. Here we report on a new category of 5–substituted pyrimidine nucleosides as potent inhibitors of Myco–bacterium tuberculosis growth in vitro. A series of 2ʹ–deoxy–, 3ʹ–azido–2ʹ,3ʹ–dideoxy–, and 3ʹ–amino–2ʹ,3ʹ–dideoxypyrimidine nucleoside analogues bearing lengthy flexible alkyloxymethyl substituents exhibited marked inhibitory activity against M. tuberculosis in vitro. 5–Dodecyloxymethyl–2ʹ–deoxyuridine was found to be a potent inhibitor of M. tuberculosis propagation in vitro. In contrast, monophosphates of the tested nucleosides were devoid of antimycobacterial activity. This new class of inhibitors seems to be a promising chemotherapeutic agent against TB and merits further studies.

3′-Amino modifications enhance the antifungal properties of N4-alkyl-5-methylcytidines for potential biocides

“…28 5-Modified nucleosides with lengthy substituents have been intensively studied for two decades as a new class of antibacterial agents, and yet, the mechanism of their antibacterial action has not been conclusively established. 14,[29][30][31][32] The bacterial cell wall disruption is considered as one of the plausible modes of their action. 33 Bearing this in mind, we assumed that the current novel N 4 -alkyl-5-methyl-2 0 ,3 0 -dideoxycytidines might have similar inhibitory properties towards Gram-positive bacteria.…”

“…-), 3.54 (dd, J = 11.9, 4.0 Hz, 1H, 5 0 -Ha), 3.67 (dd, J = 12.0, 3.1 Hz, 1H, 5 0 -Hb), 3.94 (ddd, J = 4.4, 4.0, 3.1 Hz, 1H, 4 0 -H), 5.06 (s, 1H, 5 0 -OH), 6.04 (t, J = 6.5 Hz, 1H, 1 0 -H), 7.10 (t, J = 5.7 Hz, 1H, 4-NH-), 7.65 (q, J = 1.2 Hz, 1H, 6-H). 13 32.50 (2 0 -C), 40.17 3 0 -Ethylamino-N 4 -decyl-5-methyl-2 0 ,3 0 -dideoxycytidine (14a). The product was obtained according to the general procedure using 140 mg (0.27 mmol) of 13a and 110 mg (0.35 mmol, 1.3 eq.)…”

Analogues of Pyrimidine Nucleosides as Mycobacteria Growth Inhibitors

“…The value of CD 50 in A549, Vero and Jurkat cell cultures was about 70-100 µg/mL. Of considerable interest are works on the synthesis of 5-alkyloxymethyl and 5-alkyltriazolylmethyl derivatives of pyrimidine nucleosides with long alkyl substituents (Figure 5) [44,45]. The anti-tuberculosis activity of the synthesized compounds was tested on two Mtb strains: laboratory strain H37Rv and multidrug-resistant (MDR) strain MS-115 (resistant to five first-line anti-TB drugs).…”

“…Such uracil derivatives prove to be selective inhibitors towards mycobacteria, demonstrating significant activity in vitro against two M. smegmatis strains (MIC99 67 and 6.7-67 µg/mL for mc2155 VKPM Ac 1339 strains), attenuated MtbATCC 25177 (MIC99 28-61 µg/mL) and M. bovis ATCC 35737 (MIC99 50-60 µg/mL) and two strains of Mtb, including the laboratory strain H37Rv (MIC99 20-50 µg/mL) and MDR MS-115 strain resistant to five first-line anti-TB drugs (MIC99 20-50 µg/mL). However, unlike both 5-alkyloxymethyl and 5-alkyltriazolylmethyl derivatives of 2′-deoxyuridine [44,45] and 5-alkynyl 5′-norcarbocyclic uracil derivatives [49], analogues 30 and 31 turned out to be toxic to human monocyte cells [62]. Another group of 5′-norcarbocyclic uridine analogues as Mtb inhibitors (MIC99 5-40 µg/mL) based on 5-arylaminouracil derivatives was synthesized [63,64].…”

“…Thus, the best activities among uridine analogues (MIC90 1-10 mg/mL) were found for 5-alkynyl (decynyl, dodecynyl, tetradecynyl, pyridylethynyl, etc.) uracil derivatives bearing various modifications in the carbohydrate moiety [23,[32][33][34][35][36][37]44,45,47]. At the same time, 2′-deoxypyrimidine derivatives with long 5-alkyloxymethyl or 5-alkyltriazolylmethyl substituents (5-dodecyloxymethyl-2′-deoxyuridine, Another group of 5 -norcarbocyclic uridine analogues as Mtb inhibitors (MIC 99 5-40 µg/mL) based on 5-arylaminouracil derivatives was synthesized [63,64].…”