Synthesis and in vitro anti-HIV activities of didanosine prodrugs

Figures & data

Scheme 1 Synthesis of didanosine prodrugs.

Table I.  Physical constants and anti-HIV activity of 4a-h.

Comp	R	Yield %	m.p °C	logP^a	EC50^b	CC50^c	t1/2^d
4a	Phenyl	64	201	0.78	1.28	>1000	20
4b	4-Chlorophenyl	69	185	1.34	0.64	>1000	60
4c	4-Methoxyphenyl	73	238	0.65	1.87	828	60
4d	4-Nitro phenyl	81	194	–	4.78	>1000	ND
4e	Benzyl	69	231	0.44	2.2	>1000	ND
4f		76	247	1.04	1.16	560	ND
4 g		70	>260	0.87	3.12	380	ND
4 h		78	256	1.06	0.82	770	ND
DDI	–	–	–	− 1.1	4.8	>1000	–

^a logP values calculated with Chem office 2004 software

^b effective concentration of compound (μM) achieving 50% protection in MT-4 cell lines against the cytopathic effect of HIV-1

^c CC₅₀ cytotoxic concentration of compound (μM) required to reduce the viability of control infected CEM cells by 50%

^d In vitro hydrolysis t_1/2 (min), 4 h contains methyl group at 3-position of piperazine moiety.