6-Azathymidine-4′-thionucleosides: synthesis and antiviral evaluation

Figures & data

Figure 1 Structures of 1, 2 & 3.

Scheme 1 Reagents and Conditions: (i) TBDMSCl, imidazole, DMF, 3.5 h (ii) thiocarbonyldiimidazole, CH₂Cl₂, 40°C, 8 h then r.t. 12 h (iii) Bu₃SnH, 1,1′-azobis(cyclohexene-carbonitrile), toluene, 100°C, 30 min (iv) Dowex 50W (H⁺), MeOH, 24 h.

Scheme 2 Reagents and Conditions: (i) 6-Azathymine, BSA, CH₃CN, 30 min then 7, TMSOTf, CH₃CN, 50°C, 12 h (ii) CH₃NH₂ (35% aqueous), 50°C, 30 min.

Table I.  Cytotoxicity and antiviral activity of novel 4′thionucleosides 2 and 3.

	Minimum Inhibitory Concentration^a (μM)
Compound	HSV-1 (KOS)	HSV-2 (G)	HSV-1/TK^–	Vaccinia virus	MCC^b (μM)
1 [1]	1.3	3.2	18	2.2	>200
2	12 ± 0	12 ± 0	12 ± 0	12 ± 0	100
3	>100	>100	>100	>100	>100
Acyclovir	0.4	0.4	150	>250	>250
Ganciclovir	0.032	0.032	50	>100	>100
Brivudin	0.048	30	250	10	>250

^a Required to reduce virus-induced cytopathogenicity by 50%

^b Required to cause a microscopically detectable alteration of normal cell morphology

Table II.  Thymidine kinase affinity of dideoxynucleoside 2.

Compound	IC50^a (μM)
	TK-1	TK-2	HSV-1 TK	VZV TK
2	> 500	> 500	34 ± 2	427 ± 27

^a 50% Inhibitory concentration required to inhibit dThd kinase-catalyzed conversion of [³H]dThd (1 μM) to its 5′-monophosphate derivative.

Maslen HL, Hughes D, Hursthouse M, De Clercq E, Balzarini J, Simons C. 6-Azapyrimidine-2′-deoxy-4′-thionucleosides: Antiviral agents against TK+ and TK– HSV and VZV strains. J Med Chem 2004; 47: 5482–5491

 PubMed Web of Science ®Google Scholar