Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.

A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.

Synthesis and antiviral activity of novel isonucleoside analogs.

A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses. The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereospecifically achieved starting from 1,2-isopropylidene-D-xylofuranose (10). An efficient two-step reduction of the anomeric center of bis-acetate 18 involved formation of the chloride intermediate 19, followed by diisobutylaluminum hydride reduction. Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anions. Several members of this new class of compounds possess activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpesviruses, in particular, HSV-1 and HSV-2. Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 microM. Although the antiherpetic activity in vitro of 7 is less than that of acyclovir (1), compound 7 displays superior efficacy in mouse model infections. The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selective activity against HSV-1 and VZV, with no cytostatic effect on WI-38 cell growth at > 800 microM. Compound 8 is active against simian varicella virus and is efficacious in the corresponding monkey model.