J. W. T. Selway

Antirhinovirus structure—activity relationships of 6-substituted-9-(4-methylbenzyl)-2-trifluoromethyl-9H-purines

Abstract To evaluate the effect of different 6-substituents on antirhinoviral activity, a series of 6-substituted-9-(4-methylbenzyl)-2-trifluoromethyl-9 H -purines was synthesized and tested. A matrix map of space adjacent to the 6-position was constructed to facilitate structure—activity analysis. This study provided evidence that a lipophilic pocket exists on the virus capsid surface, which accomodates the methyl group of the 6-methylaminopurines.

Synthesis and anti-viral activity of 6-amino- and 6-dimethylamino-9-(aminoacylamidobenzyl) purines

Abstract Several aminoacylamido derivatives of 9-benzyladenine and of 9-benzyl-6-dimethylaminopurine were synthesized for evaluation in anti-viral and anti-bacterial screens and in tests for inhibition of protein synthesis. The 9-(aminoacylamidobenzyl)purines were synthesized in two steps from the appropriate 9-(aminobenzyl)adenine 3 or 9-(aminobenzyl)-6-dimethylaminopurine 4 . Amines 3 and 4 were acylated with an N -carbobenzoxyamino acid via the mixed anhydride method to give the 9-( N -carbobenzoxyaminoacylamidobenzyl)purines 5–10 . The N -carbobenzoxy groups were removed by catalytic hydrogenolysis or with hydrogen bromide in acetic acid to give 9-(aminoacylamidobenzyl)purines 11–16 . Against rhinovirus serotype 1B, 6-dimethylamino-9-(3-phenylalanylamidobenzyl)-9 H -purine 16b had in vitro activity with an IC 50 = 17 μM.

6-(3-Fluoroanilino)-9-(substituted-benzyl)-2-trifluoromethyl-9H-purines with antirhinovirus activity

Abstract A series of 6-(3-fluoroanilino)-9-(substituted-benzyl)-2-trifluoromethylpurines was synthesized and tested for antirhinovirus activity. Most of the compounds were prepared by alkylation of a 6-anilino-2-trifluoromethylpurine with a benzyl halide or by amination of a 6-chloro-9-benzylpurine with an aniline. Compounds with a variety of para -benzyl substituents had activity against rhinovirus serotype 1B. The 6-(3-fluoroanilino)-9-(3-fluorobenzyl)-2-trifluoromethylpurine 15 had good activity (IC 50 s = 0.4–13 μM) against 80% of the 47 serotypes tested, but pharmacokinetic studies indicated poor oral bioavailability.

Acyclic Nucleosides. Synthesis and Antiherpetic Activity of 9-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Guanine and 1-[[[2-Hydroxy-1-(Hydroxymethyl)Ethyl]Thio]Methyl]Cytosine

Abstract The synthesis and antiherpetic activity of 9-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy1]guanine (4) and 1-[[[2-hydroxy-1-(hydroxymethyl)ethyl]thio]methy]cytosine (6), the side-chain thio analogues of ganciclovir (3) and BW A1117U (5), are described. The sidechain synthon 1,3-bis(benzyloxy)-2-[(chloromethyl)thio]propane (11) was prepared in four steps from 1,3-bis(benzyloxy)-2-propanol (7). Alkylation of 2-amino-6-chloro-9H-purine with 11 provided the intermediate 9-substituted-2-amino-6-chloropurine 12, which was conveniently converted to 4 in two steps. Reaction of a fivefold excess of cytosine with 11 provided the desired 1-isomer 14, which was debenzylated to give 6. In contrast with ganciclovir (3) and BW A1117U (5), neither 4 nor 6 had significant in vitro activity against human cytomegalovirus.